key: cord- -mq a u authors: fabbri, marilyn; maslow, melanie j. title: hantavirus pulmonary syndrome in the united states date: journal: curr infect dis rep doi: . /s - - - sha: doc_id: cord_uid: mq a u since the first outbreak of hantavirus pulmonary syndrome (hps) in , understanding of the vast distribution and potential impact of hantaviruses has grown. at least cases of hps have been documented in the united states. the full clinical spectrum has yet to be elucidated, and one outbreak suggested the possibility of person-to-person transmission. new research has identified the β- integrins as cellular receptors for hantaviruses and has determined the pivotal role of the immune system in pathogenesis. rapid diagnosis has been facilitated by a new immunoblot assay to detect sin nombre virus infection. treatment remains primarily supportive; however, a placebocontrolled trial of ribavirin is ongoing. extracorporeal membrane oxygenation may be a potential therapy in severe cases; inhaled nitric oxide needs further study. vaccines developed against hantaviruses associated with hemorrhagic fever and renal syndrome might be effective against hps-associated strains. an outbreak of an acute febrile illness characterized by respiratory failure, hypotension, and shock was reported by physicians in the four corners region of the united states in may . a previously unknown hantavirus was subsequently identified as the cause [ ] . unlike the previously characterized hantaviruses, which cause fever, hemorrhagic manifestations, and acute renal failure (hemorrhagic fever with renal syndrome), the newly named hantavirus pulmonary syndrome (hps) presented with a brief prodromal illness followed by rapidly progressive noncardiogenic pulmonary edema [ ] . the earliest known case of hps to be confirmed by serology occurred in utah in [ ] . the mortality rate associated with hps is % to %, although mild and even asymptomatic cases are now recognized. in the united states, hps is caused by at least four hantaviruses: the sin nombre virus (snv, responsible for the four corners outbreak), the black creek canal virus (isolated from the florida cotton rat) [ ] , the bayou virus in louisiana [ ] , and the new york hantavirus [ ] . several other closely related viruses have been identified in canada and south america. an estimated to cases of hantaviral infections occur each year worldwide. hantavirus pulmonary syndrome is a febrile illness characterized by bilateral diffuse interstitial edema on chest radiography in a previously healthy person; respiratory compromise develops within hours of hospitalization. the syndrome should be suspected in cases of unexplained fatal respiratory illness in which autopsy examination shows noncardiogenic pulmonary edema without an identifiable cause. clinical suspicion is confirmed with serology, detection of hantaviralspecific rna by polymerase chain reaction, or detection of hantaviral antigen by immunohistochemical testing of clinical specimens (table ) . hantaviruses are lipid-enveloped, tri-segmented, negativesense rna viruses belonging to the bunyavirus family. the genus hantavirus was named for the first virus isolated in from a striped field mouse near the hantaan river in south korea. unlike other members of the bunyavirus family that are transmitted to humans by arthropod vectors, hantaviruses are transmitted via inhalation of viruscontaminated aerosols of rodent saliva, urine, and feces. the hantavirus genome consists of three segments. the large (l) segment encodes a protein with replicase, transcriptase, and endonuclease activity. the medium (m) segment encodes a precursor protein that is processed to form the surface glycoproteins g and g , one or both of which play a role in viral neutralization, fusion of infected cells, and hemagglutination. the small (s) segment encodes the nucleocapsid protein, which forms the filamentous helical nucleocapsid of this virus and elicits the humoral immune response. hantaviruses have been characterized by genetic and antigenic methods. point mutations appear to account for most of the genetic drift among hantaviruses [ ] . rna viruses with segmented genomes, such as influenza virus, since the first outbreak of hantavirus pulmonary syndrome (hps) in , understanding of the vast distribution and potential impact of hantaviruses has grown. at least cases of hps have been documented in the united states. the full clinical spectrum has yet to be elucidated, and one outbreak suggested the possibility of person-to-person transmission. new research has identified the β- integrins as cellular receptors for hantaviruses and has determined the pivotal role of the immune system in pathogenesis. rapid diagnosis has been facilitated by a new immunoblot assay to detect sin nombre virus infection. treatment remains primarily supportive; however, a placebocontrolled trial of ribavirin is ongoing. extracorporeal membrane oxygenation may be a potential therapy in severe cases; inhaled nitric oxide needs further study. vaccines developed against hantaviruses associated with hemorrhagic fever and renal syndrome might be effective against hps-associated strains. can reassort their rna segments when dual infection of a target cell occurs. genetic reassortment has been demonstrated in nature and in vitro for bunyaviridae that cause arthropod-borne disease, but little information is available about hps-associated strains. two previous studies analyzing genomic snv rna sequences from humans and rodents suggest that the rna segment has been reassorted in nature between snv genetic variants [ , ] . rodriquez et al. [ ] analyzed progeny virus from co-cultures of closely related snv strains with identical rodent hosts and of snv and black creek canal virus, which have different rodent hosts. reassortants were observed frequently between closely related strains but were rare between hantaviruses with different rodent hosts. these data suggest that genetic reassortment in nature may contribute to the emergence of new hantaviruses. hantaviruses are subdivided into genogroups on the basis of nucleotide sequence analysis of s and m segments. each genogroup usually infects a single rodent species. the new world hantaviruses are more closely interrelated than the old world viruses, and vice versa. the hps-associated hantaviruses belong to the new world group; these include sin nombre, bayou, black creek canal, new york, and andes viruses ( table ). the old world group includes hantaan, dobrava, seoul, and puumala viruses, which cause hemorrhagic fever with renal syndrome (hfrs). each hantavirus is maintained in nature by asymptomatic infection of a single rodent species. hantaviral infection has been documented in cats, birds, and bats, but these hosts play no documented role in human transmission [ •] . rodents shed infectious virus in saliva, urine, and feces for prolonged periods despite the presence of neutralizing antibody [ ••] . rodents are infected horizontally through biting and scratching other rodents, as reflected in a higher prevalence of infection in older male mice [ ] . phylogenetic relationships between virus and rodent host demonstrate a co-evolution over thousands of years. studies in which hantaviral gene sequences are compared to rodent mitochondrial gene sequences allow nearly identical phylogenetic trees to be constructed [ ] . several hantaviruses can be found in one geographic area, each circulating within its specific rodent host. human transmission usually occurs after inhalation of aerosols of infected rodent excreta. the virus may also be transmitted after rodent bites, after inoculation of infected rodent excreta through skin lesions or eyes, and possibly through ingestion of contaminated food or water [ ] . the incubation period ranges from to days (mean range, to days). the risk for human disease is proportional to the frequency of exposure to infected rodents. rodent populations may vary seasonally and can increase tenfold in months. navajo oral tradition recognized outbreaks of a disease similar to hps when large rodent populations were present [ ] . in the fall of , heavy precipitation in a previously drought-stricken area expanded the deer mouse population tenfold by the time of the may outbreak [ ] . vertical transmission of hantaviruses in pregnant women with hps has not been demonstrated. in a recent review of five cases of hps in pregnancy [ •] , there was no pathologic or immunohistochemical evidence of hps in placental and fetal tissue from two in utero deaths, or serologic evidence of hantaviral infection in the two live births. this review identified one potential case of perinatal transmission of hfrs from korea. no evidence suggests transmission via breast feeding in humans or animal models. the issue of person-to-person transmission is controversial. in a study of health care workers exposed to patients, to patients' body fluids, or to laboratory specimens during the outbreak, serologic testing done within weeks of exposure found no evidence of infection [ ] . serosurveys performed on household contacts of patients with hps revealed no igm antibody reactive with snv [ ] . person-to-person transmission may have occurred during an outbreak of hps caused by the andes virus in el bolson, argentina, in . polymerase chain reaction products of partial sequences of m and s viral rna segments were studied from clinical samples to assess homology. samples from epidemiologically linked cases from this outbreak were (fig. ) and in canada and south america. the overall us mortality rate is %, compared with % in the first us cases [ ] ( table ). the mean patient age is years. men make up % of the total cases. caucasians account for % of cases, and native americans for %. three quarters of the cases come from rural areas. children represent few cases of hps in the united states but account for a larger proportion of cases in south america [ ] . after the four corners outbreak, a serosurvey was done to identify milder, unreported cases. outpatients presenting with a syndrome of fevers and myalgias resembling the hps prodrome were surveyed; no patient had igm antibody reactive with snv [ ] . recently however, five cases of acute snv infection documented by serology were identified, with a clinical illness less severe than hps [ •] . several mild and even asymptomatic cases of hps have also been reported in south america [ ] . risk factors for hps identified from a case-control study during the outbreak included peridomestic cleaning or agricultural activities. more rodents were trapped around the homes of case patients than the homes of controls [ ] . the clinical manifestations of hps can be divided into prodromal, cardiopulmonary, and convalescent phases (fig. ). in the prodromal stage, which usually lasts to days, the most frequent symptoms are fever, chills, and myalgias. abdominal pain, nausea, vomiting, headache, and dizziness may occur. respiratory symptoms are often absent. sore throat, coryza, and meningismus are uncommon, and their presence may be useful in differentiating hps from other viral infections. physical examination, laboratory data, and chest radiographs may be normal in this stage. the cardiopulmonary stage, heralded by cough and dyspnea, can progress rapidly; pulmonary edema and respiratory failure may develop within hours of presentation. physical examination is notable for tachypnea, tachycardia, and hypotension. chest radiographs usually show interstitial edema and basilar or central air space disease. these findings contrast with those for acute respiratory distress syndrome (ards), in which interstitial edema is rare and air space disease is usually peripherally distributed early in the course. hemodynamic measures are characterized by low initial pulmonary artery occlusion pressure, high systemic vascular resistance, and depressed cardiac output, consistent with a noncardiac cause of pulmonary edema [ ] . pleural effusions may occur in up to % of patients [ ] . the pleural fluid is initially transudative but may become exudative during recovery because fluid shifts as cardiac function normalizes. severe cardiopulmonary dysfunction appears to predict a poor prognosis. in fatal cases, the cardiac index progressively decreases, with severe oxygen debt and elevated lactate levels. survivors can be extubated as early as to hours, but extubation generally takes place between and days. the classic laboratory findings in hps are hemoconcentration and thrombocytopenia. other laboratory findings are leukocytosis, with a left shift and atypical lymphocytosis; elevated coagulation indices (disseminated intravascular coagulation is uncommon); and elevated aminotransferase levels. serum creatinine levels can be elevated (< . mg/dl) in severe cases, but frank renal failure is uncommon. metabolic acidosis with lactic acidemia can be seen in severe cases. moolenaar et al. [ ] compared the clinical and laboratory characteristics of patients with hps with those of patients with bacteremic pneumococcal pneumonia, influenza, and unexplained ards. the presence on hospital admission of dizziness, nausea or vomiting, and absence of cough, in association with thrombocytopenia, hemoconcentration, and acidosis, identified all patients with hps and excluded hps in at least % of patients with unexplained ards. the convalescent phase of hps is marked by diuresis, with improvement in oxygenation and decrease in hematocrit. complete recovery can be rapid, even in patients on maximum ventilatory and inotropic support. cognitive impairments, especially involving memory, have been described in two hps survivors year after recovery [ ] . it is unclear, however, whether this is a consequence of anoxic brain damage or viral-induced brain injury. terajima et al. [ ] used a quantitative reverse transcription polymerase chain reaction assay for snv to analyze samples from patients with hps. twenty of the initial samples were positive for viral rna. the mean virus copy number in positive cases was . ± . /ml. fatal cases had one log higher mean rna copy number compared with survivors. the viral rna copy number correlated with the peak hematocrit value and lowest platelet count. viremia decreased promptly after resolution of fever in eight survivors studied. show some clinical variations. in black creek canal, bayou, and andes viruses, renal insufficiency and elevated creatinine kinase levels were more frequent [ ••] . in andes virus infection, bleeding manifestations and petechiae were also reported [ ] . cases of acute, seropositive snv infection that do not fit diagnostic criteria for hps have been reported [ •] . these patients presented with classic prodromal symptoms but did not progress to severe pulmonary involvement. several of the laboratory findings associated with hps, including thrombocytopenia, atypical lymphocytosis, and elevated aminotransferase levels, were seen. possible explanations for the milder clinical illness include a weaker immune response to the virus, altered receptors, and virologic factors. the differential diagnosis of hps depends on the clinical stage of infection. the prodromal phase is indistinguishable from many other viral infections. once infection progresses to the cardiopulmonary stage, the differential diagnosis includes leptospirosis, legionellosis, chlamydial infection, mycoplasma infection, meningococcemia, influenza, q fever, pneumonic plague, tularemia, and disseminated fungal infections. the diagnosis of hps is confirmed in a clinically compatible illness with serology or detection of hantaviral antigen in tissue by immunohistochemical or polymerase chain reaction. hantavirus can be cultured, but this is time consuming and requires at least category iii containment facilities. serology detects igm and igg antibodies by enzyme-linked immunosorbent assay, using recombinant nucleocapsid proteins of different hantaviruses. serum samples from acute and convalescent phases in patients [ ] . among snv-specific igg antibodies reported in one study [ ] , the most prevalent were igg ( %), igg ( %), igg ( %), and igg ( %). it is postulated that the cytokines produced in snv infection may preferentially stimulate production of igg subclass antibody. in this study, antibody titers were similar in patients who died and those who survived. igg antibody persists for years. reinfection with homologous hantaviruses is not known to occur in humans. the major difficulty with serologic diagnosis is the delay in obtaining results. a rapid antibody test for snv in the form of a strip immunoblot assay has been developed; this test takes about hours to complete. the assay incorporates antigens derived from synthetic peptide and recombinantexpressed forms of snv glycoprotein and nucleocapsid protein, as well as recombinant-expressed seoul virus nucleocapsid protein. in studies, this assay identified all patients with acute snv infection from the earliest clinical samples with no false-positive results in controls [ ] . gross pathologic examination of the lungs from patients with hps shows edema and large serous pleural effusions. microscopic examination reveals intra-alveolar edema and interstitial lymphocytic infiltrates. minimal hyaline membrane formation and rare neutrophils help distinguish hps from ards. a viral cytopathic effect is notably absent [ ] . immunohistochemical analysis has demonstrated viral antigen distributed in the capillary endothelium of multiple organs, most markedly in the pulmonary vasculature [ ] . the pulmonary endothelial cells and pneumocytes show no evidence of direct viral injury, which may account for the rapid recovery observed in survivors. the increased pulmonary capillary permeability with structurally intact cells and interstitial lymphocytic infiltrates suggests a pathogenic role for the immune system. activated t cells, primarily cd + cells, are prominent in lung lesions and blood. it is postulated that t cells recognize and act on the heavily infected pulmonary cells, resulting in the secretion of inflammatory mediators such as interferon-γ and tumor necrosis factor. these lymphokines may mediate the reversible increase in vascular permeability resulting in pulmonary edema [ ••] . mori et al. [ ] demonstrated specific localization of cytokine-producing cells in the lungs of patients with hps, paralleling the distribution of hantaviral antigens. testing detected cells that produced both monocyte-derived cytokines (including interleukin- α, interleukin- β, interleukin- , and tumor necrosis factor-α) and lymphocyte-derived cytokines (including interferon-γ, interleukin- , interleukin- , and tumor necrosis factor-β). cytokine production by both activated t lymphocytes and monocytes probably contributes to the pathogenesis of the capillary leak syndrome in hps and the renal failure observed with hfrs. the cellular receptor for pathogenic hantaviruses has recently been identified as the β- integrins [ •]. integrins help regulate vascular permeability and platelet function. specific integrins expressed on platelets and endothelial cells permit entry of hps-associated hantaviruses. the hantavirus-integrin interaction, by altering normal endothelial cell barrier functions, may be responsible for the abnormal vascular permeability associated with hps. in tissue culture, the entry of hps-associated hantavirus into cells was partially blocked by antibodies to the integrins, suggesting a possible future therapeutic intervention [ •] . variation in receptor molecules is one explanation for the spectrum of illness observed with hps [ •] . others include specific viral differences, inoculum differences, and host factors, such as hla haplotype [ ] . immunologic responses mediating viral clearance and recovery from hps may also be important. in one study of patients with hps of varying clinical severity, neutralizing antibody titers at hospital admission were lower in patients with severe disease (requiring intubation) than in patients with mild disease, suggesting a role for immunotherapy [ ] . in animal models, passive administration of immunoglobulin after exposure protected against infection, but no human trials have been performed [ ] . the prodrome of hps is indistinguishable from other viral infections. serologic testing is usually not performed until respiratory symptoms develop, at which point progression to death can be rapid. treatment remains primarily supportive, including attention to proper fluid administration and cardiopulmonary support. antimicrobial therapy is often initiated for other potentially treatable diseases in the differential diagnosis. an open-label trial of ribavirin for suspected hps was conducted between june and september , . ribavirin was selected on the basis of a prospective, double-blinded, placebo-controlled trial of ribavirin for hfrs in china [ ] . this study suggested that mortality was lower if the drug was administered within days of diagnosis [ ] . the investigators also reported that the drug had an acceptable safety profile, and they showed in vitro susceptibility to ribavirin. the study enrolled patients; hantavirus infection was confirmed in patients, and the mortality rate was %. the investigators could not assess the efficacy of intravenous ribavirin, but comparison of the study patients who had hps with untreated patients with hps who were not enrolled in the study showed no difference in survival between the groups. anemia developed in % of patients, % of whom had transfusion. in , a double-blind, placebo-controlled trial of ribavirin sponsored by the national institutes of health, was initiated to evaluate efficacy in hps. patients with suspected hps in the prodromal as well as cardiopulmonary stages are eligible [ , ] . the observation that severe cardiopulmonary failure in hps is reversible led to treatment with extracorporeal membrane oxygenation (ecmo) [ •] . the characteristic rapid recovery in the convalescent stage would only require a short duration of ecmo, which has its own related complications. inclusion criteria for ecmo therapy were risk factors that have been shown to be associated with a % predicted mortality rate in a series of hps-related deaths, including a cardiac index less than . l/min/mm, lactate level greater than mmol/l, ventricular fibrillation or tachycardia, pulseless electrical activity, or refractory shock. patients with irreversible neurologic or multiorgan failure or those on prolonged ventilation were generally excluded. between and , ecmo successfully provided support in two patients with hps. a third eligible patient developed ventricular fibrillation before transfer to the ecmo unit and died. the hemodynamic improvement in the two survivors was dramatic in the first hours of ecmo. both patients were weaned off the ventilator within to days. early transfer of patients with hps to a center offering ecmo should be considered. a -year-old boy with hps was successfully treated with inhaled nitric oxide [ ] . oxygenation in this patient rapidly improved, and the boy was extubated hours after initiation of therapy. nitric oxide is a potent vascular relaxant. local administration delivers it directly to the pulmonary vascular epithelium, leading to reduced pulmonary artery pressure; this may be the mechanism that improves pulmonary edema. although it is difficult to reach any conclusions about efficacy of nitric oxide on the basis of a single case report, this may be a modality for future study. limiting exposure to rodents and excreta is the most effective way to decrease the risk of hps. elimination of food sources and nesting sites for rodents is crucial. rodenticides are useful, but fleas should be eliminated first in plague-endemic regions. areas where rodent infestation is suspected should be well ventilated before humans enter. brooms or vacuums should be avoided to prevent aerosolization of potentially infected rodent excreta. the centers for disease control and prevention has published detailed recommendations for the prevention of hps [ ] . vaccines for hantavirus infections have been developed against strains associated with the hfrs form of disease. an inactivated hantaan virus vaccine is licensed for use in korea. in one study, % of patients receiving this vaccine produced neutralizing antibody after the first booster dose; however, the humoral response was short-lived [ ] . hantaviral g , g , and nucleocapsid proteins are known to be immunogenic. this finding has prompted interest in developing recombinant vaccines using baculovirus and vaccinia-expressed glycoproteins. in rodents, these vaccines could elicit neutralizing antibody responses and protect against hantaan virus infection [ ] [ ] [ ] . additional studies using recombinant dna vaccines in animal models have shown similar success. in rodent studies, use of either seoul virus m or s genome segments in dna vaccines elicited seoul-specific neutralizing antibody responses; however, only m segment vaccination protected rodents from infection [ ] . dna vaccines against hantaviruses that cause hps are being developed [ ] . the discovery of hps in was followed by a rapid accumulation of information. within weeks of recognition of this syndrome, the etiologic agent and its reservoir in nature were identified, and a trial of a potential therapeutic agent was initiated. new viruses continue to be discovered in both humans and rodents throughout the americas, and milder forms of disease are now recognized. with the discovery of new viruses, questions continue to arise about the spectrum of clinical illness, routes of transmission, the role of the immune system in pathogenesis, and future treatment. papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance isolation of the causative agent of hantavirus pulmonary syndrome hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease hantavirus pulmonary syndrome: the first us cases isolation of black creek canal virus, a new hantavirus from sigmodon hispidus in florida a fatal illness associated with a new hantavirus in louisiana new york and sin nombre viruses are serotypically distinct viruses associated with hantavirus pulmonary syndrome hantaviruses: a global disease problem naturally occurring sin nombre virus genetic reassortments complete nucleotide sequences of the m and s segments of two hantavirus isolates from california: evidence for reassortment in nature among viruses related to hantavirus pulmonary syndrome genetic reassortment among viruses causing hantavirus pulmonary syndrome hantavirus infections: epidemiology and pathogenesis this review focuses on the virology, ecology, and transmission of hantaviruses this is an excellent comprehensive review of hantaviral infections, including a discussion of evidence of hantaviral infection in the british isles long-term studies of hantavirus reservoir populations in the southwestern united states: a synthesis persistent hantavirus infections: characteristics and mechanisms hantavirus infection hantavirus pulmonary syndrome hantaviruses and hantavirus pulmonary syndrome hantavirus pulmonary syndrome in pregnancy evidence against person-to-person transmission of hantavirus to health care workers a case-control study of hantavirus pulmonary syndrome during an outbreak in the southwestern united states hantavirus pulmonary syndrome outbreak in argentina: molecular evidence for person-to person transmission of andes virus this interesting study investigates an outbreak of hps in argentina. the authors conclude that person-to-person transmission has been demonstrated using comparative analysis between different viral sequences from human cases. . centers for disease control and prevention: all about hantaviruses an outbreak of hantavirus pulmonary syndrome in chile evaluation of the magnitude of the hantavirus outbreak in the southwestern united states acute sin nombre hantavirus infection without pulmonary syndrome, united states this is an important case series of five patients identified in the united states with acute snv infection that did not fit the hps case definition. these cases established the presence of milder clinical illness cardiopulmonary manifestations of hantavirus pulmonary syndrome pleural fluid characteristics in hantavirus pulmonary syndrome clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory illnesses neuropsychological impairments following hantavirus pulmonary syndrome high levels of viremia in patients with hantavirus pulmonary syndrome spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome this is an excellent review of the clinical spectrum of disease and pathogenesis of hantaviral infections characterization of human antibody responses to four corners hantavirus infection among patients with hantavirus pulmonary syndrome rapid and specific detection of sin nombre virus antibodies in patients with hantavirus pulmonary syndrome by a strip immunoblot assay suitable for field diagnosis sin nombre virus (snv) ig isotype antibody response during acute and convalescent phases of hantavirus pulmonary syndrome hantavirus pulmonary syndrome high levels of cytokineproducing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome b integrins mediate the cellular entry of hantaviruses that cause respiratory failure this study identifies the β- integrins as the cellular receptors for hantaviruses and investigates the roles of different integrins in facilitating the entry of pathogenic versus nonpathogenic strains of hantavirus hantavirus pulmonary syndrome: cd and cd cytotoxic t lymphocytes to epitopes on sin nombre virus nucleocapsid protein isolated during acute illness humoral immune responses in the hantavirus pulmonary syndrome intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during year of open-label experience successful treatment of adults with severe hantavirus pulmonary syndrome with extracorporeal membrane oxygenation this is a review of the use of ecmo in three patients with hps. it discusses the rationale for use, inclusion criteria, clinical course, and outcome hantavirus pulmonary syndrome treated with inhaled nitric oxide hantavirus infection-southwestern united states. interim recommendations for risk reduction antibody responses in humans to an inactivated hantavirus vaccine a vaccinia virusvectored hantaan virus vaccine protects hamsters from challenge with hantaan and seoul viruses but not pumaala virus antigenic subunits of hantaan virus expressed by baculovirus and vaccinia virus recombinants immunity to hantavirus challenge in meriones unguicalatus induced by vacciniavectored viral proteins dna vaccination with hantavirus m segment elicits neutralizing antibodies and protects against seoul virus infection update: hantavirus pulmonary syndrome -united states key: cord- -mcxbl mv authors: vijayan, vannan k. title: diagnosis of pulmonary parasitic diseases date: - - journal: parasitic diseases of the lungs doi: . / - - - - _ sha: doc_id: cord_uid: mcxbl mv the protozoal and helminthic parasites that traverse the respiratory tract during their life cycles can cause lung diseases, though the most common habitats of these parasites are the gastrointestinal tract and the blood or lymphatic circulations. these diseases are commonly encountered in the tropical regions of the world. however, parasitic lung diseases are increasingly being reported from other parts of the world due to an increase in the occurrence of immunosuppression (acquired immunodeficiency syndrome, organ transplantations, the use of immunosuppressive drugs) and transcontinental travel. the lung diseases that may result from these infections range from asymptomatic phase to life-threatening acute respiratory distress syndrome. these diseases can also mimic common respiratory diseases such as bacterial pneumonias, pulmonary tuberculosis, lung cancer, bronchial asthma, interstitial lung disease, and pulmonary hypertension. the diagnosis of parasitic lung diseases is a challenge to physicians, if they are not aware of the entity or these diseases are not investigated properly. the diagnosis of these diseases is based on the identification of the causative organism in the stool, sputum, other body fluids, or tissue specimens. radiological imaging studies of the thorax including chest radiographs, high-resolution computerized tomograms, and ultrasonograms may aid in the diagnosis. in certain situations, invasive investigations such as fiberoptic bronchoscopic evaluation (transbronchial lung biopsies and bronchoalveolar lavage studies) and thoracic surgical procedures (thoracoscopy and open lung biopsy) may be required for a diagnosis and also to exclude other lung diseases. serologic and molecular diagnostic methods are being developed for accurate diagnosis of the parasitic diseases. pulmonary parasitic lung diseases are commonly diagnosed in countries where the prevalence of parasitic infection is high. however, there is an increase in the number of patients diagnosed as parasitic lung diseases recently, even in countries of low prevalence of parasitic infection which demands an awareness of such diseases in these countries. this increase in diagnosis in countries with low prevalence with parasitic infections has been attributed to an increase in the numbers of immunosuppressed individuals due to various reasons, organ transplantations and global travel [ ] . the parasites can cause a wide spectrum of lung diseases varying from mild self-limiting bronchitis to life-threatening acute respiratory distress syndrome [ ] . in addition, parasitic lung diseases may mimic diseases such as bacterial pneumonias, pulmonary tuberculosis, bronchial asthma, lung cancer, interstitial lung disease, and pulmonary hypertension. both protozoal and helminthic parasites can cause lung diseases and helminthic lung infections are important causes of eosinophilic lung diseases [ ] . though the treatment of parasitic lung diseases is with specifi c antiparasitic drugs, the physicians treating such diseases should be competent in tackling the specifi c issues related to lung injury and sequel that may follow such infections. the lung diseases that may result from infections with parasites are listed in table . [ ] . the important protozoal parasites that cause pulmonary diseases are entamoeba histolytica , leishmania donovani , malarial parasites ( plasmodium vivax , p . falciparum , p . malaria , p . ovale , and p . knowlesi ), babesia spp. ( babesia microti and babesia divergens ), and toxoplasma gondii . amebiasis results from ingestion of mature entamoeba histolytica cysts in fecally contaminated food, water or from hands. infection with entamoeba histolytica can lead to intestinal colonization, colitis or extraintestinal manifestations resulting from the hematogenous spread of infection from the intestine. about % of intestinal colonization is with nonpathogenic species, entamoeba dispar and entamoeba moshkovskii . invasive amebiasis occurs in % of persons colonized with e . histolytica . patients with amebic colitis present with several-week history of cramping abdominal pain, weight loss, and watery or bloody diarrhea. extraintestinal amebic infection can manifest as amebic liver abscess, splenic abscess, brain abscess, empyema, and pericarditis. nearly % of cases of amebic liver abscesses occur in the right lobe. the most common complication of amebic liver abscess is rupture into the pleural space resulting in pleuropulmonary amebiasis [ ] . the main symptoms in pleuropulmonary amebiasis are fever, cough, hemoptysis, right upper quadrant abdominal pain, and chest pain. some patients may present with respiratory distress and shock. lung abscess, hepatobronchial fi stula, and bronchopleural fi stula with pyopneumothorax have also been reported. expectoration of anchovy saucelike pus indicates amebiasis [ ] . the fi ndings of elevated hemidiaphragm, tender hepatomegaly, pleural effusion, and basal pulmonary involvement are suggestive of pleuropulmonary amebiasis. amebiasis can be suspected in patients with a history of immigration from or travel to developing countries and many patients give history of dysentery and alcoholism. amebiasis is commonly diagnosed by microscopy and cysts or motile trophozoites can be identifi ed on a saline wet mount of a stool specimen [ ] . microscopic examination of fresh stools, sputum or pleural pus, rectal smears or rectosigmoidoscopy materials, pus from liver abscesses, and colonic biopsy samples may reveal motile trophozoites, even though it is a relatively specifi c test but is not sensitive for the identifi cation of e . histolytica . the presence of ameba in the stool does not indicate that the disease is due to pathogenic e . histolytica as two other nonpathogenic species found in humans ( e . dispar and e . moshkovskii ) are indistinguishable morphologically [ , ] . this method can, therefore, give false-positive results if entamoeba dispar or entamoeba moshkovskii infection is present. however, it has been reported recently that several different genotypes of e . dispar can be potentially responsible for tissue damage similar to that observed with e . histolytica [ ] . a nonpathogenic entamoeba gingivalis which is present in the oral cavity has to be differentiated from entamoeba histolytica in sputum samples. a combination of serological tests with identification of the parasite by antigen detection by pcr is the best approach to diagnosis. in vitro culture by inoculation of portions of stool, liver abscess, or empyema fl uid into sterile culture media and incubating it at °c is also useful in the diagnosis of amebiasis. the culture media is examined for the growth of amebic trophozoites, which, if present, can be seen on the walls of test tubes or in debris [ ] . antibody detection and antigen detection are other important immunodiagnostic methods. indirect hemagglutination (iha) test is used for routine serodiagnosis of amebiasis. antigen consists of a crude soluble extract of axenically cultured organisms. the enzyme immunoassay (eia) test detects antibody specifi c for e . histolytica in approximately % of patients with extraintestinal amebiasis, % of patients with active intestinal infection, and % of asymptomatic persons who are passing cysts of e . histolytica . detectable e . histolytica -specifi c antibodies may persist for years after successful treatment, so the presence of antibodies does not necessarily indicate acute or current infection. specifi city is % or higher and false-positive reactions rarely occur. e . histolytica -specifi c antigen detection may be useful as an adjunct to microscopic diagnosis in detecting parasites and to distinguish between pathogenic and nonpathogenic infections. detection of circulating antigens in the serum has been found to be an important advancement in the diagnosis [ ] . polymerase chain reaction (pcr) assays are useful for the differentiation of e . histolytica , e . dispar , and e . moshkovskii and for genetic typing of isolates [ , ] . however, these tests are time-consuming and expensive and, hence, are not practical in areas endemic for amebiasis. infection with leishmania donovani causes visceral leishmaniasis and is transmitted by various species of phlebotomus , the sand fl y [ ] . there are no clinical symptoms and signs that are pathognomonic of visceral leishmaniasis (vl) or kala-azar. the symptoms and signs suggestive of visceral leishmaniasis are irregular fever, weight loss, enlargement of liver and spleen, and anemia. pneumonitis, septal fi brosis, pleural effusion, and mediastinal adenopathy are reported in patients coinfected with human immunodeficiency virus (hiv) [ ] . leishmaniasis has also been reported in lung transplant patients [ ] . leishmania amastigotes can be found in the alveoli, pulmonary septa, and bronchoalveolar lavage (bal) fl uid. diagnosis of leishmaniasis is by the demonstration of the parasites in bone marrow aspirates and by the identifi cation of specifi c dna sequences in tissues by molecular biology techniques [ ] . the differential diagnosis of leishmaniasis includes malaria, cirrhosis with portal hypertension, miliary tuberculosis, brucellosis, histoplasmosis, lymphoma, and leukemia [ ] . the diagnosis of leishmaniasis is based on the microscopical demonstration of leishmania amastigotes in the relevant tissue aspirates or biopsies such as bone marrow, spleen, lymph nodes, or liver, skin slit smears, or in the peripheral blood buffy coat [ ] . the smears can be stained with romnowsky's, hematoxylin-eosin, or immunoperoxidase stains. the amastigote stage seen in clinical samples is known as leishman-donovan (ld) bodies. the amastigotes observed in the smears have to be differentiated from "dot"-like structures (e.g., histoplasma spp., platelets) by looking for the characteristic size ( - mm in diameter), shape (round to oval), and the internal organelles (the nucleus and kinetoplast). culture of these specimens on solid nnn medium will demonstrate promastigotes. immunological methods of diagnosis include indirect fl uorescent test (ifa), direct agglutination test (dat), and enzymelinked immunosorbent assay (elisa) to detect antibodies against leishmania [ ] . antigen detection tests are better means of diagnosis of active leishmaniasis [ ] . the antigen detection is the ideal test in immunocompromised patients, where antibody response is very poor. pcr is found to be the most sensitive and specifi c molecular test and is useful in molecular epidemiological studies besides diagnosis [ ] . malaria is caused by the obligate intraerythrocytic protozoa of the genus plasmodium and is primarily transmitted by the bite of an infected female anopheles mosquito. five species of malarial parasites ( plasmodium vivax , p . falciparum , p . malariae , p . ovale , and p . knowlesi ) infect man [ ] . the main symptoms of malaria are periodic fever, chills, malaise, headache, abdominal pain, and vomiting, usually manifesting - days after mosquito bite. anemia and splenomegaly are other important fi ndings in malaria. falciparum malaria is the most deadly type. the pulmonary manifestations range from cough to severe and rapidly fatal non-cardiogenic pulmonary edema and acute respiratory distress syndrome (ards) ( fig. . ) [ ] . acute lung injury and ards have also been reported to occur in infection with p . vivax and p . ovale [ , ] . there has been no convincing evidence for the existence of true malarial pneumonitis, and if it occurs, it may be due to viral and secondary bacterial infections. diffusing capacity was signifi cantly impaired in patients with severe malaria. in addition to ards, falciparum malaria can cause many other severe complications such as cerebral malaria, acute renal failure, severe anemia, thrombocytopenia, bleeding, and gastrointestinal, hepatic, and metabolic complications [ ] . microscopic examination of the giemsa-stained blood smears is the gold standard for the diagnosis of malaria. microscopic diagnosis is based on staining thick and thin blood fi lms on a glass slide to visualize the malaria parasite [ ] . it is inexpensive, able to differentiate malaria species and quantify parasites. the detection threshold in giemsa-stained thick blood fi lm has been estimated to be - parasites/μl. plasmodium species can be correctly recognized in thin blood fi lm. sometimes malarial parasites cannot be detected in peripheral blood smear, but malaria pigments may be seen in circulating phagocytic leukocytes. this is a pathognomonic sign of recent infection. the parasite count, number of circulating pigment-containing phagocytes, and the presence of late asexual stages of the parasite observed in the blood smear are all positively correlated with a fatal outcome. bone marrow aspirate can also demonstrate malarial parasites, if thin smears of the peripheral blood do not show the parasites. quantitative buffy coat (qbc) method involves staining parasite deoxyribonucleic acid (dna) in micro-hematocrit tubes with fl uorescent dyes (e.g., acridine orange) and its subsequent detection by epifl uorescent microscopy. the parasite nuclei fl uoresces bright green and the cytoplasm appears yellow-orange [ ] . rapid diagnostic test (rdt) is a device that detects malaria antigen in a small amount of blood, usually - μl, by immunochromatographic assay with monoclonal antibodies directed against the target parasite antigen and impregnated on a test strip [ , ] . the result, usually a colored test line, is obtained in - min. histidine-rich protein (hrp- ) which is specifi c for p . falciparum is the most common malaria antigen targeted [ ] . plasmodium lactate dehydrogenase (pldh) enzyme is the other group of targeted antigens. monoclonal antibodies against pldh and aldolase enzymes are available for the detection of plasmodium spp. (pan malaria). hrp- often persists in the patient's blood for weeks after successful treatment. molecular methods such as pcr allow the specifi c amplifi cation of a selected region of the malarial genome. this is a specifi c and sensitive method and permits genotyping. drug-resistant parasites and mixed infections can be detected by pcr using single nucleotide polymorphism. a pcr-based detection of plasmodium falciparum in human urine and saliva samples has been described. the antibodies against asexual blood stages of malaria parasite can be detected by the immunofl uorescence assay (ifa). serological tests are useful in epidemiology surveys and are not suitable for the acute diagnosis of malaria [ ] . babesiosis is caused by hemoprotozoan parasites, babesia microti and babesia divergens [ ] . man gets the infection by the bite of an infected tick, ixodes scapularis , and can also be infected from a contaminated blood transfusion [ ] . the parasites attack the red blood cells and can be misdiagnosed as plasmodium . the symptoms are fever, drenching sweats, tiredness, loss of appetite, myalgia, and headache. acute respiratory distress syndrome occurring a few days after initiation of medical therapy is the important pulmonary manifestation [ ] . chest radiological features include bilateral infi ltrates with an alveolar pattern and thickening of the septa. the peripheral blood smears may show, in addition to ring forms, tetrads inside the red blood cells. these tetrads, known as maltese cross formations, are pathognomonic of babesiosis because they are not seen in malaria [ ] . specifi c diagnosis is made by examination of a giemsastained thin blood smear, dna amplifi cation using pcr, or detection of specifi c antibody [ ] . toxoplasmosis is caused by one-celled protozoan parasite, toxoplasma gondii . cats are the primary carriers of the organism [ ] . man gets the infection by eating parasitic cyst-contaminated raw or undercooked meat, vegetables, or milk products. the symptoms of toxoplasmosis are fl u-like syndrome, enlarged lymph nodes, or myalgia. chronic toxoplasmosis can cause chorioretinitis, jaundice, encephalitis, and convulsions. pulmonary toxoplasmosis has been reported with increasing frequency in patients with hiv infection. toxoplasma pneumonia can manifest as interstitial pneumonia/ diffuse alveolar damage or necrotizing pneumonia [ ] . diagnosis of toxoplasmosis is based on the detection of the protozoa in body tissues. antibody levels can be increased without active disease. a real-time pcr-based assay in bal fl uid has been reported in immunocompromised hiv-positive patients [ ] . the important helminthic parasites that cause lung diseases include cestodes ( echinococcus granulosus and echinococcus multilocularis ), trematodes ( schistosoma haematobium , schistosoma mansoni , schistosoma japonicum , and paragonimus westermani ), and nematodes ( ascaris lumbricoides , ancylostoma duodenale , necator americanus , strongyloides stercoralis , wuchereria bancrofti , brugia malayi , brugia timori , dirofi laria immitis , dirofi laria repens , toxocara canis or cati , and trichinella spiralis ). the parasite species that cause hydatid disease in man are echinococcus granulosus and echinococcus multilocularis . the adult e . granulosus resides in the small intestine of the defi nitive hosts, mainly dogs. the intermediate hosts including man are infected by ingestion of eggs excreted in the feces of the dogs. primary pulmonary cystic hydatid disease is usually single. multiple cysts may be seen in % of cases and may be unilateral or bilateral [ ] . secondary metastatic pulmonary cystic hydatid disease may occur by the rupture of a liver cyst in vena caval circulation or a heart cyst in the right ventricular cavity. patients are asymptomatic in the initial stages of infection. pulmonary symptoms include cough, fever, dyspnea, and chest pain [ ] . signs and symptoms can occur due to compression of adjacent tissue by the cysts. rupture of the cysts into a bronchus may result in hemoptysis and expectoration of cystic fl uid containing parasite membrane and can cause anaphylactic shock, respiratory distress, asthma-like symptoms, persistent pneumonia, and sepsis [ , ] . rupture of the cyst into the pleural space can result in hydropneumothorax, pleural effusion, and empyema. diagnosis of pulmonary hydatid cyst is based on thoracic imaging studies (chest radiography, thoracic computerized tomography (ct), and thoracic ultrasonography) [ ] and an uncomplicated cyst presents as a well-defi ned homogenous round (cannonball) opacity that may be lobulated by contiguous bronchovascular axes ( fig. . ) [ ] . chest radiographs show solitary or multiple round opacities that may mimic lung tumors. ct is helpful in doubtful cases, because the internal structure of the cyst can be analyzed and its density measured. ct is also useful to assess the state of the neighboring parenchyma and to evaluate the whole thorax and abdomen for associated cystic lesions or anomalies. ultrasonography using a portable ultrasound scanner has been found as reliable, inexpensive, and rapid technique in community-based screening surveys for cystic hydatid disease. the crescent sign, cumbo's sign (onion peel sign), water lily sign, and air-fl uid level are seen on chest radiography and computed tomography (ct) [ ] . inverse crescent sign, signet ring sign, and serpent sign are recognized as features of pulmonary hydatid cysts in computerized tomogram. laboratory tests are complementary to clinical and imaging investigations. eosinophilia and elevated immunoglobulin e (ige) levels are seen when the hydatid cyst ruptures [ ] . serologic tests are less sensitive in patients with lung hydatid disease than in those localized in liver. falsepositive tests may be observed in patients suffering from other helminthic infections. immunologic tests may be helpful to confi rm the hydatid origin of a cystic lesion and permit the serologic monitoring of medically or surgically treated patients [ , ] . pulmonary alveolar echinococcosis (ae) is due to hematogenous dissemination from hepatic lesions. the liver is the fi rst target of the parasite, with a silent and long incubation period ( - years). exogenous proliferation causes infi ltration of adjacent tissues and pressure necrosis. it can metastasize to distant organs mainly to lungs, brain, and bones [ ] . lung involvement results from metastatic dissemination or direct extension through the diaphragm of hepatic echinococcosis with intrathoracic rupture into the bronchial tree, pleural cavity, or mediastinum. direct extension to the right atrium through the inferior vena cava with recurrent episodes of pulmonary embolism has also been reported. imaging studies with radiography, ultrasonography, ct, and magnetic resonance imaging (mri) may help in the diagnosis of metastatic lung disease [ ] . biopsy may be needed to confi rm the diagnosis [ ] . serologic the schistosomes that cause human disease are schistosoma haematobium , schistosoma mansoni , and schistosoma japonicum . the fi nal habitat of s . haematobium is urinary bladder vesicle beds and of s . mansoni and s . japonicum is the mesenteric beds. the schistosome eggs are passed in urine ( s . haematobium ) or in feces ( s . mansoni and s . japonicum ) by the infected humans. the parasites can cause schistosoma dermatitis at the site of skin penetration. pulmonary schistosomiasis can manifest clinically as an acute form and a chronic form [ ] . acute symptoms can develop - weeks after skin penetration [ ] . the acute form, also known as katayama syndrome, presents with fever, chills, weight loss, diarrhea, abdominal pain, myalgia, and urticaria and is seen in nonimmune patients [ ] . pulmonary manifestations include shortness of breath, wheezing and dry cough. patients with chronic schistosomiasis present with features of pulmonary hypertension and cor pulmonale [ ] . massive hemoptysis and lobar consolidation and collapse have been reported in schistosomiasis [ ] . hepatosplenomegaly due to portal hypertension has been reported in patients infected with s . mansoni or s . japonicum [ ] . chest radiographic abnormalities range from multiple nodules to diffuse interstitial infi ltrates. small pulmonary nodules in ct have been described in acute schistosomiasis [ ] . diagnosis of chronic schistosomiasis is based on the demonstration of eggs in stool or urine by direct microscopy or rectal/bladder biopsy [ ] . multiple examinations of specimens are required in mild and chronic infections. in active infections, eggs contain live and mature miracidia. the incubation period of the infection is usually months and hence eggs can be detected after months of last known contact with fresh water. peripheral blood eosinophilia with mild leukocytosis, abnormal liver function test results and elevated ige levels are reported in acute schistosomiasis. hyperglobulinemia is observed in chronic schistosomiasis. serological tests with elisa are available, but cannot differentiate active from past infections [ ] . bronchoscopy and transbronchial biopsy may reveal eosinophilic pneumonitis. paragonimiasis is a food-borne zoonoses and is caused by infection with paragonimus species and manifests as subacute or chronic infl ammation of the lung. though more than species are known to cause paragonimiasis in man, the main species that cause paragonimiasis is paragonimus westermani . adult worms live in the lungs and the eggs are voided in sputum or feces. the man gets infection, when raw or undercooked crabs or crayfi shes infected with infective metacercariae are ingested. the parasite from the human gut passes through several organs and tissues to reach the lung. pulmonary paragonimiasis manifests as fever, chest pain, chronic cough, and bloodtinged sputum [ ] . the cough is dry at fi rst and later productive with blood-stained, rusty-brown tenacious sputum. occasionally, there is profuse hemoptysis. pulmonary paragonimiasis is confused with tuberculosis as the symptoms in both diseases are similar. chest radiographs may show infi ltrative, nodular, and cavitating shadows. pleural effusion or pneumothorax is an important fi nding in paragonimiasis [ , ] . ct scan may show single or multiple nodules in the lung parenchyma, calcifi ed spots and pleural thickening with interlobar pleuritis, and pleural effusion. mri may show conglomerated lesions with hemorrhage or tunnel signs. defi nitive diagnosis is based on the demonstration of eggs in sputum samples, bal fl uid, or lung biopsy specimens. ascaris lumbricoides is the most common intestinal helminthic infection. respiratory symptoms in ascariasis are due to larval pulmonary migration, airway hyper-reactivity, and bronchospasm. symptomatic pulmonary disease may range from mild cough to loffl er's syndrome [ ] . loffl er's syndrome is a self-limiting infl ammation of the lungs and is associated with blood and lung eosinophilia. this syndrome can occur as a result of parasitic infestations (especially ascariasis in children) and exposure to various drugs. patients may present with general symptoms of malaise, loss of appetite, fever lasting - days, headache, and myalgia. the respiratory symptoms include chest pain, cough with mucoid sputum, hemoptysis, shortness of breath, and wheezing [ ] . there may be rapid respiratory rate and rales can be heard on auscultation. leukocytosis particularly eosinophilia is an important laboratory fi nding. chest radiographs demonstrate unilateral or bilateral, transient, migratory, and non-segmental opacities of various sizes. these opacities are often peripherally situated and appear to be pleural based [ ] . the severity of symptoms will depend upon the larval burden. rarely chronic eosinophilic pneumonia or symptoms of upper airway obstruction can occur. a diagnosis of pulmonary disease due to ascariasis can be made in an endemic region in a patient who presents with dyspnea, dry cough, fever, and eosinophilia. sputum may show charcot-leyden crystals and the chest radiograph may reveal fl eeting pulmonary infi ltrates. because of the occurrence of respiratory symptoms during larval pulmonary migration, stool examination usually does not show ascaris eggs and stool samples may be negative until - months after respiratory symptoms occur, unless the patient was previously infected. however, larvae can sometimes be demonstrated in respiratory or gastric secretions [ ] . it has been suggested that measurement of ascaris -specifi c igg by elisa may be useful in the serodiagnosis of ascariasis [ ] . hookworm disease in humans results from infections with two species, ancylostoma duodenale and necator americanus . during pulmonary larval migration, patients may present with fever, cough, wheezing, and transient pulmonary infi ltrates in chest radiographs. this is associated with blood and pulmonary eosinophilia [ ] . the other characteristic feature is iron defi ciency anemia due to chronic blood loss [ ] . in severe hookworm anemia, patients may present with fatigue, exertional dyspnea, poor concentration, and cardiac murmurs. during massive infection from oral ingestion of hookworm larvae, patients can present with nausea, vomiting, cough, dyspnea, and eosinophilia, and this condition is termed as wakana disease. prominent gastrointestinal symptoms in hookworm disease are abdominal pain, nausea, anorexia, and diarrhea. a direct microscopical examination of stool demonstrates the presence of characteristic hookworm eggs. concentration method may be used when the infection is light. eosinophilia in the peripheral blood is a prominent fi nding. a peripheral blood smear examination will reveal microcytic hypochromic anemia. a polymerase chain reaction (pcr) to differentiate between a . duodenale and n . americanus has been developed [ ]. strongyloides stercoralis is seen worldwide and the unique feature of the life cycle of s . stercoralis is that it can complete its life cycle either in the human host or in the soil. it has been observed that - % of chronically infected people may be asymptomatic. although symptoms in individuals with chronic strongyloides stercoralis infection are usually mild, it can persist for many years due to autoinfection. this may occasionally progress to the hyperinfection syndrome with high mortality especially in immunosuppressed individuals [ , ] . the relative risk of s . stercoralis infection is increased in elderly men and patients who had recently used corticosteroids, had a hematologic malignancy, and had prior gastric surgery. other risk factors include chronic lung disease, use of histamine blockers, or chronic debilitating illness. strongyloidiasis is a chronic relapsing illness of mild to moderate severity characterized by gastrointestinal complaints (diarrhea, pain, tenderness, nausea, vomiting), peripheral blood eosinophilia, and hypoalbuminemia. pulmonary signs and symptoms include cough, shortness of breath, wheezing, and hemoptysis. in patients at high risk for strongyloidiasis, adult respiratory distress syndrome and septicemia due to intestinal transmural migration of bacteria can occur as a result of hyperinfection or disseminated strongyloidiasis [ , ] . in addition, acute anemia, acute renal failure, and systemic infl ammatory response syndrome are also reported in hyperinfection. strongyloidiasis can manifest as eosinophilic pleural effusion in both immunocompetent and immunocompromised individuals. rare pulmonary manifestations include acute respiratory failure due to respiratory muscle paralysis, granulomatous reaction in the lung with interlobular septal fi brosis, and pulmonary microcalcifi cations. a paradoxic therapeutic response of asthma to glucocorticosteroids, in which bronchial asthma symptoms worsened after treatment with parenteral corticosteroids, has been described in patients with strongyloides superinfections [ ] . exacerbations of chronic obstructive pulmonary disease and worsening of symptoms in idiopathic pulmonary fi brosis have also been reported in strongyloides stercoralis infection. in immunocompetent patients with strongyloidiasis, the parasite load is usually low and the larval output is irregular. as a result, the diagnosis of strongyloidiasis by examination of a single stool specimen using conventional techniques usually fails to detect larvae in up to % of cases [ ] . the diagnostic yield can be increased by examination of several stool specimens on consecutive days. examination of stool by agar plate culture method was found to be superior to direct smear and modifi ed baermann technique [ , ] . strongyloides stercoralis larvae can be demonstrated in duodenal aspirate. in disseminated disease, larvae and adult parasites can be seen in sputum, urine, bronchoalveolar lavage fl uid, and other body fl uids [ ] . a serological test using centers for disease control (cdc) enzyme immunoassay (eia) for detection of antibodies to strongyloidiasis was found to have a sensitivity of . % in patients with proven infection [ ] . tropical pulmonary eosinophilia (tpe) results from immunologic hyper-responsiveness to human fi larial parasites, wuchereria bancrofti and brugia malayi [ - ] . tpe is a systemic disease involving mainly the lungs, but other organs such as liver, spleen, lymph nodes, brain, and gastrointestinal tract may also be involved. the disease occurs predominantly in males, with a male to female ratio of : , and is mainly seen in older children and young adults between the ages and years. the systemic symptoms include fever, weight loss, and fatigue. patients with tpe usually present with respiratory symptoms that include paroxysmal cough, breathlessness, and wheeze and chest pain [ , ] . the symptoms occur predominantly at night, but can persist during the day. severe cough can lead to fractured ribs. sputum is usually scanty, viscous, and mucoid. the sputum often shows clumps of eosinophils, and rarely charcot-leyden crystals are observed. on examination, patients are often breathless. bilateral scattered rhonchi and rales may be heard on auscultation [ , ] . leukocytosis with an absolute increase in eosinophils in the peripheral blood is the hallmark of tpe. spontaneous fl uctuations in the eosinophil count can occur. absolute eosinophil counts are usually more than , cells/mm and may range from , to , [ ] . microfi lariae are rarely seen in the peripheral blood. as patients with tpe especially from endemic areas can be simultaneously infected with other helminthic parasites, stool examination may reveal ova or larvae of other helminthes ( ascaris , ancylostoma , whipworm, and strongyloides ) in % of patients with tpe. this observation does not deter the physician from making a diagnosis of tpe, if other conditions for diagnosis are fulfi lled. the chest radiological features of tpe include reticulonodular shadows predominantly seen in mid and lower zones and miliary mottling of - mm in diameter often indistinguishable from miliary tuberculosis (fig. . ) . twenty percent of patients have a normal chest radiograph. in patients with a long-standing history, a few patients have honeycomb lungs. radiological improvement occurs on specifi c therapy with dec, but some degree of radiological abnormality persists in some patients. lung function tests reveal mainly a restrictive ventilation defect with superimposed airway obstruction [ , ] . single breath carbon monoxide transfer factor (tlco) is reduced in % of untreated patients with tpe. the reduction in tlco is due to reduced pulmonary membrane diffusing capacity (dm) [ ] . the criteria suggested for the diagnosis of tpe are (a) appropriate exposure history (mosquito bite) in an endemic area of fi lariasis, (b) a history of paroxysmal nocturnal cough and breathlessness, (c) chest radiographic evidence of pulmonary infi ltrations, (d) leukocytosis in blood, (e) peripheral blood eosinophils more than , cells per cu mm, (f) elevated serum ige levels, (g) elevated serum antifi larial antibodies (igg and/or ige), and (h) a clinical response to diethylcarbamazine citrate [ , ] . pulmonary dirofi lariasis is a zoonotic infection caused by fi larial nematodes, dirofi laria immitis and dirofi laria repens . humans are accidental hosts of this parasite which is transmitted to man by the mosquito. the parasites are usually seen in the pulmonary artery where they produce an embolism ultimately leading to the formation of a pulmonary nodule or "coin lesion" [ ] . nearly % of subjects infected with dirofi lariasis are asymptomatic. clinical symptoms are chest pain, cough, fever, hemoptysis, and dyspnea. ct scan may show a well-defi ned nodule with smooth margin connected to an arterial branch [ ] . positron emission tomography scan can demonstrate hypermetabolic activity in a pulmonary infarct secondary to dirofi lariasis [ ] . a pcr-based diagnosis of d . repens in human pulmonary dirofi lariasis has been reported [ ] . a defi nitive histopathological diagnosis of pulmonary dirofi lariasis can be made tissue specimens obtained by wedge biopsy, by video-assisted thoracoscopy, or rarely by fi ne needle biopsy. toxocara larva migrans syndromes are important zoonotic infections. certain nematode parasites entering into an unnatural host (e.g., man) may not be able to complete their life cycle and their progress is arrested in the "unnatural host." the common parasites that cause visceral larva migrans (vlm) and eosinophilic lung disease in man are a dog ascarid ( toxocara canis ) and less commonly a cat ascarid ( toxocara cati ) [ ] . human toxocariasis occurs in all parts of the world wherever there is a large pool of infected dogs. visceral larva migrans (vlm) is characterized by leukocytosis and eosinophilia. the larva induces a granulomatous reaction in the tissues containing eosinophils and multinucleated giant cells. larvae can get encapsulated within the granuloma where they are either destroyed or persist for many years in a viable state. granulomata are found in the lungs, liver, central nervous system, and eyes. later fi brosis and calcifi cation occur. larval antigens can cross-react with human a and b blood group antigens. visceral larva migrans is usually reported in young children with a history of pica. a history of exposure to puppies or dogs supports the diagnosis of vlm. these children usually present with fever, cough, wheezing, eosinophilia, and hepatomegaly. however, most of the children infected with toxocara spp. are asymptomatic. the main symptoms in patients with visceral larva migrans are fever, cough, wheezing, seizures, anemia, and fatigue. pulmonary manifestations are reported in % of cases and patients may present with severe asthma [ ] . scattered rales and rhonchi are heard on auscultation. there will be intense blood eosinophilia. skiagram chest may reveal focal patchy infi ltrates. in some cases, severe eosinophilic pneumonia may lead to respiratory distress [ ] . other clinical features include generalized lymph node enlargement, hepatomegaly, and splenomegaly. skiagram chest may show patchy infi ltrates. nonspecifi c changes include hypergammaglobulinemia and elevated isohemagglutinin titers to a and b blood group antigens. serological tests by elisa method using excretory-secretary proteins obtained from cultured t . canis may be useful in the diagnosis. cross reactivity with other helminths limits the usefulness of this test in endemic areas. detection of ige antibodies by elisa and toxocara excretory-secretary antigens by western blotting procedure have also been reported for diagnosis [ , ] . however, serodiagnostic procedures cannot distinguish between past and present infections. histopathological examination of lung or liver biopsy specimens may demonstrate granulomas with eosinophils, multinucleated giant cells, and fi brosis. since man is not the defi nitive host of toxocara sp., eggs or larvae cannot be demonstrated in the feces. human trichinellosis is an important food-borne zoonosis. the most important species that infect man is trichinella spiralis . the parasite has a direct life cycle with complete development in one host (pig, rat, or man). man gets infection from raw and partially cooked pork, when infected pig's muscle containing larval trichinellae is eaten by man. the common symptoms of trichinellosis are muscle pain, periorbital edema, fever, and diarrhea [ ] . pulmonary symptoms include dyspnea, cough, and pulmonary infi ltrates. dyspnea may be due to the involvement of diaphragm [ ] . leukocytosis, eosinophilia, and elevated levels of serum muscle enzymes (creatine phosphokinase, lactate dehydrogenase, aldolase, and amino transferase) are important laboratory fi ndings. an enzyme-linked immunosorbent assay (elisa) for detection of anti-trichinella antibodies using excretory-secretary antigens may be useful in the diagnosis. a defi nitive diagnosis can be made by muscle biopsy (usually deltoid muscle) that may demonstrate larvae of t . spiralis [ ] . is the incidence of parasitic lung diseases increasing, and how may this effect modern respiratory medicine? emerging and 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disease (or how to slice pie) ascariasis and hookworm possible approach for serodiagnosis of ascariasis by evaluation of immunoglobulin g response using ascaris lumbricoides somatic antigen nature and causes of hookworm anemia differentiation between the human hookworm ancylostoma duodenale and necator americanus using pcr-rflp biology and immunology of human strongyloidiasis disseminated strongyloides stercoralis in human immunodefi ciency virus-infected patients: treatment failure and review of literature pulmonary manifestations of strongyloidiasis strongyloides stercoralis infestation associated with septicemia due to intestinal transmural migration of bacteria corticosteroidinduced asthma: a manifestation of limited hyperinfection syndrome due to strongyloides stercoralis diagnosis of strongyloides stercoralis infection a simple modification of the baermann method for diagnosis of strongyloidiasis evaluation of three methods for laboratory diagnosis of strongyloides stercoralis infection diagnosis of pulmonary strongyloidiasis by bronchoalveolar lavage serology and eosinophil count in the diagnosis and management of strongyloidiasis in a non-endemic area tropical pulmonary eosinophilia acute tropical pulmonary eosinophilia: characterization of the lower respiratory tract infl ammation and its response to therapy tropical pulmonary eosinophilia: analysis of antifi larial antibody localized to the lung pulmonary eosinophilia: progress in respiration research tropical pulmonary eosinophilia re-examination of the diagnostic criteria of tropical pulmonary eosinophilia the course of lung function in treated tropical eosinophilia diffusing capacity in acute untreated tropical eosinophilia pulmonary membrane diffusing capacity and capillary blood volume in tropical eosinophilia persistent lower respiratory tract infl ammation associated with interstitial lung disease in patients with tropical pulmonary eosinophilia following treatment with diethylcarbamazine how to diagnose and manage common parasitic pneumonias? public health aspects of dirofi lariasis in the united states pulmonary dirofi lariasis: computed tomographic fi ndings and correlation with pathologic features pet fi ndings in pulmonary dirofi lariasis detection of dirofi laria (nochtiella) repens dna by polymerase chain reaction in embedded paraffi n tissues from two human pulmonary locations highlights of human toxocariasis visceral larva migrans associated with the hypereosinophilic syndrome and the onset of severe asthma acute respiratory failure due to toxocara infections evaluation of an immunenzymatic assay detecting specifi c anti-toxocara immunoglobulin e for diagnosis and post treatment follow up of human toxocariasis application of the western-blotting procedure for the immunodiagnosis of human toxocariasis clinical aspects of infections with trichinella spp tropical infectious diseases: principles, pathogens and practice key: cord- -hyvu nuq authors: salman, huda; cooke, kenneth r.; lazarus, hillard m. title: fibrosing alveolitis in hematologic malignancy patients undergoing hematopoietic cell transplantation date: - - journal: pulmonary involvement in patients with hematological malignancies doi: . / - - - - _ sha: doc_id: cord_uid: hyvu nuq although advances in antineoplastic therapy have considerably improved the survival of patients with hematological malignancies, current treatment modalities increase the risk of late complications. several forms of chronic pulmonary dysfunction due to infectious or noninfectious causes commonly occur in the months to years after chemo-radiotherapy and can be fatal or result in long-term morbidity. the judicious use of prophylactic antimicrobial agents has tipped the balance toward noninfectious etiologies. hence, while opportunistic infections still contribute to chronic lung disease, late sequelae resulting from antineoplastic therapy have been identified and reported. patients who proceed to receive hematopoietic cell transplantation (hsct) are particularly prone to developing lung complications. pulmonary dysfunction occurring after hsct may manifest with obstructive or restrictive pulmonary mechanics and may range in severity from subtle, subclinical functional changes to frank respiratory failure. insights generated using animal models suggest that the immunologic mechanisms contributing to lung inflammation after hsct may be similar to those responsible for graft-versus host disease. in sum, chronic fibrotic pulmonary dysfunction is a frequent and significant complication facing survivors of hematologic malignancies and their practitioners. the high incidence and suboptimal response to current support care and immunosuppressive therapy underscore the need for heightened awareness and continued research in this area. a -year-old man patient with de novo acute myelogenous leukemia (aml) was induced into complete remission with chemotherapy consisting of idarubicin and cytarabine. after consolidation with high-dose cytarabine, he later received conditioning with cyclophosphamide mg/kg/day intravenously for days and fractionated total body irradiation (tbi) , cgy followed by allogeneic hematopoietic cell transplant (hsct) using a hla-identical sibling donor. graftversus-host disease (gvhd) prophylaxis consisted of tacrolimus and short-course methotrexate. his clinical course was uncomplicated, but after withdrawal of immunosuppression he developed extensive chronic gvhd involving skin and liver. this complication was controlled with the re-institution of tacrolimus. surveillance pulmonary function testing completed days after hsct showed evidence of mild reductions in forced expiratory volume in s (fev ) with preservation of forced vital capacity (fvc). follow-up study revealed significant and rapid worsening of obstructive lung disease (old) despite resolution of hepatic and skin gvhd and continued prophylaxis against viral, fungal and pneumocystis infections using acyclovir, fluconazole and trimethoprimsulfamethoxazole, respectively. reductions in pulmonary function ultimately were associated with shortness of breath and dyspnea with exertion. subsequent workup revealed ground-glass opacities with air trapping on chest computed tomography (ct) scan and evidence of progressive afo on pulmonary function testing based on reduction of fev ( % of predicted normal), a ratio of fev to fvc of . and a residual volume of . l ( % of predicted normal). bronchoalveolar lavage was negative for infection. video-assisted thoracoscopic biopsy of the lungs revealed changes consistent with bronchiolitis obliterans with early fibrosis. the patient continued to receive tacrolimus, and ultimately a course of oral prednisone ( mg/kg/day) and etanercept mg subcutaneous once weekly was initiated. clinical symptoms resolved and pulmonary function improved. he remains in complete remission regarding the aml. fibrosing alveolitis (fa) is a progressive and often fatal disorder characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. historically, idiopathic pulmonary fibrosis (ipf) encompassed a heterogeneous group of histologic and clinical entities arising in an idiopathic setting [ ] . patients with hematologic malignancies treated with chemotherapy, radiation or hsct, such as the patient described above, commonly develop a wide variety of late and chronic pulmonary dysfunction states [ ] . these complications share many of the clinical and pathologic features described in typical idiopathic fa. this spectrum of pulmonary toxicity observed during fa can be simplified by considering the time of diagnosis in relation to institution of therapy, whether the radiographic abnormalities are focal or diffuse, and by underlying histopathology. in addition, there are individual patient factors that should be considered when formulating a differential diagnosis. these include: radiotherapy delivered to the chest wall or as part • of total body irradiation (tbi) exposure to pulmonary-or cardio-toxic chemother-• apeutic agents current or prior immunosuppressant therapy • history of high-dose chemotherapy exposure prior • to autologous or allogeneic hsct history of opportunistic pulmonary infection (fun-• gal or otherwise) in the case described herein, the patient was exposed to radiation therapy in preparation for hsct and received an allogeneic graft from his hla-matched sibling. while his early posttransplant course was uncomplicated, he developed chronic gvhd of the skin and liver lung after immunosuppression was tapered. the widespread and appropriate use of prophylactic antibiotics has shifted the spectrum of pulmonary dysfunction in hsct recipients from infectious to noninfectious etiologies. this chapter will address the chronic lung complications that lead to pulmonary fibrosis and persistent organ dysfunction in each context with specific focus on hematologic malignancy patients treated using hsct. in patients with hematologic malignancies, severe lung infections frequently lead to the development of acute respiratory distress syndrome (ards). bacterial infections predominate (see table . ) and arise because of severe immune suppression inherent to these disorders and their treatments. the pathology of ards involves severe alveolar epithelial cell damage, hyaline membrane formation, and festinate myofibroblast proliferation and fibrosis in the intra-alveolar spaces. affected hsct recipients who deteriorate and require intubation and mechanical ventilation for ards experience a high mortality. in one series, overall intensive care unit (icu) mortality was % [ ] . in recent years, advancements in supportive care have resulted in significant improvement in survival [ ] . however, longterm survivors continue to have residual lung dysfunction that may progress over time. in one series, autopsy evaluation revealed pulmonary fibrosis in % of such patients, underscoring the importance of dysregulated reparative mechanisms in the lung after an acute insult [ ] . factors influencing progression to the fibro-proliferative phase of ards versus resolution and reconstitution of the normal parenchymal architecture are poorly understood. abnormal repair and remodeling may be profoundly affected by both environmental and genetic factors. in this context, mechanical ventilation may affect the macromolecules that constitute the extracellular matrix (collagen, elastin, fibronectin, laminin, proteoglycan and glycosaminoglycans) and impact the biomechanical balance within the lung parenchyma. fungal infections also may follow a chronic course of prolonged inflammation with focal or diffuse scarring ultimately resulting in significant pulmonary dysfunction. invasive aspergillosis (ia) occurs frequently in hematologic malignancy patients, particularly after an allogeneic hsct, presenting classically as angio-invasive or airway-invasive disease. angioinvasive ia is characterized histologically by invasion and occlusion of small to medium-sized pulmonary arteries by fungal hyphae. this effect leads to the formation of necrotic hemorrhagic nodules or pleuralbased, wedge-shaped hemorrhagic infarcts. the "halo sign" (nodules surrounded by areas of ground-glass attenuation) on chest ct scan strongly suggests a diagnosis of ia [ ] . airway-invasive aspergillosis is characterized by the presence of organisms in the basement membrane of the bronchioles and within the airway lumen. positive yield from respiratory samples such as sputa examination or broncho-alveolar lavage (bal) is more likely in this subtype of ia than in the angio-invasive variety. clinical manifestations of acute airway-invasive aspergillosis include: acute tracheobronchitis, exudative bronchiolitis and bronchopneumonia. using high-resolution ct, the associated bronchiolitis is characterized by the presence of peri-bronchial consolidation, centri-lobular micro-nodules, and branching linear or nodular areas of ground-glass attenuation having a "tree-in-bud" appearance [ ] . this form of airway-invasive aspergillosis can be associated with pseudo-membranous necrotizing tracheal involvement that can cause pneumo-mediastinum and has a high [ ] . airway-invasive aspergillosis can also follow a chronic course known as chronic necrotizing aspergillosis. this condition is characterized by an indolent, granulomatous cavitary infection that may mimic reactivation of tuberculosis radiographically [ ] . mortality is lower compared with the other forms of ia and often is related to the underlying disease of the patient. hematologic malignancy patients treated with chemotherapy or chest wall radiation therapy, or those who proceed to receive a hsct may develop a wide variety inflammatory noninfectious lung disorders that ultimately may lead to pulmonary fibrosis. radiation-induced lung injury first was described in , soon after the development of roentgenograms [ ] . in the distinction between two separate types of radiation-induced lung injury, radiation pneumonitis and radiation fibrosis, was made [ ] . an entire chapter from drs. gallego and rello in this book is dedicated to radiation-related lung injury. radiation-induced lung injury results from the combination of direct cytotoxicity upon normal lung tissue and, perhaps more importantly, the development of fibrosis triggered by radiation-induced cellular signal transduction. the cytotoxic effect is largely a consequence of dna damage and death in normal lung epithelial cells. the development of fibrosis that can compromise lung function is mediated by a number of different cytokines. clinically, the most extensively studied radiation-induced cytokine is transforming growth factor beta (tgf-b), which can induce fibroblast collagen deposition. a normal plasma tgf-b concentration at the conclusion of a clinical course of radiotherapy has been observed to be a predictor for the risk of pneumonitis [ ] . other proinflammatory cytokines, including, but not limited to, interleukin il- , tumor necrosis factor-alpha tnfa and il- , are upregulated immediately after irradiation. increased il- plasma concentrations correlate with an increased risk of radiation-induced lung injury [ , ] . platelet-derived growth factor (pdgf) and basic fibroblast growth factor (bfgf) are upregulated in animal models of lung irradiation injury and antedate the development of fibrosis [ ] . factors affecting the development of radiation-induced lung disease are numerous and are included in table . [ ] [ ] [ ] [ ] ; all have been reported to raise the risk of radiation pneumonitis. radiographic and bronchoscopic findings are nonspecific, and the diffusion capacity for carbon monoxide (dl) typically is depressed in patients with radiation-induced lung damage. long-term glucocorticoids may be effective in the treatment of radiationassociated lung injury in which cop is the leading pulmonary involvement; however, symptoms and radiographic abnormalities, as well as immunologically mediated lymphocytic alveolitis frequently recur with discontinuation of therapy [ , ] . early studies suggested that pentoxifylline may have a role •• method of irradiation such as conformal radiation therapy or specialized techniques including intensity-modulated radiation therapy and stereotactic body radiation therapy [ ] [ ] [ ] [ ] in the treatment of radiation-induced fibrosis involving the skin and subcutaneous tissues as this agent also inhibits experimental bleomycin-induced pulmonary fibrosis in rats, likely via its anti-tnfa effects [ ] . pentoxifylline showed a significant protective effect for both early and late lung radiotoxicity. amifostine is a pro-drug that is de-phosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. this drug can reduce the toxic effects of chemotherapy by acting as a scavenger of free radicals generated in tissues exposed to radiation. early evidence suggests that amifostine may decrease radiation-induced pulmonary injury without diminishing the therapeutic effect [ , ] . captopril and other ace inhibitors also have been shown to reduce radiation-induced lung fibrosis in rats [ ] , but there are no published data in humans. improvements in the perfusion and ventilation of radiation-injured lung tissue may be expected from to months after radiation therapy. beyond months, however, further significant improvement appears unusual [ , ] . patients with hematologic diseases are exposed to a host of traditional and newer chemotherapeutic agents that can cause lung injury at an incidence that ranges from less than % to as high as % [ , ] . the increased complexity of multi-modality treatments and high-dose protocols designed to augment antineoplastic efficacy, particularly in the context of hsct, has increased the incidence of pulmonary complications. the diagnosis of drug-induced respiratory disease often is complex because: ( ) patients may be exposed to several pneumo-toxic drugs concurrently or in sequence due to earlier treatment failure; ( ) time to onset of pulmonary toxicity may be delayed, making it difficult to ascertain which agent is responsible for the pulmonary reaction; ( ) the combination of drugs to treat malignant hematologic conditions may lead to unexpected drug interactions, producing enhanced toxicity compared with the toxicity of each agent considered separately; and ( ) radiation therapy to the chest or tbi. other factors that play a role in the development of pulmonary toxicity include advanced age, current smoking, abrupt withdrawal of corticosteroids and the use of hsct (allogeneic vs autologous). changes in blood neutrophil counts, thrombocytopenia, coagulation deficits, volume overload or left ventricular dysfunction also can influence the spectrum and severity of pulmonary drug toxicity. in addition to overt pulmonary toxicity, subclinical drug-induced lung dysfunction often occurs in the form of reduced dlco and lung volumes or changes in cell populations in bal fluid. upon cessation of exposure to the agent, most of these changes reverse slowly in a few weeks or months. drug-induced lung injury can manifest in several patterns ( the majority of cases) , azathioprine, chlorambucil, cyclophosphamide, procarbazine and, rarely, vinca alkaloids. the onset of this condition is unpredictable; symptoms may develop a few days to years after exposure. the clinical picture includes increasing dyspnea, dry cough, high fevers and rash. the severity of illness can vary from mild to progressive respiratory failure, and associated radiographic findings may range from bilateral (usually symmetrical) interstitial or alveolar opacities to extensive consolidation with air bronchograms and volume loss [ ] [ ] [ ] . pleural effusions and mediastinal lymph node enlargement have been reported in patients with methotrexate-induced lung injury [ , ] . bal fluid usually shows lymphocyte predominance. a low ratio of cd to cd lymphocytes is suggestive, but not specific, for drug-induced lung disease. other bal findings include neutrophilia or a combined pattern of lymphocytosis with neutrophilia or eosinophilia [ ] . appropriate stains, cultures and molecular techniques in bal fluid should be performed to exclude opportunistic infections. a lung biopsy may be required in selected cases. histopathologic features include interstitial inflammation and pulmonary granulomas. fibrosis can be present, but is generally not the dominant histopathologic feature. alveolar edema or hemorrhage may be found as a manifestation of severe methotrexate pneumonitis [ ] . high-dose corticosteroids may be indicated with more advanced disease, as drug-induced nsip can lead to mortality if it is not treated promptly, but in milder cases, symptoms can subside after simple drug withdrawal [ ] . although rechallenge with the drug may be safe, it is not generally recommended [ ] . eosinophilic pneumonia (ep) is an unusual and unpredictable pattern of response to chemotherapeutic agents as opposed to that described following the use of some antibiotics. ep in patients with hematologic malignancies can result from treatment with fludarabine and, rarely, interferons, inhaled or parenteral pentamidine, and radiographic contrast media [ ] . although methotrexate and procarbazine pneumonitis can often be associated with peripheral eosinophilia, bal and histopathologic features are not those of eps. typically, the syndrome of ep develops during or shortly after termination of treatment. a history of an allergic disorder, or repeated courses of treatment with the specific drug, may predict for a higher risk. the diseases could manifest as acute pneumonia and progress to respiratory failure [ , ] . radiograghic findings of ep include alveolar infiltrates and the classic pattern of "photographic negative" pulmonary edema [ ] . it also could cause faint ground-glass opacities, or kerley's "b" lines (dense and diffuse). ep is diagnosed by the presence of increased percentages or numbers of eosinophils in blood, bal, or lung tissue. a lung biopsy is rarely required, but discontinuance of the offending drug is essential. corticosteroid drug therapy is suggested in cases with severe involvement. the prognosis for this condition usually is good. chemotherapy-induced organizing pneumonia (op) may manifest with chest pain, dyspnea and diffuse radiographic abnormalities with [ ] or without acute respiratory failure [ ] , or may be discovered incidentally on chest imaging [ ] . nodular op typically is seen in patients exposed to chemotherapy who develop round-shaped foci that localize mainly in lung bases, may abut the pleura and simulate metastatic nodules [ ] [ ] [ ] . nonspecific findings are retrieved from bal, such as increases in the percentage of lymphocytes, neutrophils or eosinophils. open lung biopsy guided by the results of ct scan is the procedure of choice. the nodules correspond to sterile aggregates of mononuclear cells. histology reveals interstitial inflammation, superimposed on the dominant background of alveolar and ductal fibrosis. lung nodules with the histopathologic features of cryptogenic organizing pneumonia or of localized fibrosis can be observed after treatment with bleomycin, cyclophosphamide, vinblastine and, rarely, fludarabine [ ] [ ] [ ] [ ] . drug discontinuation and, if required, corticosteroid therapy usually are followed by improvement in most cases. organizing pneumonia (formerly boop) can be seen following hsct and is described in detail later in the chapter. diffuse alveolar damage (dad) is a serious form of pulmonary pathology that may develop in the context of drug-related lung injury. single chemotherapeutic agents (e.g., bcnu or other nitrosoureas, bleomycin, busulfan, chlorambucil, cyclophosphamide, melphalan, procarbazine, vinblastine) or multiagent cytostatic chemotherapy have been reported to cause this lung toxicity [ ] . some regimens may be associated with a greater likelihood of dad than others even if they differ in one agent only. for instance, in patients with de novo-treated hodgkin's lymphoma, the substitution of gemcitabine for dacarbazine, e.g., abvg rather than abvd (doxorubicin, bleomycin, vinblastine and gemcitabine instead of dacarbazine), was associated with a % incidence rate of pulmonary toxicity [ ] . likewise, the substitution of gemcitabine for etoposide in the dose-escalated beacopp regimen (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone and gemcitabine rather than etoposide) significantly escalated the likelihood of pulmonary toxicity [ ] [ ] [ ] . concurrent administration of radiation therapy to the chest or use of tbi, supplemental oxygen and possibly colonystimulating factors (csfs) may increase the risk of dad. time to onset of dad can vary from shortly after the first administration of the offending drug to much later into the treatment course [ ] . restrictive lung function patterns and hypoxemia are typical. dlco abnormalities often precede clinical symptoms. the clinical evolution of drug-induced dad varies from an isolated decrease in dlco [ , ] or evidence of fibrosis in trans-bronchial or pulmonary biopsies [ , ] as the only manifestation of toxicity to bilateral, interstitial and alveolar infiltrates [ , ] . severe cases progress to an ards picture and death [ ] . high-resolution ct scanning may show groundglass opacities and intra-lobular septal thickening, and the extent of changes correlates with clinical severity [ ] . dysplastic pneumocytes may be retrieved by bal [ , ] . a lung biopsy is reserved for patients with an atypical presentation or for those who do not improve with empirical antibiotic and corticosteroid treatment [ ] . the main histopathologic feature of dad is consistent with hyaline membranes and fibrin deposits lining the alveolar border, dysplasia of type ii cells, free alveolar fibrin, cells and debris in alveolar spaces and various stages of interstitial edema, inflammation and organization [ ] . dad may be reversible after discontinuation of drugs or after the addition of corticosteroids, or both [ ] . the usual doses of oral corticosteroids may not prevent the condition from developing, but higher doses are reported to reduce the incidence [ ] . the high incidence, severity and unpredictability of dad associated with chemotherapy suggest that it is reasonable to discontinue such treatment once the dlco has decreased % compared with pre-therapy values. although smaller decrements in dlco do not equate to toxicity and should not lead to withdrawal of chemotherapy, a precipitous decrease in the dlco indicates impending toxicity [ ] . when radiation therapy is planned after the administration of chemotherapeutic agents, it is advisable to wait for any chemotherapy-induced decrease in the dlco to stabilize or show a trend toward improvement before starting radiation. finally, drug-induced pulmonary fibrosis may develop in patients receiving cytotoxic agents, such as bleomycin, busulfan, bcnu, lomustine, ccnu chlorambucil, cyclophosphamide, melphalan, vinca alkaloids, radiation therapy and tbi [ ] . this entity more often is diagnosed months or years after termination of treatment. early signs of this disease are basilar or diffuse streaky opacities and volume loss. this condition can progress to honeycombing and fibrotic changes; reversal of this toxicity and the response to corticosteroids are unpredictable and often unsatisfying. histologic exam can demonstrate the characteristic dysplasia of type ii pneumocytes that reflects exposure to alkylating agents and radiation therapy. in a few patients, especially children treated for hematologic malignancies, pleural or pulmonary fibrosis may develop [ ] . this process results in thoracic deformity, encasement of the lungs and severely restricts lung physiology. an accelerated variant of pulmonary fibrosis, acute interstitial pneumonia (formerly termed the hamman and rich syndrome), has been described after treatment with chlorambucil and methotrexate [ ] [ ] [ ] . the prognosis of this condition is poor despite drug withdrawal and institution of high-dose corticosteroids. as seen in the patient description at the start of this chapter, a decline in lung function long has been identified as a significant complication in the months to years that follow allogeneic hsct. a clinical pearl from dr. bergeron in this book also very nicely describes this type of pulmonary involvement. noninfectious conditions now represent the major pulmonary causes of morbidity and mortality after hsct. idiopathic pneumonia syndrome (ips), discussed in another chapter in this book, remains one of the more common and serious pulmonary complications occurring within months after hsct. although graft-versus-host reactions may play an etiologic role, the major contributing factor is conditioning-related toxicity. among lung conditions that are more closely associated with gvhd, both bronchiolitis obliterans (brob) (onset months to years after hsct) and bronchiolitis obliterans with organizing pneumonia (cop) may lead to fa. the term cop should not be used interchangeably with bronchiolitis obliterans (bo) to describe a patient with chronic lung dysfunction after hsct, although such usage unfortunately is widespread. the two disorders differ with respect to histopathology, pulmonary function characteristics and, most importantly, response to therapy. brob is an inexorably progressive condition, whereas cop behaves similarly to idiopathic cop seen in other populations. cop after hsct usually is quite responsive to corticosteroids and in other settings may resolve spontaneously, whereas brob is not [ , ] . organizing pneumonia also is associated with restrictive (rather than obstructive) changes on pulmonary function testing (table . ). in allogeneic hsct recipients, the disparity in match between the donor graft and the recipient for the human leukocyte antigens (hlas) mediate both gvhd and graft rejection (host-versus-graft reaction). the presence of alloreactive injury to the lung attributed to gvhd is poorly defined and remains debated. in the skin, liver and intestine, gvhd produces a characteristic t-lymphocyte-mediated epithelial destruction. there are few data to support such a defined lesion with the exception of lymphocytic pneumonitis [ ] . a variety of pulmonary complications have been described as manifestations of gvhd, but these associations are based primarily on the simultaneous occurrence of pulmonary abnormalities, the absence of an infectious agent and nonspecific histopathologic lesions in the setting of established gvhd in other organs. nevertheless, both acute and late-onset lung injury syndromes have shown a clinical association with gvhd, including ips, engraftment syndrome, diffuses alveolar hemorrhage, brob and cop [ ] . several murine models also demonstrate pathologic lung changes in the setting of gvhd, thus supporting a mechanistic relationship between gvhd and lung injury. old and chronic afo are the most common noninfectious late pulmonary complications of allogeneic hsct. these entities are manifested on pulmonary function testing by a diminished fev or fev /fvc. the incidence of these syndromes ranges from % to %, depending upon the definition of afo applied in each study [ , ] . typically, the presentation occurs beyond the third month after hsct [ ] . among patients who develop chronic gvhd, new-onset afo may develop in up to one third of the patients. in a study of cases the underlying process accounting for afo was brob in % [ ] . histologically, this process demonstrates fibrous obliteration of the lumen of respiratory and membranous bronchioles. in the absence of histopathologic evidence, new onset afo after allogeneic hsct often is referred to as "bronchiolitis obliterans syndrome" (bos). in addition to chronic gvhd, risk factors for the development of afo include increasing recipient age, pre-transplant reduction in the ratio fev /fvc, low serum immunoglobulin levels, use of methotrexate and a history of respiratory viral infection within the first days [ ] . the onset typically is insidious with presenting symptoms including dry cough ( - %), dyspnea ( - %) and wheezing ( %), but fever is uncommon [ , , ] . the chest radiograph is usually normal, but high-resolution ct scans often demonstrate evidence of expiratory air trapping, hypo-attenuation and bronchial dilation [ , [ ] [ ] [ ] . demonstrating persistent afo using pulmonary function testing and exclusion of other causes of afo such as asthma, tobacco-related emphysema, and viral or bacterial respiratory infection establish the diagnosis. except for its utility in excluding an infectious etiology, bal is usually nonspecific [ ] , and transbronchial biopsies typically are nondiagnostic due to the patchy nature of this small airway process and the limited size of samples obtained. surgical lung biopsy is rarely indicated. the etiology of new onset afo after hsct is unknown. those recognized causes in otherwise normal hosts rarely include recurrent aspiration, viral infection (influenza, adenovirus, measles) and bacterial infection (mycoplasma sp.) [ ] . immunologic mechanisms inducing bronchial epithelial injury are suggested by the strong association between chronic gvhd and new onset afo. indeed, the lung epithelium may be the target of immune-mediated injury induced by donor cytotoxic t cells in chronic gvhd [ ] . thus, brob after hsct may represent a manifestation of gvhd in the lung. disease progression is variable; however, the syndrome is associated with significantly increased mortality rates, and improvement in lung function is uncommon. many patients develop a progressive decline in lung function resulting in respiratory failure [ , ] . there are no prospective studies of the treatment of new onset afo after hsct. old in the presence of chronic gvhd is managed primarily by controlling gvhd. various immunosuppressive agents have been reported to result in stabilization of lung function in - %, but improvement in only - % [ , ] . in the hope that early recognition and treatment may improve outcome, routine spirometry among patients with chronic gvhd is encouraged to detect the insidious onset of this process. restrictive lung disease (rld) is defined by reductions in fvc, total lung capacity (tlc) and dlco as measured by standard pulmonary function tests (pfts). in rld, the ratio fev /fvc is maintained near % [ , ] . rld is common after hsct. significant decreases in fvc or tlc have been reported in as many as - % of allogeneic hsct recipients by day . a decline in tlc or fvc after hsct (even if the absolute values for each measurement remained within the normal range) has been associated with an increase in nonrelapse mortality. tbi-containing conditioning regimens and the presence of acute gvhd have been associated with rld, in addition to obstructive lung disease [ ] [ ] [ ] ; however, the impact of age on the development of rld is less clear. early reports suggested that the incidence of rld is lower in children compared to adults and that the incidence increases with advancing recipient age [ ] . more recent studies have revealed significant rld in children receiving hsct [ ] . organizing pneumonia after hsct falls under the rld pattern on liver function tests and recently was shown to be associated with prior acute and chronic gvhd. organizing pneumonia has been described in case reports as occurring after both allogeneic and syngeneic hsct; these data suggest an association of the lung lesion with chronic gvhd and intestinal ulcerations. in addition, corticosteroid therapy appeared beneficial in the resolution of the lesion. in a recent case control study, freudenberger et al. reviewed cases of histologic cop [ ] . the clinical features of cop in this population were similar to idiopathic and other etiologies with an association between acute and chronic gvhd and the subsequent development of cop. affected patients were more likely to have skin involvement with acute gvhd and chronic gvhd affecting the gut and oral mucosa. the causes of cop following hsct remain enigmatic, but possible etiologies include direct allo-immunologic reactions, atypical infection or atypical manifestations of ips. regardless, the clinical presentations and responses of cop are similar to other cases of idiopathic cop. the published literature contains a paucity of therapeutic trials for chronic lung injury after hsct. a study by payne and colleagues showed that the use of cyclosporine and methotrexate as gvhd prophylaxis prevented the development of old when compared to historic controls receiving prednisone and methotrexate [ ] , but results of prospective, randomized trials in this setting are not available. three recently published case series have exploited the antiinflammatory effects of azithromycin to treat old in both allogeneic hsct and lung allograft recipients. each study suggested a beneficial effect of this drug on pulmonary function when administered for or more weeks [ ] [ ] [ ] . the potential role for tnfa in the pathogenesis of both old and rld suggests that agents such as etanercept may have promise, and several studies have demonstrated a potential benefit of this drug in some hsct patients with chronic lung injury [ , ] . the immunologic mechanisms responsible for chronic, fibrotic pulmonary dysfunction after hsct remain poorly defined, in large part because of the lack of correlative data obtained from afflicted hsct recipients and the paucity of suitable sct animal models for either rld or old. chronic pulmonary disease following allogeneic hsct likely involves an initial insult to lung parenchyma followed by an ongoing inflammatory process involving the interplay between recruited donor-derived immune cells and the resident cells of the pulmonary vascular endothelium and interstitium. mechanistic insights into old following hsct have been derived from studies of lung allograft rejection. data generated from both humans and mice support the hypothesis that the development of brob in this scenario involves the secretion of inflammatory cytokines and chemokines, along with interactions between apcs and activated lymphocytes [ , ] a tri-phasic model of chronic noninfectious lung injury after hsct has been proposed [ ] . in phase i, an acute pneumonitis develops as a consequence of an allogeneic immune response, resulting in the sequential influx of lymphocytes, macrophages and neutrophils into an inflamed pulmonary parenchyma. in phase ii, a persistent inflammatory signal, in the setting of dysregulated repair mechanisms, promotes the transition from acute to chronic injury. if the inciting injurious stimulus predominantly involves bronchiolar epithelial cells, phase ii is associated with the concentric infiltration of lymphocytes and collagen deposition in the peri-bronchiolar areas resulting in the development of chronic bronchiolitis. if, however, the alveolar epithelium is the primary target, leukocyte recruitment and matrix deposition are confined primarily to the interstitial space. as chronic inflammation proceeds to phase iii, lung fibroblasts increase dramatically in number and contribute to the enhanced deposition of collagen and granulation tissue in and around bronchial structures, ultimately resulting in complete obliteration of small airways and fixed old. by contrast, fibroblast proliferation and intra-septal collagen deposition during phase iii ultimately result in interstitial thickening, septal fibrosis, significant volume loss and severe rld. clinical and experimental data suggest that the progression to a chronic, pro-fibrotic form of pulmonary toxicity involves the secretion of cytokines and chemokines [ ] [ ] [ ] , and in this context, tnfa may be a central factor in the proposed tri-phasic model of disease. evidence for a role of tnfa in the transition from acute to chronic lung injury comes from studies using targeted over-expression of tnfa in the lungs of rodents [ ] . in these models, early lung histopathology includes a lymphocytic infiltrate similar to that seen in experimental ips models [ , ] , whereas the histologic changes associated with more prolonged exposure to tnfa show both interstitial and peribronchial inflammation that closely resemble changes seen at later time points after hsct [ , ] . fa is characterized by sequential acute lung injury that can culminate in scarring and end-stage lung disease. despite the high success rate in treating hematologic malignancies with or without using hsct, this sequence of events continues to be a significant contributor to nonrelapse morbidity and mortality in patients with hematologic malignancies because of either the disease itself or as a result of treatment modalities employed. the pathophysiologic mechanisms contributing to the initiation and progression of disease remain poorly defined. to this end, current treatment options remain suboptimal and primarily limited to supportive care measures and antiinflammatory agents, such as corticosteroids or other immunosuppressant therapy. 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disease in bone marrow transplant recipients key: cord- - jsaxirt authors: lan, yanqiu; wu, dezhi; jin, yunrui; shui, min; fan, xianjun title: danhong injection in the treatment of idiopathic pulmonary fibrosis: a protocol for systematic review and meta-analysis date: - - journal: medicine (baltimore) doi: . /md. sha: doc_id: cord_uid: jsaxirt background: many studies have reported that the effects of danhong injection on idiopathic pulmonary fibrosis. however, its effects are still not well understood. the aim of this study is to assess the effects of danhong injection in the management of idiopathic pulmonary fibrosis. methods: electronic databases such as pubmed, medline, embase, web of science, cochrane library, china national knowledge infrastructure, wanfang, the chongqing vip chinese science and technology periodical database, and china biomedical literature database will be searched without limitations of language and geographical location. two researchers will independently conduct research selection, data extraction, and research quality assessment. the revman . software and stata . software are used for statistical analysis. results: this study will provide high-quality comprehensive evidence for the effectiveness and safety of danhong injection in the treatment of idiopathic pulmonary fibrosis. conclusions: the results obtained from this study will define the basis for the effectiveness and safety of danhong injection in the treatment of idiopathic pulmonary fibrosis. idiopathic pulmonary fibrosis is a serious, progressive, and even fatal disease, and there is no exact and effective cure for this ailment at present. [ ] respiratory viral pneumonia such as coronavirus disease , especially in severe cases, is more likely to progress into pulmonary fibrosis. [ ] currently, there is a lack of specific drugs in the treatment of idiopathic pulmonary fibrosis. [ ] early corticosteroids and other drugs have not been recommended for clinical application because of their poor efficacy and serious side effects. [ ] even though the new drugs pyrifenidone and nidanib are able to achieve symptomatic relief and improve the rate of deterioration of the pulmonary function to some extent, their overall curative effect is still insufficient. [ , ] moreover, these drugs have been associated with way too many adverse reactions and their economic profile is poor. [ , ] therefore, there is still an urgent need to come up with more effective drugs. in recent years, traditional chinese medicine has provided new ideas and methods for the treatment of idiopathic pulmonary fibrosis. [ ] [ ] [ ] danhong injection is a traditional chinese medicine injection derived from salvia miltiorrhiza and carthamus tinctorius via modern technology. [ ] it is capable of alleviating the clinical symptoms and pulmonary function of patients with idiopathic pulmonary fibrosis without generating any obvious adverse reaction. [ ] to further evaluate the efficacy and safety of danhong injection in the management of patients with idiopathic pulmonary fibrosis, a meta-analysis of related randomized controlled trials (rcts) was conducted. private information must not be divulged. this systematic review must not endanger the participants' rights. ethical approval is not required. the results may be published in a peer-reviewed journal or disseminated at relevant conferences. this study was registered through prospero (prospero registration number: crd ). we organized this study based on the preferred reporting items for systematic reviews and meta-analyses protocols guidelines. [ ] ethical approval is not required as there is no patient recruitment and personal information collection, and the data included in our study were all extracted from published literature. . inclusion criteria for study selection . . . type of studies. we only selected rcts focusing on the effect of danhong injection in the treatment of idiopathic pulmonary fibrosis, regardless of the language, and publication status restrictions. rcts including patients diagnosed with idiopathic pulmonary fibrosis were enrolled, irrespective of the nationality, race, age, gender, and source of cases. the control group was treated with conventional western medicine treatment modalities (e.g., pifenidone, nidanib, prednisone, n-acetylcysteine, etc). the treatment group received both danhong injection and western medicine treatment regimens. type of outcome measures. the main outcome measure was the clinical effective rate. the clinical effective rate was determined according to the clinical efficacy criteria in the guidelines for diagnosis and treatment of idiopathic pulmonary (interstitial) fibrosis (draft). the secondary outcomes: oxygen tension (pao ); carbon monoxide diffusing capacity (dlco); transforming growth factor-b (tgf-b ); hyaluronic acid (ha); laminin (ln); type iii procollagen; forced vital capacity in second/forced vital capacity ratio; type iii collagen; blood urea nitrogen; adverse reactions. . incomplete data or misrepresentation of data reports. . repeated publication of documents. . case reports, reviews, etc. . inability to obtain original documents. a comprehensive search of electronic databases such as pubmed, medline, embase, web of science, cochrane library, china national knowledge infrastructure, wanfang, the chongqing vip chinese science and technology periodical database, and china biomedical literature database was effected to collect rcts on the integration of danhong injection in the treatment of idiopathic pulmonary fibrosis. we also skimmed other resources for relevant articles. all document sources were not restricted by language and publication status. the search strategy performed for pubmed is illustrated in table . search of other databases was also performed similarly to this search strategy. two reviewers independently screened the literature, extracted data, and cross-checked the information. in case of disagreement, a third party was consulted to assist in the judgment, or we tried to contact the author to supplement the missing piece of information. when selecting documents, we first read the title and abstract, and after excluding obviously irrelevant documents, we read the full text to determine whether or not it should be included. the data extracted mainly comprises: basic information of the included literature, such as the authors, date of publication, country, sample size, age, doses administered, content and duration, intervention time, intervention details, etc; specific details of the intervention measures, including the usage of danhong injection, dosage administered, etc; baseline characteristics of the included subjects; risk of bias in the key elements of evaluation; the prognostic indicators and data measurement, such as the clinical effective rate, pao , dlco, tgf-b , ha, ln, etc. the literature selection process is displayed in figure . two researchers used the rct bias risk evaluation tool in the cochrane system review manual . . to evaluate the bias risk of the included rct and cross-check the results. the main items consist of: randomization plan; group concealment; blinding method; incomplete data reporting; selective outcome report; were used for statistical analysis. for dichotomous variables, odds ratio were implemented for statistical analysis. meanwhile, for continuous variables, standardized mean difference was selected with different tools or units of measurement, and all the above were represented by effect value and % confidence intervals. if the statistical heterogeneity between the results of each study does not exist or is negligible (i < %, p > . ), the fixed-effects model is used for meta-analysis; on the other hand, if there is large statistical heterogeneity detected between the results of the studies (i ≥ %, p < . ), then we further analyzed the source of heterogeneity. after excluding the influence of obvious etiologies of clinical heterogeneity, the random effects model was used for meta-analysis. the level of meta-analysis was set to a = . . obvious clinical heterogeneity was solved by subgroup analysis or sensitivity analysis, or only descriptive analysis. dealing with missing data. if the relevant data in the literature was incomplete, the first author or corresponding author would be contacted by email or phone to obtain the missing piece of information. if the missing data still could not be obtained through the aforementioned method, we would attempt to synthesize the available data in the preliminary analysis. in addition, a sensitivity analysis would be used to gauge the potential impact of the missing data on the overall results of the study. . . . subgroup analysis. the subgroup analysis was based on danhong injection dose, course of treatment, and sample size. to test the stability of the metaanalysis results of indicators, a one-by-one elimination method was adopted for sensitivity analysis. . . . reporting bias. if the number of included study was ≥ , a funnel plot was used to qualitatively detect publication bias. [ ] egger and begg tests were used to quantitatively assess any potential publication bias. over the past couple of years, studies have demonstrated that idiopathic pulmonary fibrosis is involved in a variety of molecular pathways, including pro-inflammatory cascade, intracellular signal transduction, myofibroblast activation, and so on. [ ] [ ] [ ] so far, there is no satisfactory treatment for pulmonary fibrosis. [ , ] commonly used drugs include glucocorticoids, immunosuppressants/cytotoxic drugs, and antifibrotic agents. [ ] danhong injection is principally composed of salvia miltiorrhiza and safflower extracts, and it has been demonstrated to improve the degree of pulmonary fibrosis. [ ] to obtain a thorough picture of the clinical effect of danhong injection as adjuvant and alternative therapy in the management of idiopathic pulmonary fibrosis, we conducted a meta-analysis. this article will provide comprehensive and high-quality evidence for the integration of danhong injection in the treatment of idiopathic pulmonary fibrosis. as could be expected, our meta-analysis may have some limitations. first and foremost, including both chinese and english research literatures may increase the level of bias. secondly, the diversity of race, age, drug dosage, and treatment course resulted in higher clinical and statistical heterogeneity. in summary, this study will help determine the effectiveness and safety of danhong injection in the treatment pf idiopathic pulmonary fibrosis. we genuinely hope that this study can supply higher-quality evidence for the effectiveness and safety of danhong injection in the management of idiopathic pulmonary fibrosis. clinical value of biomarkers in diagnosis and treatment of idiopathic pulmonary fibrosis a fatal case of coronavirus disease (covid- ) in a patient with idiopathic pulmonary fibrosis chinese herbal medicines compared with nacetylcysteine for the treatment of idiopathic pulmonary fibrosis: protocol for a systematic review french practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis- update. short-length version model-based meta-analysis on the efficacy of pharmacological treatments for idiopathic pulmonary fibrosis updated evaluation of the safety, efficacy and tolerability of pirfenidone in the treatment of idiopathic pulmonary fibrosis is pirfenidone effective for idiopathic pulmonary fibrosis? systematic review and network meta-analysis of idiopathic pulmonary fibrosis treatments citrus alkaline extracts prevent fibroblast senescence to ameliorate pulmonary fibrosis via activation of cox- probing into the mechanism of alkaline citrus extract promoted apoptosis in pulmonary fibroblasts of bleomycin-induced pulmonary fibrosis mice effectiveness and safety of chinese medicine for idiopathic pulmonary fibrosis: a systematic review and meta-analysis danhong injection in cardiovascular and cerebrovascular diseases: pharmacological actions, molecular mechanisms, and therapeutic potential ability to suppress tgf-b-activated myofibroblast differentiation distinguishes the anti-pulmonary fibrosis efficacy of two danshen-containing chinese herbal medicine prescriptions preferred reporting items for systematic review and meta-analysis protocols (prisma-p) : elaboration and explanation the performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed current and future idiopathic pulmonary fibrosis therapy senotherapeutics: targeting senescence in idiopathic pulmonary fibrosis current advances in idiopathic pulmonary fibrosis: the pathogenesis, therapeutic strategies and candidate molecules pharmacotherapy and adjunctive treatment for idiopathic pulmonary fibrosis (ipf) the therapy of idiopathic pulmonary fibrosis: what is next? the future of pharmacological treatment in idiopathic pulmonary fibrosis key: cord- - lkkez n authors: nan title: invited speakers date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: lkkez n nan the physiology of respiration reaches its extreme limits when man is exposed to the effects of high altitude, which is basically a decrease in ambient pressure and temperature. the process of acclimatization of humans to high altitude occurs within minutes of ascent, starting with increases in cardiac output, and ventilation. these result in acute changes in pao and paco . slower changes of acclimatization include increase in hemoglobin concentration (polycythemia), and muscle capillarity, but decrease in mitochondrial volume density and cellular aerobic capacity. through acclimatization, animals and human inhabitants of high altitude areas have developed adaptations that allow them to function as near normal as those living at sea level. humans who undergo acute ascent to high altitude could acclimatize, but some fail to do so. if there is failure to acclimatize, oxygen diffusion impairment results, due to decreased partial pressure, and lower affi nity of hb for oxygen. in addition, there is signifi cant increase in ventilation/perfusion heterogeneity. the resulting hypoxia leads to hypoxic pulmonary vasoconstiction (hpv) which results from multiple components: changes in epithelial cell wall that lead to intracellular calcium increase and/or calcium sensitization. subsequently, pulmonary hypertension develops, with actual breaks in the capillary endothelium leading to an infl ammatory process (seen more during exercise), and decrease in alveolar fl uid clearance. these mechanisms contribute to the development of alveolar edema, high altitude pulnary edema (hape), which is one of the two major diseases due to acute mountain sickness (ams). both hape and the other ams, high altitude cerebral edema (hace) could be potentially fatal, and must be recognized and treated early. knowledge of the pathophysiology of the ams would allow more rational approaches to their prevention and treatment. high altitude illnesses can develop among healthy individuals who sojourn for recreation and work: cerebral form called acute mountain sickness (ams) and potentially fatal pulmonary form called high altitude pulmonary edema (hape). ams is generally self-limited. high-altitude cerebral edema (hace) is likely a continuum of ams and the end-stage of ams. ams is not a precondition for the development of hape. hape develops in non-acclimatized mountaineers after rapid ascent to altitudes above m. hape may develop even in the absence of ams. severe ams may be a risk factor for hape. the altitude, the rate of ascent to new altitude, (> m/day to an altitude above m), and individual susceptibility are major determinants of ams and hape. on ascent to high altitudes all people have swelling of the brain. patient with ams often experience "hangover headache." other symptoms occur within the fi rst to h. these include malaise, anorexia, nausea and vomiting, and insomnia. ams patient must be evaluated for signs of global encephalopathy rather than focal fi ndings, although retinal hemorrhage is commonly seen. when these are present, the subject has hace until proven otherwise. patient may die if not treated promptly. brain herniation is the usual cause of death. the hallmark of hape is an excessively elevated pap which precedes the development of pulmonary edema. symptoms are incapacitating fatigue, chest tightness, dyspnea with effort, orthopnea, cough, and pink frothy sputum in advanced stage of disease. prevention of all altitude complications requires ascending at an increment rate to allow acclimatization. at > m, one should not spend subsequent nights m higher than the previous night. trekker must take a rest day every to days. anyone with ams should not ascend until symptoms are resolved. acetazolamide and dexamethazone are effective in prevention and treatment of ams from proceeding to hape or hace. at the fi rst sign of hace, patients should descend to a lower altitude while supplementary oxygen is given. increasing oxygenation is the highest priority in the treatment of and prevention of hape. if supplemental oxygen is unavailable, then descent, use portable hyperbaric chamber, or both become lifesaving. nifedipine is necessary only when supplemental oxygen is unavailable or descent is impossible. because of its pulmonary vasodilatory effects, phosphodiesterase inhibitors can be used for prevention and treatment of hape. rudolf virchow in described that the determinant risk factors for venous blood clot formation are stasis, endothelial injury and hypercoagulable state. dr simpson et al , a british surgeon observed that during the london blitz, the world war ii, britons who were forced to remain on sitting in cramped position and deck chairs for hours during the air raids developed fatal pulmonary embolism. it was suggested in by homans that "prolonged dependency stasis" or immobilization is one factor that predisposes patients to develop thrombosis in the deep veins of the legs. several risk factors have been identifi ed for developing venous thromboembolism (vte). travel is one of the transient risk factors. it is not confi ned to one mode of travel such as air travel. it is also incriminated to other modes of land travel such as car, bus and train. the term "economy class syndrome" was proposed by symington and stock ( ) and by the group of cruickshank ( ) for venous thromboembolism occurring in patients during air fl ight travel. it is usually seen in patients sitting in limited or cramped circumstances in the economy coach or tourist class seats, however it is also found out that patients who were also seated in the business class also develop this syndrome. factors implicated were the long duration of travel, immobilization or inactivity in sitting position, and the low cabin pressure, low humidity and dehydration during air fl ights. in several studies performed on large airports in europe, the presence of genetic factors such as factor v leiden and environmental factors such as the use of oral contraceptives predispose patients several fold to develop venous thromboembolism. signs and symptoms pertaining to vte develop not only during and after the fl ight but also several weeks after the travel. nowadays, airlines as well as bus companies have advisories and measures impose to prevent development of vte and deaths due to vte during the travel period. with the steadily increasing use of air travel, more and more patients with pulmonary disease are fl ying long distances, at high altitude in partially pressurised aircraft. this is associated with long periods of reduced mobility and exposure to reduced inspired pressures of oxygen and reduced barometric pressure. some individuals therefore may be at risk of barotrauma, hypoxia or venous thrombo-embolism (vte). therefore it is important to identify these individuals and adequately assess the real risk entailed by fl ying. the effect of reduced atmospheric pressure is a potential risk for patients with recent or pre-existing pneumothorax but otherwise is unlikely to be associated with risk other than that due to the associated reduced inspired oxygen fraction (fio ), typically . ( %) in a commercial aircraft at cruising altitude. the reduced (fio ) may be problematic for patients with hypoxic lung disease or in patients with other co-morbidities that may exacerbated by hypoxia. medical history, lung function and resting oxygen saturation will help identify patients at risk although it is diffi cult to predict the clinical effects of altitude from tests (even hypoxic challenge tests) conducted at sea level. there is currently a lack of good data defi ning the clinical outcomes due to hypoxia during fl ight in patients with lung or other diseases. the risk of vte increases with duration of fl ight above four hours, presumably related to the duration of immobility, although the role of prolonged hypoxia remains to be determined. preventive measures are now currently invoked on most airlines and guidelines for the use of antithrombotic agents are available, stratifi ed by risk. it is anticipated that guidelines will continue to be updated as new data are made available. cardio-pulmonary exercise testing is now well accepted as an appropriate test for the investigation of shortness of breath on exertion. in addition the test has been found to be useful for the assessment of pulmonary vascular dysfunction and the assessment of fi tness for major thoracic surgery. even though there are well described and internationally accepted protocols to perform the test, the interpretation of a cardio-pulmonary exercise test often leaves the interpreting physician confused. importantly with the multiple facets of the test (respiratory, cardiac, peripheral vascular) that need to be interpreted it is easy for the interpreting physician to look at a certain aspect of the test relating to their specialty and to give the other facets relatively little attention. in this presentation we review the process of interpreting cardio-pulmonary exercise tests. in addition we will interpret a number of tests based on our previous discussion on how to interpret these tests. finally we will review the literature regarding new interpretive strategies for exercise induced pulmonary vascular disease. bronchoscopy as an image-guided intervention has benefi tted from advances in optical and non-optical imaging technologies. some current bronchoscopy advances incorporate higher resolution ccd (charged-couple device) digital-"chip" technology and magnifi cation lenses to enhance the image resolution. the hope is that improved visualization combined with analysis of concomitant tissue biopsies may realize so-called "in-vivo endoscopic diagnosis" without the need for tissue biopsies, however studies of highmagnifi cation endo-cytoscopy, co-focal micro-endoscopy and optical coherence tomography (oct) remain investigational. further limiting these near-histologic resolution imaging modalities is the need for an initial screening of "highly suspicious" mucosa to focus attention upon. to facilitate identifi cation of abnormal airway mucosa, there are advances in the bronchoscopic detection of dysplastic and malignant mucosa. newer generations of autofl uorescent (af) bronchoscopes combine video ccd technology with af signaling to enhance the visual resolution of the images. non-af technologies being evaluated for the same purpose include fi ltered-light narrow band imaging (nbi) and post image-capture processing by a number of other spectral estimation technologies (set). bronchoscopic image guided interventions (bigi) also benefi tted from advances in non-traditional bronchoscopy technologies. foremost has been endobronchial ultrasound (ebus), initially designed as radial probes modeled after intravascular us and modifi ed for the airways. while useful in advancing our understanding of endobronchial mucosal structure, predicting tumor invasion depth and responsiveness to endobronchial interventions, radial ebus did not permit real-time guidance. dedicated linear-array ebus bronchoscope has changed this dramatically as the . mhz needle-puncture ebus bronchoscope has increased diagnostic accuracy of peri-bronchial lymph nodes/masses from a previous average of < % to > % for even small targets (< cm) in experienced hands. simultaneously miniaturization of radial ebus probes (thin . mm) and incorporation of guide-sheaths have increased the utility of ebus in evaluating parenchymal lung pathology. concomitant work in image processing of radiology imaging data (dicom data of chest ct images) has made available a number of "virtual bronchoscopic navigation" programs to assist the bronchoscopists in navigating towards smaller peripheral focal targets, and to improve the historic diagnostic yield of smaller (< cm) peripheral nodules from - % up to - %. these systems include passive endobronchial "road-maps" view (similar to "mapquest"/"google earth") and more technology enhanced electromagnetic navigation bronchoscopy (enb) (similar to gps guidance). all these ancillary technologies have spurred improvements in the basic bronchoscope, as thinner bronchoscopes capable of reaching peripheral segments ( . mm and . mm with . mm working channel; . mm with . mm working channel) are coupled with new biopsy instruments. the eventual development of steerable single fi ber scanning endoscopes with multi-wavelength imaging may change our current concepts of the bronchoscopes and how we can use them. journal compilation © asian pacifi c society of respirology pg - diagnostic tests pleural effusions are common and often present diagnostic challenges. the new british thoracic society guidelines on investigation of pleural effusions detailed some of the new approaches to undiagnosed pleural effusions. traditional teaching recommends measurement of blood and pleural fl uid protein and ldh levels as the fi rst step of investigation to categorize the effusion into a 'transudate' and 'exudate' using light's criteria. the need to apply this to all effusions is questionable in . current efforts focus on the development of disease-specifi c diagnostic tools incorporating clinical, radiologic and biochemical parameters. • elevated ntpro-bnp levels in pleural fl uids are useful in confi rming cardiac failure as the etiology of a pleural effusion, especially in patients whose fl uid may be falsely elevated into the 'exudative' range by concurrent diuretic therapy. • pleural ntpro-bnp levels are elevated in cardiac failure effusions, but not in other transudative effusions (eg hepatic hydrothorax). • pleural fl uid ntpro-bnp appears a better marker than pleural fl uid bnp. variations in accuracy may also in part depend on the commercial kits used. adenosine deaminase: • ada measurements in pleural fl uids are useful in the diagnosis of tb pleural effusions with a sensitivity and specifi city of and % respectively. limiting the test to lymphocytic pleural effusions will further improve the diagnostic accuracy. • ada is cheap and fast to perform and is now widely used in endemic countries. false positives can occur with bacterial infections, rheumatologic effusions, and occasionally malignant effusions. false negatives are uncommon, and therefore present a valuable 'rule-out' test in regions of low tb rates. • ada is at least as diagnostically useful as pleural fl uid total interferon-gamma levels. • igras have been tested in pleural fl uid and blood of patients with tb pleural effusions in several studies. the diagnostic sensitivity and specifi city are poor and igras are not recommended for the investigation of tb pleuritis. • serum mesothelin is a fda-approved test for the diagnosis and monitoring of mesothelioma. • pleural fl uid mesothelin adds information to pleural fl uid cytology in the diagnosis of mesothelioma, providing a diagnostic sensitivity of % (specifi city %). elevated pleural fl uid mesothelin levels suggest epithelioid or biphasic mesothelioma or occasionally metastatic carcinomas. procalcitonin: • early evidence suggest that serum level of procalcitonin may aid differentiation of pleural infection from pleural effusions of non-infective etiologies. the value of pleural fl uid procalcitonin level is limited. management strategies imaging guidance for pleural procedures: • pleural procedural complications are often under-estimated and underreported. studies have now shown that mandatory imaging guidance (especially bedside pleural ultrasound), and restricting procedural privilege to certifi ed trained clinicians can signifi cantly reduce complication rates from pleural procedures. this practice is now incorporated into many national and professional society guidelines. intrapleural therapy for pleural infection/empyema: • recent clinical trials on intrapleural delivery of fi brinolytics alone have failed to improve important clinical outcomes of pleural infection. however, the combination of tissue plasminogen activator and dnase has shown promising results. • recent studies have revealed increasing concerns of complications of talc pleurodesis, and randomized studies have shown a much lower success rate than previous non-randomized literature, even in selected patients. the concept of drainage without needing to create pleurodesis has growing appeal and the use of indwelling pleural catheters is now regarded as fi rst-line therapy in increasing number of centers. chronic respiratory disease (crd) is non-communicable respiratory disease including asthma, chronic obstructive pulmonary disease (copd), allergic rhinitis, idiopathic pulmonary hypertension, hypersensitivity pneumonitis, occupational respiratory disease. among these crd asthma and copd are important for regional health. facts of asthma million people suffer from asthma. , people died of asthma in . prevalence of asthma has increased or is increasing. asthma is the most common disease among children over % of asthma death occurs in low and lower-middle income countries. asthma is underdiagnosed and under-treated (who, ). facts of copd copd is a life-threatening lung disease that interferes with normal breathing. it is more than a "smoker's cough". an estimated million people have copd worldwide. more than million people died of copd in , which is equal to % of all deaths globally that year. almost % of copd deaths occur in low-and middle-income countries. the primary cause of copd is tobacco smoke (through tobacco use or second-hand smoke). the disease now affects men and women almost equally, due in part to increased tobacco use among women in high-income countries. copd is not curable, but treatment can slow the progress of the disease. total deaths from copd are projected to increase by more than % in the next years without interventions to cut risks, particularly tobacco smoking (who, ). prevention and control of crd in asia pacifi c were held by dokkyo medical university group, later designated as who collaborating centre for prevention and control of crd (du-wcc). seven countries and a district in asia pacifi c joined the meeting. prevalence of asthma in adults was reported from . to . % with a median of . % based on reports. prevalence of childhood asthma ( - y/o) was from . to . % with median of . % based on reports. prevalence of copd was . to . % with a median of . % based on nation-wide surveys. in spirometry-based survey reported, prevalence of copd was . % in adults years and over in japan, % in adults years and over, and . % in adults years and over in china. management in most of the countries gina and gold were adopted for their national guidelines. major risk factors for crd, especially for copd were smoking and indoor air pollution for cooking/heating. pharmacological early interventions have been reported to improve the prognosis of asthma and copd. occupational respiratory diseases are disorders which are induced by occupational and industrial conditions. providing information of the risks of industrial activities would reduce this disorder. strategic direction for the prevention and control of crd most of crd are treatable and at least partially preventable. development of user-friendly guides for prevention and control of crd for offi cials in health care, fi rst-line health-care givers and patients and their family and its implementation would decrease the burden of these crd. the scientifi c foundation of asthma diagnosis and management has grown in leaps and bounds. evidence-based strategies to control asthma and treat its exacerbation are published yearly in the gina guidelines. the -year finland study showed that these strategies work. while cases treated did increase (through better detection), the hospital days and cost per case markedly decreased. the study also showed that widespread adaption and effective implementation of these strategies is best done through a national program. cmes for medical practitioners are important but are of limited reach. all stakeholders must be enlisted to buy-in. for asthma, the target stakeholders are the health care personnel, nurses and village health volunteers included; the patients and their families; the government and its public health offi cials; the asthma advocacy groups; the community-at-large; and the pharmaceutical industry. the idea is to present the problem to them, include their inputs in the formulation of the plan, collegially decide on target indicators of success and engage them to work for the implementation of the program in the context of what each one can do best. duplicating the finnish experience is a big challenge in the asia pacifi c region. while most countries have their own adaptation of the gina guidelines, few have working national asthma programs. in developing economies, the health infrastructure is not that well developed yet to absorb all guideline recommendations. spirometry may not be widely available nor affordable. government spending for health is commonly below the % of gdp level that who recommends. in the philippines, signifi cant out-of-pocket health expense is borne by the patient. furthermore, programs like tb control, dengue treatment and malaria eradication, which are no longer concerns in developed countries, compete for the meager public health funds. for low income countries, the international recommendations may have to be rewritten to emphasize on simple algorithm for separating non-infectious from infectious respiratory illnesses; practical objective measurements for diagnosis and management such as peak fl ow; available, affordable, and low-risk medications recommended for asthma control; and a simple regimen for recognizing severe asthma (gina). to be viable, the national asthma program will have to piggy back to the existing national health delivery infrastructure which must ensure, among others, access to free or cheap medication. lung cancer and copd commonly coexist in smokers, and the presence of copd increases the risk of developing lung cancer. in addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, to develop new methods of prevention, diagnosis and treatment of lung cancer and copd. common mechanisms may involve infl ammation, abnormal repair, oxidative stress, epithelial-mesenchymal transition, altered nicotine receptor biology and epigenetic alterations. strategies to study genomics and epigenomics, in addition to gene-environment interaction, will yield greater insight into the shared pathogenesis of lung cancer and copd. copd clinical guidelines are important to guide diagnosis and management of people with copd. the australian 'copdx' guidelines are evidence-based guidelines that are prepared by the australian lung foundation and thoracic society of australia and new zealand. relevant literature is searched regularly and evaluated by a clinical committee. updates are then produced regularly during the year. challenges regarding critical appraisal, resources and dissemination to clinicians will be discussed. national copd guidelines in this region are different from country to country, but basically are adapted from gold. copd prevalence in asia pacifi c countries and region estimated by regional copd working group was . %. vietnam has the highest prevalence: . %. the copd management and guideline implementation problems in the asia pacifi c region are: smoking, biomass using are common; continuous medical education (cme) for health workers are not compulsory; lack of device and personnel for performing proper spirometric tests; over burden for health workers; low access to medical care and low affordability for copd medications. all of these problems result in that copd diagnosis are mostly in late stage, high rate of emergency room visit, icu admission and hospitalization. the consensus is expected to cover following resolutions: reducing the smoking and biomass smoke exposure, screening for copd in large scale using questionnaires and confi rming by spirometry, advocacy for compulsory cme on copd, establishing asthma and copd outpatient care unit (acocu) in different levels of health care settles and introducing copd medications into insurance medication list. infections caused by environmental mycobacteria are more common than tuberculosis in many parts of the world. the more than species of mycobacteria have similarities, but generally the diseases and hosts fi t in specifi c patterns. disease due to environmental mycobacteria can be diffi cult to diagnose and treat and can confuse workup for tuberculosis. mycobacteria have low virulence and even lower invasiveness. they form biofi lms that protect them and allow long term persistence. the treatment is often frustrating for the patients and physicians. learning their metabolic mechanisms and attacking them should be the strategy for combating the disease caused by these organisms. lung cancer and copd commonly coexist in smokers, and the presence of copd increases the risk of developing lung cancer. in addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, to develop new methods of prevention, diagnosis and treatment of lung cancer and copd. common mechanisms may involve infl ammation, abnormal repair, oxidative stress, epithelial-mesenchymal transition, altered nicotine receptor biology and epigenetic alterations. strategies to study genomics and epigenomics, in addition to gene-environment interaction, will yield greater insight into the shared pathogenesis of lung cancer and copd. airway epithelial cells, which are the fi rst line of cells to contact with inhaled substances such as microorganisms, play an important role in the host defense by two major mechanisms. first, they actively contribute to the innate immune system by recognition of the pathogen and production of antimicrobial substances and cytokines. second, they provide a passive barrier function that prevents invading microorganisms, air pollutants and airborne allergens into the internal milieu. on the other hands, airway epithelial cells are involved in the production of airway infl ammation in asthma and copd by excessively and un-regulatory expressing pro-infl ammatory and pro-allergic cytokines, executing apoptosis and losing barrier function. there is very close relationship between epithelial barrier function and innate immune response of epithelial cells. for instance, losing barrier function results in not only allowing foreign substance and pathogens to invade into the internal milieu but also enhancing innate immune responses. asthma and copd are different diseases, but they may have the same mechanism in the pathogenesis of exacerbation of these diseases in term of losing epithelial barrier functions. in this symposium, we will present the latest information on and the regulatory mechanism of airway barrier function and discuss in the context with asthma and copd pathogenesis and exacerbations. key words; airway epithelial cells, barrier function, asthma, copd patients with severe and diffi cult-to-treat asthma ("refractory asthma", approximately % of total asthma) have impaired health status refl ected by persistent symptoms, severe airfl ow limitation and frequent asthma exacerbations despite taking maximally recommended doses of inhaled corticosteroids and long-acting β -agonists. a better understanding is thus needed regarding factors associated with such troublesome condition and, in our cross-sectional observational study, clinical and demographic characteristics of patients fulfi lling the american thoracic society workshop criteria for refractory asthma (ajrccm, , group a) were compared with those of patients with severe persistent asthma defi ned on the basis of the gina guideline (group b). there were no signifi cant differences between the two groups with respect to age, gender, smoking status, disease duration, pulmonary function (fev , pef, dlco), or markers of airway infl ammation in the induced sputum (eosinophils, neutrophils, ecp, tryptase). however, in contrast to group b, all patients in group a were adult-onset, and % of the patients already had severe symptoms at the time of disease onset. prevalence of atopy, postbronchodilator fev /fvc ratio and fev reversibility were signifi cantly less in group a than in group b. patients in group a complained of copious amounts of phlegm associated with chronic sinusitis and/or chronic bronchitis, and showed high concentrations of mucin (muc ac + muc b) in the sputum. in addition, nasal clearance time assessed by saccharine test was signifi cantly longer in the group a than in the group b patients, indicating impairment of airway mucociliary clearance. these fi ndings and other pathophysiological and clinical data suggest that "refractory asthma" may be a different form of asthma (phenotype) rather than a progression of asthma severity during follow-up of natural history of the disease. furthermore, it is likely that irreversible airway narrowing possibly due to airway remodeling and airway mucus hypersecretion are important factors contributing to the pathogenesis of severe and diffi cult-to-treat (refractory) asthma. the results prompt for further longitudinal studies and interventions to defi ne the mechanisms of this unique phenotype of asthma. journal compilation © asian pacifi c society of respirology drug development is a long and expensive process. on average it takes at least years and more than a billion dollars to develop a compound from basic science discovery through clinical trials and fi nal approval by regulatory authorities of a new therapeutic. one of the main obstacles to development of new compounds is the diffi culty in obtaining good pre-clinical proof of effi cacy for a new drug. most of this is currently obtained from experiments using animal models of disease or cell lines, neither of which refl ect well human disease nor predict whether responsiveness in these models predicts responsiveness in human disease. recent studies have focused on developing methods that employ human cells or tissues taken from the relevant organ and from relevant patient populations. of these models, the explant model, which uses whole tissue samples, is the closest to the in vivo situation because it maintains the complex cell-to-cell interactions. in asthma, studies have shown that this model can sometime be even better than in vivo study. thus, for example, the explant model vivo offers several advantages over in vivo allergen challenge of asthmatic volunteers. first, repeat bronchoscopy to sample the airways after initial allergen challenge is not required. second, tissue responses of more severe asthmatics, who for safety reasons cannot be challenged with allergen in vivo, can be studied. third, problems of dilution of secreted mediators during bal are avoided and released mediators are not consumed by in-coming infl ammatory cells, thus increasing the sensitivity of the model. finally, and most importantly when seeking pre-clinical proof of concept of drug effi cacy, the model allows testing of novel compounds at an early stage before its full safety profi le is established, a process that is both expensive and time-consuming. we have previously shown that the asthmatic airways generate increased t cell chemotactic activity compared to healthy controls. using a highly selective ccr antagonist we have recently shown that the ccr -chemokine axis plays a key role at least in the traffi cking of t cells into the asthmatic airways. having established this, we then showed that predominantly the ccr + t cells are recruited in response to allergen stimulation. we have further shown that the selective removal of these ccr + t cell from blood signifi cantly reduced allergic infl ammation as shown by a marked reduction in the production of the th cytokines il- , il- and il- but with no consequences for th responses. taken together, our studies have strongly suggested that inhibiting the migration of t cell to the asthmatic airway by targeting ccr is likely to abrogate the allergic infl ammation in the airways without affecting immune responses that serve to protect against infection. these studies have also shown the value of using such ex vivo models of asthma to provide proof of concept for new drugs, giving the pharmaceutical industry the necessary pre-clinical proof to proceed with confi dence into further clinical development. sleep-disordered breathing (sdb) or obstructive sleep apnea (osa) is a prevalent but largely undiagnosed sleep disorder. apnea-hypopnea index (ahi: the number of apneas and hypopneas per hour of sleep) is used to classify sdb severity. in icsd- (international classifi cation of sleep disorders ver. ), "osa syndrome" was defi ned as ahi ≥ with hypersomnolence/ daytime symptoms or as ahi ≥ regardless of the symptoms. epidemiological studies clarifi ed that sdb is associated with increased likelihood of hypertension, cardiovascular disease, stroke, motor vehicle accidents, depression, diminished quality of life, and even mortality. clinical guidelines for hypertension put weights on sdb as a cause of hypertension. international diabetes federation (idf) made a consensus statement on sleep apnea and type diabetes. "overlap syndrome" (coexist of copd and sdb) was reported to have much higher mortality than sdb alone. sleepiness was thought to be a major symptom for osa syndrome. it is true that there is a signifi cant trend that the severe the sdb is the more the subjects had sleepiness. however, the majority of sdb subjects (even the majority of subjects with ahi ≥ ) do not have sleepiness (ess: epworth sleepiness scale > ). the berlin sleep questionnaire was used to screen high or low risk subjects for sdb. four-item screening tool was also developed (gender, bmi, blood pressure, snoring frequency). these tools may be useful, when certifi ed with sleep monitoring in each population. prevalence of ahi ≥ , estimated from two-stage sampling, was - % in male and - % in female. two-stage sampling is oversampling the subjects with sleepiness or snoring to perform sleep monitoring, and weighting of results to the survey sample. when all the participants underwent sleep monitoring, the prevalence of ahi ≥ was - % in male and - % in female. there is a strong need for better recognition, screening and treatment of sdb. more studies are needed, especially for long-term outcomes of asymptomatic sdb. genome-wide association studies may be useful to elucidate causes or underlying mechanisms of sdb. continuous positive airway pressure (cpap) is a standard treatment for patients with obstructive sleep apnea (osa), especially for moderate to severe osa. the mechanism of action is to provide a pneumatic splint to preserve upper airway. the pressure level required to maintain airway patency is determined by manual pressure titration by a sleep technologist during attended laboratory polysomnography (psg) to eliminate obstructive respiratory-related events (e.g., apneas, hypopneas, respiratory effort-related arousals [rera], and snoring). despite wide acceptance as a standard therapy for treatment of osa patients, very few pap titration protocols have been published so far, and there are inconsistency and variations in cpap titration protocol among clinical sleep laboratories. for this reason, the pap titration task force developed evidence-and consensus-based standardized pap titration protocol and published its guideline entitled "clinical guidelines for the manual titration of positive airway pressure in patients with obstructive sleep apnea" in journal of clinical sleep medicine . in this lecture, i will explain about manual cpap titration guidelines as below based on publications which are recommended by positive airway pressure titration task force of the american academy of sleep medicine (aasm): ( ) important considerations prior to cpap titrations. ( ) criteria for cpap pressure to be increased. ( ) minimum and maximum starting cpap pressure. ( ) an interval and minimum pressure to eliminate obstructive respiratory events. ( ) different algorithms for cpap pressure to be increased to eliminate obstructive respiratory events observed for patients ≥ years and < years. interventional bronchoscopy has typically been associated with obstructive tumor removal to regain central airways patency; such interventions, whether with rigid or fl exible instruments were also limited to the navigable fourth or fi fth generation airways. tissue destructive techniques included ablative heat techniques (laser, electrocautery and argon plasma coagulation), cold techniques (cryotherapy) and mechanical coring with the rigid bronchoscope. a current new crop of tissue debridement devices include modifi cations of established technologies: fl exible co laser fi ber usable beyond the trachea, cryotherapy using non-contact surface cryospray, rotational microdebrider devices adopted from otolaryngology, pulsating balloon resectors. the latter three devices do not involve heat that may cause post-treatment infl ammation and cartilage destruction and subsequent airway fi brosis or malacia. previous direct intra-lesional injection, with mitomycin or steroid was directed towards non-malignant fi brotic lesions, conversely on-going studies with cytotoxic agents ( fu) and compounds thought to have immune adjuvant effects (pts) are demonstrating potential utility in endobronchial tumors. photo-dynamic therapy (pdt) compounds with shorter half-lives require fewer bronchoscopies and have shortened photo-toxicity side effects. therapeutic bronchoscopic image guided interventions (bigi) have benefi tted from advances in "virtual bronchoscopic navigation" software available to improve reaching small peripheral lesions. for radiation therapy for focal lung lesions not resectable because of patient co-morbidities or preference, the accurate placement of fi ducial markers (gold) are used to direct high-dose rate external-beam intentiy modulated radiation therapy (imrt) including cyberknife machine. trials also demonstrate feasibility and effi cacy of treating peripheral lesions by high-dose rate (hdr) brachytherapy through catheters placed with image guidance. one area of new focus is bronchoscopy in the management of chronic obstructive lung diseases (old) including emphysema and severe asthma. based on lung volume reduction surgery for severe emphysema with heterogeneous distribution and air-trapping, non-surgical bronchoscopic lung volume reduction (blvr) has taken on a number of innovative approaches including exclusion by spigots (watanabe), valves (emphysys, spiration), metallic coil retraction (pneumrx), airway bypass to relieve trapped gas (broncus), atelectasis by bio-glue (aeris) or by heat steaming (uptake). although none of the clinical devices in trials have shown unqualifi ed success, some devices are now being marketed (europe), or are available on a compassionate basis for management of broncho-pleural fistulas (bpf). airway radio-frequency ablation (rfa) of airway smooth muscle is usa-fda approved for management of severe asthma. future innovations in interventional bronchoscopy will likely incorporate advances in diagnostic bronchoscopy such as video-autofl uorescence and "in-vivo biopsy" techniques to guide local endobronchial therapies for in-situ cancers; image processing software to design custom stents for compromised airways; and drug-eluting stents to maintain airway integrity in a variety of malignant and benign airway diseases. pleuroscopy describes a minimally invasive procedure that provides the physician a window into the pleural space. it refers to a procedure that is performed in an endoscopy suite or operating room with the patient under conscious sedation and local anesthesia. increasingly these procedures are being performed by nonsurgeon pulmonologists to diagnose pleural pathology such as pleural effusions or pleural carcinomatosis; talc pleurodesis and chest tube placement under direct visual guidance. pleuroscopy was fi rst conceived in a report dated , which documented the fi rst endoscopic examination of the pleural space by richard cruise in a year old girl with empyema. it did not gain widespread application until when hans christian jacobaeus published his technique also known as the jacobaeus operation. in this procedure he created a pneumothorax by severing adhesions using galvanocautery that collapsed the underlying lung, and allowed safe entry as well as unobstructed examination of the pleural space. since then, pleuroscopy has been applied both as a diagnostic and therapeutic tool. for a hundred years, rigid endoscopic instruments such as stainless steel trocars and telescopes have been pivotal in the technique. smaller telescopes and instruments have been applied with excellent views of the pleural space and comparable diagnostic yield. a signifi cant advance is the creation of fl exrigid pleuroscope that is fashioned like the fl exible bronchoscope. the fl ex-rigid pleuroscope consists of a handle, and a shaft that measures mm in outer diameter, -cm proximal rigid portion and -cm fl exible distal end. the fl exible tip is movable by a lever on the handle, which allows -way angulation degrees up and degrees down. it has a . mm-working channel that accommodates biopsy forceps, needles and other accessories, and is compatible with various electrosurgical and laser procedures. the fl ex-rigid pleuroscope allows autoclaving. a notable advantage is its easy interface with existing processors and light sources made by the manufacturer for fl exible bronchoscopy or gi endoscopy at no additional costs. although certain endoscopic characteristics such as nodules, polypoid masses and "candle wax drops" are suggestive of malignancy, early stage mesothelioma can resemble pleural infl ammation. autofl uorescence and narrow band imaging have been incorporated to white light pleuroscopy to enhance diagnostic accuracy. both modes of imaging discriminate early malignant lesions from non-specifi c infl ammation, aid in selecting appropriate sites for biopsy and better delineate tumor margins for more precise staging, but are of little value at present in clinical practice since most patients with malignant pleural effusions have extensive pleural involvement that is easy to diagnose with white light pleuroscopy for pleuroscopic guided pleural biopsies, specimens obtained with the rigid forceps are larger than those with the fl ex-rigid pleuroscope since they are limited by size of the fl exible forceps, which in turn depends on the diameter of the working channel. the fl exible forceps also lacks mechanical strength in obtaining pleural specimens of suffi cient depth, which can be overcome by the use of insulated tip (it) diathermic knife. full thickness parietal pleural biopsies are obtained with it knife, and the electrocautery knife is particularly useful when smooth thickened lesions are encountered, of which nearly half are due to mesothelioma. to improve analgesia before talc poudrage, lidocaine can be administered to the parietal pleura via spray catheter inserted through the working channel of the pleuroscope. similarly talc poudrage can be administered under visualization using the spray catheter. with the introduction of the fl ex-rigid pleuroscope, similar in design and handling to the fl exible bronchoscope, and compatible with standard light source and video processor available in most bronchoscopy suites, pleuroscopy will enjoy an expanded interest as more practitioners acquire the skill. the fl exrigid pleuroscope is a signifi cant invention in the history of minimally invasive pleural procedures and will revolutionize the practice of pulmonary medicine by replacing conventional biopsy methods in future. the common known causes of interstitial lung disease (ild) are drug toxicities, environmental exposures and collagen vascular disease (cvd). among these causes, drug or environmental exposures can be excluded by medical history. however, cvd-related ild may often be confused with idiopathic interstitial pneumonia (iip) because the radiological and histological characteristics of cvd-related ild are often indistinguishable from those of their idiopathic counterparts and occasionally, systemic manifestations of the underlying cvd develop several months or years after the diagnosis of ild. early diagnosis of occult cvd is very important in patients presenting with ild, because there are signifi cant differences in prognosis between the iip and cvd-ild groups. patients with cvd-ild survive longer than those with iip. additionally, different treatment regimens and evaluation for additional systemic involvement or malignancy may be needed in patients with cvd-ild. although, cvd-ild and iip is often considered indistinguishable, there are some clues that can help clinicians detect occult cvd in patients presenting with ild. first, a thorough medical history and physical examination can detect occult cvd. its importance cannot be overemphasized. the cvds frequently associated with ild are scleroderma, rheumatoid arthritis (ra), polymyositis/dermatomyositis (pm/dm), sjögren's syndrome, mixed connective tissue disease (mctd), undifferentiated connective tissue disease (uctd) and systemic lupus erythematosus (sle). therefore, symptoms and signs that occur frequently in these cvds should be searched for. these symptoms and signs include raynaud's phenomenon, gastro-esophageal refl ux disease, telangiectasis, dry eyes, dry mouth, arthritis, the characteristic skin lesions of dm (heliotrope rash, gottron's papule, mechanic's hand) and various serositis etc. second, certain fi ndings on hrct can help in the diagnosis of cvd. although the parenchymal abnormalities are similar to their idiopathic counterparts, the presence of airway-related abnormalities -mosaic attenuation, bronchial wall thickening, and nodules -are more common in cvd-ild. the presence of extrapulmonary abnormalities may also provide important clues to the underlying diagnosis. patients with cvd more frequently have pleural and pericardial effusions, pericardial thickening, enlarged pulmonary artery and esophageal dilatation. hrct can also show joint abnormalities or soft tissue calcifi cations. third, there are some serologic tests that can help in the diagnosis of cvd even in patients with obscure symptoms. high titers of antinuclear antibody and rheumatoid factor are often found in patients with cvd. other more disease specifi c tests currently available are anti-ssa/ssb antibody for primary sjögren's syndrome, anti-scl- antibody for systemic sclerosis, anti-jo- antibody for pm/dm, anti-u ribonucleoprotein (rnp) antibody for mctd, antibody to cyclic citrullinated peptides (ccp) for rheumatoid arthritis and so on. fourth, the frequent pathologic patterns of ild associated with cvd are nsip, uip, op, lip and dad. among them, nsip is the most frequent pathologic pattern in cvd-ild. therefore, pathologic pattern consistent with nsip should raise suspicions about the possibility of cvd. other pathologic fi ndings that may be suggestive of an underlying cvd include follicular bronchiolitis and lymphoid follicles. however, it is still impossible to diagnosis all occult cvds at the outset of ild because the initial clinical presentations can be essentially indistinguishable from those of iip. therefore, close follow up for a developing cvd is very important especially in patients with nsip. the role of pathological diagnosis for non-neoplastic lung disease is important and critical. however, agreement of pathological diagnosis in iips may not be that high. despite the expectations after publication of ats/ers classifi cation of idiopathic interstitial pneumonias (iips), interobserver variability in the pathological diagnosis of iips is still problematic. there are several major reasons for the poor agreement in pathological diagnosis of iips in which the biggest reason is a lack of specifi c and diagnostic fi nding to any type of iips. in the session, i would fi rst share the virtual steps of making diagnosis on surgical lung biopsy with audience, indicate recent data of inter-observer agreement in iips cases, and then, introduce factors behind the poor agreements followed by several possible solutions to this important issue. children's interstitial lung disease (child) differs from adult interstitial lung disease in that certain classic idiopathic pneumonias described in adults are not seen in children and unique forms of interstitial lung disease are found in infants and young children but not in adults. the most common form of idiopathic interstitial pneumonia in adults is idiopathic pulmonary fi brosis (ipf), also known as cryptogenic fi brosing alveolitis (cfa), a progressive and fatal disorder, defi ned pathologically as usual interstitial pneumonia (uip). uip is characterized by a heterogeneous mixture of normal lung, mild infl ammation, and fi brosis and the presence of fi broblastic foci, felt to be the leading edge of fi brosis. previously, although many infants and children were given the diagnosis of ipf, cfa, or uip, they did not have the characteristic fi broblastic foci. thus although the uip pattern is occasionally seen in the context of another primary disorder, such as abca mutations, true ipf/uip does not exist in children. the tendency to use the term ipf in children merely serves to obscure the real diagnosis and creates anxiety in families whose affected children may not actually have a fatal disorder. unique conditions have been described mainly in infants and young children that do not occur in adults. these include growth abnormalities, inborn errors of surfactant metabolism, neuroendocrine cell hyperplasia of infancy (nehi), and pulmonary interstitial glycogenosis (pig). growth abnormalities occur as a consequence of an early insult to the lung that results in retarded or arrested lung development and alveolar simplifi cation. risk factors associated with growth abnormalities include prematurity, congenital heart disease, and chromosomal defects, most commonly down syndrome. the major advance in child has been the discovery of genetic mutations that lead to surfactant dysfunction. these include mutations in the sp-b, sp-c, abca , ttf- , and gm-csfra genes. clinical presentation can vary from severe respiratory failure at birth leading to death (sp-b, abca mutations) to more insidious onset with chronic lung disease (sp-c, abca , ttf- , gm-csfra mutations). nehi is a chronic benign form of child presenting in the fi rst year of life with tachypnea, crackles, hypoxemia, characteristic features of symmetric ground glass densities in the right middle lobe and lingula and central lung regions on hrct, and a mixed restrictive/obstructive pattern on infant lung function testing. lung biopsy shows increased numbers of neuroendocrine cells and neuroepithelial bodies in the distal airways with otherwise normal lung architecture. pig is another benign form of child seen in infants and characterized by interstitial widening with glycogen-rich interstitial cells. pig is seen as a primary disorder ("pure" pig) and as a patchy disorder seen in the background of some other primary disorder, such as a growth abnormality ("patchy" pig). in conclusion, it is important to recognize the differences between pediatric and adult interstitial lung disease so that the proper diagnosis and prognosis can be given and the appropriate treatment applied. journal compilation © asian pacifi c society of respirology not to treat acute bronchitis with initial antibiotics, with the following exceptions. those at high risk of serious complications because of preexisting co-morbidity, patients over years of age with acute cough and two or more of the following, or patients over years of age with one or more of the following; ( ) admission to hospital in the previous year ( ) type or type diabetes ( ) history of congestive heart failure ( ) current use of oral glucocorticoids. clinicians need to address patients' concerns, perspectives, and expectations about the treatment and explain to patients that antibiotics are not necessary for a self-limiting respiratory tract infection. physicians should tell patients that antibiotic use increases the risk of an antibiotic resistant infection. and physicians also need to spend time answering questions and offer a contingency plan if symptoms worsen, and advise patients to return for a consultation if symptoms are not starting to settle in accordance with the expected course of the illness or if symptoms worsen signifi cantly. some physicians are certain that patients will benefi t from antibiotics and prescribe for expectation of fast relief. they are mostly comfortable with their prescribing decisions by their clinical experiences. taiwan's study demonstrates substantial variations among physician groups in the practice of prescribing antibiotics for viral respiratory infections. older physicians and those practicing in clinics rather than medical centers were signifi cantly more likely to prescribe antibiotics, and dispensing doctors in contrast to those without dispensing privileges or on-site pharmacists were signifi cantly highly prescribing antibiotics. statistical data from nhic in korea showed that general physicians in clinics prescribe antibiotics in % of acute bronchitis patients, while doctors at tertiary hospitals showed less but still fairly high rate of %. efforts and interventions to reduce the potentially inappropriate prescription of antibiotics should target modifi able factors. quality improvement (qi) strategies like using active clinician education, delayed prescriptions and targeting management, may yield reductions in antibiotic use. anti-tussives are occasionally useful and can be offered for short-term symptomatic relief of coughing. a meta-analysis and systematic review found that beta- -agonists were not effective for the treatment of acute bronchitis or cough of < weeks duration in children or in adults unless airfl ow obstruction was present. summary acute bronchitis is one of most commonly diagnosed and treated diseases in daily clinical practice. however, since it is mostly a self limiting disease, the standardization of diagnosis and treatment has long been neglected leaving various controversies in the management, particularly the use of antibiotics. the inappropriate prescription of antibiotics for acute bronchitis will surely lead to the emergence of resistant organisms in the community let alone the increase of socio-economic burden. further attention and research is needed for the reasonable approach to the treatment of acute bronchitis in order to prevent overuse of antibiotics and improve health-economy. prevalence acute bronchitis is one of the most common conditions encountered in clinical practice, accounted for approximately million visits to korean physicians in , and consistently ranks among the top reasons for ambulatory visits in the united states. defi nition acute bronchitis refers to a clinical syndrome distinguished by a relatively brief, self-limited infl ammatory process of large and midsized airways that is manifested predominantly by cough with or without phlegm production which lasts for up to weeks and absence of fi ndings suggestive of pneumonia. acute bronchitis should be distinguished from acute exacerbations of chronic bronchitis and acute infl ammation of the small airways -asthma or bronchiolitis. those with underlying lung disease, congestive heart failure, or a compromised immune system are considered to be at high risk for complications of acute bronchitis. etiology acute bronchitis is one of the most common causes of antibiotic abuse. in healthy communities, there is little evidence of bacterial infection in people with bronchitis, but there are few practical studies to distinguish between bacterial and viral bronchitis. within this context, the use of antibiotics to treat acute bronchitis is controversial but common in real practice. viruses are usually considered the most common cause of acute bronchitis but have been isolated in a minority of patients. those isolated in acute bronchitis include, in order of frequency of occurrence, are infl uenza, parainfl uenza, respiratory syncitial virus (rsv), coronavirus, adenovirus, and rhinovirus. the yield of specifi c pathogens varies according to several factors, including the presence or absence of an epidemic, the season of the year, and the infl uenza vaccination status of the population. bacterial pathogens are thought to play a very minimal role in acute bronchitis. the bacteria that have been causally linked to acute bronchitis in otherwise healthy individuals include only mycoplasma pneumoniae, chlamydophila pneumoniae and bordetella pertussis. antibiotic treatment of patients with pertussis is indicated to limit transmission, but there are no compelling data to support the prospect that cough will be less severe or less prolonged with antibiotic therapy. clinical manifestations acute bronchitis cannot be distinguished from upper respiratory infections in the fi rst few days. acute bronchitis is suggested by the persistence of cough for more than fi ve days, and most often lasts from to days. approximately % of patients with acute bronchitis report the production of purulent sputum. it usually represents sloughing of cells from the tracheobronchial epithelium, along with infl ammatory cells, and does not signify bacterial infection. pulmonary function test fi ndings consistent with bronchial hyperresponsiveness are common. fev less than % at the initial visit was present in % of adults from the mid western united states with no history of underlying lung disease. pft abnormalities are usually transient, typically resolving after to weeks, although they may last as long as months. fever is a relatively unusual sign in acute bronchitis and, when accompanying cough, suggests either infl uenza or pneumonia. diagnosis acute bronchitis is established in a patient who has the sudden onset of cough, with or without sputum expectoration, and without evidence of pneumonia, the common cold, acute asthma, or an acute exacerbation of chronic bronchitis. the absence of the following fi ndings reduces the likelihood of pneumonia suffi ciently to eliminate the need for a chest radiograph: ( ) heart rate > beats/min; ( ) respiratory rate > breaths/min; ( ) oral body temperature of > °c; and ( ) chest examination fi ndings of focal consolidation, egophony, or fremitus. chest radiography should be reserved for use in patients with any of these fi ndings or cough lasting > weeks. an exception, however, is a cough in elderly patients; pneumonia in elderly patients is often characterized by an absence of distinctive signs and symptoms. rapid diagnostic tests exist for several pathogens currently linked to acute bronchitis. patients with severe paroxysmal cough, with or without post-tussive vomiting should be evaluated for pertussis regardless of the immunization history. rapid tests should be used primarily when the suspected organism is treatable, the infection is known to be circulating in the community, and the patient has suggestive symptoms or signs. treatment statistical data from korea national health insurance corporation (nhic) shows that approximately - % of patients with acute bronchitis receive antibiotics despite the evidence that, with few exceptions, they are ineffective. meta-analyses of randomized, controlled trials all concluded that routine antibiotic treatment is not justifi ed. the decision not to use an antibiotic should be addressed individually and explanations should be offered because many patients expect to receive an antibiotic based on previous experiences and public expectations. main challenges for appropriate antibiotic use in acute bronchitis are the diagnosis is based on clinical fi ndings, without standardized diagnostic methods and sensitive or specifi c confi rmatory laboratory tests. how to identify accurately the few patients who are seriously ill or whose symptoms could be meaningfully ameliorated by prompt antibiotic treatment is not standardized. recent studies have suggested that the annual decline in fev is greater in gold stage ii than in later stages of the disease. ( ) if the decline in pulmonary function predominantly occurs early in the course of the disease, then it is logical that diagnosis and intervention aimed at reducing the progression of the disease should mainly occur in the early stages of the disease. severity of copd at diagnosis differs enormously on where it is done: population based studies, screening or hospital patients. epidemiologic studies: prevalence, underdiagnosis and severity there are increasingly more data on the prevalence and distribution of copd from around the world. the prevalence of chronic obstructive pulmonary disease (copd) varies from country to country, mainly due to the effects of cumulative exposure to smoking and the increased life span of the population. ( ) ( ) ( ) ( ) systematic review of epidemiological studies concluded that the prevalence of copd, in adults aged years and more, worldwide ranges around - %. ( ) these differences may be related, at least in part, to differences in genetic background, smoking habits and exposure to other environmental risk factors, and are accompanied by differences in diagnostic rates and in management of the disease around the world. there is a large underdiagnosis of copd with about only one out of three or four of all subjects fulfi lling diagnostic criteria of copd identifi ed by the health care system. ( ) ( ) ( ) copd in general population is diagnosed at earlier stages. data from latinamerica (platino), similar from those from spain, showed severity was distributed as follows: stage i, % and stage ii, . %. screening for copd screening, combined with smoking cessation advice, help motivated smokers to attempt quitting smoking. ( ) in general practice, when individuals were preselected on the basis of smoking age and respiratory symptoms chronic cough was a better predictor of airfl ow obstruction than other symptoms, such as wheeze and dyspnoea. age was also a good predictor of obstruction; smokers over with cough had a % chance of having an obstruction. ( ) diagnosis at the hospital the decrease in lung function is gradual. the disease is usually diagnosed late because patients may adapt to the condition or doctors may not notice the symptoms. by then, the patient is diagnosed at the hospital, when lung function is often poor, sometimes less than % of normal. the relationship between lung disease and increased body weight can take two forms: the effects of increased body weight on the normal respiratory system and the association of increased body weight with diseases of the respiratory system. obesity (body mass index, bmi, greater than kg/m ) can reduce normal static lung volumes (principally functional residual capacity, but also total lung capacity and residual volume at very high bmi), ventilation (particularly during sleep and exercise) and gas exchange (increased gas transfer). the epidemic of overweight and obesity has been associated with the increased prevalence of asthma through proposed mechanisms such as dietary effects, reduced lung volumes and lung recoil affecting airway responses to breathing, a general infl ammatory effect and through associated sedentary lifestyle. however more recent epidemiological data suggests the association between asthma and obesity is not as close as once thought. overweight and obesity clearly are associated with the high prevalence of obstructive sleep apnoea with increased body weight increasing the likelihood of upper airway collapse on a background of reduced upper airway dimensions and snoring and reducing minute ventilation in patients with obstructive sleep apnoea, predisposing to hypoventilation and chronic hypercapnoeic respiratory failure. the increased load to breathing also affects breathing, especially during sleep, in patients with respiratory muscle weakness or abnormal chest wall mechanics due to kyphoscoliosis or previous chest wall surgery such as thoracoplasty. increased body weight will also exacerbate the effects on symptoms of existing chronic respiratory diseases including asthma, chronic obstructive pulmonary disease and interstitial lung diseases. avoidance of weight gain and continued efforts at weight loss remain an important goal in patients with respiratory disease. this presentation will be a review of recent fi ndings and implications from imaging studies in asthma. the use of -dimensional imaging in asthma has provided useful insights into the understanding of pathophysiology of disease, which may have implications on how asthma is treated. small airways disease plays a major role in asthma and has traditionally been diffi cult to probe. however, the combined use of new imaging methods combined with complex lung function has provided useful insights into pathophysiology. findings and implications from hrct, pet, spect and mri will be discussed. the assessment of pulmonary function has changed very little over the past to years. all techniques performed in the laboratory still view the lung as a very simple single compartment unit. measures of volume and fl ow only assess disease in the medium to large airways whilst the small airways receive relatively little attention. however there are a number of emerging techniques on the horizon that have the potential to give great insight in to the periphery of the lung where most respiratory disease emanates. the measurement of mechanics using the forced oscillation technique and gas mixing using the multiple breath nitrogen washout test are now emerging as very powerful tools for assessment of peripheral lung function. in this presentation we will be discussing the state of the art in terms of assessing pulmonary function and what may we expect to see in the future. copd is a major public health problem in asia. copd prevalence was . % ( . % in males and . % in females) in china (> yrs), . % in japan (> yrs). in most of the developing countries in asia, copd is always underdiagnosed by physicians owning to lack of routine spirometry test and only based on symptomatic diagnosis. smoking is the most important risk factor contributing to development of copd. however, copd prevalence was . % in chinese non-smokers (> yrs) and . % in korea (> yrs), similar to those in mexico city ( . %) and caracas ( . %). in china, non-smokers accounted for . % of copd patients compared with . % in usa and . % in the uk. exposure to environmental tobacco smoke (passive smoking) and indoor air pollution (particularly the coal and biomass combination) may contribute to the higher prevalence of copd in developing countries. to reduce the risk factors (smoking, coal or biomass fuel for cooking, indoor and outdoor air pollution) are the priority for reducing the prevalence in the asian developing countries. government in some countries had made some effect in tobacco control and reducing air pollution. unlike hypertension or diabetes, the management of copd is only based on symptomatic treatment, owing to lack of specifi c biomarkers. annual lung function test with spirometer is the only parameter in detecting early stage of copd. data showed that more reversibility of fev was demonstrated in stages i-ii copd patients with ics/laba or tiotropine administration, as compared with those in stages iii-iv. an intervention study at the community level has shown that early intervention (improvement of indoor ventilation, bronchodilators) was able to reverse rapid annual fev, decline in copd patients. more affordable medication should be developed in the low income countries. data showed that oral administration of carbocysteine (thio compounds) reduced exacerbation rate by . %, which was consistent with inhaled administration of fluticasone/formoterol (seretide) or tiotropine. in addition, orally administered low dose teophylline ( mg, bid) improved pre-bronchodilator fev, and reduced exacerbation rate. there was a synergistic effi cacy in fev , with the combination of teophylline and inhaled corticosteroids. chronic obstructive pulmonary disease (copd) is characterized by the presence of airfl ow limitation due to loss of lung elasticity and/or airway narrowing. the pathological hallmark of loss of lung elasticity is emphysema and airway wall remodeling contributes to the airway narrowing. using computed tomography (ct) these lesions can be assessed by measuring low attenuation areas (laa) and airway wall thickness/luminal area, respectively. recently, copd has been widely recognized as a systemic infl ammatory disease, and body weight loss is one of its clinical features. traditionally, the patients who had copd with predominant emphysema and a low body mass index (bmi) were called "pink-puffers". however, the relationship between body weight loss and emphysema had not been assessed. based on these back ground, we have evaluated the body composition, emphysema and airway dimensions in copd patients using ct images. bmi was signifi cantly lower in the emphysema dominant phenotype compared to the airway dominant phenotype. furthermore, bmi correlated with laa% (ρ = − . , p < . ) but not with wa%. chest subcutaneous fat mass was also correlated with laa% (ρ = − . , p < . ). these data indicated that the "pink-puffer hypothesis" is correct in some aspects. next, we postulated that reduced leptin and leptin receptor signaling could contribute the development of emphysema. serum leptin was correlated with bmi which was correlated with dl co /v a . the expression of leptin and leptin receptor was evaluated pcr in human lung tissues. both genes were detected in the lung tissues, but the expression of leptin gene was low. the leptin receptor gene expression was signifi cantly lower in copd patients and it was signifi cantly correlated with dl co /v a . the leptin receptor gene expression in the lung did not correlated with body weight. these data suggested that the patients' physique can be associated with the relative contribution of emphysematous lesions in copd and leptin and leptin receptor system might affect the mechanism of developing emphysema. nutritional support has been one of possible clinical approaches as a copd therapy these days. however, its effect is still controversial. to clarify the relationship between low bmi and emphysema and to classify the phenotypes of copd based on the patients' physique may help to fi ne the defi nite targets for nutritional support even in the early stage of copd. journal compilation © asian pacifi c society of respirology sy - at present copd is often only treated in gold stage iii or iv . it is without question possible to diagnose copd earlier. if spirometry would be more readily performed in general practice, copd could be diagnosed in gold stage i and ii, as is evident from the practice of "spirometry days" organized by the belgian thoracic society in which the majority of the patients were diagnosed in gold stage ii . whether gold stage i and ii truly represent the "early" stages of the disease may be debated , but this defi nition of early copd could certainly be used as an operational defi nition. it is clear now that spirometry is required for early diagnosis of copd . although at present there is no irrefutable evidence that early treatment of copd is warranted, there is accumulating suggestive evidence that early treatment of copd may result in better outcomes. this evidence is primarily related to secondary analyses of the torch and uplift , studies. first, it was demonstrated in a secondary analysis of the torch study, that inhaled corticosteroids, long-acting betaagonists and their fi xed combination reduced the rate of decline of fev by , and ml, respectively . if treatment indeed reduces the progression of the disease, then an easy case for early treatment is made. in addition, a subgroup analysis demonstrated that except for the effect on the sgrq (st. george's respiratory questionnaire) all other treatment effects were numerically larger in gold stage ii than in gold stage iii and iv . a subgroup analysis of the uplift study demonstrated numerically greater treatment effects in gold stage ii as well. in addition, tiotropium reduced the rate of decline of fev in these patients (albeit only by ml/year), which was not the case in the later gold stages . finally, in patients not taking any medication at the onset of the study (maintenance naïve patients) tiotropium substantially reduced the rate of decline of fev and the rate of deterioration of the sgrqscore . taken together these data demonstrated that: ) large treatment effects were obtained in early disease; ) indications of disease modifi cation were present in early disease. hence, they support early treatment of copd. pulmonary rehabilitation is now the standard of care for patients with chronic obstructive pulmonary disease (copd) who remain symptomatic despite bronchodilator therapies. combining the best of interprofessional, personalized and evidence-informed care, pulmonary rehabilitation allows clinicians and their patients to realize signifi cant benefi ts in a variety of important patientcentered copd outcomes. the fundamental elements required for an effective pulmonary rehabilitation program will be discussed, and the scientifi c evidence supporting their effectiveness will be summarized. issues relating to optimal site of delivery, components of effective rehabilitation programming, duration of rehabilitation, timing of rehabilitation and target populations will be reviewed. recent developments in this rapidly expanding area will also be highlighted. lastly, methods to establish or enhance an existing pulmonary rehabilitation program will be discussed, with the goal of fully realizing the many substantive benefi ts of pulmonary rehabilitation in copd. however, only very low gene transfer seen after a second dose with either day and day spacing. we attribute this to rapid upregulation of neutralizing antibodies against adenovirus. anti-tumor humoral immune responses were seen almost all patients with reactions seen against known meso tumor antigens (sv large t antigen and mesothelin) and against unknown proteins in cell lysates. given the caveats of phase trials (small numbers, different doses, heavily pretreated patients), we still saw clinical responses (defi ned as prolonged stable disease, prolonged survival, partial or complete responses by modifi ed resist criteria, decreased metabolic tumor activity by pet scanning, or "mixed" responses) in about / of the patients. we are currently administering two doses spaced only three days apart. this appears to be well tolerated. based on strong preclinical data supporting the combination of gene therapy and chemotherapy, we have started a trial using ad.inf instillation into the fi rst treatment cycle of fi rst line (cisplatin/pemetrexed) or second line chemotherapy (gemcitabine). our groups is also generating "designer chimeric t cells" in which a single chain antibody fragment is linked to the transmembrane and cytoplasmic regions of the t-cell receptor. this artifi cial t-cell receptor is then transduced into t-cells that are then reinfused. the t-cells are then activated by cells expressing mesothelin. preclinical data show striking activity against mesothelin-expressing tumors in mice. mesotheliomas make large amounts of the immunoinhibitory cytokine, transforming growth factor-beta (tgf-β). preclinical studies using tgf-β blockers have shown activity in mouse models of mesothelioma and a clinical trial using an anti-tgf-β antibody is now underway at the university of pennsylvania. in summary, gene-based and immunotherapies are being actively studied in mesothelioma and have shown some promising results. future trials are focusing on combining these approaches with chemotherapy and surgery. given the relatively mild and non-overlapping toxicities, we believe these, or other gene therapy and/or immunologic approaches will soon become part of the standard therapeutic armamentarium. the burden of asbestos-related diseases (ards), in particular mesothelioma, has been shouldered mostly by the developed countries of the west. this is a consequence of the heavy dependence on asbestos use up to around the s by those countries. in contrast, the majority of asian countries started to depend on asbestos since then and has not yet reached the suffi cient latency time for the related diseases to manifest. japan is an exception, because it heavily used asbestos during the period to catch-up with the west. japan has now become one of the global epicenters of ards. it is a tragic consequence of experiencing the burden of ards that many developed countries decided to move towards banning asbestos or a de facto non-dependence. in the asia-pacifi c, this group comprises australia, new zealand, japan, korea and singapore (the "forerunner" group in terms of ards). in contrast, the many other countries in asia still use asbestos at substantial levels, turning asia into the world's center of asbestos consumption today. however, as these countries start to use up the latency time, and manage to improve medical recognition, reporting and recording, ards will soon emerge as a major public health issue in the region. early indications of this forecast do exist. not only should lessons be learnt from the experiences incurred by the "forerunner" group of countries, but more importantly, they should crystallize in international collaboration involving national administrators, academia, ngos and international organizations, for the effective recognition and countermeasures of ards. i will also refer to the progress made and hurdles encountered by the asian asbestos initiative and the who global plan of action on the elimination of asbestos-related diseases. at the international level, ards present a domino-effect that needs to be coped with. sy - interstitial pneumonia (ip) can be classifi ed into two groups in terms of known causes. pneumoconiosis, drug-induced pneumonitis, radiation-induced pneumonitis, and hypersensitivity pneunonitis (hp) are categorized as ip with known causes. on the other hand, idiopathic interstitial pneumonias (iips), which include idiopathic pulmonary fi brosis (ipf), nonspecifi c interstitial pneumonia (nsip), cryptogenic organizing pneumonia (cop), and desquamative interstitial pneumonia (dip), have no known causes. most physicians tend to diagnose of ip patients as iips without intensive examinations. however, some environmental and occupational lung diseases, especially asbestosis and chronic hp, should carefully be differentiated from iips. asbestosis is one type of pneumoconiosis, which is induced by asbestos exposure with a latent period of usually more than years. bilateral fi ne crackles can be frequently auscultated and pulmonary function test shows restrictive and diffusing impairments. chest hrct shows subpleural dot, subpleural curvilinear shadow, ground glass opacity, interlobular septal thickening, traction bronchiectasis, and honeycombing. in our case series of asbestosis (n = ) in yokosuka, a town of shipyard for more than years, honeycombing was seen in cases ( %). chronic hp is an allergic disease induced by long-term exposure to antigens. major causative antigens are avian dropping and feather, mold, and bacteria. chest hrct tends to show traction bronchiectasis and honeycombing in advanced stages, which are similar to ipf. in surgical lung biopsy, most cases are classifi ed as nsip-like and uip-like patterns. to clarify the importance of unrecognized exposure to avian antigen, we precisely reviewed patients with bird-related chronic hp. in the patients, patients were bird-breeders with direct exposure to avian antigen by contacting their own birds, whereas patients seemed to be exposed to wild birds, neighbor's birds, feather duvets, stuffed bird, and fertilizer with chicken droppings without recognition of avian contact. number of patients is very limited both in asbestosis and chronic hp, which suggests that there is a small group of subjects who are susceptible to develop pulmonary fi brosis after exposure to asbestos or antigens. however, genetic background of susceptibility to pulmonary fi brosis has not elucidated. in our case series of chronic hp (n = ), cases ( %) had the fi rst-degree family members with ip, who might have common environmental and/or genetic factors. further studies are needed to determine host susceptibility to pulmonary fi brosis, which might contribute to clarify the pathogenesis of ip. long acting beta- agonists has been in the doctors' armory of asthma medications for about years (available in in uk and in usa). there is little doubt that laba when combined with inhaled corticosteroids can improve asthma symptoms for a subsection of people with asthma, and is generally superior to add-on leukotriene receptor antagonist. indeed addition of laba to inhaled corticosteroids is in all major asthma guidelines as a step-up therapy. however, after the salmeterol multicentre asthma research trial was prematurely halted, a focus on effi cacy and safety of the wide use of laba severe pulmonary arterial hypertension (pah) is a fatal condition associated with complex pathobiology. vasoconstriction, thrombosis, and remodeling of the pulmonary vessel wall contribute to increased pulmonary vascular resistance in pah. the pathology of pulmonary hypertension can be classifi ed into endothelial, smooth muscle, and/or adventitial lesions, although not all compartments of the pulmonary artery wall are involved in each case of severe pah. the classic lesion of severe pah is the plexiform lesion, an abnormal proliferation of predominantly endothelial cells. smooth muscle thickening can be seen in all forms of the disease but is not a constant feature in the idiopathic pulmonary arterial hypertension. the adventitia is often markedly remodeled in patients with certain forms of collagen vascular diseases associated with severe pah, most notably scleroderma. the obligatory lining of pulmonary arteries with a monolayer of endothelial cells is disrupted in severe pah. the three-dimensional vascular pattern is rather suggestive of an intravascular tumor-like proliferation (tumorlet), instead of a retracted scar if this lesion would represent an abnormal healing to an injury to the vascular wall. the evidence of a tumorlike endothelial cell proliferation was provided by the demonstration that plexiform lesions in patients with idiopathic pah were preferentially monoclonal, whereas similar lesions in lung of patients with secondary pah due to congenital heart malformations were polyclonal. monoclonality was also observed in plexiform lesions of patients from anorexigen-induded pah. vasoconstriction has been related to abnormal potassium channels and to endothelial dysfunction. endothelial dysfunction leads to impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin (et)- . many of these abnormalities not only elevate vascular tone and promote vascular remodeling but also represent logical pharmacological targets. recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including nitric oxide, prostacyclin, et- , serotonin, angiopoietin- , and members of the transforming-growth-factor-beta superfamily. disordered proteolysis of the extracellular matrix is also evident in pah. the unraveling of the pathobiology of severe pah may lead us to novel therapies and approaches to better treat the disease. unfractionated heparin (ufh) and low-molecular-weight-heparin (lmwh), acted by enhancing the ability of antithrombin (at) to inhibit coagulation proteases, have been used as initial anticoagulant therapy for vte. they are delivered intravenously or by subcutaneous injection. subcutaneous fondaparinux, a synthetic pentasaccharide with specifi c anti-factor xa activity, is also recommended as the initial treatment for vte according to recent guideline. oral vitamin k antagonists, acting by reducing the activity of several coagulation proteases, are used for long-term anticoagulation. the major disadvantage of vitamin k antagonists is the need for frequent coagulation monitoring to maintain a therapeutic level. new anticoagulants, including oral direct thrombin inhibitors, such as dabigatran, and oral anti-factor xa inhibitors, such as rivaroxaban and apixaban, are emerging in recent clinical trials. these new drugs may replace heparins and vitamin k antagonists, which are expected to have a huge impact on the treatment of vte in the near future. thrombolytic therapy should immediately be used in patients with massive (high risk) pte. the effect of thrombolysis in patients with submissive (intermediate risk) pte remains controversial. further stratifi cation of these patients is necessary. patients with multiple poor prognostic indicators such as right heart dysfunction, thrombolytic therapy should be considered. several countries have started to support activities raising public awareness of vte, with the goal to decrease mortality and morbidity. in us, national institutes of health (nih) and centres for disease control (cdc) have fostered thrombosis activities to improve the prevention of vte and its long-term complications. in the united kingdom, a thrombosis group has been formed to promote awareness among parliamentarians about the risk and management of vte; to increase knowledge of its causes, effects, and treatments; and to monitor the implementation of government initiatives and other researches being and this program has corrected the wrong perception that pte is a rare disease in china pulmonary hypertension (ph) is a common complication of chronic respiratory diseases, such as chronic obstructive pulmonary disease (copd) or interstitial lung diseases (ild). ph associated with respiratory diseases is classifi ed as diagnostic group iii according to the current clinical classifi cation of dana point . it is suggested that the pulmonary vascular abnormalities originate at an early stage of the diseases. the functional (hypoxic vasoconstriction) and morphological factors (vascular remodeling, destruction of the pulmonary parenchyma) explain the elevation of pulmonary vascular resistance that leads to ph. the ph is mild to moderate in copd with mean pulmonary artery pressure (mpap) usually ranging between and mmhg, however, worsening during exercise and exacerbations. a small proportion of copd patients may exhibit severe ph defi ned by a resting mpap > to mmhg, whose prognosis is particularly poor. ph is relatively frequent in advanced ild, particularly in idiopathic pulmonary fi brosis, which predicts a poor prognosis. the diagnosis of ph is suggested by doppler echocardiography, but the confi rmation still requires right heart catheterization. the potential treatments of ph associated with respiratory diseases are as follows: ) treat underlying lung disease; ) provide supplemental oxygen therapy when appropriate; ) rehabilitation; ) treat right heart failure; ) consider vasomodulator therapy; and ) consider lung transplantation when indicated. journal compilation © asian pacifi c society of respirology sy - tobacco use is the most common preventable cause of death. about half of the people who don't quit smoking will die of smoking-related problems. the epidemic varies among countries and is increasingly affecting developing countries, where most of the world's smokers ( %) live. close to half of all men in low income countries smoke daily and this has been increasing. legislation the framework convention on tobacco control (fctc) was adopted by who member countries in may to commit all countries to protect nonsmokers from tobacco smoke in public places, to eliminate all tobacco advertising, promotion and sponsorship, to require warning labels of cigarette packs and to prohibit misleading tobacco product descriptors such as "light" and "mild". even though many countries have passed legislation mandating smoke-free environments and the total global population covered by comprehensive smoke-free laws increased from . % to . % in one year, the overwhelming majority of countries still have no smoke-free laws, very limited laws, or ineffective enforcement. compliance with smoke-free laws is low. treatment to aid smoking cessation support for smoking cessation or "treatment of tobacco dependence" refers to a range of techniques including motivation, advice and guidance, counselling and appropriate pharmaceutical aids, all of which aim to encourage and help tobacco users to stop using tobacco and to avoid subsequent relapse. the success of these interventions depends on their synergistic use in the context of a comprehensive country tobacco-control strategy. in many countries, provision for treatment, training of health-care providers, education and information on the wide use of cessation is scarce. therapies, as well as fi nancial resources are limited and rarely incorporated into standard health care. also, smoking cessation is not seen as a public health priority and is not necessarily approached as a key tobacco-control strategy. smoking cessation services are most effective when they are part of a coordinated tobacco control programme. brief cessation counselling is relatively inexpensive when integrated into existing primary health-care services, is usually well received by patients, and is most effective when it includes clear, strong and personalized advice to quit. communication technologies -such as telephone quitlines, text messaging, interactive telephony, and online counselling -as well as psychological and behavioural modifi cation therapies, offer important support. cessation prescription medicines, available in many countries like nicotine replacement therapies, bupropion and varenicline can double the likelihood that someone will successfully quit. bronchiectasis is an old disease that we all treat, but surprisingly little about this disease has been well studied. the defi nition, diagnosis, natural history, pathogenesis and treatment are all uncertain. this talk examines these points in the light of new information about biofi lms and "normal" bacteria. it asks more questions than it answers, but the questions raise thoughts on whether our usual approaches are the best. the mediastinum is generally split into three compartments strictly for the purpose of classifi cation of the most likely abnormality in the individual compartment. there are no anatomical boundaries or fascial planes that divide one compartment from the other. classically, the compartments have been classifi ed as anterior, middle, and posterior. a recent change in classifi cation has used the categories of anterior, middle-posterior, and paravertebral compartments. approximately % of mediastinal tumors are located in the anterior compartment, % in the middle compartment, and % in the posterior compartment. asymptomatic masses are more likely to be benign than malignant, and symptomatic masses are more likely to be malignant than benign; however, there is a large variation the most common tumors in the anterior mediastinum consist of thymoma, lymphoma, germ cell tumors, and thyroid tumors. thymoma is by far the most common anterior mediastinal tumor and approximately / are encapsulated and non-invasive while / are invasive. the most common paraneoplastic syndromes associated with thymoma include myasthenia gravis, hypogammaglobulinemia, and pure red blood cell aplasia. benign teratomas occur in both male and females, while malignant germ cell tumors of the mediastinum are almost exclusively in males. lymphoma can occur most commonly in the anterior or middle mediastinum and may be associated with systemic symptoms and occasionally superior vena cava syndrome. the most common abnormalities in the middle mediastinum include lymphoma, granulomatous disease, and developmental cysts. bronchogenic cysts are almost always benign, although they can cause symptoms such as obstructive pneumonia and are generally treated with surgical resection. recent mediastinal compartment classifi cation has switched from posterior mediastinum to naming this the paravertebral compartment. it is located posterior to an imaginary line drawn to connect the anterior aspects of the vertebral bodies on the lateral chest radiograph. the most common tumors in this location are neurogenic tumors, meningoceles, or thoracic spine lesions. the most common neurogenic tumors in adults are neurilemomas, and they are almost always benign. neurofi bromas also occur in this compartment. they are frequently benign, but may be malignant, especially in patients with neurofi bromatosis. in these individuals, malignant tumors of the nerve sheath origin are more common. ganglioneuroma, ganglioneuroblastoma, and neuroblastoma are more common neurogenic tumors in children or adolescents.. cough is an important lung defense. in a refl ex manner, noxious agents are expelled from the airways as these are sensed by the receptors in the airway epithelium. in addition to appreciating its cleansing function, understanding cough refl ex is important in the diagnosis and treatment of common clinical conditions. most diseases associated with cough are transient. a problem arises when cough persists and becomes chronic. an in-depth search for the underlying pathology is warranted since treatment directed to the cause of the cough is curative in over % of cases. an anatomic-diagnostic protocol ensures a systematic search for cough etiology but unfortunately, this approach can be lengthy and in many settings, impractical. thus an empiric syndromic approach is now recommended. this paradigm shift is borne by the following premises: ( ) the current awareness of the relative frequency of the disorders (alone or in combination) that can cause cough; ( ) the sensitivity and specifi city of many (but not all) diagnostic tests in predicting the cause of cough has been established; ( ) a sequential evaluation and treatment for the common causes of cough using a combination of selected diagnostic tests and empiric therapy has been proven effective; and ( ) a sequential and additive therapy is often crucial because more than one cause of cough is frequently present. a recent study by dr. aileen wang on "the management of chronic cough in a tertiary center: an asian perspective" showed that even in a filipino immunocompetent population, the most common causes of chronic cough is asthma, post-nasal drip syndrome (pnds) and gastroesophageal refl ux disease (gerd). the study concluded that: ( ) the accp recommendations are generally applicable to an asian setting. research of viruses, their structure, pathogenicity and host-interactions has burgeoned. we now understand how viruses infect cells, how they replicate, how they interfere with host defences and how they interact with other tissue events and pathologies. rhinovirus infection causing the common cold is the most frequent and 'common' infection in humans. it is also implicated in most exacerbations of asthma and copd. the patho-biology of rhinovirus will be used to illustrate virus pathogenicity, virus-host-interactions and to highlight potential future therapeutic options. sy - much hope has been placed in the discovery of biomarkers to help understand the mechanisms of diseases such as copd, help stratify the disease better and guide treatment. it is also hoped that some of these could speed up drug discovery by serving as surrogate markers that respond to novel drugs within a shorter timescale than is the case with current drug trials in which the main outcome is the spirometric measurement of forced expiratory volume in one second (fev ). although studies in patients with copd have identifi ed several biomarkers, most of these need to be validated and their prognostic value is unclear. many of the markers have been identifi ed in blood and although it is recognised that there are non-pulmonary consequences of copd, some of which can be viewed as systemic biomarkers measured and/or generated in the lungs are likely to be most informative. there are several methods to identify and quantify biomarkers of copd and different biological samples (blood, bal, sputum and lung tissue) can be used to provide material for such analyses. whilst most studies to date used commercial immunoassays (elisa), there has been a keen interest in applying unbiased approaches such as proteomics. we have recently completed a large programme of work which applied -dimenshional electrophoresis and mass spectrometric analysis to identify biomarkers of copd. induced sputum was obtained from copd patients with a spectrum of disease severity and control subjects. two-dimensional gel electrophoresis and mass spectrometric identifi cation of differentially expressed proteins was fi rst applied to induced sputum from gold stage copd patients and healthy smoker control subjects. initial results thus obtained were validated by a combination of immunoassays (western blotting and elisa) applied to a large subject cohort. the biomarkers were localised to bronchial mucosa by immunohistochemistry. of individual protein spots identifi ed, were quantitatively and qualitatively different between the two groups. protein spots were subjected to tandem mass spectrometry, which identifi ed separate protein species. seven of these were further quantifi ed in induced sputum from individuals. using this sequential approach, two of these potential biomarkers (apolipoprotein a and lipocalin- ) were found to be signifi cantly reduced in copd patients when compared to healthy smokers. their levels correlated with fev /fvc, indicating their relationship to disease severity. in summary, a potential role for apolipoprotein a and lipocalin- in innate defence has been postulated previously; our discovery of their reduction in copd indicates a defi cient innate defence system in airways disease that could explain increased susceptibility to infectious exacerbations. persistent chronic infl ammation, repetitive tissue injury, and dysregulated epithelial repair leading to tissue remodeling and fi brosis are the hallmarks of chronic lung diseases, such as chronic obstructive pulmonary disease (copd), chronic asthma, pneumoconiosis, pulmonary fi brosis and sarcoidosis. the innate immunity system with its pattern recognition receptors are recently identifi ed to involve in the pathogenesis of these chronic lung diseases. the neutrophilic infi ltration of the airway mediated through t h and il- family may play an important role in steroid-resistant asthma and status asthmaticus. in addition, the epigenetic modifi cation of gene expressions and cellular senescence may modulate the progression of chronic asthma and copd. histone deacetylase (hdac ), which can be inactivated by oxidative stress or pi k-akt pathway, may regulate corticosteroid-related anti-infl ammatory response. manipulation of hdac activity is a new treatment direction in steroid-resistant asthma and copd. sirt , a nad + -dependent deacetylase, is an important signaling pathway related to cell survival, dna repair, and apoptosis. the sirt is decreased in alveolar macrophages of smokers and copd patients, and associated with pro-infl ammatory response through the activation of nf-κb. understanding the complexity of infl ammatory and epigenetic regulations in chronic lung diseases may potentiate the development of novel therapies. fibrosis is a common fi nding in chronic lung diseases, with tgf-β-related pathways play important roles. myofi broblasts are the principal effective cells in the fi brogenic process. they can be evolved from the activation of resident pulmonary fi broblasts, marrow-derived fi brocytes, or the trans-differentiation of pulmonary epithelial cells through epithelial mesenchymal transition (emt). further understandings on the emt process in lung tissue repair may help to elucidate the mechanism of lung remodeling and fi brosis. in addition, lung stem/progenitor cell study appears to be a new and potential fi eld in lung injury and repair. it is anticipated that more clear mechanisms behind lung remodeling and fi brosis can be identifi ed and new treatment modalities be developed accordingly. sy - cancers are genetic diseases with constitutional genomic variations that are present in normal cells contributing to an individual's risk of developing cancer such as lung cancer. furthermore, cancer cells acquire genetic mutations and genome wide changes in their dna as well as their epigenome compared to their normal cellular counterparts. some of these mutations have turned out to be important driver mutations and are associated with exquisite sensitivity to targetted cancer therapies. some of these genetic changes include egfr and eml -alk fusion gene mutations. epigenetic changes include methylation abnormalities as well as histone modifi cations, and possess the characteristic of potential reversibility which is attractive for the development of new therapies. the human genome project and rapid technological advances including deep dna sequencing have contributed signifi cantly to the ability to detect cancer specifi c genetic, genomic and epigenomic aberrations. these genetic and genomic abnormalities have promise across the translational spectrum from identifying individual susceptibility to cancers, early diagnosis markers, molecular pathology and tailoring of treatment (predictive biomarkers) as well as informing on outcome (prognostic biomarkers). much work remains to be done to validate clinical utility and translate these potential useful biomarkers into useful clinical tools. this session will review some of the developments in the genomics and epigenomics of lung cancer and mesothelioma. asthma is a disease that is diagnosed largely on a history of variable symptoms and the demonstration of variable airway narrowing. it is associated with airway infl ammation (cd t-lymphocytes, b-cell lymphoid aggregates, macrophages, eosinophils and, in adults, neutrophils) and airway wall remodelling (airway wall thickening, principally increased airway smooth muscle and deposition of collagen below the basement membrane, with minor encroachment on the airway lumen). it is not associated with a prominent effect on the lung parenchyma. the cause(s) of asthma remains unknown and the severity of disease remains largely constant. copd is diagnosed with a spirometer and is defi ned as a fi xed reduction in fev , relative to fvc. when caused by cigarette smoke it is associated with airway infl ammation (cd t-lymphocytes, b-cell lymphoid aggregates, macrophages and neutrophils) and airway remodelling (mild increase in airway wall thickness including airway smooth muscle with encroachment on the airway lumen) and tissue destruction (emphysema and loss of small conducting airways). the severity of copd increases with age and continued exposure to irritants. copd has many causes including smoking cigarettes, burning of biomass fuels, asthma and early life respiratory illness and exposures (viral infections, bronchopulmonary dysplasia). as a group, patients with asthma have reduced lung function, in relation to disease severity, and may have a slightly increased rate of decline in lung function. patients with asthma who smoke have reduced lung function and an accelerated decline in lung function. apart from stopping smoking there is no current treatment that can improve the rate of decline in lung function in patients with asthma or copd. therefore prevention, early intervention and uncovering the unknown environmental and genetic contributions to airway diseases remain critical. sy - situation the isaac and ariap studies have showed the different prevalence but heavy burden caused by asthma in asia pacifi c countries is common. goals with inhaled corticosteroids and other medications, the goals in managing asthma in developing countries should attain those stated in gina: control of symptoms, maintaining normal activity levels, normal pulmonary functions, preventing asthma exacerbations, avoiding adverse affects and preventing asthma mortality. in developing countries, avoiding the abuse of short-acting beta agonists, systemic corticosteroids and antibiotics is also a major problem. accessing medical care and medications is crucial. steps a core group, preferably at an university medical center, is the basic step. the asthma and copd outpatient care unit (acocu) run by this core group will help in getting experience and capacity building. the following steps are gina dissemination and implementation, patient club formation, increasing awareness, training doctors and nurses, advocacy, researches, efforts for the availability of affordable asthma drugs, and multiplying acocu in the whole country. the sustainability of acocu is assured by successful implementation of gina. a network of acocu will encourage and improve the activities of acocus. successful provincial acocu will encourage the building of district and even commune acocus. diffi culties the continuous medical education for all doctors on gina, the medication affordability, spirometers and mechanism to maintain an acocu. despite the advances in asthma diagnosis and treatment, slta cases continue to present in the er, sometimes leading to unnecessary mortalities. these are highly preventable situations with inhaled steroid based chronic therapy. with expert care, most patients get through er/icu urgent phase with good outcomes. these strategies are published and updated regularly in the international asthma guidelines. the finnish experience confi rms that a national program that pushes for implementation of guideline recommendations is able to reduce asthma hospitalizations and cost of care. not all countries have such a program but in most developed economies, the cost of asthma care including medications is covered provided the guidelines are followed. unfortunately, even in these affl uent countries, a subset on patients still lands in the er with sltas. while there may have been a failure of health care delivery, the cross-country existence of this problem raises the prospect that some patients are prone to life-threatening exacerbation. sltas may have its own specifi c risk factors that are distinct from the risk factors for simple hospital admission for acute severe asthma. by defi ning risk factors for slta within the population of those admitted to hospital with acute asthma, we may be able to develop specifi c interventional strategies to reduce its occurrence. reported slta risk factors include advancing age, chronic severe asthma, increased infl ammation markers, asthma exacerbated by pneumonia and low nutritional status. other risk factors include recent hospital admission, prior intubation, steroid dependence, non-adherence to inhaled corticosteroids, psychological or psychosocial problems, lack of access to medical care, lower fev , and current cigarette-smoking. a specifi c phenotype of severe brittle asthma has been reported. the backbone of er management for slta includes quick assessment of severity, oxygen therapy, early use of systemic steroids and repetitive saba bronchodilator administrations. enhancements include the use of saba with high intrinsic effi cacy, the addition of ipratropium in refractory cases and the concurrent administration of inhaled corticosteroid for its non-genomic, airway edema-reducing effect. mgso can also be considered for refractory cases. when ventilator support is needed, niv may be attempted in some patient. for intubated cases, the ventilatory strategy includes low tv and rr, high i : e ratio, and monitoring for the development of dynamic hyperinfl ation. the burden of the slta problem can be mitigated by identifying its phenotype a priori, providing preventive therapy before actual exacerbation occurs and putting in the er/icu the appropriate treatment protocols. journal compilation © asian pacifi c society of respirology available treatment of asthma using inhaled corticosteroids and long-acting inhaled β -agonists (labas) is highly effective and safe. importantly, it is also relatively inexpensive. however, many patients remain poorly controlled despite the use of optimal treatment. most advances in asthma therapy have been achieved by improving these drugs and more recently several promising once-a-day labas have been developed. new corticosteroids are also being developed with differential effect on trans-activation and trans-repression of pro-infl ammatory transcription factors, thus giving them a better therapeutic index. the big challenge in asthma is posed by corticosteroid unresponsiveness which is relative and therefore requires high doses to achieve symptom control which inevitably leads to side-effects. one option being pursued is to develop activators of the nuclear enzyme histone-deactylase (hdac) which is recruited to the gene initiation site of pro-infl ammatory mediators. there is an increasing appreciation that asthma is not a single disease and is increasingly seen as a syndrome consisting of several phenotypes. so far, two relatively clear subsets have been identifi ed: eosinophilic and neutrophilic forms of asthma. with this notion in mind, attempts are being made to develop more-specifi c inhibitors for a range of mediators with the hope that sub-phenotypes of asthma will be identifi ed that respond well to either single mediator inhibitors or a combination of these. a number of cytokine modulators have been tested in clinical trials, the most notable example being anti-tnf inhibitors which is felt to be more relevant to neutrophilic asthma. unfortunately, large clinical trials with tnf inhibitors have not found them to be very effective. treatment with blocking antibody for the eosinophils growth factor, il- , has been slightly more effective, with early clinical trials showing that the treatment reduces the frequency of exacerbations in patients who have eosinophilia. whilst the exact mechanisms leading to the development of these two subphenotypes is not fully understood, it is thought that eosinophilia represents a risk factor for exacerbations which has led to eosinophils counts in sputum being used as a guide to treatment; this has been benefi cial in reducing exacerbations. neutrophilic forms of asthma represent a special challenge because patients with neutrophilia tend not to respond well to corticosteroids, making them reliant on bronchodilators. such patients' asthma may be driven by mechanisms that involve il- which induces the production of neutrophil chemoattractants by the epithelium, which makes il- and its chemo-attractant axis a target for novel therapies. the major unmet need in asthma is the treatment of infections. there are early indicators of antibiotic treatment (macrolides) being effective in the treatment of severe asthma. but the real hope comes from novel strategies aimed at the effects of viruses which are the cause of most acute exacerbations, both in milder and more severe forms of disease. recent studies have identifi ed a defi ciency in type i interferons (ifn), the production of which by the bronchial epithelium -the prime target of virus infection -has been shown to be reduced when epithelial cells from asthmatic are grown in culture and infected ex vivo. in the acute care setting, niv must usually start without delay to avoid further deterioration and an increased likelihood of failure. thus, the decision to start must be made quickly based on a bedside assessment. i recommend a simple two step process, the fi rst of which is to assess the patient's need for ventilatory assistance. if the patient has increased dyspnea (moderate to severe) and evidence of increased work of breathing including tachypnea (> /min in obstructive diseases and > /min in hypoxemic respiratory failure), increased accessory muscle use or abdominal paradox, the patient needs ventilatory assistance. arterial blood gases are helpful in making this assessment, but i discourage awaiting blood gas results before starting if the need is obvious, because the window of opportunity may close if initiation is too delayed. i do recommend obtaining baseline blood gases, however, and using them for comparison with later measurements to make certain that the patient is responding. the second simple step is to make sure patients have no contraindications to niv. these include patients with a need for immediate intubation by virtue of a respiratory arrest, hypotensive shock, or uncontrolled arrhythmias or upper gastrointestinal bleeding. the inability to fi t a mask because of a facial deformity, recent facial surgery or burns is also a contraindication. relative contraindications include agitation that prevents the patient from tolerating the mask, increased secretions or diminished ability to protect the airway. patients with these contraindications are at increased risk of failure if placed on niv and should be promptly intubated. patients with multiple risk factors for niv failure should be started only by experienced personnel under very close monitoring. in patients with hypercapneic respiratory failure, these include higher acute physiology scores, marked tachypnea, greater acidemia at baseline and a worse neurological score. in hypoxemic respiratory failure, risk factors for niv failure include the diagnosis of ards or pneumonia, greater age, hypotension and the failure to improve oxygenation substantially within the fi rst hour. although patients at high risk of niv failure can still be given a trial if the clinicians judge it to be indicated, but they must be watched very closely in an icu, with plans to intubate if there is no improvement within the fi rst hour or two. just as the decision to endotracheally intubate a patient in respiratory failure is a clinical judgment that requires the consideration of multiple factors, so is the decision to implement noninvasive ventilation. in the largest rct to date, cpap and nppv performed similarly, both improving dyspnea scores and ph more rapidly than with oxygen alone, but neither lowered intubation nor mortality rate (the major outcome variable) compared to oxygen-treated controls. however, this study enrolled patients whose intubation rate was slightly below % in all of groups, including controls, suggesting that they were too mildly ill to manifest a signifi cant mortality benefi t. meta-analyses of the rcts on cpap or nppv compared with o therapy alone have confi rmed the benefi ts described above, even showing a signifi cant mortality benefi t with cpap. meta-analyses comparing the modalities show equivalency of nppv and cpap with regard to reduction of intubation, lengths of stay and mortality, and with similar myocardial infarction rates. therefore, by virtue of its greater simplicity and potentially lower cost, cpap alone is generally regarded as the initial noninvasive modality of choice for cardiogenic edema patients. but because some studies have found that nppv reduces dyspnea and improves gas exchange more rapidly than cpap alone, nppv is preferred by some initially and can be substituted for cpap if patients treated initially with cpap remain dyspneic or hypercapnic. the success of noninvasive positive pressure to treat cardiogenic pulmonary edema has encouraged its extension into the pre-hospital setting. an emerging trend is to provide cpap devices on ambulances for initial therapy of cardiogenic pulmonary edema, a practice that has been associated with decreased need for intubations in the fi eld. patients with advanced chronic obstructive pulmonary disease (copd) experience poor quality of life and very high levels of symptom burden, including intractable shortness of breath, activity limitation, fatigue, social isolation, anxiety and depression. many of the these burdens are shared with caregivers, and resources in the community to support individuals and their families with chronic illness in the community are often lacking. with the recognition that patients with advanced copd and their caregivers have so many unmet needs, there is a growing acceptance for the need to improve the care and quality of life for patients with advanced copd. while signifi cant gaps in our knowledge and understanding of this area remain, factors contributing to these adverse experiences will be discussed. the importance of prevention, relief, reduction, and soothing of symptoms, without affecting a cure, will be emphasized as an integral component of the care provided for these patients. techniques and tools to optimize the care of patients with advanced copd, including optimizing pharmacologic therapies, inter-professional team care, anticipating and appropriately initiating end-of-life planning, patient and caregiver advocacy, as well as timely and effective communication will be reviewed. withdrawal or withholding life support in medically futile cases has been recognized as an ethical and a legal procedure. it is based on the inherent right of a person to autonomy in making health care decisions. the western model however may not apply to the asian setting being widely varied in terms of cultures, religions and economic progress. more than an individual decision, it may actually be a communal decision with a heavy reliance on input of relations, especially the elders. life support withdrawal often entails complete discontinuation of all measures. efforts to avoid feelings of guilt or abandonment may make families opt for partial withdrawals even when they are not shown to be any more benefi cial. studies have shown that distrust with the medical system does play a major role. active discussions may be diffi cult with reticent cultures or when there are gender differences between patients or their families and the physicians. in this era of globalization and migrations, an understanding of these differences may minimize potential confl icts that arise out of these discussions. awareness that the western approach may not fi t the asian medical model allows the health care providers to be sensitive to the needs and wants of their patients and their families. it is hoped that the data reviewed spurs the development of asia pacifi c guidelines that try to fi nd some uniformity in the diversity of the region. screening for lung cancer is not currently recommended by any major medical organization. multiple phase ii non-randomized trials of computed tomography (ct) screening have yielded enticing results. they have demonstrated that ct screening detects smaller size lung cancer of - mm in diameter. it has been documented that the chest radiographs miss - % of the cancers detected by screening ct. in prevalence studies, - % of detected cancers are stage i. when ct screening results were compared to a validated control group, ct has been shown to detect times more lung cancer than would be expected and results in ten times more thoracic operation than would be expected. additionally, no decrease in advanced stage cancers or decrease in lung cancer deaths were observed. to date, multiple small randomized controlled screening trials (rct) have been reported, but they have been too small to assess if ct screening reduces mortality. a meta-analysis of baseline fi ndings from six small randomized controlled trials observed more stage i and more total lung cancers in the ct screened group. for every individuals screened with low dose ct, stage i nsclc and false positive nodules were detected and thoracic operations were performed for benign nodules. the two large rct of ct screening that may defi natively answer the question of ct screening and its ability to decrease lung cancer mortality are the national cancer screening trial (nlst) and the nederlands-leuvens longkanker screenings onderzoek (nelson) trial. mortality results from those two trials are anticipated in and respectively. a recent report from the nelson trial validated the use of ct volumetric assessment of nodules to assess malignancy and determine which nodules should be treated surgically. currently, there is considerable effort to identify susceptibility genes for lung cancer with particular interest in q - which is strongly associated. this region contains several genes of interest, including three genes that encode nicotinic acetylcholine receptor subunits. however, these genes may just be associated with nicotine dependence. a recent report utilizing gwas (genome wide association scan) methodology identifi ed snps at q . associated with lung cancer susceptibility in never smokers. an enormous research effort is underway related to biomarkers in airway epithelial cells, blood, sputum, breath, and urine for early diagnosis or prediction of high risk. intense efforts are devoted to develop models of risk for determining which individuals should be offered screening. journal compilation © asian pacifi c society of respirology sy - lung cancer is the leading death-related cancer worldwide. molecular targeted therapy appears to be an alternative approach for patients with non-small cell lung cancer (nsclc). the epidermal growth factor receptor (egfr) is one of these targets, responsible for the cell growth, proliferation, apoptosis and metastasis of the tumors. egfr-tyrocine kinase inhibitor (tki) has been applied to target egfr and suppress the development of tumors. some egfr-tkis, including gefi tinib and erlotinib, have been approved, while the others are still under development or in clinical trials. several studies demonstrated that egfr somatic mutations might predict the high response rate and greater survival benefi t of egfr-tki. in addition, egfr amplication, k-ras mutation, met amplication or the egfr t m mutation might predict the clinical effect of these drugs. both erlotinib and gefi tinib have been undergoing several clinical trials for nsclc treatment as a single drug or in combination with chemotherapy. br. trial showed that erlotinib improved survival with previously treated nsclc patients in a randomized multicenter during phase iii study. thus, erlotinib was approved to be the second or third-line treatment of advanced nsclc patients. however, isel failed to demonstrate a statistically important benefi t of gefi tinib in overall survival as compared with placebo. different study population, dosing and drugs of br. and isel might explain the different results. in ipass trial, clinical selected nsclc patients with asian origin and characterised by adenocarcinoma histotype were treated with gefi tinib or paclitaxel/carboplatin doublets as the fi rst line therapy. the results showed that gefi tinib had the superiority in terms of progression free survival (pfs) in patients with egfr mutation. in eortc and perol trials, gefi tinib and erlotinib maintenance therapy showed the trend of improved pfs, but not overall survival in advanced nsclc patients. the toxicity of gefi tinib and erlotinib includes diarrhea, rash, etc., which can be well-tolerated. novel egfr-tkis include vandetanib, sorafenib, sunitinib, and cediranib, of which some are under evaluation in phase iii trials as monotherapy or in combination with standard chemotherapy. vandetanib targets both egfr and vegfr and was tested in the second phase trial, suggesting the addition of vandetanib to the single chemotherapy might improve response rates and survival. sorafenib has been applied to different carcinoma histology and in combination with different chemotherapy. when combined with paclitaxel and carboplatin to treat patients with squamous cell cancer, no survival benefi t was seen. however, another clinical trial was launched to investigate the effect of sorafenib, in which squamous cell cancer were not eligible. novel egfr-tkis are under development with hope of overcoming resistance to egfr-tki gefi tinib and erlotinib. there is a great need of further clinical trials. egfr-tki is one of the important alternatives in treatment of nsclc and has shown promising potential in the future. more promising results may come out if the combination and sequence of egfr-tki with traditional therapies, like chemotherapy, radiotherapy and surgery, can be optimized. there is also a need of disease-specifi c biomarkers to predict the effect of the drugs and identify the patients most likely to benefi t from the drugs. lung cancer is the number one cause of cancer death. most cases are found after distant metastasis, and outcome of drug therapy for these patients used to be disappointing. however, we have faced a new paradigm shift, i.e., the molecular targeted therapy and the individualized therapy. many promising data has reported from not only western countries but also asian countries such as the effi cacy of egfr tki to tumors with mutated egfr, that of alk inhibitor to tumor with eml -alk fusion protein, and that of pemetrexed to non-small non-squamous cell lung cancers. new questions have emerged from these new evidences derived from some important clinical trials. among them, questions regarding with ethnic difference would be one of the most important issues. is survival data same between asian and caucasian? (data from japan lung cancer registry study as well as some global trials have shown survival of asian patients with lung cancer appears to be obviously better than that of caucasian.) why egfr mutation is frequent in asian patients? is only egfr gene status related with prognosis of lung cancer? what would be the cause of alk abnormality? is the criteria of pathological diagnosis for lung cancer same between asian countries and western countries? here, newest evidences for treatment of lung cancer will be presented, and importance of ethnic difference and asian trials will be discussed. the burden of chronic obstructive pulmonary disease (copd) is growing. despite these growing numbers, many patients with patients with copd remain undiagnosed, the greatest number being those with milder disease. delays in the diagnosis of copd are common. evidence suggests that patients with mild copd experience increased symptoms, reduced activity levels and exercise capacity, and impaired health-related quality of life. this growing body of evidence has made it clear that mild copd is not 'normal'. with recognition of this reality and efforts to appropriately recognize copd at an earlier stage, clinicians must be aware of the various therapeutic options for their patients. the defi nition of mild copd will be discussed, as well as effective strategies for the targeted early diagnosis of copd. the numerous and varied disease manifestations and consequences for patients with milder copd will be reviewed. in addition, practical and effective management options available to clinicians caring for patients with mild copd will also be examined. clinicians have been long aware that neither the traditional distinctions of "emphysema" versus "chronic bronchitis" nor the traditional clinical phenotypes of "blue bloater" and "pink puffer" are suffi cient to categorize patents that suffer from chronic obstructive pulmonary disease (copd). recently, the global initiative for chronic obstructive lung disease (gold) workshop has used quantitative measures (fev and fev /fvc ratio) to defi ne copd, but this defi nition fails to take into account the full heterogeneity of copd. with an increased understanding of pathophysiologic variation, copd now clearly represents a spectrum of overlapping diseases with important extrapulmonary consequences. a "phenotype" describes the outward physical manifestations of a particular disease, and comprises anything that is part of the observable structure, function or behavior of an individual. such phenotypic distinctions in copd include: frequent exacerbator, pulmonary cachectic, rapid decliner, airways hyperresponsiveness, impaired exercise tolerance, and emphysema versus airways disease. these variable manifestations, each with unique prognostic, clinical and physiologic implications, represent distinct phenotypes within copd. while all of these phenotypes have smoking as a common risk factor, the other risk factors that determine these phenotypes remain poorly understood. an individual smoker has variable expression of each phenotype and there is mounting evidence that copd phenotypes have different clinical outcomes. these phenotypes can be broadly classifi ed into one of three groups: clinical, physiologic and radiographic. thus, the paradigm that copd is one disease may be incorrect, and suggests that copd should be considered as a spectrum of smoking-related diseases. failure to consider copd phenotypes is likely to limit the power of therapeutic trials since not all copd patients are likely to benefi t from each therapy. the challenge to future copd researchers is to better characterize these phenotypes and identify their risk factors. measurement of fractional exhaled nitric oxide (feno) is an attractive biomarker of diseases where airway eosinophilia dominates. indeed even before any randomized controlled trials were published some were advocating treatment tailored in accordance to feno data. commercially available bench-top and portable feno analyzers are now readily available and in some countries, feno measurements attract a payment. however, despite the ease of measuring feno, it has its drawbacks in biological and measurement issues. biologically feno is signifi cantly infl uenced by atopy, intake of caffeine, exercise, ethnicity, etc on the measurement front, variabilites include: feno measured by different analyzers may provide different values and on-line vs off-line measurements. the cut-off for determining 'abnormally high results' is yet unknown. not surprisingly, there is discordance on the effi cacy of tailoring asthma medications in accordance to sputum eosinophils [ ] and feno [ ] in people with asthma, although both are eosinophilia infl ammatory markers. tailoring of medications in accordance to sputum eosinophilia (compared to standard practice) significantly reduced exacerbations in adults with asthma (odds ratio . , %ci . , . ). in contrast, the benefi t of tailoring of medications in accordance to feno was, at best, modest. the utility and limitations of using feno levels in the clinical setting will be discussed in this talk. shortness of breath and activity limitation are cardinal symptoms experienced by patients suffering from respiratory illness or disease. cardiopulmonary exercise testing (cpet) allows for the objective evaluation of these symptoms, recognizing that exercise involves the effective integration of respiratory, cardiovascular, neuromuscular and metabolic functions. the organs involved in these varied and important roles have a sizeable reserve, with the consequence that clinical manifestations of a disease state or abnormality may not become readily apparent until the functional capacity of the organ(s) is markedly impaired. objective assessment of various parameters during exercise, which places an increased physiologic demand on the functional reserve capacity of these organs, can provide a sensitive method for the early detection of abnormal function and responses(s). the results from exercise testing also parallel functional capacity and quality of life more closely than measurements obtained only at rest, and have been shown to accurately predict important outcomes, such as mortality, in a variety of patients and clinical circumstances. a brief overview of normal exercise physiology and characteristic responses demonstrated by patients with various disorders frequently assessed by the pulmonologist will be offered. in addition, a summary of the indications, conduct, and practical interpretation of cpet will be presented in this session. effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (uplift): a prespecifi ed subgroup analysis of a randomised controlled trial obstructive lung disease and low lung function in adults in the united states: data from the national health and nutrition examination survey international variation in the prevalence of copd (the bold study): a population-based prevalence study chronic obstructive pulmonary disease in fi ve latin american cities (the platino study): a prevalence study prevalence of copd in spain: impact of undiagnosed copd on quality of life and daily life activities global burden of copd: systematic review and metaanalysis prevalence of chronic obstructive pulmonary disease in china. a large, population-based survey diagnostic labeling of chronic obstructive pulmonary disease in fi ve latin american cities copd prevalence in a random population survey: a matter of defi nition treatment of copd: the sooner the better clinical copd phenotypes: a novel approach using principal component and cluster analyses offi ce spirometry signifi cantly improves early detection of copd in general practice: the didasco study salmeterol and fl uticasone propionate and survival in chronic obstructive pulmonary disease clinical trial design considerations in assessing long-term functional impacts of tiotropium in copd: the uplift trial a -year trial of tiotropium in chronic obstructive pulmonary disease mortality in the -year trial of tiotropium (uplift) in patients with chronic obstructive pulmonary disease effi cacy of salmeterol/fl uticasone propionate by gold stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled torch study effects of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (uplift): a prespecifi ed subgroup analysis of a randomised controlled trial tiotropium as a first maintenance drug in copd: secondary analysis of the uplift trial treating tobacco use and dependence: update. clinical practice guideline tobacco atlas the mpower package. geneva, world health organization implementing smoke-free environments. geneva, world health organization curbing the epidemic: governments and the economics of tobacco control clinical and public health signifi cance of treatments to aid smoking cessation we report that pulmonary emphysematous lesions appear to be a dynamic phenomenon that involves not only the gradual loss of alveolar structure, but apoptosis, cellular proliferation, and cellular senescence as well. cellular proliferation compensates for increased alveolar cell apoptosis in chronic obstructive pulmonary disease (copd) patients. however, smoking, age, and the increased cell cycle turnover that compensates for apoptosis accelerate alveolar cell senescence, thereby halting cellular proliferation and tipping the balance toward apoptosis, which, in turn, promotes the formation of emphysematous lesions. as a result, alveolar cells disappear and the emphysematous lesions progress. at the same time, cellular senescence is thought to induce infl ammation. more specifi cally, senescent alveolar cells induce infl ammation by producing various infl ammatory cytokines in tissue. lymphocytes and clara cells may also age more rapidly in the lungs of copd patients. lymphocyte senescence may induce an autoimmune reaction and increase susceptibility to infection, and clara cell senescence may impair airway regeneration as well as sustain airway infl ammation. thus, cellular senescence may be involved in arrested tissue repair, chronic infl ammation, and increased susceptibility to infection, which are the typical features of copd. there is increasing recognition that copd is an increasing global burden. new drug treatments continue to emerge suggesting that copd is more responsive to treatments than previously thought. however, there is still much that is unknown about copd that will contribute to further advances in treatment and management. pulmonary imaging can contribute by providing information on how structure and function relate to relevant clinical parameters, such as disease progression, treatment responses and exacerbations. in other words, imaging can help characterise copd in terms of clinical outcomes or phenotypes. there have been many advances in imaging methodology, including ct, mri, spect and pet. recent fi ndings from research studies using innovative methods of studying structure and particularly function, in copd will be reviewed. their clinical implications will be discussed. the spectrum of children's interstitial lung disease (child) encompasses a large, heterogeneous group of pediatric diffuse lung disorders that are diffi cult to diagnose and treat. as the differential diagnosis is large, a systematic approach is needed for accurate diagnosis. the classic fi rst step of obtaining a detailed history and performing a careful physical examination remains essential for providing diagnostic clues as well as assessing severity of illness. as examples, a history of hemoptysis and fatigue would suggest an alveolar hemorrhage syndrome; exposure to avian antigens, hypersensitivity pneumonitis; and a history of adenovirus pneumonia, bronchiolitis obliterans. the presence of growth failure, crackles, loud p , and clubbing on physical examination would point to a severe and progressive lung process with cor pulmonale. recent advances in diagnostic modalities have greatly improved the ability of clinicians to identify these disorders. in infants and children with diffuse lung disease, genetic testing can be diagnostic for surfactant dysfunction mutations (sp-b, sp-c, abca , ttf- , gm-csfra receptor). infant lung function testing has proven useful for assisting in the diagnosis of certain disorders, such as neuroendocrine cell hyperplasia of infancy (nehi) and distinguishing nehi from surfactant mutations. hrct may detect extent and severity of disease, but can also be useful in diagnosing specifi c disorders, such as nehi (symmetric ground glass densities in the right middle lobe and lingula and the central lung regions), bronchiolitis obliterans (mosaic perfusion, vascular attenuation, and central bronchiectasis), hypersensitivity pneumonitis (ill-defi ned centrolobular micronodules), and pulmonary alveolar proteinosis (crazy-paving). bronchoalveolar lavage can aid in the diagnosis of specifi c conditions, such as alveolar hemorrhage syndromes (hemosiderin-laden macrophages), aspiration (lipid-laden macrophages), hypersensitivity pneumonitis and sarcoidosis (lymphocytosis), eosinophilic pneumonias (eosinophilia), and histiocytosis (cd a + cells). lung biopsy performed by video-assisted thoracoscopic surgery (vats) has largely supplanted conventional open lung biopsy as the procedure of choice as it is equally accurate, but associated with less morbidity. although lung biopsy remains the gold standard for diagnosis of child, it must be interpreted in the context of the clinical and radiologic fi ndings. it should be emphasized that although lung biopsy can be diagnostic in some disorders, such as bronchiolitis obliterans, it may not be necessary because less invasive studies such as hrct may be suffi cient for diagnosis. finally, some pulmonary vascular disorders, such as pulmonary vein stenosis or atresia, may mimic child. for these disorders, echocardiography, mra, or cardiac catheterization may be required for diagnosis. with a systematic approach and improved diagnostic capabilities, it is reasonable to expect that a specifi c diagnosis can now be made in the vast majority of child cases. key: cord- -tyrlpl authors: dsouza, kevin; pywell, cameron; thannickal, victor j. title: late noninfectious pulmonary complications in hematopoietic stem cell transplantation date: - - journal: oncologic critical care doi: . / - - - - _ sha: doc_id: cord_uid: tyrlpl hematopoietic stem cell transplantation (hsct) is an established therapeutic modality for a number of malignant and nonmalignant conditions. pulmonary complications following hsct are associated with increased mortality and morbidity. these complications may be classified into infectious versus noninfectious, and early versus late based on the time of occurrence post-transplant. thus, exclusion of infectious etiologies is the first step in the diagnoses of pulmonary complications. late onset noninfectious pulmonary complications typically occur months post-transplant. bronchiolitis obliterans is the major contributor to late-onset pulmonary complications, and its clinical presentation, pathogenesis, and current therapeutic approaches are discussed. idiopathic pneumonia syndrome is another important complication which usually occurs early, although its onset may be delayed. organizing pneumonia is important to recognize due to its responsiveness to corticosteroids. other late onset noninfectious pulmonary complications discussed here include pulmonary venoocclusive disease, pulmonary cytolytic thrombi, pleuroparenchymal fibroelastosis, thoracic air leak syndrome, and posttransplant lymphoproliferative disorders. hematopoietic stem cell transplantation (hsct) is an established therapeutic modality for a number of malignant and nonmalignant conditions. pulmonary complications following hsct are associated with increased mortality and morbidity. these complications may be classified into infectious versus noninfectious, and early versus late based on the time of occurrence post-transplant. thus, exclusion of infectious etiologies is the first step in the diagnoses of pulmonary complications. late onset noninfectious pulmonary complications typically occur months posttransplant. bronchiolitis obliterans is the major contributor to late-onset pulmonary complications, and its clinical presentation, pathogenesis, and current therapeutic approaches are discussed. idiopathic pneumonia syndrome is another important complication which usually occurs early, although its onset may be delayed. organizing pneumonia is important to recognize due to its responsiveness to corticosteroids. other late onset noninfectious pulmonary complications discussed here include pulmonary venoocclusive disease, pulmonary cytolytic thrombi, pleuroparenchymal fibroelastosis, thoracic air leak syndrome, and posttransplant lymphoproliferative disorders. hematopoietic stem cell transplantation (hsct) is an established form of therapy for a number of malignant as well as nonmalignant conditions. more than , hscts were conducted in the united states in (https://www.cibmtr.org). the two main types of hscts are autologous and allogenic. autologous hsct involves collection of stem cells from the patient that are then infused back after chemotherapy. allogenic hsct involves infusion of stem cells from a donor. the morbidity and mortality from hsctrelated complications have been on the decline over the past several years. these complications are broadly categorized based on etiology, namely, whether they are infectious or noninfectious, and the time of onset of such complications, early vs. late. pulmonary complications are the most common life-threatening complications post hsct occurring in - % of patients [ ] . we define late onset complications are occurring months after post-hsct (fig. ) . in this chapter, we discuss late noninfectious pulmonary complications in hsct, and current concepts on their pathogenesis, diagnosis, and management. the primary focus will be on bronchiolitis obliterans (bo) which is the most common and carries the highest mortality of the late onset noninfectious complications [ ] . the other late onset noninfectious complications that will be discussed include idiopathic pneumonia syndrome, organizing pneumonia, pulmonary venoocclusive disease, pulmonary cytolytic thrombi, pleuroparenchymal fibroelastosis, thoracic air leak syndrome, and posttransplant lymphoproliferative disorders. bo typically occurs between months to several years post hsct and is inclusive of the spectrum of chronic graft versus host disease (cgvhd) [ , ] . bo is characterized by progressive, irreversible airway narrowing due to circumferential small airway fibrosis. there is limited understanding of bo pathogenesis. bo is a pathological diagnosis requiring invasive surgical lung biopsy, which is uncommonly performed in the clinical setting. bo syndrome (bos) is a more useful clinical diagnosis that is made based on irreversible airflow limitation on pulmonary function testing (pft) without the need for lung biopsy. bo is the most common late onset noninfectious complication of hsct. the reported incidence of bo/bos after allogeneic hsct varies based on the diagnostic criteria used, ranging from % to % in retrospective studies [ ] . a recent prospective study to evaluate the epidemiology of late non onset noninfectious complications after allogenic stem cell transplant reported a cumulative incidence of bos months posttransplant at . % [ ] . bo/bos following autologous hsct is rare but has been reported [ , ] . clinical features of bo/bos are nonspecific. in early stages of the disease, patients are asymptomatic and are identified by airflow limitation on pfts. nonproductive cough, dyspnea on exertion, and decreased exercise tolerance are common [ ] . physical examination may be normal or reveal signs of airflow obstruction such as wheezing, hyperinflation, or diffuse crackles. other causes of such presentations, in particular, respiratory infections, should be ruled out. the chest radiograph may be normal or reveal hyperinflation. high resolution chest tomography (hrct) reveals small airway involvement with features of air trapping evidenced by mosaic attenuation on expiratory views (fig. ) . histopathology, when available, shows narrowing or complete occlusion of the bronchiolar lumen due to subepithelial inflammatory fibrosis is a hallmark of bo (fig. ) [ ] . transbronchial biopsies are insufficient to yield a diagnosis and surgical lung biopsies often prohibitively expose patients to procedural risks. in most cases, bos can be diagnosed without a histopathological diagnosis using pfts in the appropriate clinical setting. the updated national institutes of health (nih) guidelines for diagnosing bos are based on the following criteria [ ] : (b) the fifth percentile of predicted is the lower limit of the % confidence interval. (c) for pediatric or elderly patients, use the lower limits of normal, defined according to national health and nutrition examination survey iii calculations [ ] . . fev < % of predicted with % decline over less than years. fev should not correct to > % of predicted with albuterol, and the absolute decline for the corrected values should still remain at % over years. . absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, computed tomographic (ct) scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, bronchoalveolar lavage). . one of the two supporting features of bos: (a) evidence of air trapping by expiratory ct or small airway thickening or bronchiectasis by high-resolution chest ct or (b) evidence of air trapping by pfts: residual volume > % of predicted or residual volume/total lung capacity elevated outside the % confidence interval it is important to recognize that a significant number of bronchioles must be involved to manifest airflow limitation on pfts or to develop clinical symptoms. hence, early stages of bo may be missed. several risk factors for the development of bos have been identified, and most of these are closely associated with the occurrence of cgvhd [ ] . increasing age of the donor/recipient, development of acute gvhd [ ] , abo incompatibility [ ] , the presence of extra thoracic gvhd, low circulating igg, and non-caucasian race [ ] have been identified in several retrospective studies. additional risk factors include the type of transplant procedure such a peripheral blood stem cell transplant [ ] and busulfan-based conditioning regimens [ ] . use of antithymocyte globulin (atg) as part of the pretransplant conditioning regimen is associated with a decreased incidence of bos [ ] . prior to meeting established criteria for bos, a decrease in fev from pretransplant levels has also been identified to be a risk factor for the subsequent development of bos [ ] . more recently, a % decline in fev from pretransplant to day posttransplant has shown to be predictive for the development of bos [ ] . the precise pathogenetic mechanisms involved in the development of bo are unclear. the pathogenesis appears to be multifactorial and may involve diverse etiologies [ ] . airway epithelial injury is the inciting factor secondary to gastroesophageal reflux disease, respiratory infections, and chemotherapeutic drugs. this is typically followed by a dysregulated immune response that leads to the development of fibrotic changes in small airways. t cells and humoral mechanisms have been implicated [ , ] . genetic polymorphisms in nod /card have been linked to susceptibility to bos [ ] . there are currently no effective treatments for bos complicating hsct. most treatment protocols are based on combinations of immunosuppressive drugs and, until recently, were largely based on expert opinion. traditionally, immunosuppression in the form of systemic steroids for extended periods has been used; alternatively, calcineurin inhibitors and azathioprine, agents that impair lymphocyte activation and proliferation, have been employed. long-term, high-intensity immunosuppression is no longer recommended due to the increased risk of infections [ ] . most clinical studies of treatments for bos are difficult to interpret due to small sample sizes, their retrospective nature, and confounding effects of treatment for cgvhd. these studies have included systemic corticosteroids [ , , ] , rituximab [ , ] , imatinib [ ] , etanercept [ , ] , as well as extracorporeal photopheresis [ ] . a recent retrospective matched cohort study recently showed that extracorporeal photopheresis improves survival in hsct patients with bos [ ] . treatment with inhaled budesonide/formoterol led to significant fev improvements in patients with mild/severe bos after allogeneic hsct [ ] . another trial showed fev stabilization using a combination of fluticasone, azithromycin, and montelukast along with pulse dosed systemic steroids [ ] . a randomized, double-blinded, placebo-controlled trial of azithromycin alone did not reveal any change in fev in late bos post hsct [ ] . prophylactic azithromycin has been shown to prevent the onset of lung transplant-related bos, as well as stabilize fevi in post-lung transplant bos [ , ] . however, prophylactic azithromycin has not shown to be effective in bos post-hsct in retrospective studies [ ] . a prospective study on the prophylactic use of azithromycin to prevent airflow decline resulted in early termination secondary to hematological relapses [ ] ; an fda warning was issued in august until further review (https://www.fda.gov/ drugs/drugsafety/ucm .htm). prospective trials of azithromycin, bortezomib, inhaled cyclosporine, and neutrophil elastase inhibitors for prophylaxis and/or treatment of bos are underway (www.clinicaltrials.gov). current treatment strategies include high-dose inhaled glucocorticoid with or without a long acting inhaled beta agonist based on symptoms, with close monitoring of lung function with pfts. if progressive decline in fev occurs with this regimen, initiation of a combination of fluticasone, azithromycin, and montelukast (fam) therapy can be considered [ ] . occasionally, patients with chronic gvhd and refractory bos may respond to increased immunosuppression. in patients who progress despite medical therapies, lung transplantation may be the only option [ , ] . novel therapeutic approaches for bo/bos are currently being investigated. the pleiotropic small molecule p mak inhibitor, pirfenidone, has been shown to ameliorate bo in a murine model of cgvhd [ ] . an early phase clinical study evaluating the safety and tolerability of pirfenidone in bos is currently underway (www.clinicaltrials.gov; nct ). the clinical course of bos is variable, with some patients experiencing rapid declines in lung function, while others stabilize or improve. mortality from bos is most commonly due to progressive respiratory failure. bos confers a . fold increased risk of death after diagnosis [ ] . early onset of bos and lower fvc, especially within a year of transplant, is associated with a worse prognosis [ , ] . recent estimates indicate a - year survival of - %, and a -year survival of - %; this is an improvement in overall survival from a decade ago, when -year survival was %, and -year survival was %. early recognition, newer treatment strategies, and better supportive care likely account for this improved survival [ ] . idiopathic pneumonia syndrome (ips) is a severe noninfectious complication of hsct with an incidence of % when it was first described in the s; more recently, incidence is cited at - % [ , ] . ips is more common as an early complication of hsct but can occur after months. median time of onset is days posttransplant, with a range from to days [ ] . ips is an acute lung injury process characterized by diffuse alveolar damage in the absence of an identifiable lower respiratory tract infection. although the exact cause of ips remains unknown, immune involvement has been invoked; murine models involving immune mismatches between donor and recipient support this concept [ , ] . elevated levels of lipopolysaccharide (lps) and tumor necrosis factor-alpha (tnf-α) have been observed in bal samples of murine ips models [ ] . tnf-α may contribute to pathogenesis by direct toxicity, upregulation of major histocompatibility complex (mhc), increased leukocyte recruitment, and cellmediated apoptosis [ ] . donor t lymphocytes secrete chemokines which further amplify the inflammatory cascade [ ] . decreased level of pulmonary surfactant has also been associated with ips development [ , , ] . risk factors for ips include full-intensity conditioning regimens such as total body irradiation and busulfan, acute gvhd, advanced age, and underlying acute leukemia and myelodysplastic syndrome (mds) [ , , ] . reduced-intensity conditioning regimens have decreased the incidence of ips [ ] . in children, risk factors for ips include the underlying disease and busulfan-based conditioning regimens [ ] . interestingly, risk of ips increases with the number of platelet transfusions received, though the transfusion requirement could be a marker of disease severity [ , ] . the definition of ips, updated in the american thoracic society guidelines, is based on the following criteria [ radiographic findings can be nonspecific, but hrct findings include ground glass opacities that are bilateral, central, symmetric, with consolidation seen in more severe cases [ ] . recent advances in diagnostic capabilities have increased detection of occult infections which help separate ips from infectious hsct complications; the distinction is critical due to their vastly distinct treatment approaches. many patients diagnosed with ips were later discovered to have detectable pathogens, most commonly hhv- , human rhinovirus, and aspergillus, when their bal samples were re-examined [ ] . historically, treatment of ips has been largely supportive. once infections have been ruled out, systemic corticosteroids are the mainstay of treatment; ips in association with diffuse alveolar hemorrhage may require higher doses [ ] . the results of other immunotherapeutic agents such as the soluble tnf-α inhibitor, etanercept, has been mixed. a retrospective single-center study over two distinct timeperiods comparing steroids alone (earlier timeperiod) versus combined steroids and etanercept showed significant improvement in survival to hospital discharge [ ] . however, the more recent use of reduced-intensity conditioning regimens and improved supportive care may have accounted for this improvement. patients with late-onset ips who responded to etanercept have greatly improved short-and long-term mortality [ ] . results in children have been similarly promising, with complete response in % of patients [ ] . a randomized, doubleblind, placebo-controlled trial comparing corticosteroids with placebo to corticosteroids with etanercept was inconclusive due to slow patient accrual and early termination [ ] . other potential therapies are under investigation. blockade of nf-κb, a transcription factor downstream of the tnf-α receptor, has shown promise in murine models [ ] . pulmonary surfactant replacement is also being studied as an intervention to treat ips [ ] . outcomes for ips remain poor, with mortality rates between % and %. rapid clinical deterioration can occur and > % of patients requiring mechanical ventilation succumb to the disease [ , , ] . veno-venous extracorporeal membrane oxygenation (ecmo) as a rescue therapy or bridge-to-recovery has met with mixed results [ , ] . short-term survival has improved with treatment advances, but -year survival remains low. based on a small study, a more rapid peak and decline in severity of infiltrates on hrct has been linked to a more favorable prognosis [ ] . biomarkers to predict patients who at risk for ips and who respond to biologic therapy are being studied [ ] . organizing pneumonia (op), formerly known as bronchiolitis organizing pneumonia (boop), is a complication of hsct. it can occur as a part of the ips spectrum or as a stand-alone late onset pulmonary complication of hsct [ ] . op as a complication of hsct was first described by thirman et al. in [ ] . although it has been described as a complication of both autologous and allogenic hsct, it is more common following the latter. the incidence of op post-allogenic hsct ranges from . % to . % with a median time of onset post-hsct of days [ ] . among patients, who underwent allogenic hsct, cases of histological boop/op was reported, an incidence of . % [ ] . op presents with fever, nonproductive cough, and dyspnea and can be precipitated by a recent taper of immunosuppressive regimen. pfts commonly reveal a restrictive pattern, but could be normal, obstructive, or mixed with a decreased diffusion capacity of carbon monoxide (dlco) [ , ] . high resolution chest tomographic scans in patients with op are notable for airspace consolidations, ground glass opacities, and nodular opacities (fig. ) [ ] . in a study of patients with biopsy-proven op post-hsct, ground glass opacities were noted to be the most common radiological feature [ ] . bronchoalveolar lavage is useful to exclude infections. surgical lung biopsy is the gold standard for diagnosis of op, as transbronchial biopsies have lower yield; however, the latter approach may be useful in certain clinical settings [ , ] . histopathological features on biopsy include presence of the buds of granulation tissue which contain myofibroblasts and a loose connective tissue (fig. ) . these buds are intra-alveolar and can extend into the bronchioles causing obstruction with associated mild interstitial inflammation [ ] . a prior history of acute or chronic gvhd was found to be a strong risk factor for op [ ] and suggests a common pathogenesis. in a study of patients of post-allogenic hcst recipients, hla disparity, female-to-male hsct, and peripheral blood stem cell transplant (pbsct) were associated with an increased risk of developing op. in contrast, busulfan-based or fludarabine-based reduced-intensity conditioning compared to total body irradiation and t cell depletion regimens were associated with a lower risk [ ] . the precise pathogenetic mechanisms of post-hsct op are unclear. the association with gvhd and increased incidence post-allogeneic hsct suggests alloimmune-mediated lung injury. murine models of op after respiratory reovirus infections have demonstrated the role of t cells and cytokines such as interferon-α in the development of the process [ ] . hsct-associated op, as in most other cases of op, is primarily treated with high-dose systemic corticosteroids. there are no specific guidelines on the dose and duration of steroid therapy. current recommendations are based on expert opinion, and clinical judgment should be exercised. prednisone in doses ranging from . - . mg/kg/ day have been used for - months with a slow taper over - months [ ] . further studies are needed to establish ideal doses and duration of corticosteroid therapy. erythromycin in combination with corticosteroids has been reported with favorable outcomes [ ] , although the role of macrolides for treatment of op is unclear. about % of patients with hsct-associated op have a favorable prognosis with resolution or stabilization after corticosteroid therapy [ ] . clinical improvement is seen usually within a week of starting therapy followed by radiological improvement. failure to respond to treatment may result in progressive respiratory failure and death [ ] . pulmonary venoocclusive disease (pvod) resulting in pulmonary hypertension is a rare late onset complication of both autologous and allogeneic hsct [ ] . in reported cases, it was noted in patients less than years old and presented several weeks to months posttransplant [ ] . presenting complaints are usually nonspecific, primarily fatigue and exertional dyspnea. physical examination findings are similar to those of pulmonary hypertension which may be normal in early stages and become more apparent in later stages: elevated jvd, peripheral edema, and hepatomegaly. elevated second heart sound, parasternal lift and palpable second heart sounds in the second left intercostal space can be recognized in some patients along with tricuspid regurgitation murmur. computed tomographic (ct) scans of the chest may show septal thickening, diffuse or mosaic ground glass opacities, small nodules, and areas of consolidation. right heart catheterization reveals an increased pulmonary artery pressure and normal pulmonary capillary pressure. the triad of severe pulmonary hypertension in the setting of normal pulmonary artery occlusion pressure and radiographic evidence of pulmonary edema could be suggestive of pvod but is not diagnostic. pvod can be definitively diagnosed only by surgical biopsy and is characterized by the progressive intimal proliferation, fibrosis, and occlusion of the pulmonary venules as well as small veins [ ] . the pathogenesis of pvod post hsct is unclear and has been attributed to toxic endothelial injury secondary to chemotherapeutic conditioning regimens and/or viral infections [ ] but does not seem to be associated with cgvhd [ ] . there are no effective treatments for pvod and prognosis is poor. conventional arterial vasodilator therapy for pulmonary hypertension could worsen pulmonary edema in pvod and if initiated should be done with close monitoring [ , ] . reported cases of pvod post hsct have shown some favorable response to steroid therapy [ , , ] . pulmonary cytolytic thrombi (pct) is a complication of allogenic hsct and primarily occurs in children with gvhd [ ] . the incidence is between . % and % with a median onset of months post hsct [ ] . patients typically present with fever, cough, and dyspnea. ct scans of the chest shows peripheral pulmonary and pleural nodules [ ] . bronchoalveolar lavage is indicated to exclude infectious etiology. the diagnosis of pct is based on surgical biopsy of the lung nodules which are characterized by vascular occlusive and hemorrhagic infarcts secondary to thrombi containing intensely basophilic amorphous material as well as entrapped leucocytes [ ] . the prognosis of pct is favorable as it responds to treatment with systemic corticosteroids. there has not been any mortality attributed to pct in the reported literature. pleuroparenchymal fibroelastosis (ppfe) is a rare complication of hsct, grouped under rare interstitial pneumonias with a prevalence of around . % in hsct recipients [ ] . it is characterized by progressive sub pleural fibrosis predominantly in the upper lobes. ppfe has been reported post allogeneic and autologous hsct. the etiology of ppfe post hsct is unclear. chemotherapeutic drugs, radiation therapy and a possible association with cgvhd have been hypothesized [ ] to be predisposing factors. patients can present with dry cough, exertional dyspnea, and chest pain secondary to spontaneous pneumothorax [ ] . pfts reveal a restrictive or mixed picture of obstruction and restriction. ct scan is characteristic of pleural thickening, fibrosis, subpleural reticulations, and traction bronchiectasis predominantly in the upper lobes [ ] . histopathological exam reveals alveolar collapse, subpleural fibrosis, and extensive elastic deposition [ ] . the disease is progressive with worsening symptoms and poor prognosis. currently no therapeutic options are available except for lung transplantation [ ] . thoracic air leak syndrome (tals) consists of a spectrum of conditions that includes spontaneous pneumothorax, subcutaneous emphysema, pneumomediastinum, interstitial emphysema, and pneumopericardium. it occurs as a late onset complication of allogenic hsct and is associated with cgvhd. according to reported literature, prevalence of tals post allogenic hsct is reported to be . - . % with a median time range of - days post hsct [ ] . the mechanism of air leak in bos is secondary to increased intra-alveolar pressure leading to alveolar rupture into the pulmonary interstitium with subsequent retrograde dissection of air into the mediastinum and subcutaneous tissue causing pneumomediastinum and subcutaneous emphysema. similarly, rupture into the pleural space causes pneumothorax [ ] . ct scan of the chest is the imaging modality of choice and can detect air in the pleural space, mediastinum, and subcutaneous tissue. infections, cough, emesis, and other causes of a similar presentation should be ruled out. prognosis is poor with -year and -year survival of % and %, respectively [ ] . post-transplant lymphoproliferative disorder (ptld) is a rare complication following allogeneic hsct and has a cumulative incidence of % [ ] . in a study of , hsct patients' risk factors such as unrelated or hla mismatched donors, use of atg or monoclonal antibodies against t cells for gvhd prophylaxis or treatment, t cell depleted donor marrow, age > years and second hsct were identified. the incidence of ptld ranged from . % in patients with no risk factors to more than % with more than risk factors [ ] . the pathogenesis of post hsct ptld is attributed to proliferation of donor epstein-barr virus (ebv) infected b cells in the setting of weakened t-cell immunity. though post hsct is common in the lymph nodes, spleen, and liver, pulmonary involvement occurs in about % of the cases. median onset is around - months post hsct [ ] . clinical presentation varies and could range from asymptomatic to fulminant tumor lysis syndrome. ct scans of the chest are notable for multiple pulmonary nodules with basal and peripheral predominance, mediastinal and hilar lymphadenopathy, patchy consolidation, pleural effusion, and chest wall or pleural-based masses [ ] . diagnosis may require a biopsy or could be made via noninvasive methods in the appropriate clinical setting. a probable diagnosis is made by increased ebv dna levels in the setting of lymphadenopathy or hepatosplenomegaly and when other causes have been ruled out, proven disease requires a biopsy. treatment strategies include rituximab, reduction of immunosuppression, donor lymphocyte infusion, chemotherapy, and ebv-specific cytotoxic t lymphocyte infusions [ ] . the prognosis of ptld post hsct is poor compared to that occurring after solid organ transplantation [ ] . late onset pulmonary complications following hsct are a major cause of mortality and morbidity. advances in transplant techniques, earlier diagnosis, prevention, and management of infectious complications have led to better outcomes as well as shifted the focus to late noninfectious pulmonary complications in hsct. these complications are myriad and require further studies to develop more effective screening, 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required for the development of murine chronic gvhd and bronchiolitis obliterans sixth european conference on infections in leukemia, a joint venture of the infectious diseases working party of the european society of blood and marrow transplantation, the infectious diseases group of the european organization for research and treatment of cancer, the international immunocompromised host society and the european leukemia net. management of epstein-barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation etanercept and corticosteroid therapy for the treatment of late-onset idiopathic pneumonia syndrome high-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-sct outcome and treatment of late-onset noninfectious pulmonary complications after 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bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation pulmonary cytolytic thrombi: a newly recognized complication of stem cell transplantation human surfactant protein a suppresses t cell-dependent inflammation and attenuates the manifestations of idiopathic pneumonia syndrome in mice soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol tnf-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. a joint pediatric blood and marrow transplant consortium and children's oncology group study (asct ) bronchiolitis obliterans syndrome (bos), bronchiolitis obliterans organizing pneumonia (boop), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation key: cord- -tcf mr h authors: sayer, gabriel; semigran, marc j. title: acute and chronic right ventricular failure date: - - journal: heart failure doi: . / - - - - _ sha: doc_id: cord_uid: tcf mr h right ventricular failure is the subject of renewed attention as the importance of rv function in a variety of disease states has been recognized. the rv is highly compliant, and is able to accommodate a wide range of preload conditions. yet, it is afterload-sensitive, and normal physiology is dependent on its association with the low resistance of the pulmonary vasculature. changes in the pulmonary vascular resistance, either acutely or over time, provoke a series of adaptations that are designed to maintain a normal cardiac output, but ultimately lead to decompensation and rv failure. through ventricular interdependence, rv failure may impair left ventricular diastolic and systolic function, further reducing cardiac performance. both echocardiography and magnetic resonance imaging can provide detailed information about rv structure, with mri providing better assessment of ventricular volumes and rv function. right heart catheterization is often necessary for definitive diagnosis of the etiology of rv failure and for determining the best therapeutic options. the treatment of rv failure is highly dependent on the underlying etiology, which should be corrected if possible. targeted medical therapy is particularly useful in cases of pulmonary arterial hypertension, and is under investigation for broader use in other causes of pulmonary hypertension. recent research has shed new light on the importance of the right ventricle (rv) in normal cardiac physiology and its prominent role in the pathophysiology of heart failure (hf). the rv was previously overshadowed by the left ventricle (lv), whose simpler anatomy conforms better to geometric models and is more accessible to non-invasive imaging. furthermore, early experiments falsely suggested that the rv did not contribute significantly to the generation of cardiac output [ ] . however, a series of investigations over the past years have provided greater insight into the rv's distinct anatomy, its performance under normal physiological conditions, and its adaptations to specific disease states. advanced imaging, including cardiac magnetic resonance imaging (cmri), has provided critical assistance in the study of the rv, allowing for non-invasive characterization of the rv's response to stressors, as well as a tool for measuring the success of therapies. as a result, a detailed understanding now exists of the role of the rv in ischemic heart disease, congenital heart disease, pulmonary arterial hypertension (pah) and chronic left-sided hf. most importantly, studies have shown that rv failure is a crucial prognostic factor in all of these disease states. in particular, the importance of rv function in left-sided hf may outweigh the importance of lv function in terms of both morbidity and mortality. the rv can be divided into three anatomical units: the inlet from the right atrium (including the tricuspid, the apex, and the outflow tract (infundibulum). the apex contains prominent trabeculations, in contrast to the smooth, muscular infundibulum. viewed in cross-section, the rv resembles a crescent that lies over the anterior aspect of the lv. the free wall is thin and the overall mass of the rv is a fraction of the lv mass, despite a larger volume. the deep muscle fibers of the rv have a longitudinal orientation, resulting in a primarily vertical direction of contractile forces. the superficial muscle fibers of the rv are oriented in a more concentric direction and are intertwined with the superficial muscle fibers of the lv. this anatomical interaction between the muscular fibers of the two chambers is also present in the interventricular septum, which is typically displaced into the rv throughout the cardiac cycle. direct muscular continuity between the lv and rv plays a significant role in ventricular interdependence, which will be discussed in further detail below. rv contraction proceeds sequentially, initiating in the inlet, continuing through the apex and concluding in the infundibulum. the longitudinal fibers draw the apex towards the tricuspid valve, while the free wall also moves inward toward the septum. traction on the free wall is applied by lv contraction at attachment points in the superficial muscle layer. the rv is coupled with the high compliance of the pulmonary vasculature, leading to a pressure-volume relationship that is distinct from the relationship seen in the lv. whereas the lv continues to generate pressure until the closure of the aortic valve, rv pressure falls prior to the closure of the pulmonic valve. ejection continues however due to the low resistance within the pulmonary circuit ( fig. . ) [ ] . the rv takes advantage of this physiology by producing an identical cardiac output to the lv with markedly reduced work and myocardial oxygen demand. however, one consequence of this interaction is the rv's heightened sensitivity to afterload, which can be deleterious in acute pressure overload states. ventricular interdependence occurs in both systole and diastole. systolic interdependence is mediated by the shared musculature between the lv and the rv, which means that the contractile state of one ventricle can influence the performance of the in the left ventricle, pressure continues to increase slightly throughout the entire duration of ventricular ejection. in the right ventricle, intracardiac pressure falls prior to closure of the pulmonic valve (red arrow), resulting in less myocardial work. enddiastole is indicated by the black arrows (adapted with permission from redington [ ] , with permission from elsevier) other ventricle. diastolic interdependence is a result of the common pericardial sac. the pericardium is unable to stretch acutely in response to ventricular dilatation, and is limited in its ability to accommodate chronic ventricular dilatation. therefore, a volume load in either chamber will cause displacement of the septum into the other chamber, resulting in a decreased diastolic volume and an impairment of ventricular output ( fig. . ) [ ] . as the rv is the more compliant chamber, this diastolic interaction most commonly occurs in volume overload states of the rv, such as an atrial septal defect. rv pathophysiology can be broadly categorized by the mechanism of the insult and its rapidity of onset. acute events, such as a pulmonary embolism, lead to maladaptive compensatory responses, and quickly progress to rv failure. chronic disease processes, such as congenital heart defects, often present a gradual stress on the rv, allowing it to develop adaptive mechanisms to preserve cardiac output for a prolonged period of time prior to decompensation. conditions characterized by volume overload are generally well tolerated by the rv due to its compliant nature. on the other hand, the rv has difficulty adapting to pressure overload due to its afterloadsensitivity ( fig. . ) [ ] . interestingly, the timing of onset of pressure overload is a crucial determinant of the rv response. in eisenmenger syndrome, the rv is able to remain compensated much longer than in adult patients with acquired pulmonary hypertension (ph). this finding has been attributed to the preservation of the fetal phenotype, which is accustomed to systemic levels of vascular resistance [ ] . intrinsic myocardial diseases, such as various forms of nonischemic cardiomyopathies, may impair rv contractility, but rarely affect the rv in isolation. however, rv involvement in a cardiomyopathy can play a significant role in morbidity and mortality, particularly in the setting of pulmonary hypertension (ph). a list of diseases that cause rv dysfunction and rv failure can be found in following a submassive or massive pulmonary embolism (pe), there is a rapid rise in pulmonary vascular resistance (pvr) due to both obstructed blood flow and the release of vasoconstrictors [ ] . vasoconstriction may be further exacerbated by hypoxemia. the rapid rise in afterload increases rv wall tension, which quickly leads to rv dilatation and rv systolic dysfunction. as the rv pressure rises acutely, the interventricular septum shifts into the lv, reducing lv preload and further compromising cardiac output. finally, coronary perfusion is impaired by both the compression of the right coronary artery by elevated rv wall stress and the reduction in cardiac output. in the setting of the increased myocardial oxygen demand in the failing rv, the reduction in coronary blood flow leads to a significant supplydemand imbalance. the final consequence of this sequence of events is worsening cardiac output, systemic hypotension and cardiac arrest. right ventricular infarction (rvi) occurs after occlusion of the right coronary artery in a sufficiently proximal portion to prevent perfusion of the rv branches. the immediate result of an rvi is rv free wall dyskinesis due to ischemia, although this alone may not be sufficient to produce clinical rv failure. secondary effects include stiffening of the myocardium and dilation of the rv. similar to the consequences of an acute pe, the acute pressure changes within the rv, in this case provoked by diastolic dysfunction, cause septal shifting and impaired lv-rv interaction. in addition septal ischemia further compromises lv performance, and diminishes the lv's ability to compensate for rv dysfunction [ ] . ph is the end-product of many cardiovascular and pulmonary diseases and is the most common cause of a chronic pressure overload on the rv. as the pulmonary artery (pa) pressure gradually increases over time, the rv adapts to the increase in afterload through multiple compensatory mechanisms. myocyte hypertrophy and the expansion of the extracellular matrix result in increased chamber thickness. at the same time, the rv remodels into a more spherical shape with a smaller radius [ ] . through the application of laplace's law, which states that wall stress is proportional to chamber radius and inversely proportional to chamber thickness, it is evident that the primary result of these initial adaptations is to reduce wall stress, countering the effect of the rise in afterload. in addition, central venous pressure (cvp) is allowed to rise, taking advantage of the frank-starling mechanism to maintain a normal stroke volume. several mechanisms have counterproductive effects, including reversion to a fetal gene pattern and upregulation of neurohormonal systems [ ] . the result is a decrement in contractility, followed by progressive ventricular dilatation. as with acute rv pressure overload, dilatation increases myocardial oxygen demand while simultaneously reducing coronary perfusion and oxygen delivery. this supplydemand mismatch further compromises rv performance and ultimately leads to rv failure if the ph remains untreated. both cardiac output and pa pressure fall when rv contractile reserve is no longer sufficient to maintain an adequate stroke volume ( fig. . ) [ ] . the thin, distensible wall of the rv permits it to accommodate large changes in preload without incurring significant changes in pressure. states of chronic volume overload, such as an atrial septal defect, can persist for decades prior to the development of rv dysfunction. two consequences of persistent rv dilatation are distortion of the tricuspid annulus and septal shift. the dilated tricuspid annulus permits tricuspid regurgitation, which can further exacerbate the volume load on the rv. septal shift occurs when the pericardium is unable to distend any further to accommodate the dilation of the rv. as noted above, septal shift can subsequently impair lv filling and adversely affect lv performance. finally, prolonged volume overload may cause pa pressures to rise due to increased flow through the pulmonary circuit. the development of ph is often the trigger for the natural history of persistent pulmonary hypertension. as pulmonary artery pressure (pap) and pulmonary vascular resistance (pvr) climb, cardiac output (co) is initially maintained, but eventually begins to fall. when co falls sufficiently to cause advanced rv failure, pap fells as well due to insufficient pressure generation by the weak rv. pvr continues to rise despite falling pap due to the concomitant fall in co. mpap mean pulmonary artery pressure, pcwp pulmonary capillary wedge pressure (reprinted, with permission, from haddad et al. [ ] , © , with permission from lippincott williams & wilkins/american heart association/wolters kluwer) decompensation of the chronic volume overloaded state, as the dilated rv lacks the compensatory mechanisms to augment its contractility in the setting of increased afterload [ ] . arrhythmogenic right ventricular cardiomyopathy (arvc) is a cardiomyopathy characterized by fibro-fatty replacement of myocardium, with a predilection for rv involvement. it may present with focal rv dysfunction at the sites of involvement, and may ultimately progress to rv dilatation and global rv dysfunction. the typical clinical presentation is ventricular arrhythmias, with symptoms of rv failure affecting less than % of arvc patients [ ] . in most patients, rv dysfunction can be present for decades without significant symptomatology. a similar observation has been made in animal experiments, in which an isolated reduction in rv contractility does not impair cardiac output in the setting of a normal pvr. in these animals, central filling pressures rise to permit sufficient flow through the pulmonary circuit. however, when pvr is raised, there is rapid cardiac decompensation, suggesting that the progression of rv dysfunction to rv failure may require the presence of an additional stressor, such as ph [ ] . the fontan operation, in which a passive conduit is created between systemic venous return and the pulmonary arteries, takes advantage of this physiology to maintain adequate flow to the lv despite the absence of rv contractility. a thorough history and physical examination can provide important clues to the presence of rv failure, including the presence of a right-sided third heart sound, elevated jugular venous pressure, ascites and peripheral edema. a prominent pulmonic component of the second heart sound (p ) indicates the presence of ph. patients may report early satiety, abdominal fullness and fatigue. hepatic function and renal function are often compromised, and should be followed regularly in a patient with rv failure. imaging studies play a crucial role in the initial assessment and serial monitoring of rv function. echocardiography is the most frequently used imaging modality for rv assessment due to its ease of use, low cost and accessibility. however, cmri has become the gold standard for evaluation of the rv because of its ability to overcome some of the anatomic limitations of twodimensional ( d) echocardiography. while both echocardiography and cmri can provide some assessment of rv hemodynamics, invasive measurement of intracardiac pressures by right heart catheterization is often required to diagnose the etiology of rv failure and determine the appropriate therapeutic approach. rv size and function can be assessed with radionuclide ventriculography, using either first-pass or gated equilibrium techniques. while accurate measurements of volume and rv ejection fraction (rvef) can be derived, this modality does not provide additional anatomic information, and exposes patients to radioisotopes. with the widespread availability of echocardiography, radionuclide ventriculography is rarely indicated as the primary method for rv functional assessment in the current era. d echocardiography has excellent spatial and temporal resolution, enabling precise evaluation of rv anatomy and valvular function. rv dimensions can be obtained through multiple views, providing an estimate of rv size. however, due to the rv's anatomic configuration, the calculation of accurate rv volumes with d echocardiography is not possible. qualitatively comparing rv size to lv size in the apical view can provide a reasonable assessment of rv dilatation. additional anatomic information that can be easily obtained is the appearance of the tricuspid and pulmonary valves, and the presence of valvular stenosis or regurgitation. doppler evaluation of the tricuspid regurgitant jet allows the estimation of the systolic pulmonary artery pressure through the use of the modified bernoulli equation. important information is also provided by the appearance of the interventricular septum in the short-axis views. pressure overload states cause flattening of the septum, particularly during systole, which volume overload states cause flattening during diastole (fig. . ). with increasing pressure or volume overload, the septum is further shifted into the lv, leading to the hemodynamic effects of ventricular interdependence discussed previously. rv function is challenging to determine with d echocardiography due to the lack of accurate ventricular volumes and the sensitivity of the rvef to loading conditions. visual assessment is the most commonly used technique but may be limited due to the complex shape of the rv. multiple techniques are available for quantitative measurement of rv function. rv fractional area change (rvfac) measures the change in area of the rv between diastole and systole from the apical -chamber view. the tricuspid annular plane systolic excursion (tapse) measures the vertical motion of the tricuspid valve annulus, with a value of less than . cm indicating rv dysfunction. rvfac and tapse are both load-independent, and may provide varying information under different hemodynamic conditions. the rv index of myocardial performance (rimp), also known as the tei index, is less influenced by loading conditions, and may be a more accurate measure of underlying rv contractility [ ] . this index is measured with doppler of flow through the rv outflow tract, and is calculated as the sum of rv isovolumic contraction time and rv isovolumic relaxation time divided by ventricular ejection time. recent advances in cmri have established it as the best modality for obtaining accurate information about rv size and function. cmri is not affected by the anatomic limitations that prevent d echocardiography from obtaining a complete picture of the rv. cmri has excellent spatial and temporal resolution, permitting accurate assessment of rv volumes throughout the cardiac cycle. additionally, cmri provides information on ventricular hypertrophy, the presence of infiltrative diseases and the presence of fibrosis. for complex congenital heart disease, cmri offers substantial advantages over d echocardiography for assessment of rv anatomy and function prior to and following surgical interventions. barriers to more widespread application of cmri in evaluation of the rv include the time required for testing, the cost of cmri technology, and the need for technical expertise. most importantly, cmri is not compatible with most implantable cardiac devices, such as pacemakers, although the ongoing development of devices compatible with the magnetic field will allow for a broader application of cmri in the assessment of rv failure [ ] . right heart catheterization (rhc) is a critical component of rv assessment, particularly in patients with ph. measurement of the right atrial pressure (rap), pa pressure and pulmonary capillary wedge pressure (pcwp) can distinguish the etiology of rv failure and help determine the therapeutic approach (table . ). the most important information provided by rhc is about ph, which has been classified into groups by the world health organization: • group i incorporates pah, which may be idiopathic, familial or associated with specific entities such as congenital heart disease, collagen vascular disease, hiv infection or toxins • group ii includes ph that is found in conjunction with left heart disease and is the most common form of ph • group iii includes ph associated with lung disease or hypoxemia • group iv is ph due to chronic thromboembolic disease • group v is a miscellaneous category a rhc can assist in the diagnosis of pah, by identifying ph in the presence of normal left-sided filling pressures. while left heart disease is often manifested on imaging studies by a reduced lv ejection fraction or mitral valve disease, rhc can identify elevated pcwp in the absence of valvular disease or lv dysfunction (heart failure with preserved ejection fraction). distinguishing the underlying etiology of ph will direct the choice of therapy, as therapies that have proven benefit in some forms of ph have been shown to be harmful in ph related to left heart disease [ ] . beyond anatomy, rhc provides information about the severity of rv failure. for example, the rap is typically about % of the pcwp [ ] . as rv failure progresses, the rap will approach or exceed the pcwp. another sign of worsening rv failure is a decrease in the pa pressure despite a rising rap due to insufficient power generation by the rv. another key variable obtained during right heart catheterization is the transpulmonary gradient (tpg), which is the difference between the pcwp and the mean pa pressure. this takes on importance in the assessment of ph due to left heart failure (i.e. patients with a pcwp > mmhg). when the pcwp is elevated, but the tpg is less than - mmhg, ph is termed "passive" or "post-capillary", indicating that the elevation in pa pressures can be solely attributed to the elevated left-sided filling pressures. when the tpg is greater than mmhg, the ph is termed "mixed" indicating that there is both a pre-capillary and post-capillary component of the ph. this may be secondary to vasoconstriction and pulmonary arterial remodeling as a response to chronically increased pulmonary venous pres- sures. mixed ph can be further stratified into "reactive" and "nonreactive" forms through administration of a vasodilator, such as sodium nitroprusside or milrinone, to reduce the pcwp. in non-reactive ph, the tpg will remain elevated despite a lower pcwp, whereas patients with reactive ph will have concurrent decreases in the pcwp and tpg. the presence of reactive ph may indicate a more favorable prognosis, particularly when considering a patient for advanced therapies such as cardiac transplantation [ ] . whether patients with either reactive ph or nonreactive ph will benefit from selective pulmonary vasodilators is a subject of ongoing investigation. when world health organization group i pah is present, the administration of selective pulmonary vasodilators, such as nitric oxide or epoprostenol, provides both prognostic and therapeutic information. patients in whom the mean pa pressure drops by more than mmhg to a value less than mmhg without a reduction in cardiac output have an excellent prognosis, and typically respond well to calcium-channel blockers [ ] . non-responders have a worse prognosis, but still get a therapeutic benefit from selective pulmonary vasodilators. finally, rhc enables the calculation of the pvr, which provides a good estimate of rv afterload. pvr is both a prognostic factor, as well as a therapeutic target, that takes on considerable importance in the assessment of a patient's appropriateness for cardiac transplantation. a pvr > woods units is considered a relative contraindication to transplantation unless it can be lowered with medical therapy or mechanical circulatory support [ ] . frequency-domain analysis is an investigational method that accounts for the pressure wave reflected backwards into the main pa during late systole, and may provide a more accurate assessment of rv afterload [ ] . rv dysfunction plays a defining role in the pathogenesis of multiple diseases, ranging from left-sided hf to congenital heart disease to ph. in each of these entities, rv failure is the culmination of chronic pathophysiological disturbances, and often marks the transition to an advanced disease state. numerous investigations have connected markers of rv dysfunction to adverse outcomes (table . ). in chronic hf with lv dysfunction, rvef, as measured by radionuclide ventriculography, invasive hemodynamics or cmri, has been correlated with exercise capacity [ , ] , ventilatory efficiency [ ] , and survival [ ] [ ] [ ] [ ] [ ] [ ] . this association has been demonstrated in both ischemic and nonischemic cardiomyopathies [ , , ] . importantly, there appears to be an additive effect of ph and rv dysfunction, leading to worse outcomes than the presence of either ph or rv dysfunction alone (fig. . ) [ ] . other imaging parameters that have been associated with outcomes in chronic hf include cmri-derived rv volumes [ ] , tapse [ ] [ ] [ ] and rimp [ ] . similar findings have been demonstrated in rv dysfunction due to pah [ ] [ ] [ ] [ ] [ ] and congenital heart disease [ , ] . the initial approach to rv failure relies on identifying and correcting the underlying etiology. as opposed to the lv, in which dysfunction is often irreversible, the rv is highly pliable, and typically regains function after the causative factors table . selected studies of the association of right ventricular dysfunction with adverse outcomes [ - , , - , , , - ] population findings studies using radionuclide ventriculography baker et al. [ ] pts. with symptomatic lv failure rvef associated with peak vo lvef not associated with peak vo lewis et al. [ ] pts. with symptomatic lv failure exercise rvef and pvr associated with v e /v co slope di salvo et al. [ ] pts. referred for oht evaluation rvef > % predictor of survival studies using rhc/thermodilution gavazzi et al. [ ] pts. referred for oht evaluation rvef lower in pts. who died or had oht ghio et al. [ ] pts. with lvef < % and nyha class iii-iv rvef and pap predictors of survival. damy et al. [ ] pts. referred for hf low tapse predictor of mortality harjai et al. [ ] pts. with lvef< % rimp > . predictive of death forfia et al. [ ] pts. with idiopathic pah tapse < mm associated with mortality ghio et al. [ ] inpatients with idiopathic pah rv diameter > . mm associated with mortality yeo et al. [ ] pts. with idiopathic pah rimp independent predictor of death moceri et al. [ ] pts. with eisenmenger syndrome tapse, rimp and elevated cvp strongest predictors of mortality studies using cmri larose et al. [ ] pts. post-mi rvef < % independent predictor of mortality bourantas et al. [ ] pts. with lvef < % rvesv predicts mortality; lvesv does not predict mortality van wolferen et al. [ ] pts. with idiopathic pah rv dilation, low rv stroke volume and decreased lv filling predict mortality knauth et al. [ ] pts. followed up at mean of . years after tof repair severe rv dilation predictor of death, vt, advanced nyha class cmri cardiac magnetic resonance imaging, hf heart failure, lv left ventricle, lvef left ventricular ejection fraction, lvesv left ventricular end systolic volume, mi myocardial infarction, nyha new york heart association, oht orthotopic heart transplantation, pah pulmonary arterial hypertension, pap pulmonary artery pressure, pvr pulmonary vascular resistance, rimp right ventricular index of myocardial performance, rv right ventricle, rvef right ventricular ejection fraction, rvesv right ventricular end systolic volume, tapse tricuspid annular plane systolic excursion, tof tetralogy of fallot, v e /v co ratio of minute ventilation to production of carbon dioxide, vt ventricular tachycardia of rv dysfunction are addressed. this is especially important in acute rv failure, where reversing the underlying disease state may drastically alter a patient's outcome. for example, coronary revascularization for an rvi reduces rv dysfunction, hemodynamic compromise and increased mortality [ ] . likewise, for an acute pe, rapid relief of the thrombotic burden through medical or surgical intervention produces a substantial survival benefit [ ] . causes of chronic rv failure are not as easily corrected, although rv function improves over time with therapy that is appropriately targeted at the underlying pathophysiology. ultimately, managing both acute and chronic rv failure requires an understanding of the roles played by preload, afterload and contractility. a management algorithm is shown in fig. . . optimizing rv performance requires adequate preload to generate a sufficient stroke volume without causing a degree of rv distention that impairs lv performance through ventricular interdependence. the ideal preload required may differ between patients and will rely on both the degree of rv contractility and the severity of rv afterload. in patients with acute rv failure, central venous monitoring can guide decision-making about the volume status. patients with rvi are often described as "volume-sensitive", and may require higher preloads to maintain cardiac output. however, too much volume may have deleterious consequences because rv dilation will increase wall stretch, worsen ischemia and cause septal shifting. although mechanical ventilation is sometimes necessary in the management of patients with acute rv failure, its use should be minimized due to the adverse effects of positive end-expiratory pressure on preload. in chronic rv failure, the focus is typically on volume removal, which is primarily achieved with loop diuretics. selecting an agent with better oral bioavailability, such as torsemide, may be preferred in the setting of rv failure due to the possibility of intestinal edema and poor absorption. thiazide diuretics can be added as needed to enhance diuresis. as with lv dysfunction, sodium and fluid restriction afterload reduction is a critical component of the management of most causes of rv failure. addressing afterload is of particular urgency in acute rv failure due to the inability of the rv to compensate for acute changes in afterload. persistently low oxygen saturations should be addressed with supplemental oxygen to alleviate hypoxia-induced vasoconstriction. if mechanical ventilation is required, tidal volumes should be minimized to prevent further augmentation of pa pressures. pulmonary vasodilators relax pulmonary vascular smooth muscle, lowering pa pressures and pvr. inhaled nitric oxide (ino) has the advantages of pulmonary selectivity, avoiding the hypotension associated with systemic vasodilators. it is also only active in ventilated areas of the lung, reducing the potential for v/q mismatching. ino is most commonly used in acute rv failure due to difficulty in administration to non-ventilated patients. short-term hemodynamic improvements have been demonstrated with the use of ino in the treatment of rvi [ ] and in a study of intensive care patients with mixed causes of rv failure [ ] , but outcomes data are limited. transitioning from ino to oral vasodilators may prevent rapid rebound of pa pressures on discontinuation. inhaled prostacyclins may be used as an alternative to ino, although they have been less extensively studied. in chronic rv failure, therapy depends on the underlying mechanism of the elevated pa pressures. in pah, there are three classes of vasodilators that have shown clinical benefit: prostacyclins, endothelin receptor antagonists (eras) and phosphodiesterase- inhibitors (pde- is). as mentioned previously, a small subset of pah patients will respond to calcium-channel blockers, and may not require any further treatment. outside of this subset, most pah patients will be started on oral therapy with an era or pde- i. as the disease progresses, these patients may need to be transitioned to intravenous prostacyclin therapy. patients who present with severe symptoms, such as syncope, often require intravenous prostacyclin therapy from the outset. when rv failure is due to post-capillary ph (i.e. lv dysfunction or valvular disease), the initial therapeutic target is the pcwp, which should be lowered into the normal range if possible. if the ph is reactive, lowering the pcwp should also reduce pa pressures and pvr. however, if pvr remains elevated, consideration should be given to pulmonary vasodilator therapy. sildenafil citrate, a pde- i, has shown benefits on hemodynamics and functional status in patients with left-sided heart failure [ ] [ ] [ ] . a large trial to assess outcomes of patients with ph related to lv dysfunction is underway. neither eras nor prostacyclins should be used for post-capillary ph due to adverse outcomes in clinical trials [ , ] . in acute rv failure, inotropes are often required to support the rv until the etiology can be treated. milrinone may be the preferred agent due to its vasodilatory properties in the pulmonary vasculature, but its use is limited in patients with significant hypotension. dobutamine and dopamine are more likely to cause tachycardia, which may exacerbate ischemia in the setting of an rvi. in some cases of rvi, mechanical support with an intraaortic balloon pump or a temporary right ventricular assist device (rvad) has been used, although neither of these approaches has been well studied. temporary rvads have also been used to treat rv failure that occurs following cardiovascular surgery or cardiac transplantation. for chronic rv failure, choices for augmenting contractility are limited. digoxin is often used as an inotrope in the management of rv failure, based on its short-term hemodynamic benefits in patients with pah [ ] . the use of intravenous inotropes for chronic left heart failure has been associated with worse outcomes. intravenous inotropes may be used for management of exacerbations of chronic rv failure, but the chronic administration of these agents has been associated with worse outcomes. when biventricular heart failure is refractory, a rvad may be placed in conjunction with a left ventricular assist device (lvad) as a means of bridging a patient to transplantation. the devices that are approved for rv support are extracorporeal (i.e. non-implantable) and are not meant for long-term support, although the development of more durable rvads is ongoing. in some cases, these devices can be explanted once stable lvad support has been established. cardiac transplantation is a definitive treatment for patients with advanced rv failure that is associated with lv failure, but this therapy is limited in use due to a shortage of donor organs. cardiac transplantation should not be attempted in patients with high pvr (> woods units) due to high risk for rv failure and graft loss postoperatively. the onset of rv failure carries a poor prognosis in multiple diseases and is often a marker of a progression to an advanced disease state. rv failure is the end result of a series of pathophysiological adaptations that are distinct from the pathogenesis of lv failure. a detailed understanding of the rv's response to specific disease states informs the clinical management of those diseases. imaging plays a critical role in the assessment of rv dysfunction, and can provide information about the severity of rv failure. hemodynamic assessment with cardiac catheterization complements the findings from imaging, directing the appropriate therapeutic approach. the treatment of rv failure due is highly dependent on the underlying etiology. acute causes respond best to removal of the offending pathophysiology. chronic rv failure requires a targeted approach, as has been applied in the setting of pah. research continues into the optimal treatment strategy for ph that is secondary to left heart failure. the absence of conspicuous increments of venous pressure after severe damage to the right ventricle of the dog, with a discussion of the 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size and function assessed by cardiac mri predict major adverse clinical outcomes late after tetralogy of fallot repair effect of reperfusion on biventricular function and survival after right ventricular infarction management of massive pulmonary embolism hemodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock response to inhaled nitric oxide in patients with acute right heart syndrome sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase- inhibition in a -year study clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension--a multicenter randomized study the short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension key: cord- -nff gfik authors: tanner, tristan george; colvin, mai o. title: pulmonary complications of cardiac surgery date: - - journal: lung doi: . /s - - - sha: doc_id: cord_uid: nff gfik cardiothoracic surgery posits an arrangement of large, significant hemodynamic, and physiologic alterations upon the human body, which predisposes a patient to develop pathology. the care of these patients in the postoperative realm requires an astute physician with deep understanding of the cardiopulmonary system, who is able to address subtle developing problems promptly, before the patient suffers further sequelae. in this review, we describe the presentation and management of an assortment of important complications which occur in the pulmonary system. in addition, we aim to shed better light upon how the physiology of a patient responds to the condition of cardiothoracic surgery. cardiac surgery is a high-risk field requiring specialized teams to manage patients in the perioperative and postoperative environment. the pulmonary system, exquisitely related in both spatial proximity and synergistic function, requires close attention and support during cardiac surgery's acute stress. pulmonary complications are common in patients who undergo cardiac surgery with outcomes such as pneumonia, pulmonary embolism, ventilation longer than h, and pleural effusions necessitating drainage being reportable to the society of thoracic surgeons [ ] . pulmonary complications after cardiac surgery result in prolonged hospital stay and increase in healthcare cost [ ] . patients prone to complications tend to have limited homeostatic reserve associated with chronic heart failure, pulmonary illness, multiple comorbidities, older age, or have completed more invasive and longer duration surgeries [ , ] . as the field continues to advance medical acumen, we seek to protect the pulmonary system better. cardiac surgery commonly uses cardiopulmonary bypass (cpb), which provides advanced physiologic support with an extracorporeal circulatory device. depending on the type of cardiac surgery, the lungs experience up to several hours of relative ischemia during bypass. under normal physiology, blood is delivered to the lungs by both pulmonary and bronchial arterial systems which share collateral circulation. during bypass, perfusion is solely provided to the bronchial system, placing the lungs in a relative state of ischemia. upon cessation of bypass, reperfusion of the lungs occurs after reinstatement of pulmonary arterial flow. in addition, bronchial arterial flow on bypass paradoxically decreases, contributing to worsening low flow ischemia, which normalizes after pulmonary arterial clamping ends [ ] . this environment generates ischemia-reperfusion injury with a proinflammatory/proapoptotic state, characterized by reduced microvascular permeability, increased arteriolar resistance with pulmonary hypertension, and pulmonary edema with impaired gas exchange. these physiological changes generate an overall predisposition to develop pulmonary complications [ ] . several changes in intraoperative care have been studied aiming to alleviate pulmonary ischemia/reperfusion. bronchial arterial flow during bypass is continuous. adding pulsatile flow to the extracorporeal output did not improve pulmonary outcomes, but parallel continuous pulmonary arterial cold perfusate infusion attenuated pulmonary ischemia-reperfusion injury [ , ] . this may preferentially benefit patients with pulmonary conditions like copd [ ] , but this practice is not standard of care and would require further study. ischemia-reperfusion injury affects the intravascular compartment adjacent to pulmonary microcirculation, causing no-reflow phenomenon. no reflow was initially coined in coronary vasculature during atheroembolism. with diminished flow and concurrent ischemia to local endothelial and interstitial tissue, cells of the vessel wall swell and protrude into the lumen, obstructing flow [ ] . activated neutrophils and platelets also likely trap red blood cells to obstruct microcirculation, causing persistent vascular insufficiency after reperfusion [ , ] . other strategies to limit lung injury during cpb are being studied and remain active areas of research. some suggested strategies include introducing prophylactic steroids to reduce the inflammatory cascade associated with cpb [ ] , biocompatible circuits to mimic endothelial surface [ ] , and leukocyte filters to preferentially remove activated leukocytes [ ] . continuous heparin infusion is maintained during cpb, with activated clotting time (act) kept within therapeutic range to offset thrombosis within the extracorporeal circuit. a primary reason for using heparin is that it is rapidly reversed with protamine sulfate, an alkaline polypeptide which reacts with the acidic heparin to generate neutral inert salt. on occasion, protamine-heparin complexes can induce nonimmunogenic anaphylaxis (anaphylactoid reactions, with classic complement activation and degranulation of mast cells), which is less severe with lower protamine dose and slower infusion rate [ ] . series report this complication in . - . % of patients, with clinically significant pulmonary reactions to protamine, including wheezing/bronchospasm, pulmonary hypertension, and noncardiogenic pulmonary edema, with worsening mortality [ ] . this protamine reaction likely exists on a spectrum. it more commonly presents subclinically with small decreases in systemic arterial pressure and increased pulmonary artery pressure noted by the operative team after use. these minor reactions, even when isolated and adjusted for preoperative and intraoperative risk factors, were associated with increased inpatient mortality [ ] . management of the protamine reaction is supportive, although patients with severe anaphylaxis are sometimes re-heparinized and temporarily placed back on cpb [ ] . managing multifactorial coagulopathy is a large component of bypass care during cardiac surgery, and venous thromboembolic disease associated with the venous access cannula (and embolization into the pulmonary circulation) is a rare, catastrophic complication during cardiac surgery. the circulation during cardiac surgery is in a focally static state with endothelial injury, fulfilling virchow's triad. williams et al. [ ] compiled cases of acute intracardiac thrombosis and pulmonary embolism after cpb. common features among these cases included congestive heart failure ( %), platelet transfusion ( . %), cpb duration > h ( . %), and aortic injury ( . %). thrombolytic therapy was only used in out of cases but efficacy was unclear, given frequent use of the antifibrinolytic protamine sulfate therapy ( . % of cases). intracardiac thrombosis with pulmonary embolism can present with profound refractory hypotension and biventricular failure during or after separation from bypass. one case presented with cardiac arrest after protamine administration. . % of cases were diagnosed with transesophageal echocardiography. treatment has typically been to reestablish cpb ( . %) and perform thrombectomy ( . %). this generally required additional mechanical support devices, culminating in an . % mortality rate. cardiac surgery is invasive and frequently requires therapeutic anticoagulation during cpb, which commonly requires allogeneic blood transfusion [ ] . an estimated - % of the collective blood donor supply is utilized during cardiac surgery. with restrictive transfusion strategy, over % of the patients receive perioperative transfusion [ , ] . while the chance of clinically significant microbial contamination is equal to being struck by lightning, transfusion-related acute lung injury (trali) is the primary adverse event and most common cause of death from blood transfusion worldwide [ ] . trali is defined as acute onset of hypoxia and bilateral pulmonary infiltrates after allogeneic blood transfusion that is difficult to distinguish from alternative causes of acute lung injury. the condition is more prominent in cardiac surgery patients than in other transfused groups in the inpatient setting [ ] . this condition, mediated by donor antibodies directed against host leukocytes, is thought to unfold in a "two hit" manner. the first hit involves systemic inflammatory activation in the host, activating endothelial cells within the lung to induce neutrophil sequestration. the second hit involves preformed donor alloantibodies reacting with these neutrophils to induce an inflammatory cascade that injures the pulmonary interface [ , ] . cpb is associated with neutrophil activation and inflammatory response, which may prime the environment for trali to occur [ ] . treatment is discontinuation of the inciting transfusion and supportive care. reduction in the frequency and amount of blood products transfused is beneficial, but even small sub - cc volumes of plasma have been shown to induce trali [ ] . use of a restrictive transfusion threshold for moderate-to high-risk cardiac surgery patients, even when controlled for chronic pulmonary disease, shows equivalent cardiac outcomes while allowing us to transfuse less patients and avoid this complication [ ] (table ) . atelectasis is a common cause of hypoxemia and impaired gas exchange after cardiac surgery. atelectasis is seen in - % of postoperative chest radiographs after cardiac surgery and is a major contributor to the postoperative respiratory dysfunction [ , ] . nearly all patients with general anesthesia develop atelectasis while spontaneously breathing and after muscle paralytics are administered, regardless of the use of intravenous or inhalational anesthetics [ ] . in an animal study, cardiopulmonary bypass produced large atelectasis with a corresponding increase in intrapulmonary shunt and decrease in pao [ ] . in the same study, animals who had sternotomy without cpb only had minor atelectasis in comparison. in another study using computed tomography (ct) scans to assess the degree of atelectasis in patients who underwent cabg and mvr, the area of atelectasis was considerably larger than previously seen if the patient underwent additional abdominal and lower extremity surgery on the first day after operation [ ] . the amount of atelectasis and shunt was similar in patients who had undergone mvr or cabg open surgeries [ ] . other postoperative factors worsening atelectasis include diaphragmatic dysfunction due to phrenic nerve injury, inadequate pain control, and immobilization. treatment of atelectasis includes frequent chest physiotherapy, incentive spirometry, encouraging pulmonary hygiene, as well as noninvasive ventilation and high-flow nasal cannula [ , ] . postoperative pleural effusions in cardiac surgery can have a broad range of etiologies and should be approached with care and heightened attention. thorough clinical history and pleural fluid analysis is often required to delineate the origin. timing is a key component of an effusion's etiology. early effusions (the initial postoperative days) are typically hemorrhagic, neutrophil predominant, and associated with operative trauma. later effusions tend to be lymphocyte predominant and autoimmune in etiology [ ] . after cabg, effusions are associated with low bmi, female gender, history of atrial fibrillation, history of heart failure, concurrent valve replacement, and history of anticoagulation [ ] . postoperative pleural effusion is the second most common cause of readmission in a cabg patient ( . % of patients), and the need for thoracentesis is a poor prognostic sign [ , ] . a benign, self-resolving pleural effusion can often present after harvesting the left internal thoracic artery [ ] , but harvesting of the internal mammary artery does not share the same association [ ] . pleural effusions after cardiac surgery also often represent a limited or complete presentation of postpericardiotomy syndrome. postpericardiotomy syndrome is a spectrum of pathology following cardiac surgery in approximately % of cases [ ] . while traditionally defined as pericarditis following cardiac surgery, it has evolved to define a (likely) autoimmune response to both pleural and pericardial interfaces after direct damage or entry of blood into the pericardium [ ] . in fact, isolated intraoperative pleural incision predicts development of this complication, with hazard ratio of . on one series [ ] . the clinical presentation usually includes of the following: fever without an infectious source, pleuritic chest pain, new pleural effusion, pericardial friction rub, or persistent pericardial effusion several weeks after surgery. over % of postcardiotomy syndrome cases have pleural involvement and development of effusion [ , ] , and a late atypical presentation can be with an isolated pleural effusion [ ] . the pleural fluid is typically exudative, % showing > , erythrocytes and lymphocytes > % [ ] . the syndrome was also shown to produce similar clinical presentation and fluid qualities, regardless of whether a patient was post-cardiac surgery or post-pacemaker placement [ ] . postcardiotomy syndrome-related effusions have strong predilection for the left hemithorax; % are left-side predominant, % are unilateral (> % unilateral and left sided), and % of the effusions are noted to fill greater than ½ of the affected hemithorax [ , ] . treatment of the syndrome is typically with nsaids and colchicine, and therapeutic thoracentesis should be promptly offered to those with moderate and large effusions. therapeutic thoracentesis significantly affects physical recovery rate through days mean walking distance, which is associated with reduced postoperative cardiovascular events [ ] [ ] [ ] . as discussed earlier, cardiac surgery is commonly associated with postoperative blood loss, often collected in the pericardial and pleural systems. acute-retained blood manifests with hemothorax and gross blood drainage through thoracostomy tube, which is prone to coagulate within the chest cavity or the chest tube lumen and make the situation less amenable to nonoperative drainage. subacute-retained blood presents as pleural effusion, with drainage appearing more as liquefied blood-containing pleural fluid than frank blood. chronically retained blood can manifest with fibrothorax, an outcome of prolonged inflammatory states of the involved serous membranes, which eventually deposit dense adhesive fibrotic tissue [ , ] . this continuum of complications is called retained blood syndrome, which negatively impacts hospital and -day mortality in cabg patients, prolongs icu stay, prolongs the duration of mechanical ventilation, and increases the incidence of stroke (particularly when intervention is required) [ , , ] . risk factors for postoperative bleeding in cardiac surgery patients include advanced age, low body weight, nonelective surgery, cpb time over min, high complexity of procedure, perioperative use of antiplatelet agents, and use of over bypass grafts [ ] . incidence has been estimated to be . - . % [ ] . concurrently with pleural effusions and retained blood products, there should always be concern for pulmonary infection, discussed next. the left and right phrenic nerves originate from c , c , and c within the cervical spine, moving caudally within the thorax alongside the great vessels (particularly the subclavian arteries) and pericardium bilaterally. eventually these nerves pierce the two diaphragmatic domes, relaying sensory and motor innervation. in addition, these nerves receive sensory innervation from the pericardium and the mediastinal portion of the parietal pleura. the phrenic nerves are key components to maintain successful independent respiratory function. surgical injury typically causes complete unilateral suspension of diaphragmatic function, commonly while the surgeon dissects near the internal thoracic artery [ ] . in addition, prior studies have shown that phrenic nerve injury is associated with cold-induced injury during myocardial protection strategies [ , ] . the incidence of phrenic nerve injury is unclear, with studies citing between and %, likely owing to the sensitivity of diagnostic testing [ ] . diaphragmatic dysfunction generates paradoxical diaphragmatic movement or grossly reduced diaphragmatic excursion, which can be visualized through liver and splenic windows with bedside ultrasonography. diaphragmatic atrophy is also noted with prolonged paralysis, depicted as a diaphragmatic thickness below . cm at end expiration. other ultrasound modalities used include diaphragmatic thickening and diaphragmatic excursion fraction to assess function [ ] . management of diaphragmatic dysfunction typically requires supportive care, while addressing potential differential causes. many patients fully recover the nerve function over time [ ] . debilitating cases of diaphragmatic paralysis with paradoxical diaphragmatic motion have been treated with early tracheostomy as it is felt to lessen the severity of pulmonary complications [ ] . healthcare-associated infection is one of the leading causes of non-cardiac morbidity after cardiac surgery, with pneumonia being the most common, costly, and resource-intensive infectious complication [ , ] . . - % of patients develop pneumonia after cardiac surgery, % of which occur after discharge [ , ] . ventilator-associated pneumonia also becomes problematic in postoperative patients experiencing prolonged mechanical ventilation, complicating . % of patients who remain intubated for over h [ ] . in a prospective cohort trial observed patients in centers, ailawadi et al. worked to categorize postoperative pneumonia and clinical outcome [ ] . risk factors isolated included known copd, older age, current steroid use, low hemoglobin level perioperatively, longer duration of surgery, and the involvement of lvad insertion or heart transplant. measures found which may protect against development of this complication include perioperative use of second-generation cephalosporins, under h on the ventilator, avoiding the use of a nasogastric tube perioperatively, restrictive transfusion of packed rbcs, and use of few platelet transfusions. most common isolated organisms, in order of frequency, included pseudomonas, klebsiella, then enterobacter cloacae. finally, postoperative pneumonia showed a ninefold increase in mortality and weeks increase in hospital length of stay [ ] . chlorhexidine oral care has also been shown to reduce ventilator-associated pneumonia in postoperative patients, also beneficial when administered to preoperative patients as well [ ] . in addition to preventative therapies, it is important to have standardized postoperative care to promote aggressive pulmonary toilet and mobilization. postoperative pneumonia is reduced when the head of bed is kept elevated. the patient should be given ample motivation to leave the bed for the chair (particularly during mealtime) and to ambulate (even in the post-anesthesia care unit). patients should be encouraged to perform frequent deep breathing and use incentive spirometry [ ] . patient education throughout the process is key, allowing the patient and his/her loved ones to become actively involved in their recovery. the most significant postoperative pulmonary complication is acute respiratory distress syndrome (ards), which is predominantly proinflammatory injury to the alveolar interface, characterized by a constellation of diffuse endothelial injury, severe hypoxia, and pulmonary edema not predominantly of cardiogenic origin [ ] . preoperative risk factors for ali/ards development include age > , history of copd, current or recent smoking, history of previous heart surgery, nyha iii/iv congestive heart failure, liver cirrhosis, and multiple recent transfusions. operative risk factors include low cardiac output syndrome, more than u of packed rbcs (or massive transfusion), isolated valve surgery, and development of postoperative pneumonia [ , ] . there is a multifactorial pathogenesis to this condition that overwhelms homeostasis in the pulmonary microcirculation. in addition to the previous conditions described thus far, which place injurious stress on the alveolar interface, additional stressors can include reduced respiratory function due to general anesthesia (causing impairment of vital and functional residual capacities) or other surgical factors (sternotomy, pleural dissection due to internal mammary utilization, cpb, and ischemia-reperfusion injury) [ ] . although there is paucity of information on optimal perioperative mechanical ventilation in these patients, recent data show an improved complication profile with intraoperative lung protective ventilation. this bundle emphasized keeping tidal volume below ml/kg ideal body weight, peep greater or equal to cm h o, and actively aiming to keep modified driving pressure (a surrogate for lung compliance, defined as peak inspiratory pressure minus peep) at a value lower than cm h o [ , ] . open lung strategies during cpb, defined as the provision of low tidal volumes and high peep (typically ), along with frequent use of recruitment maneuvers, did not improve postoperative pulmonary outcomes [ , ] . cpb time, restrictive transfusion, careful sternotomy with preservation of pleural integrity, and fluid restriction have been other potentially helpful preventative interventions described [ ] . mediastinal and pleural drains are routinely inserted following cardiac surgery to evacuate the postoperative bleeding, fluids, and air from the mediastinum or pleural cavities. these drains are usually removed when fluid output is minimal, accompanied by stable cardiac and respiratory status. recurrent pneumothorax with tension physiology following discontinuation of a thoracic cavity drain is a most significant and life-threatening complication. it occurs due to a one way communication between lung parenchyma and the pleural cavity leading to air entrapment in the pleural cavity. a large retrospective study looking at patients undergoing various cardiac surgical procedures showed that an overall incidence of recurrent pneumothorax after chest tube discontinuation to be approximately . % [ ] . patients should be clinically monitored closely for development of respiratory difficulty following chest tube removal. chest x-ray and/or bedside ultrasound are useful modalities to look for a pneumothorax. while routine use of the pulmonary artery catheter became less prevalent over the previous decades, it still holds a central role in the postoperative care of cardiac surgery patients. most of these catheters are placed in the operating room and remain in place to guide therapy during early recovery. complications involved with the pulmonary artery catheter are rare, but tend to be devastating. the most feared complication is rupture of the pulmonary artery, which can occur during or following catheter insertion. one series describes the incidence of pulmonary artery rupture at . %. it presents with hemoptysis, acute pulmonary hypertension in % of patients, and carries a mortality rate of % [ ] . ruptures with massive hemoptysis or signs of developing hemothorax typically require emergent thoracotomy. delayed hemoptysis following pulmonary artery catheter placement can be associated with catheter-associated pulmonary artery pseudoaneurysm, which start as a collection of blood between the tunica media and adventitia and progressively expands before rupturing [ ] . treatment includes vessel ligation, wedge resection, lobectomy, embolization, stenting, and watchful waiting [ ] . other complications to watch for carefully include pulmonary infarction (when the balloon of the catheter is inflated for a prolonged amount of time or the uninflated catheter tip migrates into distal branches of the pulmonary artery) and pulmonary embolism (when the catheter presents a foreign body nidus for inflammation and infection, accompanied by thrombosis) [ ]. as the lungs are closely interdependent with the heart, adequate pulmonary support and monitoring are paramount in the care of a post-cardiac surgery patient. it is important that the cardiothoracic intensivist remains vigilant with regard to the unique pulmonary challenges faced in the cardiac 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strategies on postoperative pulmonary complications after on-pump cardiac surgery: the provecs randomized clinical trial a perioperative surgeon-controlled open-lung approach versus conventional protective ventilation with low positive end-expiratory pressure in cardiac surgery with cardiopulmonary bypass (provecs): study protocol for a randomized controlled trial protective invasive ventilation in cardiac surgery: a systematic review with a focus on acute lung injury in adult cardiac surgical patients post pull pneumothorax following cardiac surgery pulmonary artery rupture associated with the swan-ganz catheter pulmonary artery pseudoaneurysm: etiology, presentation, diagnosis, and treatment pulmonary artery catheterization key: cord- -mljywm p authors: jain, amisha; sami-zakhari, iman r. title: pulmonary complications of obstetric and gynecologic conditions date: - - journal: pulmonary complications of non-pulmonary pediatric disorders doi: . / - - - - _ sha: doc_id: cord_uid: mljywm p the respiratory and the female reproductive systems are not embryologically or functionally related. however, the reproductive system can exert significant effects on the respiratory system as a result of the various hormonal changes that occur during a woman’s menstrual cycle and especially during pregnancy. in addition, there are several unique gynecologic and/or obstetric conditions that can directly affect the respiratory system. the following chapter reviews the effects of pregnancy on the respiratory system, as well as the special issues concerning the management of common respiratory conditions (e.g., pneumonia, asthma) during pregnancy. in addition it reviews several gynecologic disorders with unique pulmonary complications. a fundamental difference between the female reproductive system compared with virtually every other organ system in the body is that it goes through significant changes on a regular basis during the woman's healthy menstrual cycle and not only in a state of disease as is the case for virtually any other organ system. even more significant are the changes that occur during pregnancy when the entire body changes to accommodate the developing fetus. although none of these changes are directly related to the respiratory system, they do exert a significant effect in the mechanics of breathing. thus, the physician who cares for a woman with respiratory symptoms has to consider if and to what extent they are caused, complicated, or exacerbated by an underlying gynecologic or obstetric condition. this chapter focuses on the normal alterations in pulmonary physiology during pregnancy and how it may affect the natural history of specific respiratory diseases and of course how the respiratory disease may affect the pregnancy outcome. lung disorders related to gynecologic conditions are also described. profound physiological changes occur in both the pulmonary and cardiovascular systems during pregnancy. understanding these changes and how they may affect other underlying disorders helps in the management of respiratory disease during pregnancy. in the upper respiratory tract, edema of the nasal mucosa resulting in symptoms of rhinitis ("rhinitis of pregnancy") has been reported in as many as - % of pregnant women. it characteristically appears during the last weeks of pregnancy in the absence of any infectious or allergic trigger, and it completely resolves within - weeks after delivery. its exact cause is not known. various factors have been implicated in its pathogenesis including the effect of placental growth hormone on the mucosa and increases in the circulating blood volume. other alterations in the upper airways include increases in the mallampati score (that assesses the space between the base of the tongue and the roof of the mouth) and in the neck circumference. the decrease in the size of the upper airways is assumed to be caused by the overall alterations in the lung volumes that affect the caudal traction, and by fat infiltration of the tissues, and it is exacerbated in supine position. during pregnancy the configuration of the chest wall is altered in order to accommodate the enlarging uterus. the changes include increases in the transverse diameter of the thorax that results into an increase of approximately % in the subcostal angle. as a result, the diaphragm is elevated by - cm. this would significantly impair the ability of the diaphragm to move during inspiration, but it is compensated by an increase in the anteroposterior diameter as well that allows the diaphragm to maintain a fairly normal excursion. however, the overall chest wall compliance decreases. there appears to be no effect on the respiratory muscle strength although the changes in the chest wall configuration probably puts the muscle at a mechanical disadvantage, thus contributing to the increased work of breathing that pregnant women experience. interestingly, most of the alterations in the chest wall occur primarily during the first trimester of the pregnancy when the uterus is still too small to have any substantial mechanical effect. it is believed that the chest wall configuration changes as a result of hormonal action, especially of relaxin that relaxes the ligaments of the lower rib cage, thus allowing the increase in the diameters. the alterations in the configuration of the chest wall confer surprisingly relatively little change in lung volumes and even less in lung function ( table ). the most substantial change occurs in the functional residual capacity (frc) that is usually decreased by about % primarily due to a decrease in the expiratory reserve volume (erv) and residual volume (rv). this is due to elevation of the diaphragm and increased pulmonary blood volume in pregnancy. the inspiratory capacity (ic) remains essentially the same or even increases, and as a result, the total lung capacity (tlc) is only marginally decreased. there are changes in the respiratory drive and minute ventilation, both of which increase under hormonal influence. the increase in minute ventilation offsets the increased carbon dioxide production, so primary respiratory alkalosis with ph ranging from . to . and pco ranging from to is a normal finding in pregnancy. asthma asthma is one of the most common chronic respiratory diseases complicating pregnancy with an estimated prevalence of . - . % of all pregnancies. asthma is clinically characterized by recurrent episodes of reversible bronchoconstriction. there is a bidirectional interaction of asthma and pregnancy where asthma influences pregnancy outcomes and pregnancy affects asthma severity. poorly controlled asthma is associated with adverse perinatal outcomes; however, when asthma is well controlled, pregnancy is not adversely affected. the course of asthma during pregnancy improves in about one-third of women, worsens in one-third, and remains the same in the other one-third. the course is determined by the baseline asthma severity with more severe asthma prior to pregnancy conferring a higher risk of worsening during pregnancy. there is evidence that the course of asthma is similar in subsequent pregnancies. there is evidence that female fetuses are associated with worsening of the maternal asthma, suggesting the influence of hormonal causes. uncontrolled asthma increases the risk of severe maternal and fetal complications including preeclampsia, preterm birth, low birth weight, intrauterine growth restriction, and increased perinatal mortality. immunological mechanisms in asthma influence pregnancy. it has been shown that poorly controlled asthma in pregnant women is associated with immune reactions that influence fetal growth. the focus of management is to maintain adequate control of asthma during pregnancy that will improve both maternal and fetal outcomes. the diagnosis of asthma is usually known prenatally, but the symptoms may occur for the first time during pregnancy. spirometry showing lower airway obstruction that is reversible with bronchodilators is very useful in confirming the diagnosis. however, the absence of an obstructive pattern is not a contraindication to treating the patient if there is sufficient clinical suspicion. bronchial challenge tests are contraindicated during pregnancy due to the lack of safety data. performing a skin prick test during pregnancy for the possibility of allergic asthma is also not recommended due to the risk of systemic reactions. fractional nitric oxide (feno) concentration in exhaled breath is a relatively new tool to monitor asthma control. according to a recent study, feno levels are not altered in pregnancy, and they correlate with the level of asthma control. however, as in the nonpregnant population, the limitation of the feno is that it reflects primarily the eosinophilic asthma and not all types of asthma. monthly assessment of asthma control during prenatal visits is strongly recommended as well as patient education. despite the concern about administering medications during pregnancy and their effect on the fetus, it is safer for pregnant women with asthma to be treated with asthma medications than to experience exacerbations that may increase the risk of perinatal mortality. most studies have shown no increased perinatal risk with the use of beta-agonist and inhaled corticosteroids. some epidemiologic studies have shown an increased risk of congenital abnormalities (cleft palate with oral corticosteroids, gastroschisis with bronchodilators) in the offsprings of asthmatic women, but the evidence is far from conclusive. it should be noted that congenital abnormalities develop very early in pregnancy (sometimes before the woman realizes that she is pregnant), and therefore withholding the medications later in pregnancy would confer no benefit. albuterol is the preferred reliever medication because of its overall excellent safety profile. inhaled corticosteroids (ics) are the preferred controller medication with budesonide being the preferred choice due to the availability of reassuring data in pregnant women. it is important to note that no data indicates that other ics are unsafe during pregnancy, and if a patient was well controlled before, she should continue taking the same asthma medications during pregnancy. long-acting beta-agonists (labas) may be used as an alternative controller medication if clinically warranted by symptoms not controlled with ics. a recent retrospective study showed no difference in the risk profile of step-up therapy with low-dose ics/laba inhalers or high-dose ics in terms of major congenital malformations. leukotriene receptor antagonists (ltras) seem to be safe based on the animal safety data submitted to fda; however, availability of human data is scarce. the use of asthma medications should be continued during labor and delivery. lumbar epidural anesthesia is preferred over general anesthesia, if cesarean section is required, and ketamine is the preferred anesthetic. the key in asthma management is remembering that adequate control of asthma can improve the health of both mothers and their babies. cystic fibrosis (cf) is an autosomal recessive disorder affecting the body's exocrine glands, including the pancreas, sweat glands, and lungs. it is the most common life-shortening genetic disorder in caucasians with a carrier frequency rate of in and an incidence of in live births in caucasians. it is present in other races albeit less commonly with an incidence of in and in , live births in hispanic and african-american populations in the united states. the most common gene deletion in % of genes is the delta f , which leads to a misfolded cf transmembrane conductance regulator protein resulting in impaired movement of water and electrolytes across epithelial surfaces. in the last few decades, there have been improvements in treatment and survival, and the median life expectancy is now years. about - % of female patients become pregnant. malnutrition and thick cervical mucus may impair female fertility. despite the concern that pregnancy would have an adverse impact on the mother, a large us review of pregnant women with cf enrolled in the us cystic fibrosis foundation national patient registry ( to ) demonstrated that survival was actually better in the pregnant female group than in the matched control patients with cf. they had higher predicted percentages of fev and higher weights. after adjustment of age, colonization with pseudomonas aeruginosa, pancreatic function, and prepregnancy fev , the pregnancy did not appear harmful. in another case-control study, pregnancy had little effect on patients with stable cf, although poor outcomes were seen in those with severe disease. the presence of pulmonary hypertension, cor pulmonale, or fev < % predicted is a relative contraindication to pregnancy. prior to pregnancy, genetic counseling should be offered and should include a risk estimate of having a child with cf as it can be as high as % if the father is heterozygous for the gene. during pregnancy, fetal surveillance to detect early signs of growth restriction is essential. pregnant women with cf need regular monitoring by a dedicated team, to achieve favorable pregnancy outcomes. commonly reported adverse events are fetal growth restriction and prematurity which includes iatrogenic early delivery because of maternal health deterioration. women with cf are also at an increased risk of developing gestational diabetes. so screening for diabetes, baseline lung function tests as well as dietary supplementation, enzyme supplements, and chest physical therapy are important. pulmonary exacerbations should be treated aggressively with antibiotic therapy paying attention to the class of medications and using those approved for use during pregnancy. there is no contraindication to vaginal delivery; however, there is a small risk of pneumothorax if the second stage is very prolonged. general anesthesia should be minimized. there is no contraindication to breastfeeding, but mothers will need to use nutritional supplements in the postnatal period to ensure adequate caloric intake. the frequency of pneumonia in pregnancy is similar to that in the general population. infants born to women who develop pneumonia during pregnancy have a higher risk of being low birth weight and small for gestational age. pneumonia may also precipitate preterm labor. intrauterine and neonatal deaths have also been reported. poor maternal and fetal outcomes occur primarily in mothers with underlying chronic respiratory illnesses. pregnancy increases the risk of complications of pneumonia including respiratory failure, and the mortality is higher. the most common pathogens causing bacterial pneumonia in pregnancy are streptococcus pneumoniae, haemophilus influenzae, and mycoplasma pneumonia. the clinical features are similar to those in nonpregnant patients with fever, cough, dyspnea, and rigors as the presenting symptoms. a chest radiograph may be obtained to confirm the diagnosis. penicillin, cephalosporins, and macrolides are safe antibiotics for use during pregnancy. tetracyclines should be avoided as they may cause teeth discoloration in the fetus. influenza epidemics have shown that the morbidity and mortality rate in pregnant women is higher compared with nonpregnant women. influenza vaccination has been shown to reduce hospitalization rates among pregnant women; therefore, the centers for disease control and prevention (cdc) recommends inactivated influenza vaccine during the second and third trimesters of pregnancy. in , a previously unrecognized strain of influenza a (h n ) virus emerged and caused increased morbidity and mortality in pregnant women. treatment with oseltamivir in pregnant women provided better protection against maternal-fetal transmission. maternal varicella pneumonia is associated with high mortality rates. antiviral therapy with acyclovir reduces the mortality rates in pregnant patients and should be considered in the treatment of active disease. passive immunization with varicella zoster immune globulin (varizig) has been shown to reduce the risk of congenital varicella syndrome and is also effective in preventing maternal complications of varicella. the live attenuated vaccine against varicella is contraindicated in pregnancy. fungal pneumonias are not common during pregnancy. coccidioidomycosis is the most extensively studied fungal infection in pregnancy and can affect the outcome if it is disseminated. compared with the general population, the risk of disseminated infection is higher in pregnant women, especially in the third trimester of pregnancy. possible reasons are impairment of cell-mediated immunity and a stimulatory effect of progesterone on fungal proliferation. amphotericin is the preferred antifungal for disseminated coccidioidomycosis. azoles should be avoided during pregnancy due to an association with branchial cleft abnormalities. there is no evidence that other fungal infections, including blastomycosis, histoplasmosis, sporotrichosis, and cryptococcosis, are more severe during pregnancy. pneumonia complicating hiv infection in pregnancy is most commonly caused by a yeastlike fungus pneumocystis jirovecii; it should be suspected in the presence of hypoxia that is out of proportion to the chest x-ray findings. treatment is with high-dose co-trimoxazole/pentamidine with folate supplementation. pregnancy and tuberculosis have little effect on one another. patients are often asymptomatic but can present with typical symptoms of cough, night sweats, hemoptysis, and weight loss. tuberculin skin testing can be used for screening patients, and treatment should not be delayed during pregnancy. rifampicin, isoniazid, and ethambutol are standard antitubercular drugs approved by the cdc due to their acceptable safety profile. streptomycin is associated with congenital deafness and is contraindicated. guidelines for the evaluation and management of newborns born to mothers with tuberculosis should be followed. aspiration pneumonia is a major cause of maternal morbidity and mortality. the pregnant woman is predisposed to aspiration during labor and delivery due to increased intra-abdominal pressure from the gravid uterus, relaxed gastroesophageal sphincter due to the effect of progesterone, delayed gastric emptying, vigorous abdominal palpation during examinations, and sedation and analgesia given in the delivery room. aspiration of the acidic gastric contents with a ph less than . induces chemical pneumonitis and pulmonary edema. most cases of aspiration occur at the time of delivery. if general anesthesia or endotracheal intubation is needed, prophylaxis in the form of h blockers, metoclopramide, or sodium citrate is often given before intubation. the clinical presentation includes tachypnea, bronchospasm, hypoxemia, and hypotension with chest radiograph findings of either isolated or diffuse infiltrates. the timing of presentation depends on the volume of the aspirate with large volumes causing immediate asphyxiation and smaller volumes becoming apparent - h after the event. respiratory failure can sometimes manifest in the postpartum period. management is supportive and includes oxygen, bronchodilators, and ventilatory support. antibiotics should be considered early if there is suspicion of bacterial infection. the common bacterial pathogens are staphylococcus aureus, gramnegatives, or anaerobes originating from the oropharynx. restrictive lung diseases are characterized by a decrease in total lung capacity. this can be caused by abnormalities in the pleura, chest wall, and neuromuscular apparatus or alterations in the lung parenchyma. in most cases, due to the large pulmonary reserve, pregnancy is unaffected; however, in severe restriction, problems may arise during pregnancy and labor due to impaired reserve and higher oxygen demands. the gravid uterus pushes the diaphragm upward, thereby further worsening the restriction. as a general rule, patients with a fvc of < l or < % of predicted fvc and those who have pulmonary hypertension are at greater risk of cardiopulmonary complications and hence should consider avoiding pregnancy or consider a therapeutic termination. kyphoscoliosis is an abnormality of the spine characterized by posterior or lateral curvature or both. almost half of the cases are idiopathic. depending on the site of primary curvature in pregnant females, there can be cardiopulmonary complications or obstetrical complications such as cephalopelvic disproportion. other obstetrical complications experienced by pregnant women with kyphoscoliosis include prematurity and low birth weight. it is controversial if spinal curvature will worsen during pregnancy. studies have shown that the risk of progression of the curvature is low unless the scoliosis is unstable at the time of pregnancy. the presence of kyphoscoliosis during pregnancy may cause back pain. sarcoidosis is a multisystem disorder of unknown etiology that is characterized by noncaseating epithelioid granulomas. the most common site of granuloma formulation is the lungs. other organs include the lymph nodes, eyes, skin, liver, heart, and nervous system. since the disease can involve any organ system, clinical manifestations are variable ranging from dyspnea, nonproductive cough, and chest pain to fever, joint/ muscle aches, visual changes, and erythema nodosum. the disease has a variable course with spontaneous remissions occurring in nearly two-thirds of patients. sarcoidosis has not been found to adversely affect pregnancy outcomes. it is not transmitted to the fetus and does not increase the incidence of maternal or fetal complications. improvement in sarcoidosis occurs during pregnancy with a tendency to relapse in the postnatal period. factors that indicate a poor prognosis in pregnancy include parenchymal infiltrates on chest radiograph, advanced radiographic staging, low inflammatory activity, advanced maternal age, requirement for drugs other than steroids for disease control, and the presence of extrapulmonary disease. except for severely affected patients, sarcoidosis is not a contraindication to pregnancy. the diagnosis usually warrants a tissue biopsy of the involved organ that shows noncaseating granulomas. the patient may also have other laboratory abnormalities including an increased angiotensin-converting enzyme (ace) level, elevated liver enzymes, and hypercalcemia. pulmonary function tests are abnormal in many patients and generally show a restrictive pattern but may be normal or obstructed if there is endobronchial involvement, stenosis, or airway distortion from parenchymal disease. there may also be a reduction in diffusion capacity. systemic steroids are the main stay of therapy and should be continued in pregnancy. acute respiratory distress syndrome (ards) is a severe form of acute lung injury characterized by severe hypoxemia and bilateral pulmonary infiltrates resulting from increased alveolar-capillary permeability. ards in pregnancy can develop from obstetric and non-obstetric complication. the common obstetric causes are chorioamnionitis, amniotic fluid embolism, trophoblastic embolism, and placental abruption. the most common non-obstetric causes are pneumonia, sepsis, and aspiration. due to the changes in the definition of ards, it has been difficult to determine the true prevalence of the condition with estimates ranging from . to cases per , population. the prevalence of ards during pregnancy is comparable to the number in the general population: however, the mortality rates of ards for both the mother and the fetus are high. there is not enough evidence available regarding the management of ards in pregnancy, and treatment strategies are extrapolated from the studies on the general population. a multidisciplinary approach is necessary to optimize maternal and fetal outcomes and manage ards in pregnancy. acute pulmonary edema in pregnancy is an uncommon yet significant cause of morbidity and mortality with an estimated incidence of . - . %. it was reported as the fourth most common form of maternal morbidity in the scottish confidential audit of severe maternal morbidity, which is one of the largest maternal morbidity audits. acute pulmonary edema may occur during the antenatal, intrapartum, or postpartum periods. pregnant women are at an increased risk for pulmonary edema due to the hypervolemia and high cardiac output of pregnancy, the occasional need for tocolytic drugs that affect the vascular bed, and some clinical conditions unique to pregnancy. it is now recognized that in addition to fluid accumulation and retention, fluid redistribution from the systemic circulation to the pulmonary circulation also plays an important role in causation of pulmonary edema. clinically, the patient presents with acute onset of breathlessness, orthopnea, cough, tachycardia, tachypnea, and hypoxemia. chest x-ray, ecg, and echocardiography may help establish the diagnosis. in contrast to nonpregnant women, serum concentration of b-type natriuretic peptide is not widely utilized in pregnancy. transthoracic echocardiography is very helpful in diagnosis and management of the pulmonary edema as it enables assessment of cardiac systolic function. treatment is supportive and includes fluid restriction, circulation control with vasodilators, oxygenation, mechanical ventilation if needed, and close monitoring. pulmonary embolism (pe) is a leading cause of maternal mortality accounting for % of maternal deaths in the united states. the estimated incidence of pulmonary embolism is . per , with the highest risk during the postpartum period. pregnant patients are predisposed to thromboembolic disease for several reasons including ( ) an increase in several coagulation factors and a decrease in fibrinolytic activity, leading to a hypercoagulable state, ( ) venous stasis caused by uterine compression of the inferior vena cava and the left iliac vein, and ( ) trauma to pelvic veins at the time of delivery. this might account for the peak incidence of thromboembolism in the postpartum period, especially after cesarean section. other risk factors for developing thromboembolism include a past history of thromboembolism during pregnancy or while taking oral contraceptives, patients more than years of age, prolonged bed rest, complicated or cesarean delivery, and inherited coagulation defects. clinical symptoms of pulmonary embolism (pe) include acute onset of dyspnea, tachypnea, tachycardia, and pleuritic chest pain that can rapidly progress to arrhythmias, syncope, and cardiovascular collapse if the pe is massive. despite the current availability of an array of diagnostic tests, diagnosis of a pregnant woman with suspected pe is very challenging. recent ats guidelines from the american thoracic society for evaluation of suspected pe in pregnancy recommend performing a chest radiograph (cxr) as the first test; if the chest x-ray is normal, then lung scintigraphy/ventilation-perfusion (v/q) scan is recommended and finally computed tomographic pulmonary angiography (ctpa) rather than digital subtraction angiography (dsa) if the ventilation-perfusion (v/q) scan is negative. the patient can also be evaluated for the presence of a deep venous thrombosis (dvt), the presence of which increases the likelihood that the patient has a pe. again, it is very difficult to diagnose dvt during pregnancy since contrast venography, which is the diagnostic test for dvt in nonpregnant patient, is usually performed in a limited manner to minimize the radiation exposure, thus decreasing the sensitivity of the test. treatment of dvt and pe necessitates the use of anticoagulants. heparin is the drug of choice since warfarin crosses the placenta and can cause fetal dysmorphism, congenital heart defects, and growth retardation. low-molecular-weight heparin (lmwh) is an alternative to standard heparin treatment and appears to be safe in pregnancy with fewer adverse effects such as thrombocytopenia and osteoporosis. treatment should be given throughout pregnancy and continued for about - weeks after delivery. if thrombosis occurs late in the pregnancy, treatment may be required for up to months after delivery. thrombolytic therapy has also been used successfully in life-threatening thromboembolism during pregnancy. other management options for a massive pulmonary embolism in pregnancy include surgical embolectomy and catheter-directed therapy. during uncomplicated pregnancies, small amounts of amniotic fluid may enter the maternal circulation. amniotic fluid contains fetal debris, including desquamated squamous cells, meconium, lanugo hair, and mucin. in a very small percentage of deliveries (estimated at . per , deliveries), amniotic fluid embolism develops with high maternal mortality rates of - %. clinical signs include sudden onset of severe dyspnea, hypoxemia, cyanosis, cardiovascular collapse, seizures, and coma that may occur during labor and delivery. this may progress to ards and disseminated intravascular coagulation (dic). risk factors for developing amniotic fluid embolism include premature rupture of membranes, advanced maternal age, meconium staining of amniotic fluid, multiparity, and cesarean section. disruption of the uterine veins has a role in pathogenesis. two possible sites of entry are at the site of placental separation and small tears in the lower uterus and endocervix. it is unclear how much amniotic fluid is required to initiate the syndrome. the diagnosis can be made by the presence of a large amount of fetal squamous cells, mucin, and lanugo in the blood removed from the distal lumen of a wedged pulmonary artery catheter. treatment is primarily supportive for disseminated intravascular coagulation and cardiopulmonary failure. venous air embolism results from entrapment of air in the venous system. it is an infrequent complication of pregnancy but can occasionally occur during labor and delivery especially during cesarean sections, induced abortions, manual extraction of placenta, and vacuum and forceps delivery. it has been also reported as a possible complication of oro-genital sex during pregnancy. air passes beneath the fetal membranes and into the circulation of the subplacental sinuses. nonfatal air embolism during cesarean section may be more common than appreciated (studies suggest an incidence as high as %). a lethal air embolism may follow a bolus of - cc/kg of air. the clinical presentation is acute onset tachypnea, chest pain, and gasping due to obstruction of pulmonary arterial blood flow. diagnosis is very difficult and requires a high index of suspicion. transesophageal echocardiogram offers the most sensitive measurement of air trapped within the right atrium or ventricle; however, it has the limitation of being invasive. precordial doppler is less sensitive but noninvasive. management includes optimum patient positioning, aspiration of air, discontinuation of nitrous oxide, administration of % oxygen, and flooding the surgical site with saline to prevent further air entry. there are case reports of maternal and fetal death with venous air embolism, so familiarity with this syndrome is important if prompt and appropriate therapy is to be provided. pulmonary arteriovenous malformations (pavms) are abnormal communications between the pulmonary and systemic circulation, which cause a right-to-left shunt. more than half of the cases reported during pregnancy are associated with hereditary telangiectasia, an autosomal dominant disorder characterized by the development of multiple arteriovenous malformations in the skin, mucous membranes, and/ or visceral organs. these pavms may expand during pregnancy because of the increase in blood volume, cardiac output, and venous distensibility, which increases the likelihood of rupture leading to life-threatening hemoptysis and hemothorax. diagnosis is based upon transthoracic contrast echocardiography and ct scan that also help to plan percutaneous embolization, which is the treatment of choice during pregnancy. spontaneous pneumothorax is primary when it occurs in a person with no apparent lung disease or secondary as a complication of preexisting lung disease. it is rare in pregnancy. it can occur in the pre-or postpartum period but is most common during labor when the increase in alveolar intrathoracic pressure causes rupture of previously unrecognized blebs in the subpleural space. common predisposing factors for pneumothorax in pregnancy are previous respiratory infections, asthma, or a previous pneumothorax unrelated to pregnancy. the diagnosis may be obscured due to other causes of dyspnea in pregnancy or the discomfort of parturition. this is a potentially serious situation since any impairment in ventilation during pregnancy can have detrimental effects on both the mother and fetus. spontaneous pneumothorax should be considered in a pregnant woman with acute onset dyspnea, chest pain, or history of prior pneumothorax. prompt recognition and timely treatment of pneumothorax can prevent complications. the diagnosis can be confirmed with a chest radiograph with an abdominal shield. initial management is generally based on the size of the pneumothorax and may involve observation, drainage with a chest tube, or video-assisted thoracotomy (vats). if the pneumothorax occurs close to term and is large enough to require placement of a chest tube, induction of labor should be considered with the chest tube in place to avoid recurrence during labor. there is no evidence that cesarean section is necessary, and it should be performed for obstetric indications only. patients with recurrent pneumothorax, who require vats, should undergo surgery after the period of organogenesis and before the pregnancy is too far advanced. improvement in survival and quality of life in patients with lung transplants has prompted them to consider pregnancy. successful pregnancy is possible after lung transplantation, but it requires planning and a multidisciplinary team approach involving maternofetal medicine, respiratory and transplant medicine, anesthesia, neonatology, genetics, and social services. since the first successful pregnancy reported in in a patient with single lung transplant, there have been several successful pregnancies. the report of the national transplantation pregnancy registry reported pregnancies in lung transplant recipients, of which were live births. cystic fibrosis was the most common cause of lung transplant in out of recipients. according to the most recently (in ) published management update on pregnancy after solid organ transplantation, it is recommended that pregnancy should be avoided for at least year after transplant to minimize the episodes of acute rejection. it is also recommended that adequate and stable graft function should be achieved before pregnancy. patients should be counseled regarding the increased risk for both maternal and neonatal complications including prematurity and low birth weight. of note is that the frequency of congenital malformations is similar to that of the general population ( - %). the risk of rejection in patients who have stable graft function is not increased, except for patients with lung transplants who have a higher incidence of acute rejection compared with other organs (lung, %; heart, %; liver, %; kidney, %). lung transplant recipients are at a higher risk of developing hypertension and renal dysfunction. these comorbidities increase the risk of preeclampsia and preterm delivery, ( - % vs. - % in the general population). vaginal delivery is acceptable unless cesarean section is indicated for obstetric reasons. breastfeeding should be avoided to prevent exposure of the newborn to immunosuppressive drugs. physiological and hormonal changes of pregnancy may predispose pregnant women to developing osa. however, the prevalence of osa among women of reproductive age is estimated to be - %, but the exact prevalence of osa among pregnant women is not known. there is some evidence suggesting that osa is associated with adverse maternal and fetal outcomes, due to low oxygen levels during apneic episodes. there are some protective mechanisms against osa during pregnancy. high levels of progesterone have a stimulatory effect on the respiratory system, a decrease in rem sleep in later stages of pregnancy, and the rightward shift of the oxyhemoglobin dissociation curve. osa generally occurs in obese patients and is precipitated by the estrogen-induced airway mucosal edema and vascular congestion. snoring is the most common symptom of osa, but it is less specific than witnessed apneas and choking sensations during sleep for a diagnosis of osa. there are no specific guidelines for screening pregnant women for osa; however, it is prudent to evaluate pregnant women with loud snoring and witnessed apneas with overnight polysomnography. nasal continuous positive airway pressure (cpap) is generally well tolerated during pregnancy. patients should also be encouraged to follow conservative measures such as sleeping in the side position, elevation of the head of the bed, and avoiding the use of alcohol and sedatives. postpartum withdrawal of therapy with close follow-up should be considered due to rapid improvement of sleep apnea symptoms in the postnatal period. rare diseases are defined as conditions affecting less than in people (in europe) or less than , individuals (in the united states). rare lung diseases (rld) constitute % of these rare diseases. rld are chronic in character and often have a poor prognosis. advances in medicine have improved the survival and the quality of life in these patients, so they seek medical advice in planning their reproductive life. however, in certain conditions, pregnancy is contraindicated due to the adverse effect on the course of the disease. in lymphangioleiomyomatosis (lam), there is a very high risk of pneumothorax and loss of lung function, and in primary pulmonary hypertension (pph), there is a high risk of mortality. the contraceptive method should be individualized based on the personal choices of the patients and on the underlying disease process. all patients can safely use condoms. oral contraceptives should be used cautiously in patients with cystic fibrosis due to poor absorption; they are absolutely contraindicated in lam due to disease progression from exogenous estrogen. since pregnancy is contraindicated in lam, surgical sterilization should be considered in patients with lam and pph. consideration should also be given to the future possibility of lung transplantation; therefore, combined hormone contraceptives should be avoided due to the risk of pulmonary thromboembolism. currently, the experience in managing the reproductive health of women with rld is limited, but based on the current experience, individualized and multidisciplinary approach is recommended to assist patients in making the best decisions about contraception and pregnancy. endometriosis is a condition characterized by the presence of endometrial tissue outside of the uterine cavity or myometrium. it is encountered most commonly in pelvic structures such as the ovary, uterine ligaments, pelvic peritoneum, cervix, labia, and vagina. thoracic endometriosis syndrome (tes) is defined as the presence of endometrial tissue in or around the lung. endometrial tissue may be present in the lung parenchyma, visceral and parietal pleura, diaphragm, and endobronchial sites. there are four distinct clinical entities: (a) catamenial pneumothorax (b) catamenial hemothorax (c) hemoptysis (d) pulmonary nodules the clinical manifestations of tes imply the presence of endometrial tissue in the thoracic cavity that undergoes cyclical sloughing in response to the physiologic hormonal variations, and the clinical presentation depends on the affected structures. how endometrial tissue migrates to the thoracic cavity has remained elusive; however, three theories have been proposed to explain it: (a) retrograde menstruation with subsequent transperitoneal-transdiaphragmatic migration of endometrial tissue (b) coelomic metaplasia (c) lymphatic or hematogenous embolization from the uterus or pelvis the disease probably has a multifactorial etiology, since none of these theories can fully explain all the clinical manifestations of tes. since tes is a rare condition, a high index of suspicion is the key to timely diagnosis. the clinical presentation is of a woman in her reproductive years (with a peak incidence between the ages of and years), who reports recurrent episodes of chest pain, dyspnea, or cough around the time of her menstrual cycle. catamenial pneumothorax accounts for only . - % of cases of spontaneous pneumothorax in women even though it is the presenting symptom in % of cases of tes, followed by hemothorax in % and hemoptysis in %. physical examination findings are nonspecific. ct and mri have been shown to be helpful in the diagnosis. mri may be superior to ct since it helps in differentiating pleural from parenchymal implants. bronchoscopy has a limited role in diagnosis due to the peripheral location of the disease and the low diagnostic yield of bronchial washings. in the era of endoscopic surgery, vats allows direct visualization of the lung and diaphragmatic surfaces for endometrial implants. the size of the implants usually ranges from a few millimeters to a centimeter, and depending on the timing during the menstrual cycle, their color varies from brown to violet. exploratory thoracotomy now has a limited role in the diagnosis and is used in cases of failure of vats exploration. catamenial pneumothorax (cp) refers to the occurrence of spontaneous pneumothorax during mensuration. it is also known as menstruation-related spontaneous pneumothorax (msp) which was first reported in the s by maurer et al., who defined it as pneumothorax occurring within - h after onset of menses. in , lillington et al. introduced the term catamenial pneumothorax for spontaneous pneumothorax associated with menses. previously considered to be rare, current knowledge suggests that cp is a more common reason for spontaneous pneumothoraces in women of reproductive age. as mentioned in the previous section, cp is frequently associated with thoracic endometriosis syndrome (tes), but there might be other etiological mechanisms. the etiology of the remainder is obscure, but a number of theories have been proposed. during menstruation, the absence of the normal cervical mucus plug provides a connection between the ambient air and the abdominal cavity through the uterus and fallopian tubes, hence allowing the air to move across the diaphragm through right-sided diaphragmatic fenestrations into the pleural space. this may account for the fact that - % of msps are right-sided. a second theory is that bronchospasm with air trapping and pneumothorax may occur due to high levels of prostaglandin f during menstruation. the third theory is that pleural blebs or bullae are more prone to rupture during menstruation because of hormonal changes. for cases that are not clearly associated with systemic endometriosis, thoracoscopy during menstruation helps determine the etiology. successful treatment necessitates a combined medical and surgical approach. the medical therapy of tes primarily focuses on blocking the hormonal support from the ovaries that fosters the growth of the endometrial tissue. it consists of oral contraceptives, progestational agents, danazol, and gonadotropin-releasing hormone (gnrh) agonists. surgical approaches include excision, local laser ablation, or pleurodesis. the recurrence rate with medical treatment exceeds % and subsequently requires surgical management. conversely, there are reports of recurrence after surgical treatment of msp that responded to subsequent hormonal therapy, so the current opinion is a sequential medical-surgical or surgical-medical approach. lymphangioleiomyomatosis (lam) was a disease of unknown origin in the mid- s, with no effective treatment. during the last decade, substantial progress has been made in understanding the natural history of the disease with support from nhlbi (national heart, lung, and blood institute). once defined as a fatal disease of women of childbearing age, it is now known that lam occurs in postmenopausal women as well. lam is a rare, slowly progressive, multisystem disorder of women characterized by proliferation of abnormal smooth muscle-like cells (lam cells) associated with cystic lesions in the lungs and in the axial lymphatics (lymphangioleiomyomas) and angiomyolipomas. in the lungs, the cells are present along the pulmonary blood vessels, lymphatics, and bronchioles. lam occurs in association with tuberous sclerosis complex (tsc) which is an autosomal dominant syndrome characterized by multisystem hamartoma-like tumor growths or sporadically with no evidence of a genetic abnormality. sporadic lam is rare with a prevalence of - /million. in both cases, lam is caused by a mutation in one of the two tumor suppressor genes tsc or tsc that produce hamartin and tuberin, respectively. lam most frequently presents with progressive breathlessness, recurrent pneumothorax, hemoptysis, or chylothorax. extrapulmonary manifestations include an intra-abdominal hemorrhage or an abdominal mass. patients who present with dyspnea and hemoptysis generally have a more severe disease and higher mortality than those presenting with pneumothorax. lam histology score (lhs), quantitative ct scan, and pulmonary function testing including exercise testing assist in assessing severity of the disease. airflow obstruction and decreased lung diffusion capacity are the most frequent lung function abnormalities in lam. exercise tests are frequently abnormal in lam patients who have low-grade pulmonary hypertension which worsens on exercise. currently the best methods to assess the severity and progression of lung disease are frequent monitoring of fev and dlco and the -min walk test. the focus of current research is to identify possible treatment targets. studies have shown a potential role for sirolimus (rapamycin), an immunosuppressant drug that inhibits the hyperphosphorylation of ribosomal protein s and p s kinase activation which is unregulated in lam cells in the absence of tuberin (protein product of tsc gene). another potential drug doxycycline is an inhibitor of matrix metalloproteinase (mmp) and has shown improvement in fev and dlco when used in the treatment of patients with severe lam. antiestrogen therapy and oophorectomy, which were once considered conventional therapies, are no longer universally recommended. gestational trophoblastic disease (gtd) is a term used for a rare group of pregnancyrelated disorders ranging from benign, partial, and complete hydatidiform mole, invasive and metastatic mole, and malignant choriocarcinoma. trophoblastic pulmonary embolization is a rare complication of gtd and can occur following abdominal hysterectomy for invasive mole as well as after molar evacuation. the clinical course is dramatic with acute onset dyspnea, tachypnea, bilateral pulmonary infiltrates, and low oxygen levels. possible etiologies for pulmonary findings include pulmonary trophoblastic embolization, hypervolemia, aspiration, dic, and hyperthyroidism. although not very common, pulmonary trophoblastic embolization should be considered part of the differential diagnosis if a patient has acute onset respiratory distress in the postoperative period. malignant choriocarcinoma is associated with metastases to the lungs, which is the most common site of metastases. ovarian hyperstimulation syndrome (ohss) is an exaggerated response to the use of exogenous gonadotropins to induce ovulation for in vitro fertilization. the syndrome has a broad spectrum of clinical presentations ranging from abdominal pain from ovarian enlargement, ovarian cysts, ascites, dyspnea, intravascular volume depletion, and acute renal failure. ohss is characterized by increased capillary permeability resulting in fluid shift from the intravascular space to third space compartments. various factors have been previously implicated in the process including estrogen, prolactin, histamine, and prostaglandins, but recently it is thought to be related to vasoactive mediators such as interleukins, tumor necrosis factor-α, endothelin- , and vascular endothelial growth factor (vegf). risk factors to developing ohss include young age, low body weight, polycystic ovary syndrome (pcos), use of higher dose of exogenous gonadotropins, and previous episodes of ohss. pulmonary manifestations include dyspnea that may result from decreased diaphragmatic movement due to abdominal enlargement. other rare complications include pleural effusion, pulmonary edema, atelectasis, and acute respiratory distress syndrome (ards). pulmonary embolism is a life-threatening complication and may occur due to hypercoagulable state. treatment is supportive and directed at maintaining intravascular blood volume. ohss is a self-limiting disease, so most patients respond to medical therapy, and surgical intervention is required only for complications such as ruptured ovarian cyst or ovarian torsion. thoracocentesis may be needed for bilateral or persistent pleural effusions. polycystic ovarian syndrome (pcos) is a common endocrine disorder affecting almost - % of females and characterized by menstrual irregularity, hyperandrogenism, obesity, and polycystic ovaries. patients with pcos are at increased risk of various metabolic derangements such as insulin resistance, glucose intolerance, dyslipidemia, and hypertension. obstructive sleep apnea (osa) has been recently recognized as a significant contributing factor to the pathophysiology of metabolic derangements in pcos. recent studies have shown that there are two distinct clinical entities: pcos with osa and pcos without osa. pcos women with osa may be at much higher risk for the development of diabetes and cardiovascular disease than pcos women without osa. the risk for osa in pcos is -fold higher than in similarly obese women. it is proposed that osa possibly triggers one or more of three major hormonal responses that contribute to the metabolic abnormalities associated with it. they are: (a) activation of the hypothalamic-pituitary-adrenal (hpa) axis with increased cortisol production and secretion (b) increased catecholamine output from sympathetic nervous system stimulation (c) increased release of adipokines from the adipose tissue treatment of patients with osa in pcos with cpap is important as it improves the metabolic profile. pregnancy and the lung respiratory physiology in pregnancy pregnancy and the lungs asthma in pregnancy respiratory disease in pregnancy respiratory disease in pregnancy prescribing for the pregnant patient national asthma education and prevention program asthma and pregnancy working group. naepp expert panel report. managing asthma during pregnancy: recommendations for pharmacologic treatment- update asthma in pregnancyimmunological changes and clinical management pregnancy in cystic fibrosis. fetal and maternal outcome pregnancy in cystic fibrosis lung transplant recipients: case series and review report from the national transplantation pregnancy registry (ntpr): outcomes of pregnancy after transplantation pregnancy after lung transplant pregnancy after lung transplant: case report. breathe (sheff) acute pulmonary edema in pregnancy sleep-disordered breathing during pregnancy circadian variation of sleep during the follicular and luteal phases of the menstrual cycle polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance death due to air embolism during sexual intercourse in the puerperium acute pulmonary oedema in pregnant women progression of pulmonary arteriovenous malformation during pregnancy: case report and review of the literature pulmonary arteriovenous malformations. a state of the art review thoracic endometriosis: current knowledge thoracic endometriosis syndrome: case report and review of the literature gestational trophoblastic disease trophoblastic pulmonary embolization after hysterectomy for invasive complete mole. a case report update on the diagnosis and management of gestational trophoblastic disease sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis catamenial pneumothorax revisited: clinical approach and systematic review of the literature spontaneous pneumothorax contraception, pregnancy and rare respiratory diseases of thoracic radiology clinical practice guideline-evaluation of suspected pulmonary embolism in pregnancy obstructive sleep apnea and metabolic dysfunction in polycystic ovary syndrome a national heart, lung, and blood institute history and perspective on lymphangioleiomyomatosis practice committe of the american society for reproductive medicine. ovarian hyperstimulation syndrome key: cord- -ojx jsh authors: lynch, joseph p.; belperio, john a. title: idiopathic pulmonary fibrosis date: - - journal: diffuse lung disease doi: . / - - - - _ sha: doc_id: cord_uid: ojx jsh idiopathic pulmonary fibrosis (ipf) is a specific clinicopathologic ­syndrome presenting in older adults with the predominant features: dyspnea, dry cough, restrictive defect on pulmonary function tests (pfts), hypoxemia, characteristic abnormalities on high-resolution thin section computed tomographic (hrct) scans, usual interstitial pneumonitis (uip) pattern on lung biopsy. surgical lung biopsy is the gold standard of diagnosis, but the diagnosis can be established in some cases by hrct, provided the clinical features are consistent. the cause of ipf is unknown. however, ipf is more common in adults > years old, smokers (current or ex), and patients with specific occupational or noxious exposures. familial ipf, associated with several distinct genetic mutations, accounts for . – % of cases. unfortunately, the prognosis is poor, and most patients die of respiratory failure within – years of diagnosis. however, the course is highly variable. in some patients, the disease is fulminant, progressing to lethal respiratory failure within months, whereas the course may be indolent, spanning > years in some patients. therapy has not been proven to alter the course of the disease or influence mortality, but recent studies with pirfenidone and tyrosine kinase inhibitors are promising. lung transplantation is the best therapeutic option, but is limited to selected patients with severe, life-threatening disease and no contraindications to transplant. idiopathic pulmonary fi brosis (ipf) is a specifi c clinicopathologic syndrome presenting in older adults and associated with the following features: dyspnea, dry cough, restrictive defect on pulmonary function tests (pfts), hypoxemia (at rest or with exercise), characteristic abnormalities on thin section high-resolution computed tomographic (hrct ) scans, the presence of usual interstitial pneumonitis (uip) pattern on lung biopsy or ct, a progressive course [ , ] . the terms ipf and cryptogenic fi brosing alveolitis (cfa) are synonymous [ ] . ipf is associated with the histopathological pattern of uip [ ] [ ] [ ] [ ] , but uip pattern can also be found in other diseases (e.g., connective tissue disease (ctd), asbestosis, diverse occupational, environmental, or drug exposures) [ , ] . thus, the diagnosis of ipf can be established only when these and other alternative etiologies have been excluded [ ] . ipf is the most common of the idiopathic interstitial pneumonias (iips), constituting - % of cases [ , ] . other iips (e.g., respiratory bronchiolitis interstitial lung disease (rbild), desquamative interstitial pneumonia (dip), acute interstitial pneumonia (aip), lymphoid interstitial pneumonia (lip), nonspecifi c interstitial pneumonia (nsip), and cryptogenic organizing pneumonia (cop)) are distinct entities, with marked differences in prognosis and responsiveness to therapy [ , , ] . these entities are discussed elsewhere in this book. in this review, we restrict our discussion to idiopathic uip. a defi nitive diagnosis of ipf requires the demonstration of uip by surgical lung biopsy (slb) unless the hrct features are classifi ed as "definite" according to the recently published ats/ ers/jrs/alat guidelines on ipf [ a, ] . because of small sample size and disease heterogeneity, transbronchial lung biopsies or percutaneous needle biopsies are not adequate to diagnose uip [ , ] . however, slb is expensive and has potential morbidity, and many clinicians are reluctant to recommend slb for patients with suspected ipf. in clinical practice, slb is performed in < % of patients with ipf [ , ] . currently, many clinicians rely upon hrct to corroborate the diagnosis of uip [ , , ] . slbs are performed primarily in patients manifesting atypical or indeterminate patterns on ct [ , , ] . the cardinal histopathological fi ndings of uip include: geographic and temporal heterogeneity, alternating zones of normal and abnormal lung, predilection for peripheral (subpleural) and basilar regions, fibroblastic foci (aggregates of proliferating fi broblasts and myofi broblasts), excessive collagen and extracellular matrix (ecm), honeycomb change (hc) [ ] (table . ). additional features include: smooth muscle hypertrophy, metaplasia and hyperplasia of type ii pneumocytes, destroyed and disrupted alveolar architecture, traction bronchiectasis and bronchioloectasis, secondary pulmonary hypertensive changes [ ] . histopathological features of uip are discussed by drs. colby and leslie elsewhere in this book and will not be further addressed here. cardinal features of uip include dry cough, exertional dyspnea, end-inspiratory velcro rales, diffuse parenchymal infi ltrates on chest radiographs, honeycomb cysts on hrct scans, a restrictive defect on pfts, and impaired oxygenation [ , ] (table . ). physical examination reveals crackles in > % of patients with uip, and clubbing in - % [ , , ] . ipf/uip progresses inexorably over months to years [ , , ] . extrapulmonary involvement does not occur [ ] and should suggest other disorders (particularly ctd-associated pulmonary fi brosis) [ ] . however, certain diseases such as ischemic cardiac disease [ , ] , deep venous thrombosis [ ] , diabetes mellitus [ ] , and gastroesophageal refl ux (ger) [ ] are more common in patients with ipf. laboratory studies are nonspecifi c. elevations in the erythrocyte sedimentation rate occur in - % of patients with ipf; circulating antinuclear antibodies (anas) or rheumatoid factor is detected in - % [ , , ] . two recent retrospective studies cited circulating antineutrophil cytoplasmic antibodies (ancas) in a distinct minority of patients with ipf [ , ] . none of these serological fi ndings correlate with extent or severity of disease or predict prognosis [ , ] . however, for new cases of suspected ipf, we obtain serologies for ctd [e.g., ana and antibodies to ssa, ssb, scl- (scleroderma), sm, rnp, jo- , double stranded dna] [ , , ] and hypersensitivity pneumonitis (hp) to rule out those disorders as treatment and prognosis may differ from ipf. elevations of the glycoprotein kl- [ ] and lung surfactant proteins (sp)-a and -d [ ] have been noted in serum and bronchoalveolar lavage fl uid (balf) in patients with ipf, and may have prognostic value. these assays are available in only a few research laboratories, and additional studies are required to assess their specifi city and clinical role. the clinical course of ipf is heterogeneous, but most patients worsen gradually (over months to years) [ ] . mean survival from the onset of symptoms is - years [ , , , [ ] [ ] [ ] . however, the course is highly variable, and some patients remain stable for years [ , , ] . in others, the course is rapid, with fatal respiratory failure evolving over a few months [ ] . additionally, some patients have gradual progression over years, followed by acute exacerbations, associated with abrupt and often fatal hypoxemic respiratory failure [ , ] . spontaneous remissions do not occur [ , ] . ten-year survival is less than % [ , , , , , ] . the major cause of death is respiratory failure [ , ] . surveys of ipf patients in the uk and usa noted that progression of lung disease accounted for % [ ] and % [ ] of deaths, respectively. other causes include pulmonary embolism [ ] , cardiac failure, cerebrovascular accidents (primarily in the elderly), and lung cancer [ , ] . lung cancer occurs in - % of patients with ipf [ , ] . the risk is higher in smokers, but the heightened risk of lung cancer is not solely due to the effects of cigarette smoking [ ] . a subset of patients with ipf develop an accelerated course often as a terminal event, with features of diffuse alveolar damage (dad) or organizing pneumonia on lung biopsy or autopsy [ , ] . this syndrome, termed "acute exacerbation of ipf," is indistinguishable from idiopathic aip [ ] , and is similar to acute respiratory distress syndrome (ards). the factors responsible for this accelerated phase of ipf are unknown, but viral infections, high concentrations of oxygen, or drug reactions are plausible etiologic factors [ , ] . although this syndrome is usually fatal, some patients respond dramatically to high dose corticosteroids (e.g., pulse methylprednisolone) [ , ] . ipf is rare; depending upon criteria used to defi ne ipf, overall rates (per , ) range from . to . (prevalence) and from . to . (incidence) [ , , , ] . the incidence of ipf increased progressively in the uk between and [ ] . similarly, in the usa, deaths attributed to pulmonary fi brosis increased significantly from to (> % increase) [ ] . ipf typically affects older adults, with peak onset after the sixth decade of life; there is a slight male predominance [ , , , ] . ipf is more common in current or former smokers [ , [ ] [ ] [ ] . the incidence of ipf and mortality rates is markedly higher in the elderly. a retrospective study in the usa cited a prevalence (per , ) of . among persons aged - years and among those years or older [ ] . in the usa, projected deaths due to ipf (per million) in were as follows: (ages - ), (age - ), (age - ), (age - ), , (age > ) [ ] . despite its rarity, ipf accounts for more than , deaths annually in the usa [ ] . interestingly, mortality rates from ipf exhibit a seasonal variation, with the highest rates in the winter months [ ] . in the usa, mortality rates from ipf are climbing more rapidly in women than men [ ] , possibly refl ecting the impact of cigarette smoking. ipf is rare in children [except in kindreds with surfactant protein c (sfpc) mutations] [ ] . environmental factors likely play a contributory role [ ] . exposure to or inhalation of minerals, dusts, organic solvents, urban pollution, or cigarette smoke has been associated with an increased risk for ipf in some studies [ ] . a meta-analysis of six case-control studies found six exposures associated with ipf: ever smoking, agriculture farming, livestock, wood dust, metal dust, stone/ sand [ ] . interstitial lung disease (ild) is an occupational disease in coal miners, sandblasters, and workers exposed to asbestos, tungsten carbide, beryllium, and other metals [ ] , suggesting that at least some cases of "idiopathic" uip represent pneumoconioses. the considerable variability that exists in the development of pulmonary fi brosis among workers exposed to similar concentrations of fi brogenic/organic dusts implies that genetic factors likely modulate the lung injury [ ] . infections may trigger exacerbations of ipf [ ] . epstein-barr virus (ebv), cytomegalovirus (cmv), human herpes virus (hhv- ), or hepatitis c have been considered as possible agents in the pathogenesis of ipf, but the role of these (or other infectious agents) remains conjectural [ ] . chronic aspiration secondary to ger has been suggested as a risk factor for ipf [ ] , but a causal relationship between acid aspiration and ipf remains controversial. esophageal refl ux has been noted in more than two-thirds of patients with ipf awaiting lung transplant (lt) [ , ] . aspiration of stomach contents may cause lung injury and fi brosis [ ] . among lt recipients (with or without ipf), ger can cause allograft injury [ ] and appears to be a risk factor for bronchiolitis obliterans syndrome (bos) [ , ] . in a small series of patients with early ipf, aggressive treatment of ger was associated with stabilization or improvement of lung function [ ] . additional studies are required to assess the role of ger or aspiration in the pathogenesis or progression of ipf and therapeutic strategies to prevent or reduce ger. familial ipf, which accounts for . - % of cases of ipf, is indistinguishable from nonfamilial forms, except patients tend to be younger with the familial variant [ , , , ] . progression of early asymptomatic ild to symptomatic ipf may occur over a span of decades [ ] . an autosomal dominant trait with variable penetrance is suspected in most, but not all, cases [ , , ] . in some patients, genetic polymorphisms for interleukin- receptor antagonist (il- ra) and tumor necrosis factor-a (tnf-a ) may be important in determining risk [ ] . mutations in sfpc genes have been associated with familial interstitial pneumonitis (fip) that includes uip, nsip, and other histological variants [ ] . further, germ line mutations in the genes encoding telomerase reverse transcriptase (htert) and telomerase rna (htr) were implicated in dyskeratosis congenita, a rare hereditary disorder associated with pulmonary fi brosis and aplastic anemia [ ] . these mutations result in telomere shortening, which has been implicated in age-related disease. interestingly, older age and smoking also cause telomere shortening [ ] . further, short telomeres were more common in fip and sporadic ipf compared to controls, even when mutations in htert and htr were lacking [ , ] . pulmonary fi brosis may also complicate diverse genetic disorders such as hermansky-pudlak syndrome [ ] , familial hypocalciuric hypercalcemia [ ] , neurofi bromatosis [ ] , etc. ipf occurs in caucasians and in nonwhites; prevalence among different ethnic groups has not been studied [ ] . a retrospective study of ipf in new zealand cited a lower incidence in those of maori or polynesian descent than in those of european descent [ ] . differences in susceptibility to fi brogenic agents may refl ect genetic polymorphisms [ ] . animal models involving different inbred strains of rodents demonstrate dramatic variability in the lung infl ammatory/fi brotic response to injurious agents. we believe that ipf is a heterogeneous disorder caused by a number of environmental/ occupational exposures in combination with genetic predispositions. chest radiographs in ipf typically reveal diffuse, bilateral interstitial or reticulonodular infi ltrates, with a predilection for basilar and peripheral (subpleural) regions [ , ] . the proclivity for peripheral lung zones is best demonstrated by hrct [ ] (figs. . - . ). as the disease progresses, lung volumes shrink. intrathoracic lymphadenopathy or pleural thickening is not evident on chest radiographs, but may be noted on ct scans [ ] . similar radiographic features are observed in asbestosis and ctd-associated pulmonary fi brosis [ , ] . chest radiographs have limited prognostic value, but serial radiographs (including old fi lms) may gauge the pace and evolution of the disease. thin section high-resolution computed tomographic (ct) scans are invaluable to diagnose and stage ipf [ , , ] . hrct can assess the nature and extent of parenchymal abnormalities, narrow the differential diagnosis, and in some patients, substantiate a specifi c diagnosis, obviating the need for slb. cardinal features of uip on hrct scan include: heterogeneous, "patchy" involvement; predilection for peripheral (subpleural) and basilar regions; hc; coarse reticular opacities (interlobular and intralobular septal lines); traction bronchiectasis or bronchioloectasis; minimal or no ground-glass opacities (ggos) [ , , ] (table . ). the guidelines suggest that the presence of four features: subpleural, basally predominant disease; reticular abnormality; honeycombing with or without traction bronchiectasis and the absence of features listed as inconsistent with a uip pattern allow a defi nitive diagnosis of a uip pattern to be made without the need for surgical biopsy [ a ] . with advanced disease, distortion, small lung volumes, and pulmonary hypertensive changes may be observed [ ] . zones of emphysema may be found in smokers [ ] . pleural involvement is not found. hc is a key feature discriminating uip from other interstitial pneumonias [ , , ] . however, ct features of uip and nsip overlap, and distinguishing these entities may be diffi cult [ , ] . further, classical ct features of uip are present in only - % of patients with histologically confi rmed uip [ ] [ ] [ ] . ct scans that are "atypical" or "indeterminate" may represent uip, nsip, or other histological variants [ , ] . extensive ggo is not a feature of ipf, and suggests an alternative diagnosis such as dip, nsip, lip, cop, hp, pulmonary alveolar proteinosis, etc.) [ , , ] . in contrast, hc is a cardinal feature of uip and is rare in other iips [ , ] . cystic radiolucencies may be observed in other disorders (e.g., langerhans cell granulomatosis, sarcoidosis, lymphangioleiomyomatosis (lam), pneumoconiosis, etc.), but the distribution of lesions and presence of concomitant abnormalities can differentiate these disorders from uip [ , ] . characteristic physiologic aberrations in uip include: reduced lung volumes, normal or increased expiratory fl ow rates, increased forced expiratory volume in s (fev )/forced vital capacity (fvc) ratio, reduced diffusing capacity for carbon monoxide (dl co ), hypoxemia or widened alveolar-arterial pao gradient [d(a-ao )] which is accentuated by exercise, reduced lung compliance, downward and rightward shift of the static expiratory pressure-volume curve, abnormalities on cardiopulmonary exercise tests (cpets) [ ] (table . ). impairments in gas exchange (i.e., dl co ) and oxygenation may be evident early in the course of the disease, even when spirometry and lung volumes are normal [ ] . a restrictive ventilatory defect, with reduced total lung capacity (tlc), is characteristic of ipf, but lung volumes may be normal if emphysema coexists [ ] . lung volumes (e.g., tlc, fvc) are typically higher in smokers (current or former) with ipf compared to nonsmokers [ ] . when emphysema coexists, dl co and oxygenation are disproportionately reduced [ , ] . cpet demonstrates hypoxemia, widened a-ao gradient, submaximal exercise endurance, reduced oxygen consumption (vo ), high respiratory frequency, low tidal volume ( v t ) breathing pattern, increased dead space ( v d / v t ), increased minute ventilation for the level of vo , and a low o pulse [ ] . arterial desaturation and abnormal widening of a-ao gradient with exercise may be elicited with relatively simple tests, such as the -min walk test ( mwt) [ ] . several mechanisms are responsible for exercise-induced desaturation including: ventilation-perfusion (v/q) mismatching, o diffusing limitation, and low mixed venous po [ ] . supplemental o during exercise may improve exercise performance and reduce strain to the myocardium. dyspnea is a cardinal symptom of ipf and profoundly limits exercise performance. other nonpulmonary factors which limit exercise performance include: deconditioning, peripheral muscle dysfunction, and nutritional status [ ] . pulmonary arterial hypertension (pah) has been reported in - % of patients with advanced ipf [ ] [ ] [ ] [ ] . correlations of physiological parameters with pah are imprecise [ ] [ ] [ ] . however, pah is more often present when dl co is severely reduced or hypoxemia is present [ , ] . pah worsens as ipf progresses [ ] . transthoracic echocardiography (tte) is a surrogate marker of pah. estimates of systolic pulmonary arterial pressure (spap) and size and functional status of the right ventricle (rv) by tte are useful to predict pah. in one study of ipf patients, spap (estimated by tte) correlated inversely with dl co and pao and was an independent predictor of mortality [ ] . median survival rates according to spap were as follows: spap < mmhg, . years; spap ³ < mmhg, . years; spap ³ mmhg, . years [ ] . in a cohort of patients with ipf in mexico, estimated spap ³ mmhg was an independent predictor of mortality [hazard ratio (hr) . ] [ ] . in another study of patients with ipf, pah [defi ned as mean pap (mpap) > mm by right heart catheterization (rhc)] was associated with increased -year mortality ( %) compared to . % mortality without pah [ ] . given the prognostic importance of pah, we perform tte in patients with moderate to severe ipf or those requiring supplemental oxygen. however, tte may be unreliable in some patients, either by inability to estimate spap or adequately image the rv [ , ] . in addition, specifi cities and negative predictive values of tte are suboptimal [ , ] . given the limitations of tte, rhc may be considered for selected ipf patients exhibiting o desaturation or severe derangements in dl co (< % predicted). however, data regarding therapy of pah complicating ipf are limited. anecdotal responses to prostanoids or sildenafi l were cited in small nonrandomized studies [ ] but survival benefi t has not been examined [ ] . median survival from the diagnosis of uip ranges from to years in various studies. advanced age [ , , , , ] and male gender [ , , ] were associated with a worse prognosis (higher mortality) in most studies. interestingly, three studies cited improved survival among current or former smokers with uip compared to never smokers [ , , ] . however, others found no such effect [ , ] . the apparent "protective effect" of cigarette smoking may relate to inhibitory effects of cigarette smoke on lung fi broblast proliferation and chemotaxis [ ] . a recent study of patients with ipf noted that survival was improved in nonsmokers compared to former or current smokers after adjustment for composite physiologic index (cpi) levels [ ] . in that study, current smokers had less severe disease at presentation and represented a "healthy smoker" effect. interestingly, the concomitant presence of emphysema had no infl uence on survival. a recent retrospective study from mexico cited a lower median survival time among patients with ipf and coexistent emphysema compared to ipf without emphysema ( vs. months, respectively) [ ] . early studies of ipf or cfa suggested that prognosis and responsiveness to therapy were improved when slb displayed "cellularity" (as opposed to severe fi brosis) [ , ] . in retrospect, these early studies almost certainly included iips other than uip [ ] . among patients with iips, the fi nding of uip on slb is a robust and single most important factor infl uencing mortality [ , ] . not surprisingly, severe derangements in pfts or oxygenation predict a worse prognosis (lower survival) in patients with ipf [ , ] . numerous studies cited higher mortality rates when dl co or lung volumes were severely impaired [ , , ] . the "cut-off" points predicting higher mortality vary considerably. mortality increases when fvc falls below % of predicted values or when dl co is < - % predicted [ , , , ] . changes in tlc are less predictive of prognosis or survival [ , ] . the relationship between any single physiologic variable and prognosis is complex and no single parameter can reliably predict prognosis in individual patients. further, disparate results have been reported from different centers. in four studies, the following parameters correlated with mortality: % predicted fvc and widened a-ao gradient [ ] , fvc < % predicted [ ] , reduced lung volumes and abnormal oxygenation during maximal exercise [ ] , multistage pao on cpet (p = . ) [ ] . british investigators examined -year survival among a cohort of ipf patients awaiting lt [ ] . the best predictors of survival (assessed at years) were: dl co < % predicted and increased fi brosis on hrct scan [ ] . in a separate study by these investigators [ ] , nonsmokers with ipf were prospectively followed. by univariate analysis, the following parameters predicted survival: age; fev ; fvc, dl co , pao ; o saturation; hrct fi brosis score; clearance of inhaled technetium m-diethylenetriamine penta-acetic acid ( mtc-dtpa) from the lungs ( t . ) [ ] . by multivariate analysis, the following parameters were independent predictors of survival: ( t . ), percent predicted tlc, percent predicted dl co , age. inclusion of other pft or ct scores did not improve the model. although it is intuitively obvious that severe impairment in pfts or oxygenation predicts higher mortality, statistical correlations in large patient cohorts are not readily applicable to individual patients. change in pulmonary functional parameters over time may be prognostically useful. however, variability among pfts confounds interpretation. measurement of fvc is less variable than tlc or dl co [ ] and is best suited for serial measurements. improvement or stability in vc or dl co with therapy is associated with improved prognosis in patients with ipf [ , ] . conversely, deterioration in vc or dl co at or months, year, or later time points predicts a worse survival [ , [ ] [ ] [ ] . in a retrospective study, serial pfts were performed in patients with ipf [ ] . by multivariate analysis, > % decrease in fvc at months was an independent risk factor for mortality (hr, . , p = . ) [ ] . collard et al. evaluated the prognostic value of serial clinical (dyspnea score) and physiologic parameters in patients with ipf [ ] . not surprisingly, survival was worse among patients with deteriorating dyspnea scores or pfts [fvc% predicted, p(a-ao )] at or months [ ] . british investigators retrospectively reviewed the prognostic signifi cance of histopathologic diagnosis, baseline pfts, and serial trends in pulmonary functional indices (e.g., fvc, fev , dl co ) at and months in patients with iip (uip, n = ; fi brotic nsip, n = ) [ ] . survival was better in fi brotic nsip compared with uip ( p = . ) but not in patients with severe functional impairment. mortality during the fi rst years was linked solely to the severity of functional impairment at presentation (i.e., lower dl co and fvc levels). the cpi score [ ] was the strongest determinant of outcome ( p < . ) [ ] . at months, serial pfts and histopathologic diagnosis were prognostically equivalent [ ] . however, at months, serial pft trends (dl co , fvc, fev , cpi) predicted mortality better than any other covariates including histological pattern (all p < . ). in this context, d d l co provided the best prognostic information ( -year survival); histological pattern provided no additional prognostic value. hypoxemia at rest or with exertion is associated with heighted mortality in ipf [ , ] . further, -min walk distance ( mwd) correlates with dl co % predicted [ , ] and has prognostic value. in one study of ipf patients awaiting lt, survival time was shorter among patients with mwd < m [ ] . in a subsequent study of ipf patients awaiting lt, lower mwd was associated with increased mortality (assessed at months) and was superior to fvc% predicted as a predictor of mortality [ ] . patients with mwd < m had a more than fourfold greater mortality than those with mwd ³ m, even after adjustment for demographics, fvc% predicted, pulmonary hypertension, and medical comorbidities [ ] . flaherty et al. assessed the prognostic value of mwt in a cohort of patients with ipf [ ] . by multivariate analysis, mwd was not a reliable predictor of mortality, but the degree of desaturation during mwt had greater prognostic value. patients with o saturation £ % during their initial mwt had a median survival of . years compared to . years for those with baseline sao > % ( p = . ). recently, a -min step test was advocated as another way of assessing exercise capacity and prognosis in patients with ipf or other ilds [ ] . formal cpet provides additional data including measurement of maximal oxygen uptake (vo ), an integrated measure of respiratory, cardiovascular, and neuromuscular function [ ] . fell et al. evaluated vo as a predictor of survival in a cohort of patients with ipf [ ] . patients with baseline vo < . ml/kg/min had an increased risk of death after adjusting for age, smoking status, fvc, and dl co . further, vo was a stronger predictor than desaturation < % on mwt. however vo did not predict survival when examined as a continuous variable. however, cpet with arterial cannulation is invasive, logistically diffi cult, diffi cult to perform for some patients, and lacks practical value. the extent and "pattern" of aberrations on ct have prognostic signifi cance [ , , ] . the global extent of disease on ct correlates roughly with severity of functional impairment in ipf [ , ] . more importantly, the pattern on ct has prognostic value. three major patterns include: ggos, reticular or linear pattern, hc [ , ] . ggo may refl ect intra-alveolar or interstitial infl ammation, fi brosis, or a combination. reticular lines refl ect fi brosis within alveolar ducts, septa, or spaces, but an infl ammatory component may coexist. hc refl ects irreversible destruction of alveolar walls and fi brosis [ , ] . reticular or "honeycomb" patterns predict a low rate of response to therapy [ , ] . early studies in patients with ipf (not all of whom had slb) noted that a pattern of "predominant ggo" on ct predicted an improved prognosis and responsiveness to therapy when compared to reticular or mixed patterns [ , ] . however, those sentinel studies may be misleading. extensive or predominant ggo is rarely found in ipf. patients exhibiting "predominant ggo" on ct are more likely to have nsip than uip [ , ] , which likely explains the more favorable prognosis in this context. extent of fi brosis on ct (ct-fi b) correlates with functional impairment and the extent of histologic fi brosis by slb and is an independent predictor of mortality [ , , , ] . british investigators assessed risk factors for -year survival in a cohort of patients with ipf awaiting lt [ ] . by multivariate analysis, only ct-fi b scores and dl co percent predicted were independent predictors of mortality. the risk of death increased by % for each unit increase in ct-fi b score and % for every % decrease in dl co percent predicted [ ] . receiving operating curve (roc) analysis gave the best fi t (predictive value) using a combination of dl co and ct-fi b scores. the optimal points on the roc curves for discriminating between survivors and nonsurvivors corresponded to % predicted dl co and to a ct-fi b score of . . the curve resulting from the model yielded a sensitivity and specifi city of % and %, respectively, for discriminating survivors from nonsurvivors at years. flaherty et al. assessed the impact of ct fi brotic scores in a cohort of with iips (uip = ; nsip = ; rbild/dib = ; other = ) [ ] . a ct-fi b score ³ in any lobe was highly predictive of uip (sensitivity, %; specifi city, %). the presence of an interstitial score ³ in any lobe was associated with increased mortality [relative risk (rr) of . , p = . ]. the degree of fi brosis of ct is a surrogate marker for the histological pattern of uip. ct scans that are "typical of cfa/ipf" were associated with more fi brosis and a higher mortality than "atypical" ct scans [ , ] . in a study of patients with iip ( had uip and had nsip by slb), ct scans "characteristic of uip" (i.e., deemed as "defi nite" or "probable" uip by experienced radiologists) predicted a worse survival [ ] . among patients with histologically confi rmed uip, mortality was higher when ct features were typical ("defi nite" or "probable") uip compared to those with a nondiagnostic ct ( p = . ) [ ] . median survival rates were . years among patients with both histologic and ct diagnosis of uip compared to . years among patients with histologic uip but atypical ct [ ] . ct features of uip (particularly honeycombing) likely refl ect more advanced disease. a recent study retrospectively reviewed ct scans from patients with a histologic diagnosis of uip [ ] . patterns of ct scans were categorized as: ( ) defi nite uip, ( ) probable uip, ( ) suggestive of alternative diagnosis. mean survival rates were . , . , and . months, respectively, median survival rates were . , . , and months, respectively. while these differences between groups did not achieve statistical signifi cance, these data suggest that ct scans interpreted as defi nite uip have a worse prognosis. by multivariate analysis, extent of traction bronchiectasis and fi brosis scores infl uenced prognosis. serial ct scans have been used to assess evolution of the disease or response to treatment in patients with ipf [ , , ] . reticular patterns or hc never regressed whereas ggo improved in - % of patients [ , , ] . when global extent of disease lessened on ct, it was due to reduction in the extent of ggo. importantly, despite early regression of ggo in some patients, ggo usually progresses inexorably to a reticular pattern or hc [ , , ] . given the potential for fi brosis to evolve over months to years, the value of ct in predicting long-term prognosis is modest. serial pfts are more useful than ct scans to document the initial extent of impairment and monitor the course of the disease. changes in ct are usually concordant with changes in fvc and dl co [ , , ] . watters et al. developed a composite score incorporating clinical (dyspnea), radiographic (chest x-rays), and physiological parameters (i.e., the clinical-radiographic-physiologic (crp) score) as a means to more objectively monitor the course of ipf [ ] . subsequently, a modifi ed crp score (arbitrary total of points) was developed in a cohort of patients with uip [ ] . this modifi ed score incorporated the following variables: age (maximum . points), smoking history (maximum . points), clubbing (maximum . points), percent predicted tlc (maximum points), pao at maximal exercise (maximum . points), changes on chest x-rays (profusion of interstitial opacities or pulmonary hypertension) (maximum . points) [ ] . in addition, an abbreviated crp score was developed, which excluded pao at maximal exercise. importantly, the modifi ed crp scores predicted -year survival with remarkable accuracy [ ] . five-year survival rates at crp scores of , , , and points were %, %, %, and < %, respectively. the abbreviated crp was less accurate, but more adaptable to clinical practice. these quantitative crp scoring systems are invaluable for research investigations, but are cumbersome for use in clinical settings. british investigators developed a cpi incorporating ct and physiologic parameters [ ] . the cpi score evaluated disease extent observed by hrct and selected functional variables (e.g.,% predicted fvc, dl co , and fev ). exercise components were not included in this index. the cpi accounts for coexisting emphysema, which may confound pulmonary functional indexes. in the cpi, both dl co and fvc were weighted positively [i.e., higher dl co or fvc resulted in lower (better) cpi scores] whereas the fev is weighted negatively [i.e., a higher fev results in a higher (i.e., worse) cpi score]. specifi cally, the formula for cpi was as follows: [extent of disease on ct = . − ( . × percent predicted dl co ) − ( . × percent predicted fvc) + ( . × percent predicted fev )]. cpi correlated more strongly with disease extent on ct than the individual pulmonary functional parameters. more importantly, cpi predicted mortality better than pfts in all subgroups including patients with uip on slb. on univariate analysis, several variables correlated with mortality including: greater extent of disease on ct ( p < . ), greater functional impairment (dl co , fvc, tlc, fev , alveolar volume (va), pao , a-ao gradient), higher cpi scores (all had p < . ). when compared with individual pulmonary functional components, ct disease extent was a more powerful predictor of mortality. however, the cpi index was the most powerful index and predicted survival better than the extent of disease on ct or any of the individual pft components. further, the cpi was compared to the original [ ] or modifi ed [ ] crp scoring systems in patients with uip who underwent cpet. the cpi was a superior predictor of outcome than the physiologic component of the original crp score ( p = . ) and the physiologic component of the modifi ed crp score ( p = . ). additional studies using these or similar crp scoring systems would be of interest. dynamic magnetic resonance imaging (mri) may discriminate infl ammatory from fi brotic lesions in iips [ ] , but data are limited. the role of mri in the diagnosis/staging of ipf needs to be further studied. radionuclide scans have been used to assess prognosis in diverse ilds. increased intrapulmonary uptake of gallium citrate (ga ) may be a marker of alveolitis [ ] . however, ga scans are expensive, diffi cult to quantitate, inconvenient (scans are performed h after injection with the radioisotope), require exposure to radiation, and are nonspecifi c [ ] . importantly, ga scans do not predict prognosis or responsiveness to therapy and lack practical value in the staging or followup of ipf [ ] . clearance of tc-diethylenetriamine penta-acetate (dtpa) aerosol is accelerated in ipf and is a marker of increased lung permeability [ , ] . increased clearance occurs in smokers and other infl ammatory lung disorders; its prognostic value is debatable [ ] . some investigators cited changes in pulmonary vascular permeability on positron emission tomographic (pet) scans in patients with ipf [ ] , but sensitivity, specifi city, and clinical value have not been clarifi ed. we do not employ radionuclide techniques for either the staging or follow-up of ipf. fiberoptic bronchoscopy with bronchoalveolar lavage (bal) contributed signifi cant insights into the pathogenesis of ipf and other ilds but practical value is limited [ , ] . increases in polymorphonuclear leukocytes, eosinophils, mast cells, alveolar macrophages, and myriad cytokines are noted in bal fl uid from patients with ipf; lymphocyte numbers are usually normal [ , , ] . bal neutrophilia is present in - % of patients with ipf [ , , ] but does not predict prognosis or therapeutic responsiveness. by contrast, bal lymphocytosis is rarely found in ipf and suggests an alternative diagnosis (e.g., cellular nsip or hp) [ ] . although the etiological agent(s) in ipf has not been elucidated; two key features, that is, alveolar epithelial cell (ec) injury and dysregulation of fi broblasts (fbs) appear to be pivotal in the pathogenesis [ , ] . lung fbs isolated from patients with ipf demonstrate greatly enhanced proliferation and production of collagen and ecm [ ] . injury to alveolar ecs and destruction of the subepithelial basement membranes are likely early events in the pathogenesis of ipf [ ] . alveolar ecs exhibit hypertrophy/hyperplasia and ultrastructural alterations in ipf and have the potential to secrete a vast array of cytokines and growth factors [ ] . soluble mediators secreted by cells in the surrounding milieu lead to local recruitment, differentiation, and proliferation of fbs. in this context, for example, transforming growth factor-b (tgf-b ), platelet-derived growth factor (pdgf), tumor necrosis factor-a (tnf-a ), connective tissue growth factor (ctgf), and interleukin- (il- ) likely play key roles [ ] . these secreted peptides induce leukocyte infl ux and promote fi brosis. historically, it was believed that infl ammatory leukocytes were the source of these pro-fi brotic cytokines. however, alveolar ecs appear to be the most important source of these cytokines. stimulation of cytokine production by injured ecs may play a critical role in initiating fi brosis in ipf; the infl ux of infl ammatory leukocytes may be a sequela of ec activation rather than a primary event in the pathogenesis of ipf. the varying degrees of infl ammation and fi brosis in the iips are likely dependent on, and determined by, local tissue microenvironments that are pathologically altered by a combination of host and environmental factors. a distinctive feature of ipf/uip is the so-called fi broblastic foci (ff), often found at the leading edge of normal and fi brotic lung [ ] . it has been proposed that ff are a manifestation of ongoing lung injury [ ] . epithelial cell death is most prominent immediately adjacent to ff [ ] . further, fbs and myofi broblasts isolated from patients with ipf induce apoptosis of alveolar ecs in vitro, demonstrate increased production of collagens, increased expression of tissue inhibitors of metalloproteinases (timps), and a relative decrease in collagenases [ , ] . the combination of excessive production and deposition of ecm proteins and reduced proteolysis of ecm contributes to the fi brotic process in ipf [ ] . it has been suggested that ff represent "wound healing" responses to repetitive ec injury, resulting in dysfunctional epithelial-mesenchymal cross-talk [ ] . a critical aspect of this dysregulated process is the inability for alveolar ecs to regenerate, reepithelialize, and form a normal barrier across the alveolar wall [ ] . this results in a persistent "onsignal," in part mediated by chemokines, cytokines, and growth factors that activate the underlying mesenchyme. mesenchymal cells that form ff in ipf are activated and display a contractile phenotype, commonly referred to as myofi broblasts [ ] . myofi broblast differentiation and fate is controlled by soluble growth factors such as tgf-b and matrix-derived signals [ , ] . under the infl uence of tgf-b , myofi broblasts display increased production of collagen, vimentin, b -actin, and timps [ , ] . this combination of features leads to a bias towards excessive matrix deposition and wound contraction in ifp. greater understanding of mechanisms that mediate apoptosis of these cells, a process that has been described in the resolution of cutaneous wound healing [ ] , may allow development of new therapeutic targets in ipf [ ] . a pro-angiogenic environment may favor fi brosis in ipf [ ] . neovascularization is a prominent feature of fi brosis in both humans and animal models [ ] . interleukin- (il- ) and ifn-ginducible protein- (ip- ), members of the cxc chemokine family, affect fi brosis via angiogenic mechanisms [ ] . il- and its murine functional homologue macrophage infl ammatory protein- (mip- ) induce neutrophil and endothelial cell chemotaxis in vitro and stimulate neovascularization [ ] . in contrast, ip- inhibits angiogenesis and endothelial cell chemotaxis [ ] . in humans with ipf, il- is markedly elevated in bal fl uid and serum whereas ip- levels in ipf lung biopsies are reduced compared to controls [ ] . these fi ndings suggest that a pro-angiogenic environment exists in ifp and may propagate fi brosis. several other pathophysiological processes may be critical in the abnormal lung repair process in ipf. plausible mediators of the fi brotic process include: integrin-mediated intercellular adhesion molecules (icam) [ ] , abnormal surfactant proteins [ ] , imbalances in the production and/or localization of matrix metalloproteinases (mmps) and timps [ ] , predominance of type ii cytokine profi les (particularly il- and il- ), eicosanoids, oxidative stress responses [ ] . treatment options for ipf are still limited. until relatively recently, randomised, double-blind, placebo-controlled (rdbpc) studies have been lacking, and optimal therapy is controversial. historically, corticosteroids (cs) or immunosuppressive or cytotoxic agents were used, in an attempt to ablate any infl ammatory component. however, infl ammatory cells are relatively inconspicuous in ipf [ ] , and the degree of infl ammation does not correlate with disease severity [ ] . in animal models, fi brosis can occur even in the absence of neutrophils or lymphocytes [ ] . thus, it is not surprising that anti-infl ammatory therapies have limited or no benefi t in ipf [ , ] . several retrospective studies found no survival advantage with any form of therapy [ , , , ] . in , the ats/ers consensus statement on ipf concluded: "no data exist that adequately document any of the current treatment approaches improves survival or the quality of life for patients with ipf" [ ] . more recently the ats/ers/jrs/alat guidelines stated that "the preponderance of evidence to date suggests that pharmacologic therapy for ipf is without defi nitive, proven benefi t". since this statement was published. three trials of therapy have been reported that suggest some treatment effect [ a, a, b, c ] . despite the lack of proven benefi t, physicians have in the past offered treatment in an attempt to slow or prevent inexorable progression to fatal respiratory failure. in the sections that follow, we briefl y discuss treatment options. corticosteroids were the mainstay of therapy for more than decades, but are of unproven effi cacy and are associated with signifi cant toxicities [ , ] . early studies of patients with ipf cited response rates of - % with cs (alone or combined with immunosuppressive agents), but complete or sustained remissions were rare [ , , , ] . more importantly, many "responders" likely had iips other than uip (e.g., nsip, cop, or rbild/dip). in recent studies, response rates to cs among patients with histological evidence for uip were low ( - %) [ ] . large retrospective studies of patients with ipf showed no survival benefi t with cs [ , , ] . given the potential severe toxicities associated with cs, high dose cs should not be used to treat ipf [ ] . however, since anecdotal responses to cs are occasionally noted in patients with ipf, the ats/ers consensus statement acknowledged that selected patients with clinical or physiological impairment or worsening pfts should be treated [ ] . among patients requiring treatment , recommended therapy was as follows: oral azathioprine (aza) or cyclophosphamide (cp) plus low-dose prednisone or prednisolone [ . mg/kg (lean body weight per day) for weeks, then . mg/kg for weeks, then . mg/kg]. this represents a substantial departure from earlier regimens advocating high-dose prednisone (e.g., ³ mg/kg/day for ³ - weeks) [ , ] . combined therapy should be continued for months in the absence of adverse effects. treatment should be continued beyond months only if patients improve or remain stable. these recommendations [ ] refl ect expert opinion, but have not been validated in clinical trials. we believe cs should not be given to patients at high risk for adverse effects (e.g., age > years, osteoporosis, diabetes mellitus, extreme obesity, etc.) azathioprine aza has been used to treat ipf for more than three decades but effi cacy is debatable. only two prospective studies evaluated aza for ipf [ , ] . in both studies, aza was combined with prednisone. in the fi rst study, patients with progressive ipf were initially treated with prednisone alone for months [ ] . at that point, aza ( mg/kg/day) was added and both agents were continued for an additional months or longer. twelve patients ( %) responded. the independent effect of aza was diffi cult to assess since all patients received prednisone concomitantly. in a second, double-blind trial by these investigators, patients with newly diagnosed, previously untreated ipf were randomized to receive aza ( mg/kg/day) plus high dose prednisone ( n = ) or high dose prednisone plus placebo ( n = ) [ ] . at year, pfts (fvc, dl co , a-ao gradient) were similar between groups. vital capacity improved (> % above baseline) in fi ve patients receiving aza/prednisone and in two patients receiving prednisone/placebo. dl co improved (> % above baseline) in three patients receiving aza/prednisone, and in two receiving prednisone/placebo. mortality was similar at year (four patients died in each group). at late follow-up (mean years), % of aza-treated patients had died compared to % in the prednisone plus placebo cohort. this survival difference was not statistically signifi cant. aza has potential bone marrow, gastrointestinal toxicities, and is associated with a heightened risk for infections [ ] . in contrast to cyclophosphamide, aza does not induce bladder injury and is less oncogenic [ ] . aza ( - mg/kg/day) is our preferred agent for ipf patients with progressive disease. a -month trial is reasonable. however, in general toxicities associated with aza outweigh benefi t. cyclophosphamide (either oral or by intravenous pulse) has been used to treat ipf, but results are unimpressive [ , , ] . anecdotal responses to oral or pulse cp have been cited, but marked or sustained improvement is rarely achieved [ ] . toxicities associated with cp are substantial, and include bone marrow toxicity, opportunistic infections, infertility, bladder injury, and oncogenesis [ ] . we believe that the toxicities associated with cp outweigh benefi t. cyclosporin a and mycophenolate mofetil have been used to treat ipf, but data are limited to anecdotal case reports and retrospective series [ ] . infl iximab, a chimeric anti-tnf-a antibody, has been used to treat pulmonary fi brosis complicating connective tissue disorders [ ] , but data affi rming effi cacy in ipf are lacking. etanercept, a recombinant soluble human tnf-a receptor antagonist, has been used to treat ipf, but is of unproven benefi t. a rdbpc trial in patients with progressive ipf found no signifi cant differences in predefi ned efficacy endpoints [i.e., d % predicted fvc and dl co and d p(a-ao ) gradient at rest] at weeks [ ] . however, a trend in favor of etanercept-treated patients was noted in several secondary measures. additional trials are required before tnf-a inhibitors can be endorsed as therapy for ipf. colchicine displays antifi brotic effects in vitro and in animal models but was ineffective in ipf in both retrospective and prospective, randomized trials [ ] . n -acetylcysteine (nac) is an antioxidant that stimulates glutathione synthesis and attenuates fi brosis in animal models. a multicenter, rdbpc trial (ifigenia) in europe evaluated the efficacy of oral nac in ipf [ ] . all patients received "conventional" therapy with aza ( mg/kg/day) plus prednisone ( . mg/kg/day, with taper). patients were then randomized to oral nac ( , mg/day) or placebo. at the end of year, pfts had deteriorated in both cohorts. however, the rates of decline in fvc and dl co were less in patients receiving nac ( p < . ) [ ] . these changes in pfts were small (absolute difference in fvc of . % and in dl co . %) and of doubtful clinical signifi cance. the benefi t (if any) of nac as therapy for ipf remains controversial. nonetheless, nac is inexpensive and has few side effects, making this an attractive option for ipf. a multicenter rdbpc trial sponsored by the ipfnet to address the impact of nac in ipf is in progress. endothelin- (et- ) receptor antagonists reduce collagen deposition in animal models and have a theoretical role to treat ipf. a multicenter rdbpc trial evaluating bosentan use in interstitial lung disease (build- ) randomized ipf patients to bosentan or placebo [ ] . patients with severe pulmonary dysfunction (fvc < % predicted or dl co < % predicted) or concomitant pah were excluded. at months, mwd (the primary endpoint) worsened in both groups (no significant differences between groups). mean changes from baseline in fvc at months were − . and − . % in the bosentan and placebo groups, respectively. mean changes from baseline in dl co at months were − . and − . % in the bosentan and placebo groups, respectively. however, a trend in favor of bosentan was noted in the secondary endpoint [time to death or disease progression, (hr . , p = . )] [ ] . in a larger study (build- ), patients with mild to moderate ipf were randomized to bosentan (n= ) or placebo (n= ) for months [ a ] . no signifi cant difference between groups were observed in the primary endpoint (time to ipf worsening or allcause death). interferon-g (ifn-g ) attenuates collagen synthesis by fbs in vitro and attenuates fi brosis in animal models [ ] . despite initial enthusiasm for recombinant ifn-g - b in humans, this agent conferred no survival benefi t in two large, rdbpc trials [ b, c ] . given the lack of proven effi cacy of any therapeutic modality, and toxicities associated with cs or immunosuppressive agents, we reserve treatment for patients with a deteriorating course, severe or progressive symptoms, and no obvious contraindications to therapy. empirical treatment is more attractive when surrogate markers of alveolitis are present (e.g., ggo on ct or bal lymphocytosis). we offer treatment to selected patients, but only after an honest discussion with the patient and family of the low likelihood of success and the potential for signifi cant adverse effects. for patients desiring treatment, we recommend oral aza ( mg/kg/ day), either alone or combined with modest doses of prednisone (e.g., . mg/kg/day for weeks, with gradual taper). we rarely employ cp. prednisone is tapered to mg daily (or equivalent) within months. we do not recommend cs when specifi c contraindications or risk factors are present (e.g., obesity, diabetes mellitus, osteoporosis, age > years, history of psychiatric illness, poorly controlled hypertension). unless adverse effects necessitate early discontinuation of therapy, we treat for months and reassess at that point. treatment is continued only when improvement or stability has been demonstrated by objective tests (e.g., pfts or ct). single lung transplantation (slt) is advised for patients with severe disease or failing medical therapy [ ] . additional novel therapies are being studied (discussed later), but therapeutic effi cacy has not yet been shown. the following functional measurements are essential for the initial assessment and monitoring of ipf: spirometry, dl co ; mwt [ ] . fvc is highly reproducible, and correlates better with prognosis than tlc; dl co is more variable [ ] . although authors differ regarding what constitutes "signifi cance," the ats/ers defi ned the following changes as clinically signifi cant: fvc or tlc ³ - %; dl co ³ %; ³ mm increase in pao saturation or > mm increase in pao during exercise [ ] . the mwt provides a noninvasive, simple method to assess exercise capacity and the need for supplemental o [ ] . we perform serial spirometry, dl co , and mwt at - month intervals to monitor the course of the disease. more frequent studies may be necessary in the event of clinical deterioration. more sophisticated studies (such as cpep, measurement of compliance or elastic recoil) lack practical, clinical value [ ] . supplemental oxygen improves quality of life and exercise capacity in hypoxemic patients with ipf [ , ] ; impact on survival has not been studied. pulmonary rehabilitation has been advocated to improve quality of life and exercise capacity [ ] , but data affi rming benefi t are lacking. pulmonary hypertension may complicate advanced uip, but the benefi t of pah-specifi c therapy is this context has not yet been elucidated [ ] . oral codeine or other antitussive agents may be used to control cough [ ] , but are of limited benefi t. opiates have been used to reduce dyspnea in patients with severe chronic lung disease, but have not been shown to be effective [ ] . slt may be considered for patients with severe ipf [ ] . two-year survival following lt ranges from to %; year survival is to % [ , ] . international society for heart and lung transplant (ishlt) registry data for recipients with ipf cited improved survival with bilateral sequential lung transplantation (bslt) compared to slt ( p = . ) [ ] . survival rates were similar up to years, but diverged thereafter [ ] . recent data from the ishlt cited lower survival rates at months post-lt among patients with ipf ( %) or idiopathic pah ( %) compared to cystic fi brosis ( %) and chronic obstructive pulmonary disease (copd) ( %) [ ] . among patients surviving to year, ipf and copd had the worst long-term survival, most likely refl ecting older age and comorbidities [ ] . most deaths following lt are due to chronic allograft rejection or complications of immunosuppressive therapy [ ] . due to a shortage of donor organs, waiting time for lt may be prolonged (up to - years) and many patients with ipf die while awaiting lt [ ] . unless contraindications exist, patients with severe functional impairment (e.g., fvc < % predicted, dl co < % predicted), oxygen dependency, and a deteriorating course should be listed promptly for transplantation [ ] . acute respiratory failure requiring mechanical ventilation (mv) may complicate ipf (either due to progression of ipf or an intercurrent illness) [ , ] . in this context, mortality is high (> %). given the poor prognosis, mv is usually ill-advised in patients with severe ipf unless a potentially reversible process (e.g., pneumonia, pulmonary edema, pulmonary embolism, etc.) is diagnosed in a relatively young patient. current therapies for ipf based upon altering the infl ammatory component are only marginally effective. major advances await the development of novel therapies that prevent fi broproliferation and/or enhance alveolar re-epithelialization [ ] . novel agents that have been tested include pirfenidone, for which there are now four reports of rdbpc, a tyrosine kinase inhibitor and anticoagulants (discussed below). pirfenidone ( -methyl- -phenyl- -[ h]-pyridone) attenuates pulmonary fi brosis in animal models, inhibits collagen synthesis in vitro, and blocks the mitogenic effect of pro-fi brotic cytokines in adult human lung fbs from ipf patients [ ] . a phase ii rdbpc trial compared pirfenidone to placebo ( : ratio) in a cohort of patients with ipf [ ] . the study was stopped prematurely because acute exacerbations were noted in fi ve patients receiving placebo ( %) compared to no cases in the pirfenidone group. the primary endpoint (change in lowest o saturation on mwt over or months) was not met. there were no signifi cant differences between groups in mortality, tlc, dl co , or resting pao . the rate of decline in fvc at months was lower in the pirfenidone group ( p = . ), but differences between groups were small and of doubtful clinical signifi cance. in a second japanese study, patients were randomised to receive either high dose ( mg./day), low dose ( mg/ day) or placebo for weeks. the high dose group had a lower rate of reduction in vital capacity and in the incidence of progression, defi ned as either death or a decrease of > % vital capacity, compared with the placebo group [ a ] . pirfenidone has been approved for use in japan and also in china and india. two international placebo-controlled rdbpc evaluating pirfenidone as therapy for ipf were recently completed (intermune, brisbane, ca) and have been published recently. the primary end point of these over the next years, exercise capacity worsened despite relatively stable pfts. in may , he was hospitalized with an acute exacerbation of ipf that was treated with pulse methylprednisolone. shortly following discharge, he developed another acute exacerbation for which he was rehospitalized. in hospital, he required high fl ow oxygen ( l/min) and was dyspneic at rest. he underwent single lt in july two almost identical studies that included patients and that evaluated mg/day pirfenidone with placebo was change in forced vital capacity over a week period. one of the studies was positive with a magnitude of effect similar to that seen in the japanese studies. the second study did not reach its primary end point but in this and the positive study, several secondary end point indices were positive, including progression-free survival and change in distance walked in six minutes [ b ] . the european commission has recently granted marketing authorisation for esbriet (pirfenidone) for the treatment of mild to moderate ipf in the eu. infl ammation and vascular injury in ipf may lead to a prothrombotic state that could exacerbate lung injury [ ] . japanese investigators randomized ipf patients to anticoagulants (warfarin) or placebo [ ] . three-year survival and freedom from acute exacerbations were improved in the anticoagulated group. however, dropout rate was high, and selection bias may have infl uenced the study. given the risk associated with anticoagulation, additional studies involving greater numbers of patients are required before endorsing this form of therapy. recently, a placebocontrolled study evaluating warfarin therapy for ipf conducted under the auspices of the ipfnet has been discontinued for lack of effi cacy. a phase ii rdbpc study of the effect of a tyrosine kinase inhibitor bibf on the rate of decline of forced vital capacity has just been published [ c ] . the rate of reduction of forced vital capacity was reduced by % with the highest dose of active drug compared with placebo and there was effi cacy in a number of secondary end points including progression-free survival. in addition there was some evidence for a dose-response effect. this effi cacy of the drug is now being tested in two phase iii rdbpc studies. fig. . ) ipf is a heterogeneous disease, with marked differences in prognosis and disease evolution. while most patients display a gradual decline in function over months to years (case ), some patients remain stable for years even without therapeutic intervention (case ). finally, a precipitous decline in lung function and marked hypoxemia may signal an acute exacerbation of ipf (case ). current therapies for ipf are of limited effi cacy with the exception of pirfenidone and the promise of the tyrosine kinase inhibitor bibf . in the years ahead, it will be important to identify and develop new molecular agonists or antagonists designed to interrupt or reverse the fi brotic process. novel agents that inhibit fi brosis in vitro or in animal models and are worthy of study in future clinical trials include: angiotensin-ii antagonists, platelet-activating factor receptor antagonists, inhibitors of leukocyte integrins, cytokines or proteases; agents that block il- , il- , or tgf b ; imatinib mesylate, sirolimus, keratinocyte growth factor; relaxin; lovastatin; endothelin- antagonists; strategies which promote matrix resorption (e.g., by enhancing the activity of mmps) [ ] . hopefully, development of effective antifi brotic therapies may improve the outcome of what currently is a frustrating and enigmatic disease. idiopathic pulmonary fi brosis: diagnosis and treatment. international consensus statement ats/ers/jrs/ alat committee on idiopathic pulmonary fibrosis. an offi cial ats/ers/jrs/alat statement: idiopathic pulmonary fi brosis: evidence-based guidelines for diagnosis and management interstitial pulmonary and bronchiolar disorders diagnosis of usual interstitial pneumonia and distinction from other fi brosing interstitial lung diseases european respiratory society international multidisciplinary consensus classifi cation of the idiopathic interstitial pneumonias computed tomographic features of idiopathic fi brosing interstitial pneumonia: comparison with pulmonary fi brosis related to collagen vascular disease usual interstitial pneumonia assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fi brosis computed tomography fi ndings in pathological usual interstitial pneumonia: relationship to survival idiopathic pulmonary fi brosis: role of high-resolution thin-section computed tomographic scanning radiologic vs histologic diagnosis in uip and nsip: survival implications idiopathic pulmonary fi brosis: outcome in relation to smoking status connective tissue disease-associated interstitial lung disease the association between idiopathic pulmonary fi brosis and vascular disease: a population-based study association between ischaemic heart disease and interstitial lung disease: a case-control study role of diabetes mellitus and gastro-oesophageal refl ux in the aetiology of idiopathic pulmonary fi brosis high prevalence of abnormal acid gastro-oesophageal refl ux in idiopathic pulmonary fi brosis pathologic and radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia a comparison of the clinical features of ancapositive and anca-negative idiopathic pulmonary fi brosis patients pulmonary fi brosis associated with anca-positive vasculitides. retrospective study of cases and review of the literature comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia prognostic value of circulating kl- in idiopathic pulmonary fi brosis monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins a and d idiopathic pulmonary fi brosis. impact of oxygen and colchicine, prednisone, or no therapy on survival pulmonary function in idiopathic pulmonary fi brosis and referral for lung transplantation 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idiopathic pulmonary fi brosis incidence and mortality of idiopathic pulmonary fi brosis and sarcoidosis in the uk is idiopathic pulmonary fi brosis an environmental disease? early interstitial lung disease in familial pulmonary fi brosis clinical and pathologic features of familial interstitial pneumonia seasonal variation: mortality from pulmonary fi brosis is greatest in the winter heterozygosity for a surfactant protein c gene mutation associated with usual interstitial pneumonitis and cellular nonspecifi c interstitial pneumonitis in one kindred host-environment interactions in pulmonary fi brosis gastroesophageal refl ux in patients with idiopathic pulmonary fi brosis referred for lung transplantation gastro-oesophageal refl ux and gastric aspiration in lung transplant patients with or without chronic rejection lynch rd jp. chronic lung allograft rejection: mechanisms and therapy interstitial pulmonary and bronchiolar disorders genetic factors in pulmonary fi brotic disorders telomerase mutations in families with idiopathic pulmonary fi brosis short telomeres are a risk factor for idiopathic pulmonary fi brosis telomere shortening in familial and sporadic pulmonary fi brosis lower occurrence of idiopathic pulmonary fi brosis in maori and pacifi c islanders thoracic imaging for diffuse ild and bronchiolar disorders idiopathic pulmonary fi brosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension resting and exercise physiology in interstitial lung diseases six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fi brosis pulmonary hypertension in patients with idiopathic pulmonary fi brosis pulmonary hypertension and pulmonary function testing in idiopathic pulmonary fi brosis prediction of pulmonary hypertension in idiopathic pulmonary fi brosis pulmonary hypertension complicating interstitial lung disease serial development of pulmonary hypertension in patients with idiopathic pulmonary fi brosis prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fi brosis echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease sildenafi l improves walk distance in idiopathic pulmonary fi brosis pulmonary ( m)tc-dtpa aerosol clearance and survival in usual interstitial pneumonia (uip) idiopathic pulmonary fi brosis: relationship between histopathologic features and mortality the prognostic signifi cance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fi brosing alveolitis survival in patients with cryptogenic fi brosing alveolitis: a population-based cohort study diffuse interstitial pneumonitis. clinicopathologic correlations in patients treated with prednisone/azathioprine the relationship between individual histologic features and disease progression in idiopathic pulmonary fi brosis idiopathic pulmonary fi brosis: a composite physiologic index derived from disease extent observed by computed tomography prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends changes in clinical and physiologic variables predict survival in idiopathic pulmonary fi brosis idiopathic pulmonary fi brosis: prognostic value of changes in physiology and six-minute-walk test exercise testing determines survival in patients with diffuse parenchymal lung disease evaluated for lung transplantation a step test to assess exercise-related oxygen desaturation in interstitial lung disease the prognostic value of cardiopulmonary exercise testing in idiopathic pulmonary fi brosis high-resolution computed tomography in idiopathic pulmonary fi brosis: diagnosis and prognosis a clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fi brosis -t mri for differentiating infl ammation-and fi brosis-predominant lesions of usual and nonspecifi c interstitial pneumonia: comparison study with pathologic correlation other imaging techniques for idiopathic interstitial pneumonias bronchoalveolar lavage in idiopathic interstitial lung diseases. semin respir crit care med signifi cance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fi brosis emerging drugs for idiopathic pulmonary fi brosis lynch rd jp. idiopathic pulmonary fi brosis: pathogenesis and therapeutic approaches idiopathic pulmonary fi brosis. clinical relevance of pathologic classifi cation pirfenidone clinical study group in japan. pirfenidone in idiopathic pulmonary fi brosis pirfenidone in patients with idiopathic pulmonary fi brosis (capacity): two randomised trials effi cacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis azathioprine combined with prednisone in the treatment of idiopathic pulmonary fi brosis: a prospective double-blind, randomized, placebo-controlled clinical trial randomized controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fi brosing alveolitis immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders infl iximab therapy in pulmonary fi brosis associated with collagen vascular disease treatment of idiopathic pulmonary fi brosis with etanercept: an exploratory, placebo-controlled trial high-dose acetylcysteine in idiopathic pulmonary fi brosis build- : a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fi brosis build- : a randomized, controlled trial of bosentan in idiopathic pulmonary fi brosis idiopathic pulmonary fibrosis study group. a placebo-controlled trial of interferon gamma- b in patients with idiopathic pulmonary fi brosis effect of interferon gamma- b on survival in patients with idiopathic pulmonary fi brosis (inspire): a multicentre, randomised, placebo-controlled trial overview of lung transplantation and criteria for selection of candidates pulmonary rehabilitation in idiopathic pulmonary fi brosis: a call for continued investigation registry of the international society for heart and lung transplantation: twenty-fourth offi cial adult lung and heartlung transplantation report- registry of the international society for heart and lung transplantation: twenty-fi fth offi cial adult lung and heart/lung transplantation report- outcome of patients with idiopathic pulmonary fi brosis admitted to the intensive care unit outcome of patients with idiopathic pulmonary fi brosis (ipf) ventilated in intensive care unit double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fi brosis current perspectives on the treatment of idiopathic pulmonary fi brosis anticoagulant therapy for idiopathic pulmonary fi brosis key: cord- - wqdlha authors: nan title: oral session date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: wqdlha nan introduction rheumatic heart disease, predominantly mitral stenosis is a chronic disease that produces an increase in the left atrial pressure and consequently venous pulmonary hypertension. preoperative lung function which could be obtained from spirometry can evaluate respiratory reserve in cardiopulmonary patients who will undergo surgery. however, data on the use of spirometry in predicting the rate and extent of regression of preoperative pulmonary artery hypertension is limited. methods we determined the usefulness of preoperative lung function by spirometry in predicting regression of pulmonary hypertension after surgical correction of mitral stenosis among patients who underwent mitral valve surgery at philippine heart center from july to december . results among the twenty patients included in the study, one had normal spirometry and another one had mild obstructive abnormality. majority of the patients ( / ) had restrictive abnormality. nineteen patients had regression of pap. among them, patients were noted to have restrictive abnormality and one with normal spirometry. there was only one patient who did not have regression of pap and found to have a mild obstructive abnormality. correlation of the severity of restrictive lung defect with the change in pap classifi cation among nineteen patients showed lack of correlation with a spearman coeffi cient of . and p-value of . . (figure ) conclusion this study showed that majority of rhd patients particularly mitral stenosis will have a preoperative spirometric abnormality of restrictive pattern. among the study group, almost all patients ( / ) will have regression of pulmonary hypertension after surgery except for one patient with obstructive lung abnormality. though results were not signifi cant, we cannot conclude that preoperative lung function is not predictive of regression of pulmonary hypertension after surgical correction of mitral stenosis due to inadequacy of sample size. thus, further investigation is warranted. introduction drug-induced interstitial lung disease (ild), particularly pulmonary fi brosis, is a serious clinical concern and myofi broblasts have been suggested to play a major role, with it recently being revealed that some of these myofi broblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (emt). in this study, we used cultured epithelial cells to examine the emt-inducing abilities of drugs known to induce ild clinically. methods induction of emt in cultured lung epithelial cells were monitored by up-regulation of the expression of myofi broblast marker proteins and downregulation of the expression of epithelial cell marker proteins. the severity of lung injury and fi brosis in mice was assessed by various methods, such as histopathologic evaluation, histochemical analysis of collagen and determination of hydroxyproline. results emt-like phenotypes were induced by a , an active metabolite of lefl unomide having an inhibitory effect on dihydroorotate dehydrogenase (dhodh). smad interacting protein (a transcription factor regulating emt) and the notch-signaling pathway were shown to be involved. when the cultures were supplemented with exogenous uridine, the a -induced emtlike phenotypes disappeared. likewise, an a analog without inhibitory activity on dhodh produced no induction, suggesting that this process is mediated through the inhibition of dhodh. in vivo, administration of lefl unomide stimulated bleomycin-induced emt-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fi brosis, both of which were suppressed by co-administration of uridine. conclusion these fi ndings suggest that lefl unomide-dependent exacerbation of bleomycin-induced pulmonary fi brosis is mediated by stimulation of emt of lung epithelial cells, providing the fi rst evidence that drug-induced pulmonary fi brosis involves emt of these cells. we consider that this lefl unomide-dependent exacerbation of bleomycin-induced pulmonary fi brosis provides a suitable animal model of drug-induced ild, which is important to establish not only a clinical protocol for its treatment but also an assay system that will facilitate screening in order to eliminate candidate drugs with the potential to produce this type of side effect. introduction to observe the infl uence of arsenic trioxide on the bleomycininduced pulmonary fi brosis in rats and its mechanisms. methods pulmonary fi brosis was induced in sprague-dawley (sd) rats by intratracheal instillation of bleomycin(blm). the rats of the treatment group, the steroid group and model group were intraperitoneally injected with arsenic trioxide(ato), dexamethasone or normal saline(ns)respectively, while the control rats received ns both intratracheally and intraperitoneally. the effects of interference were evaluated by median survival time, hydroxyproline level in lung, semi-quantitative grading of alveolitis and pulmonary fi brosis and quantititative analysis of collagen in lung (masson's trichrome stain). apoptosis index (ai) of lung was detected by using the terminal transferase dutpdigoxygenin nick end-labeling (tunel) method and the results of the immunohistochemical staining of some cytokines were quantitatively analyzed. results ato might ( ) prolong the median survival time of blm-induced pulmonary fi brosis rats at some extent; ( ) attenuate the alveolitis and pulmonary fi brosis, reduce hydroxyproline level and collagen deposition in lung tissue; ( ) increase the ai of lung tissue at a certain phase; and decrease the levels of transforming growth factor-β (tgf-β ) and tissue inhibitor of metalloproteinase- (timp- ), increase the content of interferon-γ(ifn-γ) signifi cantly. conclusion ato might attenuate blm-induced pulmonary fi brosis in rats via increasing the ai of lung tissue. introduction combined pulmonary fi brosis and emphysema (cpfe) is a syndrome involving both emphysema and diffuse parenchymal lung disease with fi brosis on chest computed tomography (ct). the clinical characteristics of cpfe have been described; however, the differences between the syndrome and interstitial pneumonia (ip) or chronic obstructive pulmonary disease (copd) are not fully understood. the purpose of this study was to clarify the differences in respiratory resistance and reactance using a forced oscillation technique. methods the subjects included patients with cpfe, with ip, and with copd. respiratory resistance and reactance were measured using most-graph- (chest mi co., ltd., tokyo, japan), and pulmonary function tests were also performed on the same examination day. results the fev and fev /fvc values were signifi cantly lower in copd patients compared to those with cpfe and ip. there was no signifi cant difference in vc between cpfe, ip, and copd patients. the carbon monoxide transfer coeffi cient values were signifi cantly lower in cpfe and copd patients compared to those with ip. resistance at hz (r : cmh /l/s) was significantly elevated in patients with copd (cpfe, . ; ip, . ; and copd, . , respectively, p < . for cpfe vs. copd), while r was elevated in patients with ip and copd compared to those with cpfe (cpfe, . ; ip, . ; and copd, . , respectively, p < . for cpfe vs. ip and for cpfe vs. copd). the resonant frequency (hz), a parameter of reactance, was signifi cantly higher in copd patients compared to cpfe and ip patients (cpfe, . ; ip, . ; and copd, . , respectively, p < . for cpfe vs. copd and for ip vs. copd). conclusion cpfe patients exhibited no airfl ow limitation or restrictive impairment, but showed severe gas exchange abnormality similar to that in copd patients. the absence of an elevation of respiratory resistance or reactance refl ects homogenous ventilatory mechanics in cpfe, thereby differentiating it from ip and copd. these results suggest that cpfe is a distinct syndrome differing from ip or copd. pneumonectomy is a surgical removal of a lung. it poses several adverse consequences as it substantially diminishes diffusion capacity by reducing total number of alveoli and vasculature available for gas exchange. the challenge is to maintain adequate gas exchange following resection of the lung tissue. literature revealed a good prognosis for pneumonectomized infant. there is enhancement of diffusion capacity in remnant lung through generation of new pulmonary gas exchange units. this was evidenced by normal lung volumes of the pneumonectomized infants after years. in this article, we present a day old female who was noted to be tachypneic, with chest indrawing and subcostal retractions. chest roentgenogram done revealed collapsed right lung, dextrocardia with hyperinfl ated and hyperluscent left lung. d echo showed no anatomic anomaly, except for dextroposed heart probably secondary to the collapsed right lung. impression then was congenital cystic adenomatoid malformation versus congenital lobar emphysema, left lung. extensive work-up was done. chest ct scan showed overly infl ated and hyperluscent lung segment arising from left lower lobe which is characteristic of a congenital lobar adenomatoid malformation. lung perfusion scan demonstrated diminished perfusion of the left lung with differential contribution to the total perfusion of the % left lung and % right lung. patient then underwent open thoracotomy with pneumonectomy of the left lung. biopsy revealed congenital cystic adenomatoid malformation type ii. three months after the surgery, she has gained weight, not receiving any medications and is symptom free. introduction despite the importance of infection and infl ammation in the pathogenesis and management of bronchiectasis, there are few published data on lower airway microbiology and cellularity in these children. methods children attending a single centre ( to ) with non-cystic fi brosis bronchiectasis who underwent bronchoalveolar lavage (bal) within weeks of diagnosis were identifi ed. the point prevalence of infection (> colony-forming units (cfu)/ml of respiratory bacterial pathogens), its effects upon airway cellularity and the impact of clinical and demographic variables on infection risk were evaluated. results of children with bronchiectasis, ( %) had bal evidence (> cfu/ml) of infection, which was frequently polymicrobial and caused mostly by haemophilus infl uenzae, streptococcus pneumoniae and moraxella catarrhalis. in contrast, pseudomonas aeruginosa was uncommon and mycobacterial and fungal species were undetected. upper airway commensal organisms were also isolated in large numbers (> cfu/ml) from ( %) bal cultures. the median (interquartile range; iqr) bal fl uid total cell counts (tcc × /l) and neutrophil percentages were signifi cantly higher in those with, than without, infection [tcc ( - ) vs ( - ); p = . and neutrophil percentage % ( - ) vs % ( - ); p = . respectively]. only age at diagnosis was associated with infection. conclusion bal microbiology of children with newly diagnosed bronchiectasis substantially differs from adults. children have marked airway neutrophilia, particularly when bacterial loads were high. younger children were more likely to have a lower airway infection at diagnosis. the role and interactions of respiratory bacterial fl ora in initiating and progressing airway damage in bronchiectasis requires further study. the radiological defi nition of airway dilatation and bronchiectasis in children has substantial limitations. bronchoarterial ratio is a commonly used criterion to defi ne airway dilatation despite the lack of normative pediatric data. the objective of our study was to determine the range of normal bronchial to accompanying arterial diameter ratio on high resolution ct scan of the chest in children and compare it with the available adult data. methods children undergoing mdct chest for non-pulmonary conditions at a single centre were prospectively identifi ed. high resolution reconstruction was performed on those included and both airway and vessel diameters were measured in the upper and lower lobes of both lungs. mean bronchoarterial (ba) ratio was calculated for each included child and its correlation with age assessed. results forty one children were included, the mean (sd) ba ratio was . ( . ) (range . to . ). this ratio was clinically similar though statistically lower than comparable adult data [combined mean (sd) . ( . ); p = . ]. no correlation was found with age in our cohort (r = − . , p = . ). there was no difference in the ratio based on laterality or lobe. conclusion in pediatric age-group, the airway is signifi cantly smaller than the adjoining vessel. using the radiological criteria of ba ratio greater than one to defi ne bronchial dilatation would under estimate the presence and extent of bronchiectasis leading to delayed and missed diagnosis. this highlights the need to redefi ne the criteria for bronchial dilatation in children. introduction sleep disordered breathing, especially obstructive sleep apnea syndrome, has been found to be associated with endothelial dysfunction in both adult and paediatric populations. however, the role of non-apnoeic snoring on endothelial function has not been investigated. methods children aged - years with habitual snoring were recruited from our sleep disorder clinic. non-snoring controls were recruited from participants of a community growth survey. all participants underwent nocturnal polysomnography (psg) and ultrasonographic fl ow mediated dilation (fmd) evaluation on the same day. fasting blood was taken for glucose level and lipid profi le determination. subjects with an obstructive apnoea hypopnoea index (oahi) < but reported by parents to have habitual snoring (at least nights per week) in the past months were defi ned as primary snorers (ps). those having an oahi < without habitual snoring in the past months were grouped as non-snorers. children with body mass index of greater than the th percentile of the local reference were defi ned as overweight. subjects were divided into groups of normal weight, overweight, non-snorers and ps for comparisons. results in total, children, of whom were boys, with a mean (sd) age of . ( . ) years were recruited. sixty-six of them were ps. subjects with ps had signifi cantly reduced fmd than non-snoring controls for both the normal weight group (p = . ) and the overweight group (p = . ) ( table ) . multivariate linear regression model showed that primary snoring (p < . ) were independently associated with fmd after controlling for possible confounders including overweight, gender, baseline vessel diameter and log-transformed oahi. conclusion primary snoring in children is independently associated with impaired endothelial function. introduction children with cyanotic congenital heart disease live with baseline oxygen saturations in the mid s, so hence they exist on the steep part of the oxyhemoglobin dissociation curve. these patients are at increased risk for the hemodynamic variations occurring during apneas/hypopneas. longterm outcomes for children with congenital heart disease could be adversely affected since the etiology of pulmonary hypertension is believed to be secondary to the hypoxia and hypercarbia seen in chronic airway obstruction paired with the sympathetic overstimulation caused by frequent sleep arousals. methods a prospective two part questionnaire for the screening of sdb for pediatric patients was performed. part one consists validated pediatric sleep questionnaire (psq). part two consisted of subjective assessment of the subject's cardiovascular and respiratory symptom. all odd ratios of greater than with p-values less than . were considered signifi cant covariates. results a total of children met the inclusion criteria and were included in the fi nal analysis. the prevalence of sleep disordered breathing (sdb) was high at . %. among the factors analyzed, an increased frequency of pulmonary diseases (greater than times/year) was statistically correlated with increased psq scores (p = . ). likewise, early palliative repair (p = . ) was statistically associated. a high total cardiac score is almost four times associated with increased psq ratings (p = . ). conclusion increased frequency of pulmonary diseases and early palliative repair was statistically correlated with increased pediatric sleep questioner scores. a high total cardiac score is almost four times associated with increased psq ratings. hence patients with congenital heart disease and sleep disordered breathing are more likely to have worse cardiac symptoms. patient with congenital heart disease shoukl be routinely examined for the presence of sleep disordered breathing because these sub group of pediatric patients are x have more high risk for developing sleep disordered breathing. introduction atelectasis, is a common pulmonary complication of patient who underwent open heart surgery. deep breathing exercise is one of the interventions implemented to prevent the occurrence of this complication postoperatively. among preschoolers however, making them perform this breathing exercise and maintaining compliance is a challenge since children in this age group have a short attention span and may get bored easily. with this problem at hand, the investigators conceptualized an innovative technique, blowing bubbles as a breathing exercise, in order to prevent atelectasis among post open heart surgery preschoolers. methods this study is an open-label randomized control trial that compared blowing bubbles with the traditional deep breathing exercise among preschoolers who underwent open heart surgery. it took months to complete the study and there were patients screened but only qualifi ed based on the inclusion/exclusion criteria. thirty were assigned randomly to the blowing bubbles group and to the deep breathing exercise. atelectasis as documented on chest x-rays was the outcome measured. results out of the participants in the deep breathing group, developed atelectasis while in the blowing bubbles group, out had atelectasis this generated a p-value of . which is statistically signifi cant, favoring the blowing bubbles group. furthermore, risk analysis showed an absolute risk reduction of . % and a relative risk of less than which means that atelectasis is less likely to occur in the blowing bubbles group in comparison to the traditional breathing exercise group. conclusion blowing bubbles signifi cantly reduces the occurrence of atelectasis among post-open heart surgery preschoolers as opposed to deep breathing exercise. the use of blowing bubbles as a deep breathing modality incorporated through play activity is recommended among preschoolers. introduction severe acute respiratory syndrome (sars) is a novel contagious respiratory infection caused by the sars coronavirus (sars cov). in adults, a mortality rate of % has been reported, and respiratory complications can occur in up to % of survivors. the disease pattern is different in children [ , ] but prevalence of longer term respiratory complications in children is unknown. the aim of this study was to investigate the aerobic capacity of children at years after the diagnosis of sars. methods twenty-seven patients (mean age of . years) who completed both pulmonary function and maximal aerobic capacity (peak vo ) tests at and months after the acute illness were invited for re-assessment. they underwent anthropometric assessment, full pulmonary function and exercise treadmill test. subjects with abnormal hrct at months underwent repeat scanning. results at this -month assessment, subjects refused to take part, and the main reasons of refusal were work commitments or time clashes with school activities. the remaining subjects ( % female) provided complete pulmonary function and exercise data. pulmonary function test was normal in all patients. peak vo , peak oxygen pulse, and ventilatory anaerobic threshold (vat) at this assessment were signifi cantly higher than that recorded at and months. ventilatory effi ciency (ventilatory equivalents for oxygen, ve/vo ) and perfusion to the lungs (end-tidal partial carbon dioxide pressure, petco ) signifi cantly improved since months and maintained at months. though peak vo further improved at months in patients with persistent or without radiological abnormalities, their values were % and % respectively of normal controls. conclusion this study is the most comprehensive report of post-sars exercise responses in children and adolescents. improvements in aerobic capacity over a period of months after the initial illness were demonstrated, but the values remained suboptimal when compared to normal reference. introduction domestic mites are an important source of indoor allergens responsible for the development of allergic diseases worldwide. to date, there is no local epidemiology data on the allergic sensitization to domestic mites among adult patients with asthma and allergic rhinitis. methods from november to june , we prospectively recruited adult patients with asthma and/or allergic rhinitis from an urban-based specialist medical centre in penang, malaysia, carefully profi ling their allergic sensitization to domestic mites by means of skin prick tests and clinico-demographic details. of the patients [mean age (ci) years ( - ); % male] recruited, skin allergic rates to dermatophagoides pteronyssinus, d. farinae, blomia tropicalis and tyrophagus putrescentiae were %, %, % and % respectively. there was no signifi cant difference in these rates among patients with asthma, allergic rhinitis or both. there were signifi cant associations between the number of people living in the same house with rates of d. pteronyssinus (p = . ) and d. farinae (p = . ), and the frequency of bed sheet changing with the rate of tyrophagus putrescentiae (p = . ). with younger age, there were also signifi cant higher allergic rates with d. pteronyssinus (p < . ), d. farinae (p < . ), b. tropicalis (p < . ) and tyrophagus putrescentiae (p = . ). conclusion our preliminary data shows a high prevalence of allergic sensitization to domestic mites in our local adult patients with asthma and/or allergic rhinitis. the fi ndings have implication on allergen control with the view of disease mitigation. introduction a study was carried out to compare the effi cacy and sensory perception of mometasone furoate and ciclesonide aqueous nasal spray in moderate-severe allergic rhinitis. methods a single blind study of months on patient of both sexes, > years, diagnosed as moderate-severe allergic rhinitis as per aria workshop( ) , with skin test positivity to at least two aeroallergens was carried out on patients. patients were divided into two, i.e. mometasone (group a) and ciclesonide groups (group b). group a received microgram/day of mometasone furoate and group b received microgram/day of ciclesonide, nasal spray once daily in the morning. the evaluation was made at , , , , weeks by total nasal symptoms score (tnss), visual analogue scale (vas) and sinonasal outcome test- (snot- ). sensory perception of both nasal steroids was carried out on initial visit before allocating groups, employing a sensory perception questionnaire with a sensory items ( points scale). patients were given one nasal spray, and immediate and after two minutes response was noted in questionnaire. after minutes of washout period, second drug was given and response was noted in similar way. results after months, both mometasone and ciclesonide signifi cantly decreased nasal symptoms as assessed by tnss (p-value = . ) and vas (p-value = . ) and improved quality of life signifi cantly as assessed by snot- (p-value = . ). however there was no statistically signifi cant difference among two drugs. the sensory perception, in favour of mometasone was observed immediately after drug administration, than ciclesonide by providing more comfort during administration, less irritation, odor prference (all p-value . to . ). however, after minutes of drug application, there was no signifi cant difference among both drugs in strength of taste, amount of medication rundown and irritation. the overall acceptance by patients was for mometasone over ciclesonide (p-value = . ). conclusion both mometasone and ciclesonide adequately controlled symptoms of allergic rhinitis in months. the sensory perception preference for many of the sensory attributes in mometasone group were in favour of mometasone. thus, mometasone has equal effi cacy but slightly better acceptability over ciclesonide in the treatment of allergic rhinitis. results of patients, . % were male and . % females. % patients had used alternative asthma therapies: homeopathy, ayrurveda and yoga with poor results and . % had used multiple therapies prior to visit our centre. patients reported being afraid of acute attack ( . %) and hospitalization ( . %). although inhalers were used by indian patients in . % but still oral drugs were used regularly by . % patients. compared to . % in only . % were inhaler naïve (t-value . ). only / ( . %) patients were using spacer with mdi's and % ( / ) being able to demonstrate correct use. common errors seen in mdi's use were: a) slow and steady inhalation ( . %) and b) breath holding after deep inhalation ( . %). formoterol and budesonide dpi was considered most effective by indian patients in controlling disease when asked to rate their devices and drugs. when counseled by experts % were sure to be regular on treatment but month latter % remained regular (t-value . ). fear of addiction ( . %) and cost of therapy ( . %) were cited causes for noncompliance. conclusion indian patients use alternative therapy for asthma treatment before coming to tertiary centre and still prefer oral therapy. despite extensive education being afraid of attacks become noncompliant due to fear of addiction and cost of therapy. the oesophagus and airways have a common origin. refl uxrelated respiratory symptoms may be triggered by aspiration of gastric refl uxate into airways or a vagally mediated oesophago-tracheo-bronchial. this association has not been reported previously in sri lanka. the aim of this study was to describe the association between gastro-oesophageal refl ux (gor) events and respiratory symptoms in a cohort of adult asthmatics in sri lanka. methods thirty stable, mild asthmatics (american thoracic society criteria) underwent dual-sensor ambulatory oesophageal ph monitoring. respiratory symptoms (cough, wheeze, diffi cult breathing, chest tightness) during monitoring were recorded and correlated with refl ux events. results both proximal and distal gor parameters were signifi cantly higher in asthmatics than controls (p < . ; mann-whitney u-test). however, there was no difference in any parameter between asthmatics with and without respiratory symptoms. abnormal proximal acid refl ux was documented in . % and distal refl ux in . % of asthmatics. of respiratory symptoms in all asthmatics, majority ( %) were cough episodes. in total, % of coughs, % of wheeze and all of chest tightness was refl ux-associated, where in most, refl ux events preceded respiratory symptoms. of asthmatics with respiratory symptoms, acid exposure was normal in ( %), abnormally high in proximal oesophagus in ( %) and abnormally high in the distal oesophagus in ( %) and abnormal at both levels in ( %). most refl ux events in asthmatics occurred in the upright position. conclusion asthmatics have more gor and associated respiratory symptoms than non-asthmatic volunteers, with refl ux episodes preceding respiratory symptoms in most cases. distal gor and upright acid exposure was more prominent than proximal gor. in , fi rst population-based studies to determine the magnitude of the asthma problem have been carried out in bangladesh, to defi ne the prevalence of asthma and to identify the risk factors of asthma in bangladesh. after years, same study carried out to fi nd out trends of asthma in bangladesh. methods a cross-sectional study was conducted from january to august on people and same study carried out from november to april on subjects. data collected from stratifi ed randomly selected primary sampling units of all districts. face-to-face interviews were performed with housewives or other guardians at the household level using a structured questionnaire. results in , the prevalence of asthma (wheeze in the last months) was . % ( % ci: . - . ) whereas in it is . % ( % ci: . - . ). in , prevalence of other asthma defi nitions were: ever wheeze (lifetime wheeze) . % ( % ci: . - . ); perceived asthma (perception of having asthma) . % ( % ci: . - . ); doctor diagnosed asthma (diagnosis of asthma by any category of doctor either qualifi ed or unqualifi ed) . % ( % ci: . - . ). in , ever wheeze (lifetime wheeze) . % ( % ci: . - . ); perceived asthma (perception of having asthma) . % ( % ci: . - . ); doctor diagnosed asthma (diagnosis of asthma by any category of doctor either qualifi ed or unqualifi ed) . % ( % ci : . - . ).the prevalence of asthma in children ( - years) was higher than in adults ( - years) ( . % versus . %; odds ratio [or] = . , % ci: . - . ). trends of asthma in bangladesh remains, almost static over last years although at present prevalence is more in adults than children. in adults ( - years) all categories were slightly higher than in children ( - years) ( . % versus . %; odds ratio [or] = . , % ci: . - . ). it is found to be significantly higher in house-holds with one to fi ve members than in larger households (or = . , % ci: . - . ). the poor two quintiles (or = . , % ci: . - . ) and illiterate group (or = . , % ci: . - . ) and primary level of education (or = . , % ci: . - . ) were more vulnerable to asthma attacks than the highincome group and more educated people, respectively. conclusion asthma has increased from million people to million over last years although prevalence is almost similar. introduction secretory gvpla is an inducible protein and an essential signaling molecule for airway infl ammation and airway hyperresponsiveness in immunosensitized and lps-induced ali in mice. however, identifi cation of secretory gvpla in human airway diseases has not been identifi ed previously. methods donors were classifi ed as non-asthmatic, asthmatic, copd or ipf from prior medical records. identifi cation of gvpla in airway microsections was quantifi ed by immunofl uorescence analysis. expression of gvpla in was analyzed using criteria for intensity scoring in a single-blinded method. in separate studies, airway smooth muscle cells (asmc) obtained from asthmatic and non-asthmatic subjects (regional organ bank of illinois) were cultured within h from death. adhesion was assessed by measuring the eosinophil peroxidase activity of adherent eosinophils to asmc. inhibition of adhesion was assessed using neutralizing mabs against surface adhesion molecules and mab against gvpla . results gvpla was abundantly expressed in airway smooth muscle, epithelium and endothelium of patients with a history of asthma compared to non-asthmatic. low expression of gvpla was observed in tissues from copd and ipf subjects. in cultured asthmatic asmc, surface icam- and vcam- also were upregulated. activation of asthmatic asmc with methacholine caused release of gvpla , which corresponded to augmented eosinophil adhesion; mcl- g , a mab against gvpla , prevented these responses. blockade of surface β -/β -integrin on eosinophils or its counter-ligands on asmc blocked also the adhesion. conclusion our data demonstrated that gvpla is highly expressed in asthmatic asm but not in patients having, no history of asthma, copd or ipf. gvpla secreted from activated asmc augments eosinophil adhesion; mcl- g specifi cally blocked the cell-cell ligation. these data are the fi rst demonstration that the upregulated eosinophil adhesion to the surface of asthmatic asmc is linked directly to the secretory gvpla . based on our fi ndings, it is likely that the asmc, which is the natural source of gvpla , regulates airway infl ammation and airway hyperreactivity, which are hallmarks of asthma. supported by nih grant hl- and uk gsk center of excellence in asthma. introduction currently, there is still a lack of operational research analyzing the infl uence of an adequate tb curriculum in medical school. this study, aims to determine the effi ciency of integration of tb program into the medical school curriculum, measured through the knowledge, attitudes, and practices of medical clerks on tb. methods a questionnaire-based survey on the knowledge, attitudes and practices on tuberculosis was conducted among medical clerks (fourth year medical students) in the ust hospital. in total, questionnaires were randomly distributed, of which ( % response rate) of the questionnaires were returned fully accomplished. this was done over a period of one week. the questionnaire used was developed by hong, et al ; huebner, et al ; and yu, et al . and modifi ed by the present authors. results a total of . % (n- / ) of the clerks believed that sputum exam and culture are still the standard diagnostic modalities; quadruple therapy for - months as the standard treatment regimen. in total, . % (n = / ) realized the magnitude of the problem of tb in the philippines; half of them rated the directly-observed therapy, short course (dots) program as good. in order to avoid infection, % wear masks, . % keep their distance, and only . % open windows. only . % would add two drugs to the current regimen of a patient with suspected drug resistance; while . % responded with adding just one drug. conclusion the integration of tb program in the curriculum of ust medical students is effective in enhancing knowledge and improving attitudes of the medical clerks. however, there is still a need to stress the importance of other practices aside from wearing masks in order to avoid infection, and to clarify issues on drug resistance. the study was undertaken to assess the feasibility of diagnosing pulmonary tuberculosis (ptb) by collecting two sputum samples on a single day ( -day protocol) and to compare the same with the national policy of collecting two samples on consecutive days ( -day protocol). methods five hundred and thirteen individuals with cough exceeding weeks were screened for pulmonary tuberculosis (ptb) by collecting three sputum samples, viz. day- spot sample, sample collected hour after the fi rst sample and next day morning sample. for the -day protocol, performance of the fi rst and third samples were considered, while the -day protocol was evaluated using the two day- samples. staining and microscopy were undertaken by two different technicians in a blinded manner. results out of patients, patients defaulted on second day. of the total number of patients recruited, ( . %) were smear-positive. the -day protocol was capable of detecting patients ( . %), whereas in the -day protocol patients ( . %) were smear-positive (p = . ). of the drop-out patients, ( . %) were smear-positive. comparing the variation in results between spot and morning samples, collection of morning sample exhibited no signifi cant benefi t over the collection of a second spot sample. conclusion because the -day protocol does not lead to a statistically signifi cant diagnostic difference compared to the -day protocol, the latter can be adopted as an alternative protocol, particularly in subjects who are more likely to default. introduction tuberculosis, an important preventable and treatable cause of death, is a major health problem worldwide. detecting patients with active pulmonary tuberculosis is an important component of tuberculosis control as early appropriate treatment renders these patients noninfectious and interrupts the chain of disease transmission. sputum microscopy remains the test of choice as initial work-up for symptomatic patients with tuberculosis. however, in patients with a compatible clinical picture, sputum smears do not always reveal acid-fast bacilli. patients symptomatic for tuberculosis but are found to be smear-negative are recommended to undergo further tests including fi beroptic bronchoscopy and sputum induction. the latter, however, is invasive and more costly. this study aims to compare the sensitivity and specifi city of sputum induction and bronchscopy in the diagnosis of sputum smear-negative tuberculosis by means of meta-analysis. methods computer search was done to obtain studies meeting inclusion criteria. the sensitivity, specifi city and other measures of accuracy were pooled using forest plots. diagnostic odds ratios were obtained. summary receiver operating characteristic curves were used to summarize overall test performance. funnel plots and egger regression analysis were used to examine for publication bias. results five prospective studies comparing diagnostic accuracy of fi beroptic bronchsocopy and sputum induction to diagnose sputum smear negative tb were obtained. the pooled summary indeces showed that for bronchial lavage, the sensitivity is . ( % ci, . to . ) while specifi city is . ( % ci, . to . ). whereas for sputum induction, the sensitivity is . ( % ci, . to . ) and specifi city is . ( % ci, . to . ). the summary dor for bronchial lavage was . ( % ci, . to . ) while the summary dor for sputum induction was meaning sputum induction test had a higher level of overall accuracy ( % ci, to ). conclusion sputum induction has comparable sensitivity and specifi city and higher level of overall accuracy compared to bronchial lavage in diagnosing for sputum smear negative tuberculosis. introduction much of tuberculosis control is based on the current understanding of factors that infl uence transmission of mycobacterium tuberculosis and that lead to active tuberculosis among persons who acquire the infection. one of these activities, contact investigation, is intended to identify persons who have acquired tuberculosis infection from a newly discovered active case, thereby enabling targeting of preventive treatment to a group at high risk of developing active tuberculosis, this being the main goal of activity. methods the charts of close contacts of mdrtb patients enrolled in the programmatic mdrtb management of lcp phdu from january to june was reviewed. results there were contacts of culture and dst-confi rmed mdrtb patients identifi ed from january to june . among these contacts, ( . %) were traced and underwent evaluation and screening tests. among the contacts > years old, ( . %) had a positive chest x-ray, ( . %) were afb +, ( . %) were positive for mtb culture and sensitivity. in contacts < years old, ( . %) had positive chest x-ray results, but none had positive results on afb smear, and mtb culture and sensitivity. tuberculosis was identifi ed in of contacts < years old and of contacts > years old. there were mdrtb cases identifi ed ( confi rmed by culture and dst, and treated empirically), all from contacts > years old. all identifi ed mdrtb cases were treated with category iv regimens under pmdt, while other tb (non-mdrtb) cases were managed under dots. conclusion contact tracing remains a helpful tool in public health programs at the lung center of the philippines. although the average contact per index is . , . % were successfully traced, which is comparable to other studies abroad. among the screening tools, the chest x-ray was the most commonly utilized and also the most productive; afb smear, tuberculin test, and mtb culture were performed in less than %. among identifi ed contacts, mdrtb was noted in . %. introduction active pulmonary tuberculosis (tb) requiring intensive care is rare but known to be of poor outcome. the present study aimed to describe the characteristics of patients with this condition and to identify the mortality rate and risk factors that predicts in-hospital mortality. methods from january to december , patients were admitted to tuberculosis intensive care unit (tbicu) of mackay memorial hospital, taipei, taiwan. among these, patients were enrolled and were followed up for days. incidence of in-hospital deaths was documented in the medical records and all possible parameters contributing to mortality were collected for analysis. results the patients' median age was years (range - years). the median length of intensive care unit stay was days (range - days) and the median duration of mechanical ventilation was days (range - days). overall in-hospital mortality was % ( / ). sepsis and shock were independently associated with in-hospital mortality. conclusion these data indicated a high mortality of patients with active tuberculosis requiring intensive care, especially in those with sepsis and shock. introduction we have shown that two commonly used prediction model s (va and mayo) estimate poorly the probability of malignancy of solitary pulmonary nodules (spn) in the philippines. this is due to a large proportion of spn arising from tuberculosis (tb). in the philippines, and possibly for other countries with a high tb-burden, our clinical prediction model has a better estimate to the probability of spn than both the va and mayo. methods we developed a prediction model to identify malignant lung nodules based on clinical data and radiographic characteristics among patients with spn identifi ed retrospectively (october to march ) in our institution. univariate and multiple logistic regression analysis were used to identify independent clinical variables. we applied the model to a new set of spn patients (april and august ) and described its accuracy by comparing the predicted probability of malignancy with the fi nal diagnosis. we constructed receiver operating characteristic (roc) curves and reported % confi dence interval. calibration was done by dividing the sample into fi ve equal groups based on predicted probability and plotting the median probability of each quintile against the observed frequency of malignancy for that group. results seventy-six spn patients were included in the development of the prediction model, where size, margin and smoking history were found significant in the multivariate analysis. prevalence of malignancy was %. the area under the receiver operating characteristic (roc) curve was . ; % confidence interval (ci) of . - . . the equation was obtained based on the identifi ed predictors. fifty-eight patients with spn were included in the validation sample. prevalence of malignancy was %. the roc curve was . ; % c.i. of . - . . median predicted probabilities in all quintiles were lower than the observed frequency of malignant nodules, probably refl ective of the validation sample's higher prevalence of malignancy. conclusion the local clinical model appeared to be suffi ciently accurate to inform clinical decisions about the choice and interpretation of subsequent diagnostic tests. the accuracy of the local clinical prediction model was similar to that reported in its development. introduction in a high-burden country for pulmonary tuberculosis like philippines, it's not uncommon for intracthoracic masses be treated empirically with anti-tuberculosis regimen. we aim to describe patients' profi les, determine outcomes of empiric anti-tuberculosis treatment for such lesions. methods we monitored patients with intrathoracic mass given empiric antituberculosis regimen until "end-of-treatment," decision to pursue diagnosis, or mortality. a -year prospective, observational, open-label, descriptive, cohort study, in a tertiary government hospital. percentage association analysis was done at end of the study. results in total, patients presenting with intrathoracic mass lesions on chest x-ray/chest ct scan were treated empirically with anti-tuberculosis medicines without histopathologic evidence suggestive of pulmonary tuberculosis for the mass. patients' choices, clinical and fi nancial status were factors considered by physicians in the decision for empiric treatment. there were males, females, with average age years. most common chief complaints were cough ( %), pain ( %), hemoptysis ( %), shortness of breath ( %). patients had pulmonary consult within months of initial radiography. histology of mass was confi rmed within months of pulmonary consult in patients. patients had the histopathology prior to starting empiric anti-tb treatment, which revealed non-specifi c fi ndings. a total of patients were treated empirically prior to attempts for histologic diagnosis. two of these patients never had diagnostics due to fi nancial constraints. while patients went on to pursue histopathology, which revealed underlying malignancy in eight patients. malignancy was seen more on males, older age (≥ years), signifi cant smoking history, larger mass size (∼ - cm). seven patients had clinical/radiographic improvement, two patients died, three were lost to follow-up. conclusion our study suggests no role for empiric anti-tb treatment for intrathoracic masses, even in a high-burden country like philippines. we should vigorously pursue and search for defi nite histological diagnosis, as it will translate to cost-effectiveness, avoidance in delayed diagnosis, early institution of appropriate therapeutic management. we recommend further studies with larger sample size, to characterize patients' profi les, do subset analysis, identify who may need anti-tuberculosis treatment. introduction the use of viruses as targeted cancer therapy has shown signifi cant promise for novel anticancer therapy. actually, a small number of enteroviruses, such as coxsackievirus a (cva) and echovirus, have been reported to possess oncolytic activities against various human malignancies. however, a single intratumoral administration of cva in vivo induces severe progressive muscle paralysis necessitating euthanasia of mice. in this context, we discovered that coxsackievirus b (cvb) displayed a high level of tropism and lytic activities for human lung cancer cell lines as a result of screening of representative enteroviruses. cvb specifi cally destroyed both human non-small and small cell lung carcinoma via surface virus receptors of coxsackievirus and adenovirus receptor (car) at a multiplicity of infection (moi) of . , whereas it did not destroy normal lung cells at even a higher moi of . the mts cell proliferation assay also supported those results. furthermore, our in vivo study showed that consecutive intratumor injections of cvb remarkably inhibited the growth of subcutaneously pre-established lung tumors, with signifi cantly more increased survival than untreated mice (p < . ). surprisingly, in metastatic tumor mice model, intratumoral cvb injection into primary tumors in the right fl ank also signifi cantly retarded the growth of pre-established contra-lateral tumors compared with untreated mice. according to the results of fragmented parp detection assay, the oncolytic effects of cvb against tumors could be partially attributed to their apoptosis as well as cellular degenerative destruction. furthermore, fl ow cytometric analyses showed that cvb could possess an immuno-stimulatory ability through robust infi ltrated dendritic cells maturation in treated tumors. moreover, none of mice died of cvb administration, suggesting the feasibility of clinical trials in the future, although analyses of serum biochemistry revealed moderate hepatic dysfunction due to cvb administration. conclusion our fi ndings suggest that intratumor cvb administration could be a novel therapeutic modality against not only primary human lung cancer but also metastasized lesions. introduction radio frequency ablation (rfa) is a technique that employs high-energy radio frequency waves to destroy non-small cell lung cancer. the radio frequency ablation probe, le-veen multiple array needle electrodes, is placed inside a tumor and opened like a tiny umbrella with curved prongs that spring into the surrounding tumor tissue. with this tool tumor cells are somewhat heated until they boil and become inert. methods patients with medically inoperable or unresectable single nodule nsclc underwent treatments, in different centers of bangladesh. multimodality treatment was mode of management. on the basis of intention to treat, patients were divided into fi ve groups for fi ve mode of treatment. group : percutaneous rfa (n = ); group : rfa followed by radiotherapy (n = ); group : chemotherapy with rfa (n = ); group : radiotherapy alone (n = ); and group : chemo radiation (n = ) during -year period ( - ). patients' characteristics, local recurrences and overall and disease-free survivals were compared. results in total, patients were selected for study since december . mean size of tumors were ± . (range . - . cm). follow-up range was from to months, median . months. survival rate of group : only percutaneous rfa was % at year, % at years and % at years; for group : rfa and ebrt % at months, . % at year, . % at years, and . % at years; group : patients treated rfa with chemo therapy % at year, % at years and % at years; group : with radiotherapy alone % at year, % at years, and % at years; for group : similar patients treated with chemoradiation % at year, % at years and % at years. irrespective of stages, patients with tumor size cm (n = ) had an average survival ± months. local recurrence occurred in . % having tumors size cm. developed pneumothorax and had lung infections, of them had fetal. a total of patients died of co morbid diseases while died of disease progression within years following rfa and ebrt or chemotherapy or rfa alone. conclusion the rfa followed by ebrt or rfa along with adjuvant or neo adjuvant chemotherapy for inoperable nsclc has a relatively low rate of complications that are easily managed and above all survival has improved compared with other combination therapy, i.e. chemoradiation. nb: rfa plus chemotherapy was only applied in stage ii and iii. introduction patients with chronic or debilitating illness such as lung cancer usually accompanied by some form of emotional responses such as denial, anxiety, and depression. clinician should be aware of these condition for better lung cancer management. methods hamilton rating scale for anxiety and depression questionnaire were administered to all patients diagnosed with lung cancer in dept pulmonology-respiratory medicine university of indonesia/persahabatan hospital consecutively. follow-up evaluation will be done to evaluate anxiety/depression after a -month therapy. results among lung cancer patients , ( %) has anxiety, patients ( %) has depression and all patients with depression also has anxiety. these conditions commonly found in male than female ( out of male patients ( %) vs. out of female patients ( %)). further evaluation are underway to evaluate the degree of these disorders and other factors correlate with these disorder. conclusion depression and anxiety were also found in lung cancer patients and need further evaluation and attention from clinician. to compare the preoperative classifi cation of lung carcinoma made on histological specimens by fiberoptic bronchoscopy(fob)with the postoperative classifi cation made on resected specimen and how often was used term of nsclc. methods we reviewed the records patients who had a diagnosis ofthe lung cancer made by fi beroptic bronchoscopic biopsy (at yedikule chest hospital, istanbul in ) and who underwent a lung resection.postoperative histological classifi cation were made according to the who classifi cation of the lung tumours. results fifty one of squamous carcinoma, of adenocarsinoma and of carcinoid tumours were correctly typed with the small biopsy obtained by fob. forty eight patients who had a diagnosis of lung cancer established by fi breoptic bronchoscopy were labelled as nsclc, %, % and % of them were classifi ed squamous carcinoma , adenocarcinoma and other tumour type respectively with examination of tissue obtained by surgical resection. conclusion accurate cell typing by specimens obtained at fi breoptic bronchoscopy may be extremely diffi cult.if clearcut morphological criteria can not be satisfi ed , the diagnosis of "lung cancer ,non-small cell" type should be made. introduction the nsclc patients who experienced good clinical responses even sometimes dramatic responses to egfr-tkis gefi tinib or erlotinib will inevitably develop acquired resistance. however, the clinical defi nition of acquired resistance is not clear. we investigated the clinical characteristics of acquired resistance to gefi tinib in nsclc retrospectively. methods we analyzed four hundred and forty nsclc patients who had taken gefi tinib more than months duration. all clinical data were obtained from centers of korean molecular lung cancer group (kmlcg). the timing, clinical manifestations, and the association of egfr genotype were analyzed in the aspect of acquired resistance development. the mean duration of gefi tinib prescription was . + . months. signifi cant predominance in female ( . %) and non-smoker ( . %) was noted. among the patients who examined egfr genotype, the mutation rate was . % ( / ), relatively lower than expectation. the relative ratio of local vs. systemic progression is . %: . % and symptomatic progression rate is . %. the survival time after the development of acquired resistance is . + . months. conclusion these retrospectively analyzed clinical data for the development of acquired resistance to gefi tinib will help set up the clinical defi nition of acquired resistance to egfr-tki. introduction numerous studies have documented overall effectiveness and safety of chemical pleurodesis using variety of agents. although reports regarding complications post-talc pleurodesis were minimal, concerns on the adverse effect profi les remains, especially on occurrences of serious and life threatening respiratory insuffi ciency and ards following talc pleurodesis. methods records of patients admitted at lcp who underwent talc pleurodesis from january to december were reviewed and all complications post pleurodesis were noted. results a total of charts of patients admitted at lcp who underwent pleurodesis from january to december were reviewed. the mean age was ± y/o with male predominance compared to female at ( . %) and ( . %) respectively. of the total procedures evaluated, ( . %) involved all post procedure complications, ( . %) patients developed minor complications while ( . %) had major complications. there was no statistically signifi cant association noted with age, sex, smoking history, co-morbid illness, underlying disease, and method of pleurodesis, while chest tube drainage time more than days was noted to be associated with greater incidence of major complications which was statistically signifi cant. most common minor complications were fever ( . %), followed by tachycardia ( . %), chest pain ( . %) and dyspnea ( . %). the top major complications were hypoxemia, hypotension and pneumonia. there were ( . %) patients who died post pleurodesis that is believed to be related to ards following talc slurry. conclusion talc pleurodesis is an effective agent for chemical pleurodesis but not without adverse effects. cardiovascular complications are potentially avoidable by proper patient selection and preparation prior to talc pleurodesis. respiratory failure and ards are rare but serious complications that should be promptly recognized and addressed rapidly and effectively. introduction nebulized antibiotic is an established safe and effective therapy for bronchiectasis. gentamicin are considered among the most useful classes of antibiotics for treating pseudomonas aeruginosa infections.the major drawback of aminoglycosides is the need for their relatively high dose intravenous administrations which carries the potential systemic toxicity.when gentamicin is given intravenously in maximum safe doses, only relatively low sputum concentration are achievable. these limitations can be circumvented by direct delivery of aerosolized antibiotic to the airways. methods this study was carried out in nidch dhaka. in total, patients were taken initially for the study. introduction immune-modulator nutrition may decrease mortality among patients who are mechanically ventilated due to severe community acquired pneumonia (cap). methods we compared an immuno-modulator nutrition and standard feeding formula to determine the effect on in-hospital mortality as well as days mortality among mechanically ventilated patients due to severe cap. the mean number of ventilator days, icu stay, as well as clinical parameter (clinical pneumonia infection score (cpis) and pao /fio ratio from arterial blood gas) was also compared. in total, eligible patients were randomized, double blind, to receive either immuno-modulator nutrition (supportan sp) or standard feeding formula (sf). follow-up was done on day , and on cpis and pao /fio ratio. results primary outcome was mortality. no signifi cant difference noted between the two groups (p = . ; % ci: − . to . ). the day mortality on patients revealed patients ( . %) died on sf group and patient ( . %) on sp group (p = . ; % ci: − . to . ). the mean ventilator days on the sf group and sp group was . days and . days respectively (p = . ; % ci: − . to . ), although not signifi cant, it suggests a trend favoring sp group. the mean icu stay in the sp group was noted to be signifi cantly shorter ( . days) than in the sf group ( . days) (p = . ; % ci: . to . ). the cpis and pao /fio ratio were done on day , and . on day , the mean pao /fio ratio was still signifi cantly higher on the sp group (p = . ; % ci: − . to − . ); while the mean cpis was still the same with baseline (p = . ; % ci: − . to . ). on day , no significant difference was noted (p = . ; % ci: − . to . and p = . ; % ci: − . to . , respectively), as well as those on day (p = . ; % ci: − . to . and p = . ; % ci: − . to . , respectively). conclusion we found no difference on mortality between sf and sp group. however, it suggests trend of earlier extubation and signifi cant shorter in icu stay, in patients who received immuno-modulator nutrition. introduction several equations to predict lung function of individuals of different population are available. however it is desirable that lung function laboratories use reference equations that most closely describe the population they test. the objective of the study was to develop a prediction equation for the malaysian population. methods spirometry was performed on a total of "healthy", lifetime non smoker volunteers ( males and females) all measurements met the ats acceptability and reproducibility criteria. prediction equations were derived for both men and women for fvc and fev . the equations were validated on a new group of subjects (n = , males and females) who met the same inclusion and exclusion criteria as the main cohort. introduction patients with severe asthma (experiencing previous hospital admissions and/or daily symptoms) have occasionally been seen with poor or weak complaints. several studies have analyzed the psychiatric status of the patients with severe asthma, but few studies have the japan respiratory society (jrs) has proposed new predicting scores, called the i-road system for hospital acquired pneumonia (hap) in . depending on the presence of the parameters listed below, patients with hap were stratifi ed into those with high, moderate or low-risk. the high-risk group was defi ned as patients with three or more of the following risk factors: 'malignant tumor or immunocompromised status', 'impaired consciousness', 'requiring fraction of inspired oxygen (fio ) > % to maintain spo > %', 'male aged years or older, or female aged years or older' and 'oliguria or dehydration'. the moderaterisk group was defi ned as patients with any of the secondary risk factors as follows: 'crp ≥ mg/dl' and 'extent of infi ltration on cxr covers at least / of one lung'. the low-risk group was defi ned as all other patients. the aim of this study was to confi rm whether i-road is useful in predicting severity of cap and hcap. methods all patients with an admission diagnosis of cap and hcap from january -july were reviewed. clinical and laboratory features at presentation in electrical medical records were used to calculate severity scores using the curb- ( ), a-drop ( ) and i-road ( ). results consecutive patients ( % cap) of mean age . years were included in the analysis. nineteen ( . %) patients with cap and seventeen ( . %) patients with hcap died. the roc analysis for predicting mortality at days showed that i-road score has similar predictive accuracy for short-term mortality to curb- and a-drop in patients with cap, but shortterm mortality of the patients with hcap are not similar to them. conclusion the jrs i-road could be used to assess severity of cap, and gives similar results to curb- and a-drop. os - introduction numerous asthma and copd patients repeatedly return to hospital ed for urgent therapeutic care despite referral to their primary care provider. this study was aimed to identify these respective populations with frequent ed visits and assess the current therapeutic management of acute exacerbation of asthma and copd at hospital kuala lumpur, malaysia. methods the demographic and medical data was prospectively collected and recorded in march using convenient sampling, and then descriptively analyzed using spss version . appropriate statistical analysis were applied with p < . was considered as signifi cant. the study recruited patients (male . %) with . % asthmatics and . % copd. malays signifi cantly presented to ed the most ( . %) followed by indians ( . %) and chinese ( . %). most patients were between - years old ( . %) with mean age of . . about . % were smokers ( . % ex-smokers) with an average duration of smoking . years and . pack-years. for occupational data, . % were belonging to non-professional group. about . % asthma and . % copd patients had visited ed last year with average visit of . and . times and mean number of hospitalization was . and . , per year, respectively. about . % patients without scheduled appointments and . % were not on any prescribed medications for asthma or copd. among patients with prescribed medications, . % were on saba and . % on inhaled corticosteroids. respiratory infections remained as main triggering factors of admission ( . %), followed by weather ( . %) and air pollution ( . %). average duration of treatment was about minutes with mean direct therapy cost of rm per patient excluding the standard admission fee. whil hr monitoring, the level of oxygen saturation and pefr were signifi cantly improved post treatment. oxygen-driven nebulised saba and iv hydrocortisone were the mainstay of treatment. however, the use of an anticholinergic as a step up approach in nebulised treatment was underused. most discharged patients were given oral saba ( . %) and prednisolone ( . %). pefr measurement was not practiced post treatment regularly. conclusion limited number of staff contributed towards omitted monitoring steps. involvement of ed pharmacists in respective therapeutic management is highly suggested. introduction fluid volume is an important factor when considering pleural drainage. however, there is limited literature regarding accurate quantifi cation of pleural effusion by ultrasonography. in a study by visperas et al, they quantifi ed the pleural effusion volume by measuring the length, width, and depth of the fl uid, while the patient was in a sitting upright position, and the actual volume drained. they postulated a linear regression equation to quantify estimate the pleural fl uid volume that will be drained. introduction insomnia disorder is the most common sleep disorder which affected more than people in bangladesh. people develop chronic insomnia disorder with symptoms of diffi culty falling asleep for more than minutes and last for more than month. patients with insomnia disorder in bangladesh took sleeping pills each year for insomnia disorder. however, there were still some side effects about sleeping pills such as allergy, amnesia, hallucination etc. because of the side-effects of modern medicine and because of the inability of modern medicine to cure insomnia disorder, international scientifi c interest has re-focused on the traditional uses of medicinal plants to fi nd effective cure for insomnia disorder as well as hundred of other disorders. a study of the traditional health practitioners in the habiganj district of bangladesh suggested that some of the herbal medicines prepared from medicinal plants might be quite effective for insomnia disorder. methods information was collected through a series of interviews with the traditional health practitioners, rural and urban people. field notes were recorded on the medicinal plants and their uses; following the methodology of bhat et al. ( ) and martin ( ) . the identifi ed medicinal plant specimens were stored at the bangladesh national herbarium; under the author's collector series. results the following medicinal plants or plant parts were found to be used as remedy for insomnia disorder: cyrtandra cupulata ridl., bacopa monnieri (l.) pennell, ocimum gratissimum l., lawsonia inermis l., cinnamomum camphora (l.) sieb., aconitum napellus l., datura metel l., mimosa pudica l., achyranthes aspera l., piper betle l., randia dumetorum (retz.) poir., ficus glomerata roxb., nigella sativa l., agaricus albolutescens zeller, ipomoea aquatica forssk., stephania japonica (thunb.) miers, withania somnifera (l.) duna, cannabis sativa l., calamus rotang l., uraria picta (jacq.) dc., sesamum indicum l., asparagus racemosus willd., abrus precatorius l., and brassica napus l. conclusion information on indigenous use of medicinal plants has led to discovery of many medicines in use today. it is important that modern scientifi c studies be conducted on these medicinal plants towards isolation and identifi cation of compounds through which insomnia disorder can be effectively treated. introduction existing data on the association between sleep duration and blood pressure in adolescents are inconsistent and confl icting. this study aims to determine the relationship between sleep duration and -hour ambulatory blood pressure in adolescents. methods subjects aged - . years were recruited from the community. they underwent nocturnal polysomnography (psg) and -hour ambulatory blood pressure monitoring (abpm) on the same day. daytime, nocturnal and -hour average systolic and diastolic blood pressure (sbp and dbp) were converted to z score with reference to height and gender according to normal reference. a -day sleep diary was completed prior to psg. daily sleep duration was defi ned as the average of nocturnal sleep duration plus the average of daytime nap duration over week. subjects with body mass index (bmi) greater than the th percentile of the local normal reference were classifi ed as overweight. those who were overweight and had an obstructive apnoea hypopnoea index (oahi) greater than or equal to were excluded from the analysis. results one hundred forty one subjects ( boys) with a mean (sd) age of . ( . ) years were recruited. they were divided into groups according to their daily sleep duration (< . vs. . - . vs. . - . vs. > . ). subjects with shorter sleep duration tended to have higher daytime sbp (p < . ), nocturnal sbp (p = . ) and -hour sbp (p < . ). similar results were found after converting the bp data into z score (p = . , . introduction some studies have shown decreased plasma and hair zn in human asthmatics which may indicate a state of zinc defi ciency. we have shown, in a well characterized murine model of allergic airway infl ammation, that there were marked losses of zinquin-stainable (labile) zn in the infl amed airway epithelium (ae); when these mice were placed on low zn diets, there was excessive cell death in the ae, and increased airway infl ammation. we have proposed that labile zn protects the ae from premature cell death and loss of this zn contributes to the ae fragility and infl ammation in asthma. a screen of whole lung gene expression of the two major families of zip infl ux transporters and znt effl ux transporters, indicated a marked loss of znt in the infl amed lungs. the hypotheses being tested here are ) ae zn is normally stored in vesicles within the apical cytoplasm, ) znt is responsible for transporting zn into these bodies and ) loss of znt expression in asthma may result in a failure of zn to be sequestered. methods human nasal epithelial brushings were obtained from healthy, consenting donors. lung tissue was obtained from balb/c mice sensitized and aerosol-challenged with ovalbumin or saline (controls). distributions of zinc were determined by zinquin fl uorescence or in vivo selenite autometallography (se-amg). distributions of znt were determined by immunofl uorescence. results zinquin fl uorescence of human and murine ae indicated abundant labile zn with a vesicle-like pattern of staining in the apical cytoplasm. se-amg confi rmed the presence of apical zn vesicles at an ultrastructural level. there was strong immunolabelling for znt in the same region. furthermore, there was an almost complete loss of znt protein in the bronchial epithelium of mice with allergic airway infl ammation. conclusion colocalization of znt with labile zn in ae may indicate a role for this zinc transporter in replenishing zn storage pools in this tissue. loss of znt protein during airway infl ammation would then result in failure to sequestrate zn, depleting critical storage pools of zn in the lung and airways, leading to increased ae damage and cell death. this work was supported by nhmrc project grant . introduction community-acquired pneumonia remains a major cause of mortality in developed countries. there is much discrepancy in the literature regarding factors infl uencing the outcome in the elderly population. methods data were derived from a multicentre prospective study initiated by the german competence network for community-acquired pneumonia. patients with community-acquired pneumonia (n = , ; , aged < years and , aged ≥ years) were evaluated, of whom . % were hospitalised and . % treated in the community. clinical history, residence status, course of disease and antimicrobial treatment were prospectively documented. microbiological investigations included cultures and pcr of respiratory samples and blood cultures. factors related to mortality were included in multivariate analyses. results the overall -day mortality was . %. elderly patients exhibited a signifi cantly higher mortality rate that was independently associated with the following: age; residence status; confusion, urea, respiratory frequency and blood pressure (curb) score; comorbid conditions; and failure of initial therapy. increasing age remained predictive of death in the elderly. nursing home residents showed a four-fold increased mortality rate and an increased rate of gram-negative bacillary infections compared with patients dwelling in the community. conclusion the curb score and cerebrovascular disease were confi rmed as independent predictors of death in this subgroup. age and residence status are independent risk factors for mortality after controlling for comorbid conditions and disease severity. failure of initial therapy was the only modifi able prognostic factor. introduction hospital-acquired pneumonia (hap) attributes to % of all nosocomial infections. mortality rate is as high as - %. guidelines for the management of adults with hap were recently updated. despite the emergence of evidence-based medicine, the use of these guidelines in daily clinical practice is still limited. currently, there is no literature published regarding the impact of adherence to the guidelines and clinical outcomes of hap. methods a total of patients (male: %; female: %) admitted and diagnosed with hap at our center were followed up to investigate the rate of adherence of physicians on the diagnosis and treatment of hap based on level i and ii ats/idsa recommendations and to determine its association with outcome (mortality, mechanical ventilation, icu stay, hospital stay). adherence to diagnostics and therapeutic management were computed per patient. management of patients was classifi ed as adherent if it meets more than % of the guidelines that should be enforced. results in this cohort, % of the physicians adhered to the currently recommended guidelines. age, gender, and co-morbid conditions such as hypertension, diabetes mellitus, copd, ckd and cerebrovascular disease were not statistically associated with the outcome of the study. a total of % of the subjects were eventually mechanically ventilated (p = . ). a total of % of patients who adhered to the recommendations consequently died during hospitalization (p = . ). similarly, univariate analysis of variance revealed that there is no signifi cant association of adherence to length of icu stay and hospital stay (p = . , . respectively). of the level i and ii current recommendations, request of blood culture showed signifi cant association with adherence (p = . ). however, logistic regression analysis showed that there is no association of adherence in doing blood culture to mortality. conclusion this analysis showed that compliance with the currently recommended ats/idsa recommendations is %. blood culture is the most signifi cantly associated recommendation. rate of endotracheal intubation, length of icu and hospital stay and mortality however was not signifi cantly associated with adherence. introduction reportedly high arsenic level in drinking water causes increased mortality and morbidity in adult copd patients. arsenic related health hazards include respiratory symptoms with decreased lung function added to skin lesion. currently million people of bangladesh are at potential risk of consuming arsenic contaminated drinking water and a major section of them showed many symptoms including alteration of lung function. methods the present study was conducted on chronic arsenicosis patients in selected areas of bangladesh to assess lung function status by measuring fvc, fev , fev / fvc% & pefr. in total, subjects of - years of age of both sexes were selected. apparently healthy subjects were selected from non arsenic residency as well as not exposed to arsenic in their tube-well water and were grouped as healthy control. of subjects from area exposed to arsenic contaminated tube-well water, were patients of chronic arsenicosis with skin lesions were considered as experimental group, whereas subjects without skin lesions were regarded as exposed control. results the mean measured values of the lung function parameters of nonarsenic exposed healthy control and exposed control were within normal ranges. but these values were signifi cantly lower in chronic arsenicosis patients with skin lesions. the parameters showed negative correlation with age, arsenic concentration in tube-well water but positive correlation with duration of the consumption. but these relationships were not statistically significant. all the patients of arsenocosis complained about respiratory symptoms in the morning. conclusion the present study reveals that arsenicosis patients are suffering from respiratory insuffi ciency and symptomatic respiratory illnesses. in addition, populations consuming higher arsenic concentration in drinking water are at the risk of lung function impairment and ultimately may lead to respiratory disorders, though it would be better to draw a defi nite conclusion from a further study involving large sample size. introduction despite of the detailed study of community-acquired pneumonia, the role of atypical microorganisms such as m. pneumoniae, c. pneumoniae and l. pneumophilla is not still defi ned. also there are some discussions about role of the associations of these bacteria with the other so-called typical microorganisms as s. pneumoniae and h. infl uenzae as well as the place of the viral pathogens in community-acquired pneumonia ethiology structure. the aim of our research was to defi ne the etiology of the community-acquried pneumoniae in young adults ( - years, fi rst group) and to compare the results with the data gained in aged patients (< years, second group). methods the young and aged patients with community-acquired pneumonia were screened with bacteriological, disk-diffusion with mic, pcr and other methods. antimicrobial agents resistance was checked to nccls standards and the clonality of the isolates was checked by pfge and mlst for the most frequent clones. results bacterial associations were defi ned in % versus % in the second group. m. pneumoniae was identifi ed in % vs %, c. pneumoniae . % vs %. the bacterial pathogens were represented with the species s. pneumoniae ( . %/ %), h. infl uenzae ( . %/ %), m. catarrhalis ( . %/ %). among the viral pathogens the most often was metapneumovirus in young adults ( %), and infl uenzae virus in aged patients ( %). the most prevalence bacteria were genotyped and there were revealed the relations between several isolates of m. pneumoniae and s. pneumoniae existing as association in several cases of different age groups what proved the epidemiological character of the spread of this association. so, the most frequent clone of s. pneumoniae was recognized as st , as well as st . pfge typing of atypical microorganisms also revealed the spread of the several clones. conclusion some changes in etiology structure of community-acquired pneumonia seems to be connected with the changes in immunology peculiarities of different age groups, as well as with the other epidemiology reasons. introduction despite of the detailed study, the role of acinetobacter baumanii pathogen as the a ubiquitous opportunistic nosocomial pathogen is still appreciated. the most of epidemiological aspects of this infection are still discussed though the problem of the microbiology charecteristics of this pathogen are of keen microbiology interest. it is often isolated in immunocompromised hosts in different forms of hospital-acquired infections, but more often it was recognized as the main pathogen agent of hospital-acquired pneumonia. the aim of our research was to establish clinical signifi cance of a. baumanii in development of hospital-acquired pneumonia, to defi ne its epidemiology and to characterize antimicrobial agents resistance pattern. methods we made -year surveillance of all hospital-acquired pneumonias (hap) in adult patients in the main clinics of vladivostok (hospital Ð , Ð ), defi ned etiology with standard microbiology methods. all isolates of a. baumanii were tested for antimicrobial agents resistabce according to nccls. the strains with the same antimicrobial agents resistance pattern were checked to clonality by pulsed-fi eld gel electrophoresis (pfge). results during - , we studied all cases of hap in adult patients (< years) admitted to icu and revealed that a. baumanii has taken the second place in etiology structure ( . %, cultures from patients). the fi rst place was in pseudomonas aeruginosa ( . %, strains) and the third one was in stenotrophomonas maplthophila ( . %, strains). mostly ( strains, . %), a. baumanii was isolated as monoinfection, but in other cases it was isolated in association with another strains of a. baumanii, or p. aeruginosae, s. palthophila, s. aureus, e. feacalis, e. cloaceae. there were defi ned lower resistance to ciprofl oxacin. the clonality research revealed about genotype clusters what could allow to suggest the genetic relatedness of the isolates. conclusion acinetobacter baumanii should be studied to defi ne the role in hospital-acquired infections, as well as it confi rms the fact that the importance of local surveillance programs in correctly guiding empiric therapy and local intervention programs in attempt to reduce antimicrobial resistance. introduction community acquired pneumonia (cap) is the most common cause of death associated with infectious disease. locally, it is the leading cause of morbidity and the fi fth cause of mortality according to the department of health. the initial management decision after diagnosis is to determine the site of care: outpatient, hospitalization in a medical ward, or admission to an icu. the decision to admit the patient is the most costly issue in the management of cap, because the cost of inpatient care for pneumonia is up to times greater than that of outpatient care. it is a well documented fact that signifi cant variation in admission rates among hospitals and among individual physicians occurs. physicians often overestimate severity and hospitalize a signifi cant number of patients at low risk for death. because of these issues, interest in objective site-of-care criteria has led to attempts by a number of groups to develop such criteria. the two foremost criteria are the british thoracic society criteria (curb- ) and the pneumonia severity index (psi). the idsa/ats committee preferred the curb- criteria because of ease of use and because they were designed to measure illness severity more than the likelihood of mortality. patients with a curb- score > are not only at increased risk of death but also are likely to have clinically important physiologic derangements requiring active intervention. these patients should usually be considered for hospitalization. therefore, the study was done to determine and compare mortality rates of the admitted cases of community acquired pneumonia assessed by either curb- criteria or the philippine clinical practice guidelines on cap, and to determine the applicability of curb- as a site-of-care tool in the admission of patients with community acquired pneumonia either at the wards or the intensive care unit. methods all patients seen at the emergency room and out-patient department with the diagnosis of community acquired pneumonia were included in the study. thorough history-taking and physical examination was taken by the er/opd fellow whom would determine if the patient has pneumonia. subsequently, laboratories (cxr, cbc, bun, abg) was requested. randomization was done for severity assessment: one group was assessed via the curb- criteria, while the other group was assessed using the philippine clinical practice guidelines for cap. severity assessment was done by the er fellow together with the investigator not more than one hour of the patient's arrival at the er/opd. patient was followed-up by the investigator within hours of admission (ward or icu) and until discharge or death. results a total of patients diagnosed with community acquired pneumonia (cap) were included in the study. the age range for the curb group is from to years of age with a mean age of . ± . years, while in the cpg group, to years of age with a mean age of . ± . years. no significant difference were noted (p = . ). no signifi cant difference were also noted in the gender of both groups (p = . ). there was a signifi cant difference noted in the presence of comorbidities (p = . ) between the two groups, . % and . %, curb group and cpg group, respectively. the presence of previous ptb treatment, cardiovascular disease and copd, ranks as the three most common comorbidity. dyspnea ( . %), cough ( %) and fever ( . %) were the three most common symptoms noted. there were no signifi cant difference noted in these symptoms (p = . , . , . , respectively). with regards to the physical fi ndings: crackles ( . %), tachypnea ( . %), wheezes ( . %) were the three most common signs noted. no signifi cant difference were noted in most of the signs, except for "tachypnea" and "hypotension" (p = . , . , respectively). there were no signifi cant difference in the radiographic fi ndings between both groups. no signifi cant difference were also noted in the complete blood count results be it leukocytosis (p = . ), anemia (p = . ) and leukopenia (p = . ). there is a signifi cant difference in the blood urea nitrogen (p = . ). no signifi cant difference was also noted in the arterial blood gas result: hypoxemia (p = . ) and hypercapnia (p = . ). for the curb- group, more than half of the population was assessed to have a score of (in-patient), ( . %). for the cpg group, more than half was assessed to be under the moderate risk, ( . %). all of the patients assessed in the lower severity class, either thru the curb- or the cpg, had been discharged improved. the overall mortality rate per group was: . % for the curb- group, out of the patients, and . % for the cpg group, out of the patients. mortalities were noted only on those with higher severity ratings. on further determination of mortality rate per level of severity, it revealed that those with a curb- score of ≥ has a mortality rate of . % ( out of the patients), while those on the cpg, . % ( out of the patients). conclusion in this study, we determined that all of the mortality came from the higher severity levels: curb- score ≥ ( . %), cpg-high risk ( . %), none from the lower severity ratings the curb- criteria is a useful site-of-care tool, though, the usage of curb- criteria does not offer additional benefi ts compared to the use of the cpg, in fact because of familiarity of physicians with the latter, they are more adept in using it. introduction acute exacerbation has been a major complication of interstitial lung disease (ild). the rapid recognition of a bacterial pneumonia and an acute exacerbation of underlying ild appears to be clinically important for proper treatment. procalcitonin (pct), a precursor peptide of the hormone calcitonin is commonly detected at elevated levels under bacterial infection conditions. this study was to assess whether or not serum procalcitonin levels were useful as a biomarker for the differential diagnosis of ild exacerbation from bacterial pneumonia. methods we had planned a prospective observational study. our study enrolled ild patients who had presented with recently progressive dyspnea, and newly infi ltrates of the chest in underlying ild. results nine of them evidenced bacterial pneumonia with high pct level. serum pct levels in ild exacerbation group were signifi cantly lower than in the pulmonary infection group (the mean value . ng/ml vs . ng/ml, % [ci]). sensitivity, specifi city, and negative predictive value of serum pct level were . %, %, . % respectively. conclusion the fi ndings of this study suggest that serum pct value is useful in the differential diagnosis of bacterial pneumonia from exacerbation in patients with interstitial lung disease. introduction it has been well confi rmed that malnutrition and muscle wasting are important extra-pulmonary manifestations of chronic obstructive pulmonary disease (copd), which are recognized as contributing to an increase in morbidity and decrease in quality of life. myostatin, a transforming growth factorbeta superfamily member, is mainly expressed in skeletal muscle and has been characterized as a negative regulator of skeletal muscle mass. studies have showed that myostatin is implicated in several diseases involved in muscle wasting and cachexia. recently, there is evidence of myostatin secretion and circulation in animals and human blood, and more recently, studies have shown that intramuscular myostatin expression accelerated in copd patients; while levels of circulating myostatin in copd remain unclear. we therefore analyzed serum myostatin levels to investigate the relationship between circulating myostain levels and nutritional depletion and muscle wasting in copd; and the relationship between circulating myostain levels and systemic cytokines such as tumor necrosis factor (tnf)-α and interleukin (il)- in copd. methods fifty-four male patients with stable copd and twenty-one agematched, healthy, male control subjects participated in the study. total-body skeletal muscle mass (smm) were calculated according to a validated formula by using body weight, height and age. nutritional status was evaluated by anthropometric measurements and serum protein levels; the former included body mass index (bmi), triceps skin-fold thickness (tsf) and mid-upper arm circumference (mac), and the latter included serum prealbumin, transferrin and albumin. serum levels of myostatin, tnf-α and il- were detected by elisa. results out of the patients with copd, ones ( . %) had malnutrition, with bmi less than kg/m . serum levels of myostatin were signifi cantly elevated in copd patients compared with controls ( . ± . ng/ml vs. . ± . ng/ml, p < . ), and the levels were even much higher in those with malnutrition ( . ± . ng/ml). however, smm was signifi cantly decreased in copd patients compared with controls ( . ± . kg vs. . ± . kg, p < . ). all the nutritional parameters except of prealbumin were signifi cantly decreased in copd patients compared with controls, with each p < . . there is an inverse correlation between myostatin levels and smm (r = − . , p = . ) and a positive correlation between myostatin and tnf-α levels (r = . , p = . ) in copd group, but no correlation between myostatin levels and serum proteins concentrations. conclusion this study demonstrates that circulating myostatin levels were elevated in patients with copd and that the elevated myostatin levels are closely related with malnutrition and muscle wasting in patients with copd. introduction chronic obstructive pulmonary disease (copd) is defi ned by airfl ow limitation that is not fully reversible and no medication exists that clearly improves the mortality. oxidative molecules, in particular superoxide anion, are believed to play an important role in copd-associated abnormal infl ammatory response due to increase in the level of pro-infl ammatory cytokines and chemokines and pulmonary emphysema due to proteases/antiproteases imbalance and apoptosis. superoxide dismutase (sod) catalyses the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxifi ed to oxygen and water. lecithinized sod (pc-sod) has overcome a number of previous clinical limitations of sod, including low tissue affi nity and low stability in plasma. in this study, we examine the effect of pc-sod on elastase-or cigarette smoke-induced pulmonary emphysema, animal models for copd. methods severity of pulmonary emphysema in mice was assessed by various methods, such as the number of leucocytes (neutrophils, lymphocytes and alveolar macrophages) in bronchoalveolar lavage fl uid (balf) and enlargement of airspace (increase in mean linear intercept). lung mechanics were assessed by a computer-controlled ventilator. the pulmonary level of superoxide anion was estimated by electron spin resonance analysis and the level of -hydroxy- ′-deoxyguanosine. results not only intravenous administration but also inhalation of pc-sod suppressed elastase-induced pulmonary emphysema and dysfunction. inhalation of pc-sod showed therapeutic effect against elastase-induced pulmonary emphysema and dysfunction even when it administered after the development of emphysema. inhalation of pc-sod suppressed elastase-induced increase in the pulmonary level of superoxide anion and apoptosis. inhalation of pc-sod also suppressed elastase-dependent activation of proteases and induction of expression of pro-infl ammatory cytokines and chemokines. we also found that inhalation of pc-sod suppressed cigarette smoke-induced pulmonary emphysema and dysfunction. conclusion results suggest that pc-sod protects against pulmonary emphysema through decreasing the pulmonary level of superoxide anion and resulting inhibition of infl ammation, apoptosis and activation of proteases. we propose that inhalation of pc-sod is therapeutically benefi cial for copd. introduction tiotropium is a recently developed inhaled anticholinergic in the management of copd, exhibiting a prolonged duration of action and a kinetic selectivity to specifi c muscarinic receptors, leading to a more effective bronchodilator response at once-daily dosing. we determined the effi cacy of long-term tiotropium use on clinical endpoints such as mortality, exacerbations, and hospitalizations compared to inhaled long-acting beta- agonists among patients with copd. methods search methods rcts were identifi ed from electronic databases. bibliographies and relevant reviews were also searched. the date of the last search is august , . selection criteria rcts among patients with copd comparing tiotropium monotherapy with inhaled labas with at least months follow-up were selected for inclusion. data on all-cause mortality, mortality from pulmonary causes, mortality from cardiovascular causes, rates of hospitalizations and exacerbations were identifi ed. data collection and analysis three investigators evaluated and extracted relevant data. any disagreements were discussed and consensus decisions were made. the data were analyzed using revman . studies were pooled to yield odds ratios and were reported using % confi dence intervals. results from rcts, clinical trials with a total of , patients met inclusion criteria. tiotropium did not reduce the odds of all-cause mortality (or . % ci . to . ) compared to inhaled labas. subgroup analysis also shows that tiotropium did not reduce the odds of mortality from pulmonary causes (or . % ci . to . ) but shows a trend that might increase mortality from cardiovascular causes (or . % ci to . ). tiotropium reduced the odds of hospitalizations from all causes (or . % ci . to . ) and showed a trend towards benefi t in reducing the odds of exacerbations (or . % ci . to . ). conclusion tiotropium did not reduce all-cause mortality among patients with copd compared to inhaled labas, although it showed a possible trend towards harm in causing cardiovascular mortality. it also reduced hospitalizations, although it did not decrease the odds of exacerbations among patients with copd. background patients from asia may have different outcomes compared to those from other backgrounds. we therefore examined outcomes in the subgroup of asian patients in the uplift trial. . more patients will be recruited until august in vietnam and singapore as well as in the above nine countries. this abstract contains an interim analysis. the recruited patients were mostly male ( . %) and elderly (mean age, . years). according to gold criteria, severity of airfl ow limitation was mild in . % of patients; moderate in . %; severe in . %; very severe in . %. a total of . % of patients were exposed to cigarette smoking; . % to dusty jobs. a total of . % of patients had symptoms of "chronic bronchitis -phenotype" viz. chronic cough with phlegm; . % had wheezing in the last months. a total of . % of patients were on regular medications, e.g. inhaled steroid combined with long-acting beta-agonist, theophylline, shortacting beta-agonist, tiotropium, combined inhaler of salbutamol and ipratropium, and inhaled steroid alone, in decreasing order. in the past one year, . % patients required/ were prescribed antibiotics for acute exacerbations and . % required/were prescribed oral steroids. of this cohort, % patients had unscheduled/ emergency visits to the er or were hospitalized. conclusion this interim report showed that asian copd patients are heterogeneous. a high proportion was exposed to dusty environments at their job sites and many were cigarette smokers. further studies are ongoing to fi nd out other characteristics of copd phenotypes including the infl uence of dusty job environment in the development and progression of copd in asia. introduction it is widely recognized that copd is not only a lung-based disease, but also a systemic disorder with systemic infl ammation, which further aggravates the disease progression at acute exasperation (aecopd). it is important to fi nd a systemic biomarker which is lung-specifi c and can be used to indicate the severity of the disease in the stable state (scopd) and at exacerbation. c reactive protein (crp) and tumor necrosis factor (tnf)-a have been attracted attention as they can refl ect the systemic burden of infl ammation, while they are not lung-specifi c. surfactant protein d (spd) is produced and secreted by alveolar type ii epithelial cells and clara cells. recently study has reported that spd can be used to track disease progression and predict clinical outcomes in copd. the present study was aimed to determine the value of spd as a biomarker of systemic infl ammation in staging the severity of copd and diagnosis of the exacerbation. methods we recruited three groups of subjects: patients experiencing aecopd (n = ), patients with scopd (n = ) and controls with normal lung function (n = ). elisa was used to analyze serum spd, crp and tnf-a levels. the bode scoring system was employed to evaluate health status of patients with copd, which included the four variables: body mass index, degree of airfl ow obstruction, dyspnea and exercise capacity. conclusion the present study confi rms that circulating spd levels are higher in copd and closely related with health status of the patients and severity of the disease; moreover, circulating spd can be regarded as a valid biomarker of systemic infl ammation and a potential diagnostic biomarker for aecopd. methods we reviewed all the records of bronchoscopies in our hospital from february , to january , and identifi ed patients diagnosed subsequently with primary lung cancer whose sputum cytology was negative or not performed prior to bronchoscopy. a total of patients with pulmonary tuberculosis were also identifi ed whose prebronchoscopic sputum acid-fast stains were negative or not performed. we reviewed the result of pathological examination of bronchoscopic specimens and postbronchoscopic sputum for the lung cancer patients and the result of mycobacterial culture of these specimens for the tuberculosis patients. of the lung cancer patients, postbronchoscopic sputum cytology was performed in patients and gave a positive result in ( . %) patients. the postbronchoscopic sputum was the only diagnostic specimen in ( . %) patients. meanwhile, postbronchoscopic sputum culture was performed in of the tuberculosis patients and was positive for m. tuberculosis in ( %) patients. of these patients, the culture of specimens obtained by bronchoscopy was negative in patients, of whom also had a negative result of prebronchoscopic sputum culture. conclusion postbronchoscopic sputum cytology has a limited role for the diagnosis of primary lung cancer and should not be performed in terms of cost-effectiveness. but its culture seems to provide additional information for the diagnosis of pulmonary tuberculosis and further studies are needed to determine when to obtain postbronchoscopic sputum specimens. for other malignant tumours -in ( . %) patients. in ( . %) patients with benign pathology procedures were performed for tracheomalacia -in ( . %), for tracheobronchial fi stula -in ( . %), for endobronchial lipoma -in ( . %) and for other pathology -in ( . %) patients. there were ( . %) unilateral, ( . %) -tracheal, ( . %) -tracheobronchial and ( . %) -bilateral bronchial procedures. on ( . %) occasions procedure was elective, on ( . %) -urgent and ( . %) times it was performed as an emergency. eight patients required stent replacement. stenting was performed under general anaesthesia using combination of rigid and fi beroptic bronchoscopy and in majority with intraoperative x-ray control. uncovered and covered ultrafl ex stents (boston scientifi c) have been mainly used. results there was no intra-operative mortality. eleven ( . %) patients died in hospital prior to discharge and of them died within hours after procedure. in all these patients urgent or emergency stenting was performed. tumour debulking and/or cryotherapy were required on occasions after stenting. hospital stay ranged from to (mean - . , median - ) days. in benign group there was one hospital death in a patient with tb stricture. in patients with malignant tumours total survival ranged from to (mean - . , median - ) days, in elective subgroup -from to (mean - . , median - ) and in urgent subgroup -from to (mean - . , median - ) days. all patients had signifi cant improvement of distressing symptoms. conclusion tracheobronchial stenting is rapid and effective technique of palliation in patients with malignant or in selected cases of benign tracheobronchial stenosis. it provides better outcome if performed electively. stent occlusion may be controlled by endobronchial cryotherapy. introduction in the clinical evaluation of airway disease, fi beroptic bronchosopy (fob) is a crucial tool in the diagnosis. however it is invasive, time-consuming and requires sedation. endobronchial lesions may be seen in both fi beroptic bronchoscopy and mdct virtual bronchoscopy (vb). the extensive image data acquired with vb permits the simulation of the internal as well as external appearance of the tracheobronchial tree. the objective of the study is to compare mdct virtual bronchoscopy with fiberoptic bronchoscopy in the detection and characterization of tracheobronchial (airway) pathology, particularly to determine the overall agreement in the fi ndings in both modalities. methods patients who underwent ct scan of the chest and then underwent fi beroptic bronchoscopy were included in the study. each patient was assessed into levels: trachea, carina, right mainstem bronchus, left mainstem bronchus, tracheobronchial branches. these levels were examined using virtual bronchoscopy for presence/absence of obstructive, endoluminal and mucosal lesions and compared with the actual fi beroptic fi ndings. the sensitivity and specifi city, ppv and npv of vb were determined with fob as the gold standard. results a total of patients were included in the study. sixty-fi ve (n = ; levels) levels were observed, of which / ( %) accounted for the same evaluation using fob and that of the vb. the sensitivity of vb in diagnosing endoluminal lesion was noted to be %, with specifi city of %. virtual bronchoscopy overestimated obstructive lesions with two false positive results and detected two false negative patients with endoluminal mass. none of the mucosal abnormalities (mucosal erythema, edema, etc.) are detected using vb. conclusion virtual bronchoscopy may be comparable with fi beroptic bronchoscopy in the localization, morphologic description of tracheobronchial lesions. however, it has limited capability to reconstruct subtle mucosal irregularities. consequently, it is prone to artifactual reconstruction for mucosal changes that may render a false positive fi nding. overall, virtual bronchoscopy best complements the fi beroptic bronchoscopy in thorough evaluation of the tracheobronchial pathologies and cannot obviate the need for this invasive approach in the diagnosis of early mucosal changes within the airway. results of patients ( %) were male. all patients had multiple comorbidities which include severe copd = ( %), ( %) patients each had heart failure, respiratory failure and anaemia,hypoalbuminemia = ( %), active tuberculosis = ( %), pah = ( %), cad, crf, cld in patients and age > years was in ( %) patients. all patients underwent ct thorax and fob and after localizing bleed underwent bae within h of admission. in / ( %), bae could not be done on account of technical reasons. immediate control of bleeding was achieved in / patients ( %). in total, / patients ( . %) reported no rebleed till months. none developed early rebleed (< month) while / ( . %) develop late rebleed (> months). one managed conservatively and other underwent lobectomy. only complication of bae was transient dysphagia in / ( . %). conclusion bae is safe and effective in immediate and long term control of massive haemoptysis in elderly patients with multiple comorbidities and should be considered even in such high risk group. introduction histologic specimens obtained by endobronchial ultrasoundguided transbronchial needle aspiration (ebus-tbna) often provide valuable information for diagnosis or management decisions. besides the conventional -gauge needle, a -gauge needle is now available for this procedure. the purpose of the present study was to compare the histologic specimen retrieval yields of ebus-tbna using -gauge and -gauge needles for sampling hilar/mediastinal lesions. methods sixty patients with hilar/mediastinal lymphadenopathy or a tumor adjacent to the central airway were enrolled in this study and randomized to undergo ebus-tbna using a -or -gauge needle. each histologic specimen obtained by ebus-tbna on the initial two punctures of each patient (total punctures) was interpreted separately and categorized by an experienced pathologist as follows: i, diagnostic; ii, nondiagnostic but adequate (e.g. lymphoid tissue); iii, nondiagnostic and inadequate (e.g. clot); and iv, no specimens. results median targeted lesion size in shortest diameter on ct in the group using a -gauge needle and a -gauge needle was . mm and mm, respectively. prevalence of malignancy on primary disease in each group was % and %, respectively. the specimens obtained by -gauge needle were interpreted as i in , ii in , iii in and iv in . the specimens obtained by -gauge needle were judged to be i in , ii in , iii in and iv in . the sampling yield of adequate histologic specimens (i and ii) obtained by the -and -gauge needle was % and % (p = . ). no complications were associated with the procedures. conclusion histologic specimens can be obtained with a high sampling yield by either of the needles. our study could not show any difference in sampling yield between the two needles. introduction diagnostic tuberculosis using acid fast bacilli (afb) microscopy and conventional lowenstein jensen (lj) culture remain the cornerstone but the sensitivity of these traditional methods is quite low, especially in the samples containing small number of organism. there is a need for rapid, sensitive and accurate detection of these organisms in clinical specimens to hasten the administration of appropriate antimycobacterial therapy and prevent the spread of infection in the community. sputum smear-negative pulmonary tuberculosis (ssn-ptb) is a common problem faced by clinicians. performing fi ber optic bronchoscopy (fob) and subjecting the bronchoalveolar lavage (bal) material to diagnostic methods of smear and mycobacterial culture appears to be helpful in the diagnosis of ssn-ptb. radiological and pulmonary function outcome of children with sars longer term follow up of aerobic capacity in children affected by severe acute respiratory syndrome (sars) the usefulness of virtual bronchoscopic navigation has been established for the diagnosis of small peripheral lesions. exclusive software (bf-navi) from olympus medical systems is commercially available, but because no function to display extra-airway structures has been installed, this could not be indicated for testing where the purpose is mediastinal/hilar lymph node aspiration. using an improved version of the software from olympus medical systems to permit lymph node visualization, this study evaluated the aspiration support function. methods before testing, size and position of lymph nodes for aspiration were established on mpr images of ct data. on the virtual navigation image, these were displayed in a transparent ellipse from the airway. besides rotation and back and forth movements, changes in angle of the bronchoscope tip are simulated, and a function is also available to move the virtual image fi eld up, down, left, and right. using these, the navigation image was compared with the real image, and the lymph nodes were aspirated. in patients with enlarged mediastinal/hilar lymph nodes, transbronchial needle aspiration (tbna) without using an ultrasound probe, or ebus-tbna, was selected for aspiration. results lymph nodes were aspirated under navigation in all patients. the diagnosis was primary lung cancer in fi ve patients, metastatic tumor in one patient, and sarcoidosis in two patients. depth perception was diffi cult for the transparently displayed lymph nodes, particularly # and # , and judging anterior-posterior relationships was diffi cult when nodes were superimposed. conclusion some room for improvement thus remains in the display method. however, this offers future promise as diagnostic support technology. key: cord- -xnos iud authors: ritchie, andrew i.; wedzicha, jadwiga a. title: definition, causes, pathogenesis, and consequences of chronic obstructive pulmonary disease exacerbations date: - - journal: clin chest med doi: . /j.ccm. . . sha: doc_id: cord_uid: xnos iud acute exacerbations of chronic obstructive pulmonary disease (aecopd) are episodes of symptom worsening which have significant adverse consequences for patients. exacerbations are highly heterogeneous events associated with increased airway and systemic inflammation and physiological changes. the frequency of exacerbations is associated with accelerated lung function decline, quality of life impairment and increased mortality. they are triggered predominantly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. a proportion of patients appear to be more susceptible to exacerbations, with poorer quality of life and more aggressive disease progression than those who have infrequent exacerbations. exacerbations also contribute significantly to healthcare expenditure. prevention and mitigation of exacerbations are therefore key goals of copd management. acute exacerbations of chronic obstructive pulmonary disease (aecopds) are episodes of symptom worsening that have significant adverse consequences for patients. the important causes of exacerbations include airway bacteria, viruses, and pollution; however, the interplay of these triggers must also be considered. it is recognized that defects in immunity and host defense lead to more frequent aecopds. greater frequency of exacerbations is associated with accelerated lung function decline, quality-of-life impairment, and increased mortality. furthermore, as the incidence of chronic obstructive pulmonary disease (copd) increases, exacerbations place a greater burden on health care systems, accounting for more than million unscheduled attendances per year in the united states. the direct costs of copd treatment in the united states are greater than $ billion per year, , with exacerbations estimated to account for % to % of these health care costs. exacerbations are also important outcome measures in copd, with acute treatment targeting accelerated recovery, whereas long-term maintenance therapy is designed to prevent and reduce their frequency and severity. although half of the patients treated in the community recover to their baseline symptoms by days, a study of the time course found that, despite treatment, % had still not fully recovered by weeks. moreover, in a small proportion of exacerbations, symptoms never returned to the baseline level. consequently, a substantial number of copd exacerbations can be prolonged, which culminates in greater morbidity associated with such an event. a key audit examining hospital admissions showed that more than one-quarter of patients experience another event during the following weeks. in a cohort of patients with moderate to severe copd followed up after exacerbation, % had a recurrent event within days of the first (index) exacerbation. such events are therefore complex, and an initial exacerbation seems to increase the susceptibility to a subsequent exacerbation. these recurrent events are associated with substantially increased mortality and this has driven financial incentives for health care services aiming to avoiding hospital readmission. , exacerbations definition aecopds are transient periods of increased symptoms of dyspnea, sputum purulence, and sputum volume, but they may also encompass minor symptoms of nasal blockage/discharge, wheeze, sore throat, cough, fever, chest tightness or discomfort, fatigue/reduced energy, sleep disturbance, or limited physical activity. copd exacerbations are associated with several features, including increased airway inflammation, mucus hypersecretion, and gas trapping. there is a degree of controversy over the precise definition of exacerbation events. the global initiative for chronic obstructive lung disease (gold) document aecopd definition slightly differs from this as "an acute worsening of respiratory symptoms that results in additional therapy." this definition requires the patient to seek or use treatment and is an example of a health care use (hcu) exacerbation in which the patient or clinician decides whether treatment is warranted. the disadvantage with only considering this definition is that it risks not accounting for important events in certain key scenarios; for example, those of lesser severity that do not trigger increased treatment use, where respiratory deterioration with an alternative cause is misdiagnosed, or events in resource-poor areas with a lack of access to treatment or clinicians. the alternative to an hcu definition is to measure the increase in symptoms and to classify an exacerbation when this change crosses a threshold (regardless of whether the patient receives treatment). this approach has been widely accepted in research, using several validated patient-reported outcome (pro) tools such as symptom/treatment diary cards and questionnaire tools such as the exact (exacerbations of chronic obstructive pulmonary disease tool) and cat (the copd assessment test). when implemented, it was discovered that a large number of events are unreported and untreated. studies using symptom-based definitions typically report an incidence of exacerbations that is approximately twice as high as with hcu definitions. one reason for this is that the method captures additional milder events that the hcu definition does not. although unreported exacerbations are milder than reported events, they do not seem to be inconsequential. however, the science of measuring symptoms is challenging, both in the collection of (daily) data and in their analysis. analysis challenges include defining the threshold for exacerbation, ceiling effects, and how and when to reset the baseline symptom level in the event of incomplete exacerbation recovery. two of the most extensively validated pros in exacerbation studies are the exact and cat, which seem to be valuable in the assessment of exacerbation frequency, duration, and severity and have been qualified as an exploratory end point by both the us food and drug administration (fda) and the european medicines agency (ema). a particular strength of the exact is its ability to detect unreported events, and, in the attain (aclidinium to treat airway obstruction in copd patients), comparing a long-acting muscarinic antagonist with placebo, unreported (untreated) symptom (exact)-defined events had the same medium-term health consequences as reported (treated) hcu exacerbations. moreover, the trial intervention reduced the rate of both symptom (exact)-defined and hcu events. however, a challenge with interpreting pros such as the exact tool is the discordance between hcu exacerbations and symptom (exact)-defined events, with discrepancies found in both observational studies and clinical trials. a major challenge is the heterogeneous nature of the clinical presentation, and alternative causes for acute deterioration, such as heart failure, pneumothorax, pulmonary emboli, or anxiety, must be considered. traditionally, infective exacerbations are thought to be driven by infection of the airway lumen (bronchi/bronchioles), whereas pneumonia represents alveolar infection. however, it is likely that these distinct processes overlap. a chest radiograph is not routinely performed during a copd exacerbation, and consolidation may be missed if it is early in the infective process, or through the insensitivity of the test. the latest gold guidelines define exacerbation severity by the treatment that is required. mild: treatment with short-acting bronchodilators only moderate: treated with short-acting bronchodilators plus antibiotics and/or oral corticosteroids severe: requires either hospitalization or a visit to the emergency department and may also be associated with respiratory failure. exacerbations are airway inflammatory events that are triggered by infection in most cases. respiratory viral infections are the predominant cause, although bacterial infections and environmental factors such as air pollution and ambient temperature trigger or worsen these events. , although early studies focused on bacteria as the primary cause of exacerbations, the development of highly specific molecular diagnostic techniques has highlighted the importance of viruses as key triggers for exacerbations. [ ] [ ] [ ] the primary role of different exacerbation triggers and important aspects of their interplay, including viral-bacterial fig. . overview of aecopd. egf, endothelial growth factor; ena, epithelial-derived neutrophil-activating peptide; icam- , intercellular adhesion molecule ; il, interleukin; ip, interferon g-induced protein; i-tac, interferoninducible t-cell alpha chemoattractant; gm-csf, granulocyte-macrophage colony-stimulating factor; gro, growth-regulated oncogene; mmp, matrix metalloproteinase; rantes, regulated upon activation, normal t cell expressed and presumably secreted; tgf, transforming growth factor; th, t helper; tnf, tumor necrosis factor; vegf, vascular endothelial growth factor. coinfection, deficient host response to bacteria, and the lung microbiome in exacerbation are described here (fig. ) . it has long been observed that the frequency of aecopd doubles in winter months, , with more than % of exacerbations preceded by coryzal symptoms (table ) . , , viruses earlier studies using culture-based methods underestimated the prevalence of respiratory viruses during copd exacerbations. however, with the advent of polymerase chain reaction (pcr) methods, the detection of viruses in copd exacerbations increased to % to %. the wide variations in virus detection are likely to be the consequence of whether patients were sampled at true onset of symptoms or sampling was delayed. additional factors could include variation in the range of viruses tested for, sensitivity of the assays, the study period (eg, winter vs yearlong, variation in virus epidemics; eg, respiratory syncytial virus [rsv]), population (eg, community vs inpatient, uptake of the influenza vaccine), and sampling method (eg, nasopharyngeal swabs, sputum). in studies where patients reported exacerbation symptoms at onset, there is a greater prevalence of viral infection, because viral load is higher at exacerbation onset , and may therefore be undetectable by the time patients present to hospital. , , , , , rhinoviruses are the most prevalent in most of these studies, accounting for up to % of all exacerbations. influenza viruses and rsvs are also commonly detected, being identified in up to % and % of aecopds respectively. parainfluenza viruses, human metapneumoviruses, coronaviruses, and adenoviruses are detected, but less frequently. importantly, viral aecopds are associated with more severe symptoms, greater airflow limitation, and delayed recovery compared with exacerbations where no virus is detected. , the greater incidence of rhinovirus in induced sputum, as opposed to nasal aspirates at exacerbation, further supports the theory that naturally occurring rhinovirus drive most exacerbations. although these studies have shown an association between respiratory virus infection and exacerbations, they do not prove causation because pcr detects viral nucleic acid but it cannot prove the presence of live, replicating virus. consequently, secondary causes cannot be excluded. however, in , mallia and colleagues provided novel evidence of a causal relationship between respiratory virus infection and exacerbations in patients with copd through their experimental rhinovirus infection in patients with mild copd. in their human model, they showed clearly that respiratory viruses produce symptoms that are typical of an exacerbation, confirming that respiratory viruses can infect the lower airway and contribute to inflammatory changes. chronic viral infection is another key aspect to examine when considering the role played by viruses such as rsv. although rsv infection has been seen at exacerbation, whether it alone drives the event is not entirely clear, because this virus is found incidentally within the airways of patients with copd at stable state where it is associated with increased airway inflammation. latent expression of adenoviral e a protein in alveolar epithelial cells can potentiate the effects of lung inflammation induced by cigarette smoke. it is therefore plausible that chronic viral infection could contribute to disease severity in copd, and further work is required to understand how viruses detected in the stable state relate to exacerbations. it is not fully understood why patients develop an exacerbation following respiratory virus infection but never smokers do not often go on to develop significant lower respiratory symptoms. furthermore, there is a subgroup of copd that seems to be more susceptible to infection, irrespective of disease severity (the frequent-exacerbator phenotype). copd is associated with substantial changes in innate immunity that are likely to be relevant in the pathogenesis of exacerbations. tobacco smoking impairs mucociliary clearance, and the rhinovirus binding receptor intercellular adhesion molecule (icam- ) is upregulated by bronchial epithelial cells in copd. alveolar macrophages, which are numerous and form a first line of defense in the respiratory tract, are defective in copd, with impairments in their ability to phagocytose bacteria , and clear dead and dying cells compared with alveolar macrophages from healthy smoking and nonsmoking controls. in the human experimental rhinovirus infection model, mallia and colleagues found nasal lavage viral load was significantly higher in patients with copd following rhinovirus infection compared with age-matched healthy controls. because all subjects were inoculated with the same virus dose, this suggests impairment in the immune response that controls viral replication in copd. this finding supports the work by hurst and colleagues, who earlier showed that exacerbation frequency was related to cold acquisition rather than the propensity to develop an exacerbation following a cold. the most abundant cells in the airway are bronchial epithelial cells (becs) and alveolar macrophages. interferon (ifn) deficiency has been observed in these important cells and, therefore, proposed as a potential mechanism of increased susceptibility to rhinovirus infection. respiratory viruses such as human rhinovirus (hrv) replicate within the respiratory epithelium triggering the production of type i (fn-a, ifn-b) and type iii ifns (ifn-l), which limit viral replication, protein synthesis, and protein trafficking ( table ) . however, ifn deficiency remains controversial in copd. mallia and colleagues found that bronchoalveolar lavage (bal) cells of subjects with copd had a deficient ifn-b response to ex vivo infection with hrv- , but did not identify any deficiency in bec responses. in contrast, hsu and colleagues recently showed impaired ifn responses to influenza virus in becs from copd. these findings are supported by a study that showed a decrease in expression of ifn stimulated genes in the induced sputum of copd participants compared with healthy controls. however, schneider and colleagues and baines and colleagues showed increased ifn-l responses to hrv- and hrv- b infection of copd becs respectively compared with healthy controls. further studies of ifn induction in response to viral infection in epithelial and bal cells in copd are clearly needed because this is a potential therapeutic target. viral infection in copd also leads to the production of disease-relevant proinflammatory cytokines such as interleukin (il)- (cxcl ), il- , chemokine ligand (ccl /rantes), tumor necrosis factor alpha (tnf-a), and ifn-g-induced protein (ip- /cxcl ) via the nuclear factor kb pathway leading to the recruitment of neutrophils, macrophages, natural killer cells, t cells, and dendritic cells at the site of infection enhancing viral clearance. importantly, the magnitude of this response is greater in patients with copd compared with healthy controls , , and may explain how increased airway inflammation contributes to lower airway symptoms in copd exacerbations. in general, exacerbations become both more frequent and more severe as the severity of the underlying copd increases, , although the reason some patients with copd experience more frequent exacerbations than others remains unclear. the evaluation of copd longitudinally to identify predictive surrogate endpoints (eclipse) cohort study identified a distinct frequentexacerbator phenotype. this group, irrespective of disease severity, was more susceptible to exacerbations and could be identified by a previous history of or more exacerbations in a preceding year. there is some indirect evidence that an increased susceptibility to virus infection may be a characteristic of frequent exacerbators. in studies of naturally acquired virus-induced copd exacerbations, virus infection was detected more commonly in exacerbation-prone patients. , alveolar macrophages taken from such patients (defined as having had an exacerbation during a -year period) and exposed to bacteria or tolllike receptor ligands ex vivo showed impaired induction of cxcl /il- and tnf-a, compared with macrophages from patients who were exacerbation free for a year. nevertheless, the description of frequent exacerbators remains essentially clinical and further studies are warranted to elucidate differences in the immune responses and conclusively provide an underlying mechanism to explain this phenotype. bacteria are also extremely important in the pathogenesis of copd exacerbations. studies using traditional sputum culturing techniques have isolated bacteria in % to % of exacerbations of copd. studies have also shown that bacterial colonization is common in copd and is associated with greater airway inflammation and increased risk of exacerbation. , , however, it remains unclear from these studies whether exacerbations occur because of the acquisition of new bacterial strains or an outgrowth of preexisting bacteria. the microbiome changes during chronic obstructive pulmonary disease exacerbations in up to % of aecopds showing the hallmarks of a bacterial cause, the causative pathogens are not recovered from respiratory samples by traditional culture methods. the application of microbiome techniques, which are culture independent, is giving rise to a new understanding of the interaction between the host and the millions of microorganisms that are present on bodily surfaces. studies identifying bacteria based on s ribosomal rna gene sequences have shown that the lungs of healthy people and patients with copd are colonized by rich, complex bacterial communities. [ ] [ ] [ ] recently, researchers have begun to highlight the shifts in microbial communities during copd exacerbations ( table ) . one of the first longitudinal studies, by huang and colleagues, found that the sputum microbiome did not show any significant changes in the key characteristics of community richness, evenness, and diversity. however, substantial taxonomic composition variation was seen during exacerbations, with an increase in proteobacteria the larger copd-map and aeris longitudinal studies found no significant change in shannon diversity or core taxa abundancies at exacerbation, however, both studies suggested that exacerbations result from dysbiosis caused by changes in preexisting bacteria in the lung rather than complete removal or appearance of a novel species. , overall, these findings suggest that, although the bacteria cultured at exacerbation undoubtedly drive events, enrichment of taxa closely related to a dominant pathogen could also contribute to pathogenesis. therefore, exacerbations can be considered polymicrobial infections. a study of the microbiome following experimental rhinovirus infection also showed an outgrowth in haemophilus and neisseria that were present in lower numbers before rhinovirus infection. these changes were correlated with increased neutrophil concentration and neutrophil elastase levels, and were not observed in the healthy control group. these findings support the hypothesis that the bacteria identified at exacerbation are not newly acquired but are caused by an outgrowth of preexisting bacteria that have experienced newly favored conditions. both the beat-copd cohort and copd-map cohorts identified distinct microbiome compositions between bacterial and eosinophilic exacerbations, suggesting that these are stable exacerbation phenotypes. the aeris study found that individuals with concomitant bronchiectasis had a greater abundance of haemophilus. it suggested that frequent exacerbators may have greater dysbiosis compared with infrequent exacerbators, thus providing a potential mechanism by which aecopds arise. events treated by antibiotics alone led to a reduction in the relative abundance of proteobacteria, whereas treatment with corticosteroids alone led to an enrichment of multiple taxa, including members of bacteroidetes, firmicutes, and proteobacteria. , this finding was supported by an earlier study of tracheal aspirates from intubated patients in whom the investigators observed that bacterial communities became less diverse as the duration of intubation and antibiotic administration increased, suggesting that microbial communities are influenced by therapeutic interventions. when both steroids and antibiotics were used to treat an exacerbation, a mixed effect on the airway microbiome was seen. a current hypothesis is that bacteria enter the lower respiratory tract by microaspiration during sleep or inhalation. in healthy lungs, pathogens either fill an ecological niche or are eradicated with minimal inflammation by the innate immune response. however, in patients with copd, a combination of defective innate immunity including impaired mucociliary clearance and variation in antigenic structure among strains allow these bacteria to persist and proliferate. a complex host-pathogen interaction in the lower airway determines this outcome. in a mouse model, h influenzae strains associated with copd exacerbations induced greater airway neutrophil recruitment compared with colonizationassociated strains. exacerbation-associated m catarrhalis strains interact differently with primary human airway epithelial cells, showing greater adherence and eliciting more il- . sputum immunoglobulin (ig)a levels, representing the mucosal host response to the infecting strain, were greater with colonization, whereas the systemic serum igg host response was larger during exacerbations. it is thought that a robust mucosal immune response diminishes bacterial interaction with the airway epithalamium, resulting in less airway inflammation, thus favoring colonization. recent studies focusing on the immune response to bacterial infection have shown the development of specific antibodies to important species, including h influenzae, m catarrhalis, s pneumoniae, and p aeruginosa following exacerbations. some of these show bactericidal and opsonophagocytic function, thereby aiding bacterial clearance. [ ] [ ] [ ] however, the multitude of strains may result in recurrent exacerbations with the same species and also creates a challenge for effective vaccine development. coinfection with bacteria and viruses is common, occurring in % to % of exacerbations. , , the dynamics of viral and bacterial infection have been examined by hutchinson and colleagues, who collected respiratory samples from patients with copd at exacerbation onset, and also to days later: % of patients who had a virus detected at exacerbation onset went on to have a bacterial infection. george and colleagues reported that, when hrv was detected at exacerbation onset, % of patients developed a bacterial infection at days. mallia and colleagues found comparable results in experimental rhinovirus infection in copd, with % of patients with copd showing bacterial infection in their sputum at day compared with only % in healthy volunteers. those who developed a bacterial infection had prolonged respiratory symptoms and delayed recovery compared with those in whom bacteria were not detected. exacerbations with coinfection with viruses and bacteria are associated with greater airflow limitation, increased airway inflammation, and delayed exacerbation recovery. , however, mechanisms underpinning how hrv infection leads to a secondary bacterial infection have not been fully elucidated. possible mechanisms include viral impairment of macrophage response to bacteria [ ] [ ] [ ] leading to a reduction in neutrophil recruitment and bacterial clearance or, alternatively, an upregulation of adhesion molecules in the bronchial epithelium. however, further work is needed to understand the complex pathogen-host interactions to direct further therapeutics. copd is characterized by aberrant airway inflammation. a further increase in airway inflammation is seen in most exacerbations, but this process is not uniform and inflammation is related to exacerbation cause. frequent exacerbators also show greater inflammation, and exacerbation nonrecovery is associated with persistent inflammation and a shorter time to the next exacerbation. traditionally, airway eosinophilia and t-helper cell type (th ) inflammation has been considered associated with allergic airway disorders such as asthma, and airway neutrophilia with copd. however recent studies have reported that % to % of patients with copd show sputum eosinophilia in the stable state. [ ] [ ] [ ] the spiromics (subpopulations and intermediate outcome measures in copd study) cohort has found that sputum eosinophilia at stable state is associated with more severe disease and increased exacerbation frequency. interventional studies additionally suggest that high blood eosinophilia level at stable state might predict a better treatment response to inhaled corticosteroid use and could therefore be used to guide therapy. , acute exacerbations may be associated with further enhancement of eosinophilic airway inflammation, with up to % of copd exacerbations being associated with sputum eosinophilia. , although there is biological plausibility for viral infection leading to sputum eosinophilia, studies of exacerbations to date have been conflicting. , , as a result, despite the considerable interest in the role of sputum and blood eosinophilia at stable state as biomarkers for disease outcome and steroid responsiveness, further work is needed to evaluate the significance of increased th inflammation during copd exacerbations. copd exacerbations associated with bacterial pathogens show significantly more airway neutrophilic inflammation compared with nonbacterial episodes. furthermore, the exacerbation severity and degree of airway bacterial concentration are related to the degree of neutrophilic inflammation. , important mediators of this airway neutrophilia in bacterial exacerbations include il- , leukotriene b , and tnf-a. , studies examining bacterial exacerbations have identified an il- b signature comprising tnf-a, granulocyte colony-stimulating factor (growthregulated oncogene-a), il- , cluster of differentiation (cd) ligand, and macrophage inflammatory protein (mip- ). il- a has been associated specifically with h influenzae exacerbations. neutrophil degranulation and necrosis can cause significant damage related to the release of neutrophil elastase and matrix metalloproteinases. clinical resolution of the symptoms of exacerbation is associated with a consistent decrease in mediators of neutrophilic airway inflammation, whereas nonresolving exacerbations show a sustained level of exaggerated airway inflammation. studies from experimental infections also indicate that viral infection induces airway neutrophilic inflammation and innate inflammatory meditators such as il- b, granulocyte colony-stimulating factor (gm-csf), cxcl /il- , and tnf-a. , , macrophages alveolar macrophages play a key role in the host defense against invasive pathogens by removing bacteria from the lung by phagocytosis, mediating inflammatory responses. there is increasing evidence of macrophage dysfunction in copd. alveolar macrophages and monocyte-derived macrophages show impaired phagocytosis of h influenzae, s pneumoniae, and escherichia coli compared with healthy controls. , , bewley and colleagues also found that phagocytosis of h influenzae was impaired in subjects with copd with a history of exacerbations. alveolar macrophages of exacerbation-prone subjects with copd also showed impaired production of inflammatory cytokines cxcl and tnf-a in response to h influenzae compared with nonexacerbation-prone subjects with copd, implicating macrophage dysfunction as a potential mechanism responsible for increased exacerbation frequency in copd. macrophages from patients with copd stimulated ex vivo with respiratory virus produce less ifn compared with healthy subjects. however, in vitro studies have not necessarily supported this, with similar and even increased ifn released by cells taken from patients with copd. in a murine model of copd, ifn-a and ifn-b responses as a result of virus infection were reported as deficient in study and viral clearance was impaired ; conversely, another study reported reduced ifn-l (but not in ifn-b) and no difference in virus load. therefore, it remains unclear whether production of ifn in response to virus infection is impaired in patients with copd. a reliable and objective biomarker of an aecopd would be invaluable to aid in reliable diagnosis and guide appropriate treatment. the patient samples most investigated are serum or plasma, although sputum, urine, or exhaled breath may also contain useful biomarkers. several studies have shown that the levels of a variety of immunoinflammatory cells and molecules are increased during exacerbations in respiratory samples, including exhaled breath, sputum, bronchoalveolar lavage, and bronchial biopsy ( table ). a viral exacerbation is suggested with a history of coryzal symptoms and can subsequently be confirmed by pcr from a respiratory sample. however, a reliable biomarker would be invaluable for guiding therapy and antibiotic stewardship (see tables and ). to date, serum cxcl (ip- ) seems the most promising, with bafadhel and colleagues reporting a cutoff of pg/ml to distinguish viral from nonviral exacerbations, giving a specificity of % and sensitivity of %. quint and colleagues reported an area under the curve for serum ip- alone of . ( % confidence interval, . - ) for detecting a human rhinovirus infection at exacerbation. other biomarkers have been investigated, with levels of il- , monocyte chemoattractant protein- (mcp- ), and tnf-a all being increased in viral-associated aecopd compared with viral-negative subjects and controls. procalcitonin has also been used to try to detect viral-associated aecopd, but the evidence so far is equivocal. bafadhel and colleagues suggested that a useful biomarker for determining bacterial-associated aecopd was sputum il- b, with a cutoff of pg/ml having a specificity of % and sensitivity of %. the serum biomarker best suited for distinguishing a bacterial cause in this study was c-reactive protein (crp) at a cutoff of mg/l, having a specificity of % and sensitivity of %. dal negro and colleagues also found that high sputum tnf-a level was associated with pseudomonas-related exacerbations, and, in those subjects without high tnf-a level, high levels of il- and il- b in the sputum distinguished bacterial from viral and noninfective exacerbations. an electronic nose used in the detection of cardinal volatile organic compounds has recently been used in a pilot study to distinguish bacterial from viral aecopd, although development and proof of concept are needed before this technology can play a role in outpatient diagnostics. a danish study investigating biomarkers indicative of frequent exacerbators discovered that simultaneously increased fibrinogen, crp, and white blood cell counts indicated an increased risk of frequent exacerbation. increased plasma fibrinogen level in patients at risk of frequent exacerbation has also been replicated in further studies. , the fda has gone on to qualify fibrinogen as an end point of exacerbations and mortality. high levels of serum surfactant protein d have been shown to predict exacerbations when at their highest levels. however, the most comprehensive study to date, which included patients and examined markers, in separate cohorts (spiromics and copdgene), found no biomarker showed a significant relationship to exacerbation frequency in either cohort (after adjustment for recognized confounders: age, gender, percentage predicted forced expiratory volume in second [fev ], smoking and health status [quality of life], and self-report of gastroesophageal reflux). lung function decline several studies have now shown that copd exacerbations affect disease progression. donaldson and colleagues showed that patients with a history of frequent exacerbations show accelerated decline, at around %, whereas kanner and colleagues also showed that episodes of respiratory infections affect fev decline. however, some of the earlier studies did not show a relationship between exacerbations and fev decline. [ ] [ ] [ ] a review by silverman suggested that this heterogeneity could be caused by the general/unselected or chronic bronchitis/ higher bnp levels indicate a more severe exacerbation and a longer hospital stay , plasma fibrinogen fibrinogen increases during copd exacerbation ( . g/l sd . ), and then returns to the patient's baseline over a period of to wk , this process is associated with a concurrent increase in il- a large meta-analysis of more than , participants indicated that a -g/l increase in plasma fibrinogen resulted in a . -fold increase in copd-specific mortality il- il- has been shown to be a better predictor of mortality than both crp and plasma fibrinogen urine metabolomics few biomarkers isolated from the urine are clinically useful in aecopd one study that shows promise for the future has indicated that certain metabolomics can be used to differentiate copd from asthma with a > % accuracy sputum eosinophilia sputum eosinophil levels have been found to negatively correlate with bacterial load at exacerbation serum peripheral blood eosinophil count at a cutoff of % is likely to be the best measure of sputum eosinophilia, with bafadhel et al reporting a specificity of %, sensitivity of % exhaled nitric oxide several studies of aecopd show an increase, with showing an increase of . ppb (À . to . ppb) at exacerbation , abbreviations: bnp, brain natriuretic peptide; crp, c-reactive protein; iqr, interquartile range; pct, procalcitonin; sd, standard deviation. data from refs. , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] emphysema populations studied in the early, negative studies in contrast with the copd patient populations studied in the later, positive studies. a recent copdgene study showed that the effect of exacerbations on decline was greatest in patients with mild (gold stage ) copd, with each event associated with an additional ml/y decline. on occasion, lung function following an exacerbation does not fully recover, and then a group of patients who experience frequent exacerbations (because they have more events) are likely to have a faster lung function decline than patients who have zero or few exacerbations. according to the latest global burden of disease study estimates for , copd accounted worldwide for . million deaths. exacerbations are the predominant cause of mortality, and soler-cataluñ a and colleagues showed that aecopds requiring hospitalization are independently associated with mortality (after adjusting for confounding variables such as age, fev , body mass index, and charlson comorbidity index), and that the mortality risk increases with exacerbation frequency. a canadian mortality study showed that rates after the first hospitalized copd exacerbation were % at $ years and % at $ years. the mortality risk peaks sharply in the first days after hospitalization and gradually declines over the subsequent months. with every new hospitalized exacerbation, the risk of death increased, and the interval between hospitalizations decreased over time. for aecopds requiring hospitalization, patients with older age, higher arterial paco , prolonged oral corticosteroid use, or admission to intensive care unit are more likely to die. in a large analysis of a uk primary care population, rothnie and colleagues show a clear association between both the increasing frequency and the severity of aecopds and mortality. the relationship between copd exacerbations and health-related quality of life was first reported by seemungal and colleagues, , , exacerbations also worsen patients' mental health with an increase in anxiety and depression and feelings of fatigue. hospital admission and readmission for acute exacerbations have a particularly negative impact on quality-of-life scores. , physical activity acutely at exacerbation, patients spend less time outside of their homes, and patients who experience frequent exacerbation have a faster decline in time spent outdoors compared with infrequent exacerbators. peripheral muscle weakness also deteriorates during an aecopd. patients who maintain physical activity at a low level reduce the risk of hospital admission for copd by % (p . ) compared with little or no physical activity aecopds are episodes of symptom worsening that have significant adverse consequences for patients. exacerbations are highly heterogeneous events associated with increased airway and systemic inflammation and physiologic changes. the frequency of exacerbations is associated with accelerated lung function decline, quality of life impairment, and increased mortality. they are triggered predominantly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. a proportion of patients seem to be more susceptible to exacerbations, with poorer quality of life and more aggressive disease progression than those who have infrequent exacerbations. exacerbations also contribute significantly to health care expenditure. prevention and mitigation of exacerbations are therefore key goals of copd management. global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease report. gold executive summary copd exacerbations: defining their cause and prevention relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease the epidemiology and economics of chronic obstructive pulmonary disease the clinical and economic burden of chronic obstructive pulmonary disease in the usa the economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review standards for the diagnosis and treatment of patients with copd: a summary of the ats/ers position paper time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease temporal clustering of exacerbations in chronic obstructive pulmonary disease inflammatory changes, recovery and recurrence at copd exacerbation clinical audit indicators of outcome following admission to hospital with acute exacerbation of chronic obstructive pulmonary disease antibiotic treatment of exacerbations of copd: a randomized, controlled trial comparing procalcitoninguidance with standard therapy understanding why patients with copd get readmitted: a large national study to delineate the medicare population for the readmissions penalty expansion antibiotic therapy in exacerbations of chronic obstructive pulmonary disease detection and severity grading of copd exacerbations using the exacerbations of chronic pulmonary disease tool (exact) acute exacerbations of pulmonary diseases. european respiratory society usefulness of the chronic obstructive pulmonary disease assessment test to evaluate severity of copd exacerbations patient-reported outcomes for the detection, quantification, and evaluation of chronic obstructive pulmonary disease exacerbations characterisation and impact of reported and unreported exacerbations: results from attain major air pollutants and risk of copd exacerbations: a systematic review and meta-analysis guidelines for the management of adult lower respiratory tract infections-full version pathogenesis of viral infection in exacerbations of airway disease role of infection in chronic bronchitis new strains of bacteria and exacerbations of chronic obstructive pulmonary disease seasonality and determinants of moderate and severe copd exacerbations in the torch study seasonal distribution of copd exacerbations in the prevention of exacerbations with tiotropium in copd trial epidemiological relationships between the common cold and exacerbation frequency in copd exacerbation of chronic obstructive pulmonary disease respiratory syncytial virus, airway inflammation, and fev decline in patients with chronic obstructive pulmonary disease amplification of inflammation in emphysema and its association with latent adenoviral infection susceptibility to exacerbation in chronic obstructive pulmonary disease smoking is associated with shortened airway cilia upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis defective macrophage phagocytosis of bacteria in copd phagocytic dysfunction of human alveolar macrophages and severity of chronic obstructive pulmonary disease alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells the airway epithelium: soldier in the fight against respiratory viruses impaired antiviral stress granule and ifn-b enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium reduced sputum expression of interferonstimulated genes in severe copd increased cytokine response of rhinovirusinfected airway epithelial cells in chronic obstructive pulmonary disease novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in copd inflammatory response in acute viral exacerbations of copd copd exacerbations: definitions and classifications impaired innate immune alveolar macrophage response and the predilection for copd exacerbations infection in the pathogenesis and course of chronic obstructive pulmonary disease relationships among bacteria, upper airway, lower airway, and systemic inflammation in copd a persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations analysis of the lung microbiome in the "healthy" smoker and in copd microbiome diversity in the bronchial tracts of patients with chronic obstructive pulmonary disease airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the copdmap study longitudinal profiling of the lung microbiome in the aeris study demonstrates repeatability of bacterial and eosinophilic copd exacerbations outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease chronic obstructive pulmonary disease j topic j nice lung microbiome dynamics in copd exacerbations. eur respir the role of the bacterial microbiome in lung disease haemophilus influenzae from patients with chronic obstructive pulmonary disease exacerbation induce more inflammation than colonizers moraxella catarrhalis acquisition, airway inflammation and protease-antiprotease balance in chronic obstructive pulmonary disease moraxella catarrhalis in chronic obstructive pulmonary disease host-pathogen interaction during pneumococcal infection in patients with chronic obstructive pulmonary disease strain-specific immune response to haemophilus influenzae in chronic obstructive pulmonary disease systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages viral inhibition of bacterial phagocytosis by human macrophages: redundant role of cd human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease rhinovirus attenuates non-typeable hemophilus influenzaestimulated il- responses via tlr -dependent degradation of irak- rhinovirus enhances various bacterial adhesions to nasal epithelial cells simultaneously stable copd: predicting benefit from high-dose inhaled corticosteroid treatment copd exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial association of sputum and blood eosinophil concentrations with clinical measures of copd severity: an analysis of the spiromics cohort blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials blood eosinophils and inhaled corticosteroid/long-acting b- agonist efficacy in copd viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness airway eosinophilia in chronic bronchitis during exacerbations oxidative and nitrosative stress and histone deacetylase- activity in exacerbations of chronic obstructive pulmonary disease neutrophil adhesion molecules in experimental rhinovirus infection in copd altered macrophage function in chronic obstructive pulmonary disease impaired alveolar macrophage response to haemophilus antigens in chronic obstructive lung disease differential effects of p , mapk, pi k or rho kinase inhibitors on bacterial phagocytosis and efferocytosis by macrophages in copd elastaseand lps-exposed mice display altered responses to rhinovirus infection analysis of viral infection and biomarkers in patients with acute exacerbation of chronic obstructive pulmonary disease the expression of il- , tnf-a, and mcp- in respiratory viral infection in acute exacerbations of chronic obstructive pulmonary disease the use of serum procalcitonin as a diagnostic and prognostic biomarker in chronic obstructive pulmonary disease exacerbations: a literature review update a two-stage logistic model based on the measurement of pro-inflammatory cytokines in bronchial secretions for assessing bacterial, viral, and noninfectious origin of copd exacerbations diagnosing viral and bacterial respiratory infections in acute copd exacerbations by an electronic nose: a pilot study biomarkers for predicting copd exacerbations fibrinogen and copd: now what? chronic obstr pulm dis blood fibrinogen as a biomarker of chronic obstructive pulmonary disease biomarkers in airway diseases biomarkers predictive of exacerbations in the spiro-mics and copdgene cohorts lower respiratory illnesses promote fev decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease the progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the bode cohort effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the torch study a long-term follow-up of respiratory symptoms and ventilatory function in a group of working men exacerbations in chronic obstructive pulmonary disease: do they contribute to disease progression? acute 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pulmonary disease exacerbation risk risk factors of readmission to hospital for a copd exacerbation: a prospective study determinants and impact of fatigue in patients with chronic obstructive pulmonary disease exacerbations and time spent outdoors in chronic obstructive pulmonary disease muscle force during an acute exacerbation in hospitalised patients with copd and its relationship with cxcl and igf-i influence of season on exacerbation characteristics in patients with copd seasonal variations in exacerbations and deaths in patients with copd during the tiospir((r)) trial serum ip- as a biomarker of human rhinovirus infection at exacerbation of copd an experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study lymphocyte subsets in experimental rhinovirus infection in chronic obstructive pulmonary disease a systematic review of diagnostic biomarkers of copd exacerbation c-reactive protein in outpatients with acute exacerbation of copd: its relationship with microbial etiology and severity serum inflammatory biomarkers and clinical outcomes of copd exacerbation caused by different pathogens procalcitonin to guide antibiotic administration in copd exacerbations: a meta-analysis high plasma brain natriuretic peptide levels in stable copd without pulmonary hypertension or cor pulmonale calistru pi. european respiratory journal significance of nt-pro-bnp in acute exacerbation of copd patients without underlying left ventricular dysfunction acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum il- levels inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease metabolomic profiling of asthma and chronic obstructive pulmonary disease: a pilot study differentiating diseases blood and sputum eosinophils in copd; relationship with bacterial load exhaled nitric oxide as a biomarker in copd and related comorbidities effects of exacerbations and seasonality on exhaled nitric oxide in copd bronchial microbiome of severe copd patients colonised by pseudomonas aeruginosa key: cord- -l akk i authors: kuebler, w. m.; kuppe, h. title: zelluläre pathophysiologie der pulmonalen hypertonie date: - - journal: z herz thorax gefasschir doi: . /s - - -z sha: doc_id: cord_uid: l akk i pulmonary hypertension comprises a group of diseases with heterogeneous etiology characterized by an increase of hydrostatic pressure in the pulmonary vascular bed. while secondary pulmonary hypertension predominantly results from acute or chronic left ventricular failure, characteristic gene defects or predisposing risk factors lead to various forms of primary pulmonary hypertension. despite its diverse pathogenesis, pulmonary hypertension exhibits a uniform cellular pathophysiology in the pulmonary microcirculation. the dysfunction of lung vascular endothelial cells, which are the front line in response to hemodynamic changes in the pulmonary circulation, is the pathophysiological driving force of pulmonary hypertension. endothelial dysfunction is characterized by a reduced production of vasodilative, anti-proliferative mediators and an increased release of vasoconstrictive, proliferative factors. this apparent imbalance not only enhances pulmonary vasoconstriction, but supports pathologic remodeling processes in the vascular intima and media. in addition, the pulmonary endothelium recruits platelets and leukocytes, thus, contributing to further release of vasoconstrictive and proliferative mediators and characteristic thrombus formation. these endothelium-derived pathomechanisms amplify each other, further enhance pulmonary vascular resistance, and finally result in fixation of the hypertensive state. hence, pulmonary hypertension not only describes an alteration of lung hemodynamics, but comprises a complex set of pathophysiological events in both lung parenchymal cells and circulating blood cells. for development of new therapeutical strategies, the multifactorial character of the disease should be considered. n zusammenfassung die pulmonale hypertonie umfasst eine gruppe von erkrankungen heterogener Ätiologie, die mit einem anstieg des hydrostatischen druckes in der lungenstrombahn einhergehen. während sich die sekundäre pulmonale hypertonie zumeist als direkte folge eines akuten oder chronischen linksventrikulären pumpversagens entwickelt, resultieren die primären formen häufig aus charakteristischen gendefekten oder typischen auslösemechanismen. trotz ihrer unterschiedlichen pathogenese weisen jedoch die verschiedenen formen der pulmonalen hypertonie ähnliche pathophysiologische veränderungen und zelluläre reaktionsmuster in der pulmonalen mikrozirkulation auf. die dysfunktion der pulmonalvaskulären endothelzellen, die den hämodynamischen veränderungen unmittelbar exponiert sind, ist die treibende kraft des pathophysiologischen geschehens. die endotheliale dysfunktion bewirkt durch eine verminderte freisetzung vasodilatierender, anti-proliferativer mediatoren bei gleichzeitig vermehrter produktion vasokonstriktiver, proliferativer substanzen nicht nur eine zunehmende pulmonale vasokonstriktion, sondern unterstützt auch die pathologischen umbauprozesse in gefäßintima und -media. darüber hinaus trägt das pulmonale endothel durch die rekrutierung von thrombozyten und leukozyten wesentlich zur freisetzung zusätzlicher vasokonstriktiver, proliferativer faktoren und zur bildung charakteristischer gefäßthromben bei. diese endothelial initiierten pathomechanismen verstärken sich zudem wechselseitig, führen zu einem weiteren anstieg des pulmonalen strömungswiderstandes und fixieren schließlich die pulmonale hypertonie. die pulmonale hypertonie beschreibt folglich nicht nur eine Änderung der lungenhämodynamik, sondern umfasst ein komplexes zelluläres geschehen, an dem parenchymatöses lungengewebe und korpuskuläre blutbestandteile gleicherweise beteiligt sind. bei der entwicklung neuer therapiekonzepte ist dieser multifaktorielle charakter der erkrankung zu berücksichtigen. n summary pulmonary hypertension comprises a group of diseases with heterogeneous etiology characterized by an increase of hydrostatic pressure in the pulmonary vascular bed. while secondary pulmonary hypertension predominantly results from acute or chronic left ventricular failure, characteristic gene defects or predisposing risk factors lead to var-ious forms of primary pulmonary hypertension. despite its diverse pathogenesis, pulmonary hypertension exhibits a uniform cellular pathophysiology in the pulmonary microcirculation. the dysfunction of lung vascular endothelial cells, which are the front line in response to hemodynamic changes in the pulmonary circulation, is the pathophysiological driving force of pulmonary hypertension. endothelial dysfunction is characterized by a reduced production of vasodilative, anti-proliferative mediators and an increased release of vasoconstrictive, proliferative factors. this apparent imbalance not only enhances pulmonary vasoconstriction, but supports pathologic remodeling processes in the vascular intima and media. in addition, the pulmonary endothelium recruits platelets and leukocytes, thus, contributing to further release of vasoconstrictive and proliferative mediators and characteristic thrombus formation. these endothelium-derived pathomechanisms amplify each other, further enhance pulmonary vascular resistance, and finally result in fixation of the hypertensive state. hence, pulmonary hypertension not only describes an alteration of lung hemodynamics, but comprises a complex set of pathophysiological events in both lung parenchymal cells and circulating blood cells. for development of new therapeutical strategies, the multifactorial character of the disease should be considered. n schlüsselwörter pulmonale hypertonie -endotheliale dysfunktion -vaskulärer gefäßumbau -thrombose -entzündung n key words pulmonary hypertension -endothelial dysfunctionvascular remodeling -thrombosis -inflammation in einem autopsiebefund berichtete der leipziger internist ernst romberg von einer auffälligen wandverdickung des pulmonalarteriellen gefäßbaumes ( ) , die sich bis in dessen terminale verzweigungen fortsetzte, und beschrieb damit erstmals die primäre pulmonale hypertonie. obgleich es romberg noch "unmöglich schien, die ursache dieser eigenartigen erkrankung der lungenarterie aufzufinden", folgerte er zurecht, dass "die verengerung des gefäßlumens ein bedeutendes stromhindernis bildete, dem durch die enorme hypertrophie des rechten herzens entgegengearbeitet wurde", und beschrieb somit bereits die grundlegenden hämodynamischen zusammenhänge der pulmonalen hypertonie (ph). seit der erstbeschreibung durch romberg haben die immensen fortschritte auf den gebieten der vaskulären, der zell-und der molekularbiologie unser verständnis der pathophysiologischen zusammenhänge erheblich erweitert. dies ermöglicht neue einblicke in die komplexen zusammenhänge zwischen hämodynamischen veränderungen und aktiven zellulären reaktionen in der lungenstrombahn. die pulmonale hypertonie weist dabei typische charakteristika der angiogenese, des gefäßumbaus, der thrombose und der inflammation auf. die diesen veränderungen zugrundeliegenden aktiven prozesse in gefäßintima und -media, sowie die beteiligung von blutplättchen und inflammatorischen zellen werden in dieser Übersicht in kürze dargelegt. vorab ist es allerdings erforderlich, die definition der ph zu erörtern und ihre verschiedenen formen voneinander abzugrenzen. obgleich sich folglich pathophysiologie und verlauf der schweren ph-formen nicht wesentlich unterscheiden, weisen insbesondere die idiopathischen formen, die unter dem begriff der primären pulmonalen hypertonie (pph) zusammengefasst werden, pathogenetisch eine reihe zellulärer besonderheiten auf, die hier kurz angesprochen werden sollen. die inzidenz der pph beträgt derzeit in europa und den usa ca. , zu million per annum ( ), ihre prävalenz pro million ( ). durch einnahme von appetitzüg- ) kam es allerdings in den er, er und er jahren des vergangenen jahrhunderts jeweils zu einem epidemischen auftreten der erkrankung in europa, in dessen folge die inzidenz teilweise um das fache anstieg ( ). nach dem register der national institutes of health beträgt dabei die mittlere Überlebensdauer nach krankheitsdiagnose nur , jahre ( ). pathogenetisch führen die proliferation mikrovaskulärer endothelzellen sowie hypertrophie und hyperplasie der glatten gefäßmuskulatur in pulmonalen arterien und arteriolen zu einem anstieg des pulmonalvaskulären strömungswiderstandes ( , ) . histopathologisch resultieren diese veränderungen in der prognostisch ungünstigen ausbildung typischer läsionen ( , ) , in denen die endothelzellen das gefäßlumen durch konzentrisches wachstum zwiebelschalenartig ausfüllen ( ) . diese sog. plexiformen läsionen wurden von voelkel und mitarbeitern im sinne einer "fehlgeleiteten angiogenese" interpretiert ( ) . der prominenten intimaproliferation liegt eine monokonale expansion der endothelzellen zugrunde, die Ähnlichkeit mit neoplastischen prozessen aufweist ( , ( ) . grünig und mitarbeiter identifizierten kürzlich in von betroffenen familien eine kopplung mit der pph -region, in den verbleibenden familien hingegen die kopplung mit einem benachbarten genlocus (pph -region) auf chromosom q , und berechneten die wahrscheinlichkeit für eine genetische heterogenität der pph mit , × : ( ). neben genetischen defekten bestimmter tgf-b-rezeptoren scheinen zudem auch funktionelle mutationen von bax, eines proapoptotischen mitglieds der bcl- gen-familie, zur monoklonalen expansion der endothelzellen beizutragen ( ) . diese endothelialen mutationen gehen typischerweise mit einer defizienz von dna-reparaturproteinen, d. h. einem grundsätzlich "mutatorischen phänotyp", einher ( , ) . mittels oligonukleotid-microarray-technik wurde zudem kürzlich bei pph-patienten eine veränderte pulmonale expression verschiedener onkogene, apoptosegene sowie von genen diagnostiziert, die für verschiedene angiogenese-mediatoren, proteine der tgf-b-familie, kinasen sowie spezifische ionenkanäle kodieren ( ). die pathophysiologischen konsequenzen, die sich aus diesen spezifischen expressionsmustern ergeben, sind allerdings noch weitestgehend unklar. schließlich ist vermutlich auch die verminderte expression spezifischer kationenkanäle an der pathogenese der familiären pph beteiligt. yuan et al. wiesen in pulmonalarteriellen gefäßmuskelzellen von patienten mit pph eine reduzierte gentranskription für spannungsabhängige kaliumkanäle vom typ kv · sowie entsprechend verminderte kationenströme nach ( ) . da die resultierende membrandepolarisation über einen calcium-einstrom die proliferation und kontraktion der glatten gefäßmuskulatur induziert ( ), kann auch der verminderten aktivität der kaliumkanäle hinsichtlich der pph ätiologische bedeutung zukommen. der sekundären pulmonalen hypertonie (sph) liegt pathophysiologisch eine heterogene gruppe von primärerkrankungen zugrunde. am bei weitem häufigsten wird die sph durch eine stauung des blutabflusses aus der lunge in folge eines linksventrikulären pumpversagens verursacht, kann jedoch auch aus einer pulmonalen Überperfusion z. b. auf der grundlage eines links-rechts-shunts oder aus einer abnahme des effektiven pulmonalen gefäßquerschnitts resultieren ( ). letztere entwickelt sich entweder obliterativ in folge chronisch entzündlicher oder proliferativer erkrankungen, aufgrund eines obstruktiven verschlusses pulmonaler gefäße durch thrombotische oder embolische ereignisse, oder resultiert aus einer aktiven konstriktion pulmonaler gefäßsegmente (tabelle ). aufgrund der komplexen wechselwirkungen zwischen hämodynamischen veränderungen und aktiven zellulären reaktionen überlappen sich diese kategorien zumeist. trotz ihrer unterschiedlichen pathogenese gleichen die pathophysiologischen veränderungen der schweren sph-formen in auffallender weise jenen der pph. in beiden fällen ändern sich die mechanischen druck-, scher-und dehnungskräfte, die unmittelbar auf die gefäßwand einwirken. infolge dessen ist die pulmonalvaskuläre endothelzelle die primäre effektorzelle der ph ( ). proliferation und hypertrophie der gefäßmedia kennzeichnen die ph-typischen vaskulären umbauprozesse ( ) , die insbesondere in den pulmonalen arterien und arteriolen erfolgen ( ) . dabei erstreckt sich die glatte gefäßmuskulatur teilweise bis auf die ursprünglich nicht-muskularisierten präkapillargefäße ( ), die dicke der gefäßwand beträgt schließlich ein mehrfaches des residualen gefäßlumens. die proliferation der gefäßmuskelzellen wird durch die verminderte aktivität bzw. expression spannungsabhängiger kaliumkanäle (kv) angeregt ( ). die reduktion des transmembranären kaliumstroms bewirkt eine anhaltende membrandepolarisation, die zum influx freier calcium-ionen über spannungsabhängige calcium-kanäle führt ( ) . durch den anstieg der zytosolischen calcium-konzentration werden die gefäßmuskelzellen zur kontraktion, proliferation und migration angeregt ( , , ). pulmonalarterielle gefäßmuskelzellen von patienten mit pph weisen verminderte spannungsabhängige kaliumströme mit konsekutiver membrandepolarisation und erhöhter zytosolischer calcium-konzentration auf ( ) . diesen veränderungen liegt vermutlich eine verminderte gentranskription der kaliumkanal-formenden a-untereinheit kv · zugrunde ( ) . auch hypoxie, die häufig mit der ph assoziiert ist, vermindert die aktivität spannungsabhängiger kaliumkanäle und bedingt dadurch einen anstieg der zytosolischen calcium-konzentration, dem vermutlich wesentliche bedeutung hinsichtlich der hypoxischen pulmonalen vasokonstriktion zukommt ( , ) . hypoxie führt in pulmonalarteriellen gefäßmuskelzellen zur mitochondrialen bildung reaktiver sauerstoffspezies, die als second messenger die zellkontraktion vermitteln ( ) . hypoxie inhibiert zudem aber auch die aktivität von kaliumkanälen des typs kv · b ( ), und vermindert gentranskription und proteinexpression zahlreicher kanal-formender -untereinheiten (kv · , kv · , kv · , kv · , kv · und kv · ) ( , ) . dieser effekt ist interessanterweise spezifisch für pulmonale gefäßmuskelzellen und tritt in gefäßgebieten des systemischen kreislaufs nicht auf ( , ) . die endotheliale dysfunktion unterstützt die calcium-abhängige proliferation der gefäßmuskelzellen indirekt durch die vermehrte bildung proliferativer (et- ) bzw. die verminderte freisetzung anti-proliferativer mediatoren (no, pgi ), eventuell aber auch direkt durch die interzelluläre fortleitung von calcium-fluxen. durch die aktivierung dehnungs-abhängiger kationen-kanäle ( , ) bewirkt eine druckerhöhung im kleinen kreislauf einen anstieg der zytosolischen calcium-konzentration in den mikrovaskulären endothelzellen ( ). solche endothelialen calcium-signale können gegebenenfalls über gap-junction-verbindungen an angrenzende gefäßmuskelzellen fortgeleitet werden, beispielsweise in den arteriolen des cremastermuskels ( , ) . die existenz einer derartigen interzellulären kopplung in den mikrogefäßen des pulmonalen kreislaufs ist bislang allerdings nicht erwiesen. proliferations-und hypertrophieprozesse in der gefäßwand sowie vasokonstriktive effekte werden zusätzlich durch die aktive beteiligung zirkulierender blutzellen verstärkt. diese sezernieren proliferative mediatoren wie serotonin, thromboxan a oder platelet-activating factor ( ) und setzen zusätzlich wachstumsfaktoren wie vegf (vascular endothelial growth factor), pdgf (platelet-derived growth factor) oder tgf-b (transforming growth factor-b) frei. in den folgenden abschnitten wird daher die besondere rolle von thrombozyten und leukozyten in der pathophysiologie der ph erörtert. für eine detaillierte besprechung der beteiligung verschiedener wachstumsfaktoren sei hier aus platzgründen auf die Übersichtsarbeiten von tuder & voelkel verwiesen ( , ) . die lebensdauer von chrommarkierten blutplättchen ist bei patienten mit chronisch-obstruktiven lungenerkrankungen und sph mit , d gegenüber normotensiven patienten ( , d) oder gesunden probanden ( , d) ebenso verkürzt wie bei pph-patienten ( , d) ( ) . auch im tiermodell der monocrotalin-induzierten ph ist die lebensdauer der thrombozyten vermindert ( ) und geht mit einer verstärkten sequestration der blutplättchen in der lungenstrombahn einher ( ) . diese veränderungen der thrombozytenkinetik reflektieren die gesteigerte aktivierung und vermehrte aggregation der thrombozyten ( , , ). da thrombozytopenie die entwicklung der monocrotalin-induzierten ph und der konsekutiven rechtsherzhypertrophie deutlich einschränkt bzw. sogar aufhebt ( , ), kommt den thrombozyten hinsichtlich der ph eine wichtige pathophysiologische rolle zu. diese beschränkt sich nicht auf die bildung charakteristischer thromben, die sich bei annä-hernd / der pph-patienten finden ( , ), sondern bezieht sich insbesondere auch auf die freisetzung aktiver mediatoren. in ihren elektronendichten granula speichern thrombozyten serotonin ( ), das im zuge der aktivierung, aggregation oder schädigung der blutplättchen in die blutbahn freigesetzt wird ( , ). bei patienten mit pph ist die serotonin-konzentration im blutplasma ca. um den faktor erhöht. dieses ist vermutlich thrombozytären ursprungs, da gleichzeitig die blutplättchen einen verminderten serotoningehalt aufweisen ( ). die tatsache, dass dies missverhältnis selbst nach herz-lungen-transplantation fortbesteht, weist darauf hin, dass die vermehrte thrombozytäre serotonin-freisetzung keine sekundäre hypertoniefolge darstellt. während serotonin in den gefäßen des systemischen kreislaufs eine massive vasodilatation induziert ( ), ist es in der pulmonalen zirkulation der stärkste bislang identifizierte vasokonstriktor ( ). hypoxie verstärkt diesen effekt zusätzlich ( ). serotonin bewirkt zudem als mitogen hypertrophische und hyperplastische veränderungen in endothel-und glatten gefäßmuskelzellen ( , ) . die pathophysiologische relevanz einer vermehrten thrombozytären serotonin-freisetzung ergibt sich auch aus fallberichten, in denen patienten mit einer familiären thrombozytären speicherkrankheit eine "spontane" ph entwickelten ( , ). neben serotonin setzen aktivierte thrombozyten u. a. den pulmonalen vasokonstriktor thromboxan a (txa ) sowie den arachidonsäuremetaboliten platelet-activating factor (paf) frei. die ausscheidung des stabilen txa -metaboliten -dehydrothromboxan b ist bei patienten mit pph oder sph deutlich erhöht ( ). der vermutlich zugrundeliegenden vermehrten thrombozytären freisetzung von txa könnte ähnlich wie für serotonin pathophysiologische bedeutung zukommen: werden patienten mit sph aufgrund chronisch-obstruktiver lungenerkrankungen mit dipyridamol behandelt, das die plättchenaktivierung hemmt, so sinken sowohl der pulmonalarterielle druck als auch die konzentration von txb . paf wiederum induziert bei kaninchen eine spezielle form der pulmonalen hypertonie, die durch eine fortschreitende atrophie der pulmonalgefäße gekennzeichnet ist ( ) . demgegenüber vermindern paf-rezeptor-antagonisten die ausbildung einer monocrotalin-oder hypoxie-induzierten ph ( ) . da diese rezeptorenblocker keinen unmittelbaren einfluss auf den gefäßtonus haben, ist paf vermutlich weniger an der vasokonstriktion als vielmehr an den vaskulären umbauprozessen beteiligt ( ) . sieht man von den kongenitalen speicherkrankheiten ab, so ist die der mediatorfreisetzung zugrundeliegende aktivierung der thrombozyten vermutlich im wesentlichen auf die endotheliale dysfunktion zurückzuführen. die erhöhung des hydrostatischen drucks in der pulmonalen strombahn bewirkt die exozytose endothelialer weibel-palade-körperchen ( ), der speichergranula für p-selektin ( , ) und von willebrand faktor (vwf) ( ) . als folge findet sich bei patienten mit pph oder sph eine erhöhte plasmakonzentration dieser beiden adhäsionsmoleküle ( , ), wobei die vwf-konzentration invers mit der krankheitsprognose korreliert und somit einen wichtigen prognostischen marker darstellt ( , ). endothelial exprimiertes p-selektin und vwf vermitteln durch bindung an die thrombozytären liganden psgl- (p-selectin glycoprotein ligand- ) ( ) bzw. den glykoprotein-komplex gp ib-v-ix ( ) die adhärenz der thrombozyten an der gefäßwand ( , ) und die aktivierung der blutplättchen. die vergangenen jahre haben zunehmend gezeigt, dass thrombozyten nicht nur zentrale effektorzellen der hämostase, sondern auch wesentlich an zahlreichen inflammatorischen prozessen beteiligt sind ( , ). es erscheint daher nicht erstaunlich, dass auch andere inflammatorische zellen am pathophysiologischen geschehen teilnehmen. in der tat finden sich histologisch in lungen von pph-patienten perivaskuläre infiltrationen von lymphozyten ( , ) und makrophagen ( secondary pulmonary 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hypertension hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension a human lung mast cell chymotrypsin-like enzyme. identification and partial characterization the prostacyclin-mimetic cicaprost inhibits endogenous endothelin- release from human pulmonary artery smooth muscle cells voelkel nf ( ) -lipoxygenase and -lipoxygenase activating protein (flap) immunoreactivity in lungs from patients with primary pulmonary hypertension integrated ca + signaling between smooth muscle and endothelium of resistance vessels microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension dysfunctional voltage-gated k + channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes attenuated k + channel gene transcription in primary pulmonary hypertension bq- , an eta receptor antagonist, inhibits endothelin- mediated proliferation of human pulmonary artery smooth muscle cells interaction among et- , endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins key: cord- - d yfv authors: porfyridis, ilias; plachouras, diamantis; karagianni, vasiliki; kotanidou, anastasia; papiris, spyridon a; giamarellou, helen; giamarellos-bourboulis, evangelos j title: diagnostic value of triggering receptor expressed on myeloid cells- and c-reactive protein for patients with lung infiltrates: an observational study date: - - journal: bmc infect dis doi: . / - - - sha: doc_id: cord_uid: d yfv background: differential diagnosis of patients with lung infiltrates remains a challenge. triggering receptor expressed on myeloid cells (trem)- is a neutrophil and monocyte receptor up-regulated during infection. the aim of this study was to evaluate the diagnostic accuracy of trem- and of c-reactive protein (crp) from patients with lung infiltrates to discern community acquired lung infections. methods: patients admitted to a medical ward with acute respiratory illness were enrolled in the study. neutrophil and monocyte trem- expression were measured by flow cytometry, strem- by an enzyme immunoassay and c-reactive protein by nephelometry. clinical pulmonary infection score was recorded. results: patients were diagnosed with bacterial community acquired pneumonia (group a) and with non-bacterial pulmonary disease (group b). median serum trem- concentration was . pg/ml in group a and lower than . pg/ml (p < . ) in group b. mean±se neutrophil trem- expression was . ± . mfi in group a and . ± . mfi (p = . ) in group b. monocyte trem- expression was . ± . mfi in group a and . ± . mfi (p = . ) in group b and mean±se crp was . ± mg/ml in group a and . ± . mg/ml (p < . ) in group b. a cut-off of . pg/ml of strem- with sensitivity . % and specificity % to discriminate between infectious and non-infectious pulmonary infiltrates was found. strem- at admission greater than pg/ml was accompanied with unfavourable outcome. conclusion: trem- myeloid expression and strem- are reliable markers of bacterial infection among patients with pulmonary infiltrates; strem- is a predictor of final outcome. early diagnosis of lung infections remains a challenge. there is no gold standard for diagnosing microbial infection as clinical and laboratory signs are neither sensitive nor specific enough, and microbiological studies often remain negative. the presence of a new infiltrate on plain chest radiograph is considered indicative for diagnosing pneumonia, especially when is supported by clinical and laboratory findings. however it is difficult to differentiate a chest infiltrate of bacterial origin from a chest infiltrate of non-bacterial origin solely based on radiological criteria [ ] . the diagnosis of infection is not always clear in the acute setting in patients with respiratory tract disease and a surrogate marker of infection would be a major benefit in the diagnostic armamentarium. many inflammatory mediators and acute phase reactants, like c-reactive protein (crp) and procalcitonin, have been described as reliable markers of infection; however none are specific enough, since they are also increased in non-infectious inflammatory conditions [ ] . triggering receptor expressed on myeloid cells (trem)- is a recently described receptor on neutrophils and monocytes. it behaves like a pattern recognition receptor (prr) since its activation leads to the release of pro-inflammatory cytokines, namely of tumour necrosis factor-alpha (tnfα) and of interleukin (il)- . although its ligand is still unknown, activation is mediated by bacteria and fungi [ , ] . a soluble form of trem- , namely strem- , is increased in the bronchoalveolar lavage (bal) of patients with ventilator associated pneumonia (vap) [ , ] , and in the serum of patients with sepsis, with bacterial meningitis and with acute pancreatitis [ ] [ ] [ ] [ ] [ ] [ ] . this same soluble form of trem- seems to be increased in patients bearing noninfectious processes like peptic ulcer, inflammatory bowel disease, viral infections, malignant pleural effusions and chronic obstructive pulmonary disease (copd) but also among patients after cardiac surgery or cardiac arrest. increase of strem- seems particular prominent when the latter non-infectious states are complicated with systemic inflammatory response syndrome (sirs) without infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] . several published studies yielded contradictory results for the diagnostic and prognostic usefulness of trem- and of strem- for infections [ , , [ ] [ ] [ ] . the created impression is that more data are necessary to yield definitive results for its usefulness as a diagnostic and prognostic marker of community acquired pneumonia (cap). the aim of the present study was to define whether expression of trem- on cell membranes of neutrophils (ntrem- ), of monocytes (mtrem- ) and serum strem- may help in the diagnosis of acute bacterial infections for patients admitted with a new pulmonary infiltrate or pleural effusion. in this observation trial, all consecutive admissions to the department of critical care and pulmonary services on predetermined and randomly selected emergency duty days were eligible. inclusion criteria were: i) age above yrs, ii) written informed consent; iii) acute respiratory illness and iii) presence of new pulmonary infiltrates or pleural effusion on chest x-ray or lung computed tomography. exclusion criteria were: i) human immunodeficiency virus (hiv) infection, ii) documented extrapulmonary infection, iii) neutropenia; and iv) oral intake of corticosteroids defined as any more than mg/kg of prednisone for more than month. the study protocol was approved by the ethics committee of the hospital and written informed consent was obtained from all patients within the first hrs after admission. clinical, laboratory, and imaging data were recorded for each patient including: i) clinical presentation; ii) body temperature, iii) arterial blood gas, iv) peripheral blood cell counts, v) gram stains and cultures of all biological fluids obtained (blood, sputum, bronchial secretions, bal, and pleural fluid); vi) imaging findings, vii) antigen serology (legionella spp and streptococcus pneumonia urinary antigen, serological testing for legionella pneumophila, mycoplasma pneumoniae, chlamydia pneumoniae) and viii) in-hospital mortality. the severity of illness was assessed by calculating acute physiology and chronic health evaluation (apache) ii, sequential organ failure assessment (sofa) and clinical pulmonary infection (cpis) scores at admission [ ] . a diagnosis of community-acquired pneumonia (cap) was established in any patient presenting with a combination of fever, cough and purulent sputum, shortness of breath, chest pain, and new consolidation on chest x-ray or computed tomography. the severity of pneumonia was assessed the first hours of admission according to confusion, urea nitrogen, respiratory rate, blood pressure (curb) index. patients having two or more criteria were identified to have severe pneumonia [ ] . sepsis, severe sepsis and septic shock were defined according to current recommendations [ ] . pneumonia was considered to be absent when: i) an alternative cause for pulmonary infiltrate was established (e.g. pulmonary embolus) and ii) full recovery was achieved without antimicrobial therapy. pulmonary embolism was diagnosed according to current recommendations [ ] . lung cancer was ruled out based on histology and/or cytology specimens. congestive heart failure was diagnosed according to american heart association [ ] , and interstitial lung disease according to american thoracic society guidelines [ ] . all cases were evaluated by two clinicians blinded to trem- and strem- results. agreement about the diagnosis was achieved in all cases. patients with cap were classified as having bacterial respiratory infection (group a). all other patients were classified as having non-bacterial respiratory disorders (group b). all patients assigned to group b were subject to chest computed tomography. for the measurement of strem- , mtrem- , ntrem- and crp ml of peripheral venous blood were sampled after venipuncture of the antecubitul vein under sterile conditions on the day of admission and on days and of hospitalization. seven ml were centrifuged and serum was stored in - °c until assayed for strem- . three ml were collected into edta-coated tubes (vacutainer, bd) for estimation of ntrem- and mtrem- expression. briefly, red blood cells were lysed by ammonium chloride. white blood cells were labelled by phycoerythrin-conjugated anti-trem- monoclonal antibodies (r&d inc, minneapolis, usa) for minutes in the dark. ntrem- and mtrem- expression were assessed after passage of labelled cells through a flow cytometer (epics xl/msl, beckman-coulter co, miami florida) and expressed as the mean fluorescence intensity (mfi) with gating for neutrophils and for monocytes by their characteristic fs/ss scattering. determination of strem- was performed in duplicate by a developmental enzyme-linked immunoabsorbent assay according to the instructions of the manufacturer (r&d inc, minneapolis, usa). the lower detection limit and inter-day variation of the assay were . pg/ml and . % respectively. measurement of serum crp was performed by an immunoturbidimetric assay on roche automated clinical chemistry analyzers and was expressed in mg/ml. crp was used as a comparator due to its universal application in all studies of evaluation of biomarkers. asumming that measured parameters between groups a and b differed by %, it was calculated that to patients should be assigned into each group to yield a difference at the % level with % power. values for ntrem- , mtrem- and crp are presented as mean ±se; those of strem- are presented as medians and % confidence intervals (ci) or interquartile range (iqr). comparisons between groups for ntrem- , mtrem- expression and for crp were done by anova, followed by the tukey's test for multiple comparisons. comparisons of strem- between groups were done by mann-whitney u test after bonferroni corrections for multiple comparisons. comparisons of strem- between consecutive days within one group were done by wilcoxon's signed rank test. receiver operator curves (roc) were designed to asses sensitivity, specificity, positive and negative predictive values for the estimated parameters to disclose infectious from non-infectious infiltrates. patients were divided into two categories according to serum levels of strem- upon admission: those with strem- below or equal to pg/ml; and those with serum strem- greater than pg/ml. this concentration has been proposed as a threshold defining final prognosis in septic populations [ , ] . since cap is a common cause of sepsis, this threshold was considered of merit. survival was assessed by kaplan-meier and comparisons were done by log-rank test. correlations between severity scores and measured parameters were done according to spearman. probability values less than . were considered statistically significant. all statistics and graphs were done using the statistical package for the social sciences software version . . (spss inc, chicago, il). the study flow-chart is shown in figure . demographic and clinical data of the patients are summarized in table . patients suffering from tuberculosis and enrolled in group b were presented with pleuritis. group a (n = ) consisted of patients with community acquired pneumonia (cap) likely to be caused by extracellural bacteria. seventeen had microbiological evidence of pulmonary infection, with isolation of the offending pathogens from sputum, blood or bal samples (when bronchoscopy was performed). seventeen patients were diagnosed with cap on the basis of typical clinical and radiological presentation and good response to antibiotic therapy. main radiological group b (n = ) consisted of patients with non-bacterial respiratory disorders. diagnoses were: lung cancer ( patients); pulmonary embolism (six patients); interstitial lung disease (six patients); heart failure (n = ); pulmonary tuberculosis (two patients); rheumatoid pleuritis (one patient); and q-fever (one patient). main radiological findings were: right pulmonary infiltrate (six patients); left pulmonary infiltrate (three patients); bilateral pulmonary infiltrates ( patients); right pleural effusion (four patients); left pleural effusion (one patient); both right lung infiltrate and right pleural effusion (four patients); both left lung infiltrates and left pleural effusion (two patients); bilateral pulmonary infiltrates and left pleural effusion (one patient); and left pulmonary infiltrate and bilateral pleural effusions (one patient). among patients from group a with cap nine (n = ) died; six patients were admitted to the icu and three were not admitted to the icu due to relatives' denial. mean age of patients not admitted to icu was years; the first two patients had a case-history of stroke and chronic heart failure; the third patient had a case-history of lung cancer. all three died from severe sepsis and multiorgan dysfunction syndrome (mods). mean age of patients admitted to icu was years; two patients had a case-history of aortic valve stenosis; two patients were under chronic intake of receiving corticosteroids; the fifth patient suffered from end-stage renal disease; and the sixth patient was suffering from hepatic failure due to alcohol intake. all six patients died from severe sepsis and multiorgan dysfunction syndrome (mods). all patients in the icu accomplished the clinical and radiological criteria for acute respiratory distress syndrome (ards) and were ventilated with the strategy of low tidal volume ventilation, according to current guidelines [ ] , with volume limited mode ventilation, low tidal volumes (about ml/kg ideal body weight), a maximum of - breaths per minute, high positive end-expiratory pressure (peep cmh o) and a goal plateau airway pressure < cmh o. among patients admitted in the icu, two died on the second day post-admission; one died on the third day post-admission; one on the seventh day post-admission; one the eighth day postadmission; and one on the twentieth day post admission. concentrations of strem- and of crp in sera of both groups and expression of ntrem- and mtrem- are given in table . all four parameters were significantly greater in group a than group b. roc of strem- , ntrem- , m-trem- and crp to differentiate whether a chest x-ray infiltrate is due to cap or to a non-infectious process is shown in figure . area under curve (auc) of strem- was . ± . ( %ci: . - . , p = . ). sensitivity and specificity to diagnose between a pulmonary infiltrate of infectious origin and a pulmonary infiltrate of non-infectious origin were . % and % respectively at concentrations above . pg/ml. auc of ntrem- and mtrem- were . ± . ( %ci: . - . , p = . ) and . ± . ( %ci: . - . , p = . ) respectively. sensitivity and specificity to diagnose between a pulmonary infiltrate of infectious origin and a pulmonary infiltrate of non-infectious origin were . % and . % for ntrem- above . mfi. sensitivity and • lung cancer ( ) • staphulococcus aureus ( ) • pulmonary embolism ( ) • haemophilus influenzae ( ) • congestive heart failure ( ) • pseudomonas aeruginosa ( ) • interstitial lung disease ( ) • other ( specificity to diagnose between a pulmonary infiltrate of infectious origin and a pulmonary infiltrate of non-infectious origin were . % and . % respectively for mtrem- above . mfi. auc of crp was . ± . ( %ci: . - . , p < . ). sensitivity and specificity to diagnose between a pulmonary infiltrate of infectious origin and a pulmonary infiltrate of non-infectious origin were % and % respectively at concentrations above . mg/ml. positive correlations were found between apache ii scores and expression of trem- on monocytes on day (r s : + . , p: . ); and between apache ii scores and strem- on day (r s : + . , p: . ). no significant correlations were found between apache ii scores and expression of trem- on neutrophils on day as well as between sofa scores and any of the measured parameters on day . correlations between serum levels of strem- and crp and expression of trem- on monocytes and neutrophils in relation to the identified causative pathogen of cap are shown in figure . serum levels of strem- were greater among patients with cap caused by gram (+) cocci and haemophilus influenzae than among patients with cap caused by other pathogens. death occurred in three out of patients were no pathogen was defined ( . %); in nil out of three patients infected by atypical pathogens ( %); in three out of seven patients ( . %) infected by gram-negative bacteria; and in three out of nine patients ( . %) infected by gram-positive cocci or h. influenzae (p: . between grouping according to pathogen). survival of patients with strem- on day below or equal to pg/ml was prolonged compared with patients with strem- on day above pg/ml ( figure ) . the results of the present study indicate that trem- can be used as marker of bacterial infection in patients with lung infiltrates. strem- , ntrem- , mtrem- and crp were comparable to their discriminating ability between a pulmonary infiltrate of infectious origin and a pulmonary infiltrate of non-infectious origin. strem- levels were decreased within the first hours in patients with cap with favourable outcome probably after the initiation of appropriate therapy followed by improvement of clinical symptoms. finally, strem- levels above pg/ml were an accurate independent predictor of in-hospital mortality from cap. discrimination of the infectious or non-infectious origin of a pulmonary infiltrate remains an everyday clinical problem. cpis was introduced for that purpose helping considerable in cases of ventilator-associated pneumonia (vap) [ ] . trem- is a surface receptor on cells of the myeloid lineage. activation of trem- leads to the production of pro-inflammatory cytokines [ , , ] . binding of its ligand is possibly linked to the activation of several transcription complexes that synergize with nf-b in order to elicit transcription of genes of pro-inflammatory cytokines [ ] . strem- is the soluble counterpart of trem- and it is probably shed in the systemic circulation from cell membranes of neutrophils and monocytes [ , , ] . the physiologic role of strem- remains under question despite data support a probable anti-inflammatory role [ , ] . trem- has been studied in patients with pneumonia, especially vap [ , , [ ] [ ] [ ] . few data are available on the diagnostic role of trem- and of strem- in patients with lung infiltrates. our data are in agreement with observations from the study by phua [ ] . their proposed strem- cut-off point was ng/ml, which is different than the one we found. this may be result from the different method of assaying strem- the used being western blotting. the results of our study are in contrast to those of another study [ ] that did not disclose any difference in ntrem- expression between patients with and without a bacterial lung infection probably due to the small number of patients included in that former study. el sohl et al [ ] reported elevated alveolar levels of strem- in pulmonary aspiration syndromes, but not in serum. however, serial plasma strem- levels were not obtained and the possibility that plasma levels might rise on subsequent days cannot be excluded. two recent studies [ , ] evaluated the diagnostic role of cpis and of strem- in bal fluid from patients with bilateral lung infiltrates in the intensive care unit (icu). these studies reported controversial results. however authors did not measure strem- in serum on consecutive days. the reported results of the present study are the first to our knowledge that evaluate the diagnostic value of trem- among patients with lung infiltrates to discriminate cap. they also disclose a relationship between levels of circulating strem- and causative pathogens. more precisely, infections caused by streptococcus pneumoniae, sthaphylococcus aureus and haemophilus influenzae were accompanied by greater levels of strem- and by greater expression of trem- on neutrophils than infections caused by other pathogens. although it may be hypothesized that gram-positive cocci and h. influenzae are strong inducers of trem- expression, it should be emphasized that trem- is one prr, the exact agonist of which remains to be found [ , ] . a former study of our group [ ] and another by gibot et al [ ] in heterogeneous populations of patients with severe sepsis of diverse aetiology investigated the role of early assessment of strem- as a determinant of final outcome. results revealed that concentrations greater than pg/ml are accompanied by survival benefit. the exactly opposing finding is reported here. this discrepancy may be explained by the enrolment of more homogeneous populations of patients, compared to these former studies [ , ] , all suffering with cap. our study presents two main limitations: a) no documented cases of cap by legionella pneumophila, mycoplasma pneumoniae, protozoa or parasites were enrolled in group a; b) mortality in the cap patient group was high probably due to the existence of severe co-morbid conditions. in conclusion, the presented results indicate that serum strem- and expression of trem- on neutrophils and monocytes may serve as markers of cap in patients with pulmonary infiltrates. concentrations of strem- in serum are particularly increased in cap caused by gram-positive cocci and haemophilus species. the real clinical value of strem- assay comes when trem- levels are low, allowing the clinician to withhold empiric antibiotics until culture results are available, and thus eliminating unnecessary antibiotic exposure to the patient. and finally, early serum levels of strem- greater than pg/ml in cap are associated with unfavourable prognosis. and evangelos j. giamarellos-bourboulis ass. prof. md have no conflicts of interest to disclose related to this study. evangelos j. giamarellos-bourboulis prof. md has received reimbursement for attending the th international symposium on intensive care and emergency medicine where participated as a speaker and unrestricted educational grants from abbott hellas sa; wyeth hellas sa; sanofi-aventis hellas sa. imaging of pneumonia: trends and algorithms diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia trem- (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses trem- amplifies inflammation and is a crucial mediator of septic shock does soluble triggering receptor expressed on myeloid cells- play any role in the pathogenesis of septic shock? soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia serum of patients with septic shock stimulates the expression of trem- on u monocytes clinical review: role of triggering receptor expressed on myeloid cells- during sepsis triggering receptor expressed on myeloid cells- (trem- ) is regulated post-transcriptionally and its ligand is present in the sera of some septic patients soluble triggering receptor expressed on myeloid cells- : a biomarker for bacterial meningitis increased levels of soluble triggering receptor expressed on myeloid cells- in patients with acute pancreatitis triggering receptor expressed on myeloid cells- expression on monocytes is associated with inflammation but not with infection in acute pancreatitis soluble triggering receptor expressed on myeloid cells- (strem- ): a new mediator involved in the pathogenesis of peptic ulcer disease role of soluble triggering receptor expressed on myeloid cells- in inflammatory bowel disease trem- expression in tumor-associated macrophages and clinical outcome in lung cancer activation of triggering receptor expressed on myeloid cells- on human neutrophils by marburg and ebola viruses soluble triggering receptor expressed on myeloid cells is released in patients with stable chronic obstructive pulmonary disease increased plasma levels of soluble triggering receptor expressed on myeloid cells and procalcitonin after cardiac surgery and cardiac arrest without infection the increased expression of trem- on monocytes is associated with infectious and non-infectious inflammatory processes soluble trem- is not suitable for distinguishing between systemic inflammatory response syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation prognosis of community acquired pneumonia(cap): value of triggering receptor expressed on myeloid cells- (trem- ) and other mediators of the inflammatory response timecourse of strem (soluble triggering receptor expressed on myeloid cells)- , procalcitonin, and c-reactive protein plasma concentrations during sepsis diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited infectious diseases society of america guidelines for the management of adult lower respiratory track infections acute pulmonary embolism focused update incorporated into the acc/aha guidelines for the diagnosis and management of chronic heart failure in adults: a report of the american college of cardiology foundation european respiratory society international multidisciplinary consensus classification of idiopathic interstitial pneumonias early changes of cd -positive lymphocytes and nk cells in patients with severe gram-negative sepsis the national heart, lung, and blood institute ards clinical trials network: higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome trem and trem-like receptors in inflammation and disease the trem receptor family and signal integration monocytes as a site of production of soluble triggering receptor expressed on myeloid cells - (strem- ) in the septic host soluble triggering receptor expressed on myeloid cells- modulates the inflammatory response in murine sepsis soluble triggering receptor expressed on myeloid cells- as an antiinflammatory mediator in sepsis soluble triggering receptor expressed on myeloid cells - in acute respiratory infections triggering receptor expressed on myeloid cells: role in the diagnosis of lung infections triggering receptors expressed on myeloid cells in pulmonary aspiration syndromes diagnostic implications of soluble triggering receptor expressed on myeloid cells- in bal fluid of patients with pulmonary infiltrates in the icu diagnostic utility of the soluble triggering receptor expressed on myeloid cells- in bronchoalveolar lavage fluid from patients with bilateral lung infiltrates funding source: none the present authors would like to thank all patients who participated in the current study, the doctors and nurses of the department of critical care and pulmonary services, national and kapodistrian university of athens, 'evangelismos' hospital, athens, greece for their hand work in the treatment of the patients and the doctors and laboratory personnel of the th department of internal medicine, national and kapodistrian university of athens, 'attikon' hospital, athens, greece for their most helpful support during the study. finally, the current authors thank paris praxitelous authors' contributions ip participated in the study design, the enrolment of patients, the estimation of trem- , strem- , crp, the follow-up of patients and wrote the manuscript. dp participated in the study design and in the estimation of trem- and strem- . vk carried out the estimation of trem- . ak and sap participated in study design, and drafted the manuscript. hg participated in study design and drafted the manuscript ejgb coordinated the lab job, analyzed the data and drafted the manuscript. all authors read and approved the final manuscript. key: cord- - lubp io authors: glass, daniel m.; zehrer, tara; al-khafaji, ali title: respiratory diseases of pregnancy date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: lubp io pregnant patients can suffer from the same respiratory diseases as the general population in addition to unique syndromes of pregnancy (such as pre-eclampsia and tocolytic induced pulmonary edema, and pregnancy induced cardiomyopathy). pregnancy by itself may add certain challenges such as difficult intubation. the critically ill pregnant patient requires a multidisciplinary approach and early inclusion of obstetrical expertise is paramount in managing these patients especially in the third trimester. dyspnea on exertion is a common complaint reported by gravid patients as the pregnancy progresses. the etiology is partially explained by the physiologic increase in oxygen consumption by almost % (caused by fetal and uterine demands). however, the body compensates by increasing tidal volume and to a lesser extent respiratory rate [ , ] . these changes make the partial pressure of oxygen slightly higher than normal on a blood gas, and would range from to mmhg. the partial pressure of carbon dioxide would be lower than normal for a non-pregnant patient and ranges from to mmhg [ ] . low pulmonary reserves that arise from reductions in functional residual capacity (caused by the gravid uterus and changes in the chest wall morphology) [ ] and increased oxygen consumption make pregnant women develop hypoxemia more rapidly during apnea [ ] . pulmonary edema can be broadly classified as cardiogenic or non-cardiogenic. cardiac output increases very early on and is the highest in the post-partum period. plasma volume expands due to sodium and water retention, thereby increasing preload, but afterload reduces due to vasodilation [ ] . the most common causes of non-cardiogenic acute pulmonary edema in pregnancy are, fluid overload, preeclampsia, tocolytic agents, sepsis, trauma or following aspiration of gastric contents [ , ] . preterm labor increases the risk of pulmonary edema. pulmonary edema is a frequently encountered complication in patients with pre-eclampsia with most cases occurring after delivery. initial management involves lowering the blood pressure urgently especially in patients who have severe elevation of blood pressure that persists longer than minutes. once pulmonary edema occurs, parenteral therapy is more effective, and nitroglycerin is the agent of choice as recommended by the european society of cardiology [ ] . diuretics should be instituted to promote preload reduction recognizing that the pre-eclamptic patient may have complex fluid balance needs due to low oncotic pressure. if necessary, noninvasive ventilation is recommended in patients with increased work of breathing or hypoxemia as it is known to improve these parameters and it may decrease the need for invasive mechanical ventilation [ ] . pulmonary edema due to tocolytic therapy is relatively uncommon [ ] . terbutaline is a beta agonist that may rarely cause pulmonary edema either through salt retention, tachycardia induced diastolic dysfunction or from fluid overload if infused in a large volume [ ] . management involves stopping the tocolytic therapy and treating pulmonary edema with diuretics. excessive salt and fluid intake should be avoided. these patients tend to recover well and reported mortality is low [ ] . ohss is another uncommon cause of pulmonary edema with a prevalence of - %. mechanisms are not entirely clear but involve increased vascular permeability. treatment is supportive care [ ] . certain factors such as an incompetent lower esophageal sphincter coupled with a decrease in stomach motility can increase the risk for aspiration. one must have a high index of suspicion as not all events are witnessed. treatment is usually supportive [ ] . ppcm is acute heart failure of uncertain etiology in patients with no known prior heart disease and who typically present in the last month of pregnancy and up to months postpartum. risk factors include older maternal age, african decent, multiple gestations and hypertension [ ] . the mortality rate can be as high as - % [ , ] . asthma is seen very frequently with a prevalence in pregnancy ranging from to % [ ] . certain factors easily obtained by a good history can help the clinician understand who is at increased risk of complications from asthma, such as history of exacerbations, intubations, and recent steroid use. most exacerbations are characterized by cough, wheezing, and dyspnea. the national asthma education and prevention (naep) group recommends obtaining a baseline peak expiratory flow in order to guide further management. a target oxygen saturation should be above % with consideration for invasive mechanical ventilation in those who are in impending respiratory failure. a partial pressure of carbon dioxide within the normal range of - on an arterial blood gas can be an early sign of imminent respiratory failure in the gravid patient. pharmacotherapy with inhaled beta agonists, inhaled anticholinergics and steroids are identical to that in the non-pregnant patient. care should be taken during mechanical ventilation to avoid a short expiratory time that can cause auto peep [ ] . intravenous magnesium sulfate may be beneficial in acute severe asthma in addition to bronchodilators especially in patients with coexistent hypertension or preterm uterine contractions [ , ] . large airway obstruction mostly arises due to a difficult intubation and the incidence is anywhere between . and . %. intubation may be difficult during pregnancy and the peripartum period due to upper airway edema, pharyngeal mucosal friability and diminished airway caliber, especially late in pregnancy. the gravid patient, especially in the third trimester, should be considered a difficult airway patient with high risk of aspiration and decreased oxygen reserve. other causes of airway obstruction such as tumors, hematoma and laryngeal edema are rarely encountered [ , ] . increased upper airway resistance may occur in pregnancy as a result of pharyngeal edema and increased pharyngeal tone could potentially worsen osa in pregnant women. incidence of osa is estimated to be between . % in the first trimester and . % in the third trimester [ ] . maternal risks include increased morbidity from conditions that have been associated with osa and underlying obesity such as preeclampsia, eclampsia, gestational hypertension, cardiomyopathy and gestational diabetes [ ] . these patients are at higher risk for hypoxemia during labor, and continuous monitoring is necessary. cpap therapy remains the first line of therapy and women are instructed to bring in their device when they come to the hospital during labor. varicella and influenza are the most common pathogens associated with viral pneumonia in pregnancy [ ] . estimated mortality rate amongst the h n pandemic ranged from . to . % [ ] . the risk of hospitalization is highest in the third trimester. mortality related to influenza is mostly due to secondary bacterial pneumonia, although the h n pandemic differed in this aspect with more patients dying primarily from the effects of h n virus. the most commonly implicated pathogens are streptococcuc pneumonia and staphylococcus aureus followed by hemophilus influenza, and it is reasonable to start empiric antibacterial agents at the time of presentation [ ] . streptococcus pneumonia followed by hemophilus influenza are the most commonly encountered agents [ ] . some of the risk factors for pneumonia in pregnancy include anemia, asthma, antepartum corticosteroids given to enhance fetal lung maturity, and the use of tocolytic agents to induce labor [ ] . oxygen supplementation is necessary with a goal of keeping the partial pressure of oxygen above mmhg. penicillins, cephalosporins, and macrolides are considered safe to use in pregnancy [ ] . a history of contact with farm animals should raise suspicion for q fever and therapy with macrolides is preferred [ ] . central causes of respiratory failure such as drugs, tumors, hemorrhage, and infection should be treated for in a similar manner as the general population with treatment of the underlying cause and mechanical ventilation if necessary. conditions such as kyphoscoliosis may precipitate hypercapnic respiratory failure in pregnancy [ ] . these patients should be closely monitored with arterial blood gasses, vital capacity and maximal and minimal inspiratory pressures [ ] . magnesium sulfate, which is used as a tocolytic and to prevent seizures in preeclampsia, can cause respiratory depression at levels greater than meq/l, and respiratory arrest at levels of - meq/l. careful monitoring of magnesium sulfate dosing and infusion rates, as well as monitoring maternal deep tendon reflexes and urine output, is necessary and achieved with serum magnesium levels at precise infusion rates. pneumothorax may occur because of hyperemesis, pushing efforts in labor, underlying lung disease, and without obvious precipitating cause [ ] . hamman's syndrome of intrapartum subcutaneous emphysema, pneumo-mediastinum, or pneumothorax results from the forceful "pushing" efforts during labor and about cases have been reported worldwide before [ ] . the clinical presentation is usually chest pain with breathlessness and presence of crackles or "hamman's sign" in the left lateral decubitus position in systole. most cases resolve spontaneously, but emergent chest tube placement may be required in some cases. embolic events rank among the major causes of maternal mortality in modern obstetrics. risk factors include venous stasis, advanced age, sepsis, obesity and cesarean section. hypoxemia is common. with massive embolism, circulatory failure is more prominent. diagnosis is made by compression ultrasonography and if negative perfusion study. if the diagnosis of pulmonary embolism is strongly considered, treatment with unfractionated heparin should be started immediately unless high risk or a contraindication is present for the use of anticoagulants. unfractionated heparin and low-molecular weight heparin are safe to use during pregnancy because they do not cross the placenta. tissue plasminogen activator has also been used during pregnancy although there are no controlled trials [ , ] . cystic fibrosis is the most common congenital pulmonary disease encountered during pregnancy. it is a restrictive and obstructive disorder, with a predisposition to infection. bronchodilators and chest physiotherapy should be recommended, and chest infections should be treated aggressively [ ] . pregnant women have hypocapnia due to hyperventilation at baseline. thus, the arterial carbon dioxide tension (paco ) is lower in a pregnant woman, and a normal paco is a sign of impending respiratory failure. intubation may be difficult during pregnancy and the peripartum period due to upper airway edema and diminished airway caliber, especially late in pregnancy. the goal is to rest the fatigued respiratory muscles while providing suitable gas exchange. respiratory muscle rest involves institution of invasive or noninvasive mechanical support, and the ventilator must overcome pressures related to airway resistance and elastic properties of the lung to allow adequate ventilation and gas exchange. a trial of noninvasive ventilation can be instituted early on in patients with pulmonary edema. favorable out-comes have been reported in case reports and series [ ] . for patients who require intubation and mechanical ventilation, low tidal ventilation strategy is recommended [ ] . positive end expiratory pressure improves oxygenation and should be used to provide a pao > mmhg while administering the least fio . the target paco is - mmhg since this is the normal level during pregnancy. marked respiratory alkalosis should be avoided because it may decrease uterine blood flow. maternal permissive hypercapnia may also be deleterious to the fetus because of resultant fetal respiratory acidosis although this mode of ventilation has been used safely in pregnant women in small trials. propofol infusion is the sedative drug of choice. if paralytics are indicated, cisatracurium is the preferred agent [ ] . this technique has been used a rescue therapy for refractory ards with reported maternal and fetal survival rates between % and %, respectively [ , ] . most of the published literature is from the h n influenza pandemic. early institution with careful patient selection and judicial management of anticoagulation might improve successful outcomes [ , ] . use of prone positioning in the third trimester has not been widely studied however case reports have appeared in the literature with acceptable results. as in other severe ards patients, proning requires careful attention to inadvertent decannulation of lines or extubation. the pressure points especially eyes need to be protected attention should be paid avoid hyperextension of joints. there needs to be adequate room for the abdomen to expand passively. this can be achieved by the use of appropriately sized bolsters at chest and hip level to help elevate the patient above the mattress. this also allows for anterior displacement of uterus off of the inferior vena cava, which is necessary for adequate venous return after weeks gestation. close monitoring of mother and fetus including continuous fetal cardiotocography should be in place if the fetus is of viable age [ , ] . delivery of the fetus can improve the maternal condition in several obstetrical disease states. in ards, it appears perhaps to improve oxygenation and management of the mother but does not definitively improve maternal survival [ , ] . respiratory physiology in pregnancy normal cardiopulmonary physiology during pregnancy maternal blood-gases, pao --pao ), physiological shunt and vd/vt in normal pregnancy arterial oxygen tension during apnoea in parturient women studies of colloid osmotic pressure in pregnancy-induced hypertension acute lung injury and acute respiratory distress syndrome in pregnancy clinical characteristics and outcomes of obstetric patients requiring icu admission cardiovascular implications in preeclampsia: an overview acute pulmonary oedema in pregnant women ards associated with the use of sympathomimetics and glucocorticoids for the treatment of premature labor the pathophysiology of pulmonary oedema with the use of beta-agonists pulmonary edema in obstetric patients is rapidly resolved except in the presence of infection or of nitroglycerin tocolysis after open fetal surgery diagnosis, prevention and management of ovarian hyperstimulation syndrome pulmonary aspiration-a life-threatening complication in obstetrics peripartum cardiomyopathy: current knowledge and future directions peripartum cardiomyopathy: national heart, lung and blood institute and office of rare diseases (national institutes of health) workshop recommendations and review acute pulmonary edema in pregnancy asthma during pregnancy: mechanisms and treatment implications national asthma education program working group on asthma and pregnancy. national institutes of health, national heart, lung, and blood institute difficult and failed intubation: incident rates and maternal, obstetrical, and anesthetic predictors difficult intubation in pregnancy risk factors for sleep-disordered breathing in pregnancy maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and meta-analysis pneumonia in pregnancy pandemic influenza a(h n ) virus illness among pregnant women in the united states pulmonary infections complicating asian influenza pneumonia and pregnancy antepartum pneumonia in pregnancy pulmonary disease in pregnancy glob noninvasive ventilation for chest wall and neuromuscular disorders spontaneous subcutaneous emphysema and pneumo-mediastinum during second stage of labour pleural disease in pregnancy melton rd lj. trends in the incidence of venous thromboembolism during pregnancy or postpartum: a -year population-based study epidemiology of pregnancyassociated venous thromboembolism: a population-based study in canada pregnancy and the lungs successful use of noninvasive ventilation in pregnancy implications for the pregnant patient mechanical ventilation during pregnancy: sedation, analgesia, and paralysis systemic inflammatory response syndrome, organ failure, and outcome in critically ill obstetric patients treated in an icu extracorporeal membrane oxygenation for severe ards in pregnant and postpartum women during the h n pandemic modern use of extracorporeal life support in pregnancy and postpartum prone positioning for ards following blunt chest trauma in late pregnancy how safe is the prone position in acute respiratory distress syndrome at late pregnancy does delivery improve maternal condition in the respiratory-compromised gravida? financial support: none. key: cord- -q igdvq authors: ryan, donal; frohlich, stephen; mcloughlin, paul title: pulmonary vascular dysfunction in ards date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: q igdvq acute respiratory distress syndrome (ards) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (ph). multiple factors may contribute to the development of ph in this setting. in this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ards and reported on mortality in the period to . there were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. in order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. we consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ards, including the important effects of mechanical ventilation. pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (tpg) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. the great variability in management strategies within and between studies means that no unified analysis of these papers was possible. uniquely, bull et al. (am j respir crit care med : – , ) have recently reported that elevated pulmonary vascular resistance (pvr) and tpg were independently associated with increased mortality in ards, in a large trial with protocol-defined management strategies and using lung-protective ventilation. we then considered the existing literature to determine whether the relationship between pvr/tpg and outcome might be causal. although we could identify potential mechanisms for such a link, the existing evidence does not allow firm conclusions to be drawn. nonetheless, abnormally elevated pvr/tpg may provide a useful index of disease severity and progression. further studies are required to understand the role and importance of pulmonary vascular dysfunction in ards in the era of lung-protective ventilation. acute respiratory distress syndrome (ards) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension [ ] . the single biggest advance in the management of ards has been the institution of lung protective ventilation (ardsnet) [ ] . however, mortality remains unacceptably high, ranging from the % to % reported in randomised controlled trials up to % in published observational studies [ , ] . intensivists and researchers have long been aware of the occurrence of pulmonary hypertension and cor pulmonale in ards. however, there has been uncertainty about the underlying pathophysiology and the link between the degree of pulmonary hypertension and outcome from ards. is pulmonary hypertension simply an indicator of the severity of lung injury or is it part of the underlying pathophysiological process contributing to the development of ards? recent studies have pointed to the importance of pulmonary vascular dysfunction (pvd) in predicting mortality from ards [ ] , but the exact mechanism by which pvd and mortality are linked is not known. the focus of this review is to examine the nature of the relationship between pulmonary hypertension/pvd and mortality in ards. studies were identified after a literature search using key terms (ards or acute respiratory distress or ali or acute lung injury) together with any of the following: pulmonary haemodynamics, pulmonary artery pressure, pulmonary vascular resistance, pulmonary vascular dysfunction, right ventricle, right ventricular failure, acute cor pulmonale, or pulmonary artery catheter. the references of articles found in this manner were also examined for similar studies. manuscripts that reported a relationship between pulmonary haemodynamics and mortality in ards/ali were included. in addition, papers that reported a relationship between right ventricular failure/right ventricular dysfunction and outcome were included. we have included definitions of commonly used terms in this article in table . many indices of pulmonary haemodynamics have been measured in patients with ards. pulmonary arterial pressure, wedge pressure and pulmonary vascular resistance have all been reported as well as measures of right ventricular function. the two most commonly reported measures are pulmonary arterial pressure and pulmonary vascular resistance. a number of studies (table ) have documented the changes in pulmonary haemodynamic measurements in patients with ards. all measurements were derived from the use of pulmonary artery catheter except for the study by cepkova [ ] , where pa systolic pressures were estimated using echo. some of these studies are small, and the majority were conducted before the widespread introduction of low tidal volume ventilation. nevertheless, certain observations can be made from the data. mild to moderate elevations in mean pulmonary artery pressure (mpap) are seen in most patients with ards [ , ] . squara et al. found moderate elevation in mean pulmonary pressure in patients, h after the diagnosis of ards [ ] . patients with worse pao /fio ratios had higher mpap than those with better oxygenation ( . ± . vs. . ± . mmhg, p = . ). systolic pulmonary arterial pressure (pap) was deemed to be of 'independent and sustained prognostic significance during the course of ards'. in a later study, osman et al. also found mpap to be an independent predictor of mortality in a multivariate model [ ] . other studies either found pap not to be predictive of death or else did not specifically examine for a relationship [ , [ ] [ ] [ ] [ ] ] . in patients with severe ards, beiderlinden et al. [ ] found an incidence of pulmonary hypertension of . % but did not find any association between pulmonary hypertension and death. hemilla et al., in a review of patients with severe ards who subsequently received ecmo, found evidence of moderate pulmonary hypertension using pulmonary artery catheter data acquired prior to the institution of extracorporeal support [ ] . again, direct measurements of pap were not identified as being of prognostic significance. pulmonary vascular resistance (pvr) is known to be elevated in patients with ards (tables and ). zapol and jones were the first to document that raised pulmonary vascular resistance was a common finding in patients with severe respiratory failure [ ] . they observed that pulmonary vascular resistance tended to fall in survivors but remained elevated in those who died. this is the only study to report pulmonary haemodynamic indices longitudinally. zapol and jones subsequently documented a threefold elevation in pvr in patients with ards [ ] . these in a secondary analysis of the haemodynamic data from the fluid and catheter treatment (factt) trial of patients with ards who were managed with a pulmonary artery catheter, bull et al. showed that the transpulmonary gradient (mpap-pulmonary arterial occlusion pressure (paop)) and the pulmonary vascular resistance index (mpap-paop/ci) were the only pulmonary haemodynamic indices that showed a significant difference between those who died and those who survived. multivariate analyses showed them to be independent predictors of mortality in ards [ ] . they used the term 'pulmonary vascular dysfunction' to describe these two variables. covariates in their multivariate analyses included sex, race, age, apache ii score, the presence of shock at baseline, level of positive end-expiratory pressure (peep), the pao :fio ratio and fluid treatment strategy. they did not find any difference in p:f ratios, pasp, padp, mpap, paop or cardiac index between those who survived with ards and those who did not. the pplat and peep levels were not different among the groups. it is worth noting that % of the screened patients were excluded because they had a pulmonary artery catheter in place at the time of randomization and that % of the enrolled patients showed a paop > mmhg at enrollment, therefore not meeting the abc definition of ards. this may have explained why the pap-paop gradient may have been significant, when pap was not. there are marked differences among these studies, with some showing that pulmonary arterial pressure is independently associated with mortality, and in others' findings, it is not. similarly, increased pvr was found to be a predictor of adverse outcome in some studies and not in others. before considering these discrepancies in more detail, it is helpful to examine the relationship between pap and pvr in healthy subjects and to look at the pathophysiology of elevated pulmonary vascular resistance. there is a complex, non-linear relationship between pulmonary arterial pressure and pulmonary vascular resistance in normal, non-diseased lungs. in the lungs, the pvr is conventionally calculated as follows: where pvr = pulmonary vascular resistance, mpap = mean pulmonary arterial pressure, lap = left atrial pressure and co = cardiac output. in the systemic circulation, an ohmic relationship between driving pressure and flow through the blood vessel provides a reasonable approximation ( figure a ). in such a system, the plot of pressure against flow is a straight line passing through the origin and the resistance to flow is well characterised as the ratio of the arterial pressure to the flow (cardiac output) at all points along the pressure flow line. in contrast, the blood flow through the lungs is not well described by a linear relationship passing through the origin but by a curvilinear plot that has a positive intercept on the pressure axis ( figure b ). this curvilinear relationship arises because of the marked distensibility of the pulmonary vasculature. an increase in pulmonary arterial pressure results in an increased flow due both to the higher driving pressure and the distension of the vessels so that the diameter of the vascular lumen is increased. thus, increases in pulmonary arterial pressure have a disproportionate effect on pulmonary blood flow. as a consequence, a reduction in cardiac output leads to an increase in the ratio of the pressure drop across the pulmonary circulation (pap-lap) to flow, even though there is no change in vasomotor tone ( figure b ). blood flow through the lungs also depends on the transmural pressure in the pulmonary vessels (pressure within lumen minus airway pressure) to a much greater extent than in systemic vessels. airway pressure can have a marked effect on pulmonary blood flow, as originally determined by west [ ] . lung volume has an important effect on pvr which is independent of vascular transmural pressure. whittenberger et al. [ ] described how low (near residual volume) lung volumes were associated with a slight elevation in pvr (extra-alveolar vessels are narrowed) and high lung volumes (near total lung capacity) were associated with the highest pvr (alveolar capillaries are stretched). this contributes to in the systemic circulation, the mean pressure (p)-flow (q) plot is well described as a linear (ohmic) relationship. the two points identified (open circles) show a normal cardiac output and a reduced cardiac output, respectively, in the hypertensive condition. at each of these cardiac outputs, it is clear that the ratio of p to q is the same and therefore can be used to easily characterise the resistance of the systemic circulation. (b) in the pulmonary circulation, the plot of mean pressure against flow is curvilinear with an intercept on the pressure axis that is equal to left atrial pressure. the blue curve represents a normal pressure flow curve (healthy lung), while the red curve represents pressure flow curve in the presence of hypoxic pulmonary hypertension. the two points identified (open circles) show a normal cardiac output and a reduced cardiac output, respectively, in the hypertensive condition. at each cardiac output the pulmonary vascular resistance, (ppa-lap)/q, is illustrated as the slope of the straight dashed line. even though the two points are each on the same pressure flow curve, the calculated pulmonary vascular resistance is different at the different cardiac outputs. psa, systemic arterial pressure (mean); ppa, pulmonary arterial pressure (mean); q, cardiac output (flow). a marked elevation in pulmonary vascular resistance, even if the vascular transmural pressure is kept constant [ ] . pulmonary arterial pressure is not only affected by changes in pulmonary vascular resistance but also changes in right ventricular (rv) output. rv output, in turn, is affected by factors that are extrinsic to the lung. it is evident, even from this brief summary, that pulmonary arterial pressure and pulmonary vascular resistance cannot be used as interchangeable measures of the state of pulmonary haemodynamics in patients with ards. for a comprehensive review of this problem of interpreting changes in pulmonary vascular resistance, the reader is referred to the work of vesprille and naeije [ , ] . many of the candidate mechanisms that explain an elevation in pvr in ards have been recently reviewed [ ] . we will highlight the pathophysiology of some of these mechanisms. bradford and dean were among the first to recognise that hypoxia resulted in sustained elevations in pulmonary arterial pressure [ ] . the mechanisms that underlie hypoxic pulmonary vasoconstriction (hpv) are complex and primarily relate to intracellular increases in calcium concentration and rho kinase-mediated sensitisation in pulmonary arterial smooth muscle cells [ ] [ ] [ ] [ ] . hpv causes an increase in pvr to % to % of baseline when healthy volunteers are exposed to hypoxia (po mmhg) [ ] . marshall et al. have shown that when hpv is acutely reduced in ards by the administration of % inspired oxygen, pulmonary arterial pressure was reduced by the order of % to % from its peak [ ] . this may be an underestimate of the extent of hpv in the lung, as it does not take into account the contribution of hpv in non-ventilated lung units. to assess the contribution of non-ventilated lung units to hpv, benzing et al. took a group of patients with severe ards treated by veno-venous extracorporeal lung assist and ventilated them with an fio of . for a period of min prior to taking measurements (thereby minimising hpv in ventilated lung units). they then manipulated the mixed venous partial pressure of oxygen (pvo ) by adjusting the proportion of blood flow diverted through the oxygenator in order to assess hpv in non-ventilated regions. when pvo was high ( . ± . mmhg), the total lung pvr was (± ) dyne.s.cm − .m and increased by . % to (± ) dyne.s.cm − .m when pvo was reduced to low values ( . ± . mmhg) [ ] , clearly demonstrating that hpv in non-ventilated lung units contributes significantly to the increase in pulmonary vascular resistance in ards. in addition to the influence of hpv, disruption of the endothelium in ards results in an alteration in the normal balance of mediators of vasodilation (no, prostacyclin) and vasoconstriction (thromboxane, leukotrienes, endothelin, serotonin, angiotensin ii) favouring vasoconstriction. these factors have been reviewed recently [ , ] . tomashefski et al., in a landmark post-mortem study of patients with ards, found that patients had evidence of microthrombi. nineteen had macrothrombi in the pulmonary arterial and capillary vessels [ ] . they also found endothelial injury in all stages of ards in all cases on both standard histological preparations and electron microscopy. there is now ample evidence supporting the concept of lung injury causing local, as opposed to systemic, coagulation in ards [ , , ] . tissue factor (tf) is released from endothelial cells that have been injured, in response to a variety of proinflammatory stimuli [ ] . tf is a strong activator of the extrinsic clotting cascade. increased activation of procoagulant processes occurs in the lung in ards and does not result from the systemic activation of coagulation (such as is seen in sepsis) [ , ] . animal data suggest that blockade of the tf-factor viia-factor xa complex may reduce the degree of pulmonary hypertension in ards [ ] . levels of protein c, a natural anticoagulant, are also reduced in ards [ ] while levels of plasminogen activator inhibitor- are increased in ards patients, and both are prognostic of increased mortality in ards [ ] . more recently, biomarkers of coagulation and inflammation have been shown to provide good discrimination for the diagnosis of patients with ards [ , ] , and analysis of sars-cov infection in laboratory models has shown that the delicate balance between coagulation and fibrinolysis is shifted towards fibrin deposition during infection leading to ards [ ] . therapies targeting this pulmonary coagulopathy may also have an anti-inflammatory effect and attenuate the severity of ards [ ] . therefore, ards represents a procoagulant, antifibrinolytic phenotype and results in the local formation of microthrombi, which may, in turn, act to increase the pulmonary vascular resistance by the mechanical obstruction of blood flow. fibroproliferation is a characteristic of the late stage of ards, and is present in approximately % of patients who die of this condition [ ] . it is associated with increased mortality, and the presence of fibrosis on thin cut ct scan has been used to predict outcome in ards [ , ] . in a small post-mortem study of the lungs of patients who had died with 'severe respiratory failure' , zapol et al. demonstrated that there is increasing destruction of the capillary bed as ards progresses, which may contribute to elevations in the pvr of the same patients measured ante-mortem [ ] . many mediators have been linked to the fibroproliferative response, but those that have an association with vascular effects include angiotensin ii and vascular endothelial growth factor (vegf) [ ] [ ] [ ] . tomashefski et al. [ ] noted that there was electron microscopy evidence for extensive vascular remodelling in ards. the intermediate phase was characterised by fibrocellular obliteration of the arteries, veins and even lymphatic vessels. in the late stage, vascular remodelling was associated with distorted, tortuous arteries and veins. these tortuous channels were concentrated in regions of dense or irregular fibrosis. the number of capillaries was reduced, and they were often dilated. muscularisation of the arteries was identified in the intermediate phase and was very marked in the late phase. this mechanical disruption of the course of blood vessels is likely to contribute to the sustained elevation in pvr seen in non-survivors. a key difference between normal lungs and injured lungs in ards is the use of mechanical ventilation in the latter, requiring the application of peep and positive inspiratory plateau pressures. when peep is applied to a diseased lung, the change in pvr is determined by the balance between overdistension of lung units and recruitment of areas with previously low numbers of open alveoli. when the number of open alveoli increases following a recruitment manoeuvre and application of high peep, then pvr may even fall in keeping with whittenberger's-u shaped relationship between pulmonary vascular resistance and lung volume. any increase in ventilated alveolar area may also reduce hpv. canada et al., found that the pulmonary vascular resistance index (pvri) was lowest at cm h o in the normal lung but cm h o had to be applied to the injured lung in order to achieve minimal pvri [ ] . above 'optimal peep' levels, the pvr increased, presumably due to compression of intra-alveolar capillaries by the increased airway pressure resulting in an increase in zone and characteristics [ , ] . there are very few studies which have measured pulmonary vascular resistance in ards patients ventilated with lower tidal volumes, perhaps due to the reduction in the use of the pulmonary artery catheter just as lung-protective ventilation was gaining widespread acceptance [ ] . limitation of plateau pressures has, however, been shown to be associated with lower rates of right ventricular failure than in historical studies [ , ] . the application of higher tidal volume to the patients in these studies was associated with a significant increase in right ventricular afterload [ ] . there is currently no evidence to suggest that one mode of ventilation has more or less effect than any other mode on pulmonary vascular haemodynamics. any effect of the mode of ventilation on pvr is likely to be related to the amount of peep and plateau pressure that is applied. why do the studies of pulmonary haemodynamics report inconsistent relationships with mortality? as is apparent, pvr is directly influenced by factors that are intrinsic to the lung and can be increased by the pathophysiological insults that occur in ards. in contrast, pap is affected both by factors extrinsic to the lung (e.g. rv output preload and contractility) and by factors intrinsic to the lung (pvr). in clinical practice, there is considerable variability in the preload of patients with ards. both volume loading and venous tone have a considerable influence on the amount of venous return reaching the heart. the presence of sepsis and the use of vasopressors will both affect venous tone. likewise, raised intra-thoracic pressure can have a compressive effect on the intra-thoracic veins, including the superior and inferior venae cavae [ ] and limit venous return in patients with ards. sepsis-induced cardiac dysfunction may result in rv impairment in as many as % of patients [ ] . the studies in table have reached different conclusions about the significance of pap and pvr and their relationship to outcome in ards. what might account for these differences? all except one of the studies quoted are observational in nature and did not employ standard patient management protocols. the studies were not designed to answer specific questions about the nature of pulmonary haemodynamics in ards, and the data were drawn from patients who were managed differently in terms of mechanical ventilation (mode and pressures applied), fluid status and vasopressor use, all of which adds to the statistical noise when trying to draw useful conclusions. bull et al.'s data came from patients who all had a standardised approach to ventilator management (in particular the use of low tidal volume ventilation), pulmonary artery catheter data acquisition as well as fluid management. bull et al.'s study, the largest in the modern era of 'protective ventilation' found no association between pap and outcome but showed a highly significant and independent link between two indices of pulmonary vascular dysfunction (mpap-paop and pvri) and mortality. pvr is primarily affected by factors that are intrinsic to the lung, while pap is influenced by both pvr and rv preload and contractility. when the variability in management was controlled for (as in bull et al.'s study), the measured pvr was more likely to have reflected the vascular changes induced by the disease process in ards. this is because the protocol standardised many of the extrinsic factors (airway pressure, tidal volume, fluid loading) that can influence pa pressure independently of changes in pulmonary vascular resistance. importantly, in this wellcontrolled study, indices of elevated pulmonary vascular resistance were found to independently predict greater mortality in ards. this highly significant association between mortality and measures of pulmonary vascular resistance, in a carefully controlled study, raises the question as to whether pvd directly causes increased mortality or is it associated with mortality. there are two potential mechanisms by which an elevation in pvr could cause mortality in ards. either it results in right ventricular failure, with subsequent multi-organ dysfunction or it exacerbates the acute lung injury directly. the right ventricle is more sensitive to acute increases in its afterload than the left ventricle. we know from studies of major pulmonary embolism, that a normal right ventricle cannot acutely generate pulmonary pressures greater than mmhg (mean) and quickly fails in this clinical context [ ] . is the same true for patients with ards? sustained pulmonary hypertension may result in right ventricular failure (rvf) in ards patients [ ] . over the years, the incidence of right ventricular dysfunction (rvd) has declined as improvements in mechanical ventilation have been adopted and lessened the intrathoracic airway pressure in patients with ards [ , ] , but rvd is variably defined and diagnosed among studies which makes comparison difficult. clinically, right ventricular failure has no agreed definition, but criteria (using pulmonary artery catheter data) include pulmonary hypertension associated with an rv cardiac index < . l min − m − and a right atrial pressure > mmhg [ ] . using these criteria, osman et al. found an incidence of right ventricular failure of . % in patients with ards [ ] . the presence of rvf was not associated with death. in bull et al.'s analysis of patients with ards, they reported an incidence of right ventricular failure (rvf) of % (using monchi's definition of right atrial pressure > pulmonary artery occlusion pressure [ , ] ); rvf was not predictive of mortality. the presence of rvf can also be inferred using echocardiographic criteria. acute cor pulmonale (acp) has been defined as the presence of rv dilation (ratio of rv end-diastolic area to left ventricle end-diastolic area > . ) in association with dyskinesia of the interventicular septum in response to an increased afterload [ ] . jardin et al. originally described the two-dimensional echo characteristics in a group of patients with acute respiratory failure, showing that the right ventricular enddiastolic area increased as the pvri (measured using a pac) increased and rv stroke volume declined [ ] . vieillard-baron et al. have demonstrated an incidence of echocardiographic cor pulmonale of % in a study of patients with ards [ , ] . however, acp was found to be reversible in those patients whose ards resolved, and it did not have a negative prognostic significance. similar results were found by cepkova in a study of patients with acute lung injury [ ] . in a retrospective analysis of patients with ards admitted to their unit since , jardin's group found a correlation between increasing levels of plateau pressure and the incidence of acute cor pulmonale [ ] . as measured plateau pressure increased, the incidence of acp rose up to % with plateau pressures of > cm h o. while they also noted an association between the presence of acp and mortality in the overall group, this did not hold true when the airway pressure was aggressively limited, in line with current practice [ ] . vieillard-baron's group [ , , , , ] have suggested that the increases in rv afterload due to elevations in peep and plateau pressure, as well the underlying lung injury, result in rv dysfunction that is sufficient to increase mortality. this reflects what we know of the pathophysiology of pulmonary embolism, but the evidence is not as definitive in ards. the presence of acp has not been consistently demonstrated to be associated with excess mortality in ards in the modern era of protective ventilation. perhaps this is because the authors modified their approach to mechanical ventilation in these studies when acp was recognised, in order to limit the distension of the right ventricle by reducing the airway pressures (peep and plateau) and putting the patient in a prone position [ , ] . recent echocardiographic derived data on right ventricular dysfunction from boissier et al. [ ] suggest that even when tidal volume and plateau pressure are limited in line with best practice, the incidence of acp in ards is still % and is independently associated with mortality in spite of greater use of prone positioning and nitric oxide. lheritier et al. [ ] found a similar incidence of acp ( . %) in moderate to severe ards patients ventilated with a lung protective strategy, but they could not find an association between the presence of acp and outcome. in both studies, the groups with acp had a higher use of nitric oxide and prone positioning compared to those without acp. it is unclear what accounts for the different findings in these studies. the relationship between acp/rvd and outcome in ards is therefore unclear, and it remains to be determined. it is worth asking the question as to whether there is a plausible mechanistic basis that would allow pulmonary vascular dysfunction to worsen ards. high-altitude pulmonary oedema (hape) is a condition that occurs in previously healthy individuals within to days after rapid ascent above altitudes of , to , m [ , ] . while it is not a form of ards, it is a severe form of non-cardiogenic pulmonary oedema, which can develop in susceptible individuals ( % to % of the normal population) in the presence of hypoxia alone [ ] . individuals who develop hape have an increased degree of hpv compared to unaffected members of the population. pulmonary artery pressure at an altitude of , m is about % to % higher in individuals who are prone to hape compared with non-susceptible controls, and this higher pressure precedes oedema formation [ ] . the increase in hpv can also be demonstrated at low altitude in susceptible individuals exposed to a brief hypoxic challenge [ , ] . lowering pulmonary artery pressure during the ascent to high altitude can prevent hape. a non-specific pulmonary vasodilator (nifedipine) [ ] or the phosphodiesterase- -inhibitor tadalafil [ ] reduced the prevalence of pulmonary oedema in hape-susceptible individuals after rapid ascent to , m from % to about %. this suggests that excessive hpv may contribute to the development of acute oedema, possibly by redistributing pulmonary blood flow away from areas with high degrees of hpv to other sections of the lung, with resultant hyper-perfusion, endothelial injury and capillary leak. this causes a secondary inflammation which is clinically indistinguishable from ards [ ] . the finding that a subset of the population is prone to the development of non-cardiogenic pulmonary oedema, as a result of exposure to hypoxia alone, is of relevance to our understanding of ards. ards is characterised by heterogeneous areas of alveolar hypoxia and inappropriate vascular responses to these areas of hypoxia may partially explain the finding that individuals with pulmonary vascular dysfunction have worse outcomes in ards. there is, as of yet, no evidence to support this hypothesis in the general population who present with ards. is pvd a marker of the severity of ards? as patients recover from ards, there is resolution of the pulmonary vascular dysfunction. many of the mechanisms of pvd in ards (the release of multiple vasoactive mediators, vascular remodelling and the formation of vasoocclusive microthrombi) are caused by the disruption of the normal endothelial-inflammation-coagulation pathways. pvd may be a good summative index of vascular damage from these mechanisms. nuckton et al. has previously reported that an increased dead space fraction was associated with increased mortality in ards [ ] , which they postulated might be due to injury to the pulmonary capillaries from inflammation and thrombosis and obstruction of pulmonary blood flow in the extraalveolar pulmonary circulation. there is evidence that extra-pulmonary organ dysfunction in ards is caused by the systemic inflammatory response, which in turn is driven by the initiating pulmonary injury [ ] . if pvd is primarily a downstream result of the activation of the inflammatory-coagulation cascade in the lung, then, the reason it is associated with mortality in ards may be because it reflects the severity of the underlying inflammatory process. this hypothesis may also help to explain why pvd is associated with mortality in wellcontrolled studies of patients with ards whereas right ventricular dysfunction has not been consistently shown to be associated with mortality. ards studies are rarely adequately powered to look at mortality as they do not recruit sufficient numbers of patients to be able to draw valid conclusions. using pvd as an index of disease severity might allow researchers an additional way to stratify the severity of lung injury and to test the efficacy of new treatments for ards by measuring the change in pvd, which is known to improve as the patient recovers from lung injury. in order to develop new treatments for ards, we need better methods for examining their efficacy. using pvd as an endpoint might improve the predictive value of phase ii trials prior to embarking on full scale clinical studies of new treatments. assessment of pulmonary vascular resistance may be possible using non-invasive echocardiographic technology [ ] which would increase the applicability of this approach and may be worth pursuing. pulmonary vascular dysfunction is an independent predictor of mortality in ards. an examination of the physiology of pulmonary haemodynamics in ards helps to explain why it may be a clearer mortality signal, when compared to the inconsistent link between mortality and pulmonary arterial pressure or right ventricular dysfunction. further study is needed to determine precisely the dominant pathways involved in causing pvd in ards. this is an area of research that may yet lead to greater understanding of the complex interplay between the pulmonary circulation, endothelial dysfunction and activation of the inflammatory-coagulation cascades that underlie ards. abbreviations acp: acute cor pulmonale; ards: acute respiratory distress syndrome; co: cardiac output; hpv: hypoxic pulmonary vasoconstriction; lap: left atrial pressure; mpap: mean pulmonary arterial pressure; no: nitric oxide; p:f: ratio of partial pressure of oxygen to fraction of inspired 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and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial adult respiratory distress syndrome secondary to high altitude pulmonary edema pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy echocardiography based estimation of pulmonary vascular resistance in patients with pulmonary hypertension: a simultaneous doppler echocardiography and cardiac catheterization study pulmonary vascular dysfunction in ards. annals of intensive care convenient online submission rigorous peer review immediate publication on acceptance open access: articles freely available online high visibility within the fi eld retaining the copyright to your article submit your next manuscript at springeropen.com key: cord- - v yfa authors: zisman, david a.; keane, michael p.; belperio, john a.; strieter, robert m.; lynch, joseph p. title: pulmonary fibrosis date: journal: fibrosis research doi: . / - - - : sha: doc_id: cord_uid: v yfa idiopathic pulmonary fibrosis (ipf) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (uip) on surgical lung biopsy. the estimated prevalence in the united states is between , and , cases, and evidence suggests that the prevalence is increasing for ipf. risk factors associated with pulmonary fibrosis include smoking, environmental exposures, gastroesophageal reflux disease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors. the diagnosis requires a careful history and physical examination, characteristic physiological and radiological studies, and, in some cases, a surgical lung biopsy. the natural history of ipf is not known, but evidence supports the concept of a continuum of idiopathic interstitial pneumonias that may overlap in time. most patients with ipf succumb to respiratory failure, cardiovascular disease, lung cancer, pulmonary embolism, infection, and other health problems. the median survival time for patients with ipf is less than yr. factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy, and prominent fibroblastic foci on histopathologic evaluation. conventional therapy (corticosteroids, azathioprine, cyclophosphamide) provides only marginal benefit. lung transplantation should be considered for patients with ipf refractory to medical therapy. in light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. emerging strategies to treat patients with ipf include agents that inhibit epithelial injury or enhance repair, anticytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches. the diagnosis and management of idiopathic interstitial pneumonias (iips) remains a challenge to the clinician. recently, there have been substantial changes in our understanding and approach to theses diseases. with greater comprehension of the clinical relevance of the different histopathological subgroups that make up the idiopathic interstitial pneumonias, the term idiopathic pulmonary fibrosis (ipf) is now reserved to patients with idiopathic usual interstitial pneumonia (uip) on surgical lung biopsy. the following review will provide an updated discussion of the epidemiology, risk factors, diagnosis, natural history, morbidity and mortality, prognosis, and conventional therapy of ipf, as well as emerging strategies for the treatment of patients with this disease. the true prevalence of ipf, also known as cryptogenic fibrosing alveolitis (cfa), is unknown. despite the poor quality of the data and the changes in diagnostic criteria and classification, there is evidence suggesting that ipf is increasing ( ). there are approx to . cases of ipf per , in the general population ( - ). the prevalence increases with older age, history of smoking, and male gender ( , , ) . in a population-based study in bernalillo county, new mexico, the prevalence for adults from age to yr was . per , , but surpassed per , for individuals older than yr ( ). the prevalence of ipf is higher in men ( . cases per , ) than in women ( . cases per , ) ( ). the estimated prevalence in the united states is between , and , cases ( ). the incidence of ipf is estimated at . cases per , per year for males and . cases per , per year for females ( ). vital statistics figures are limited and incomplete. in , there were , hospitalizations and deaths in the united states owing to pulmonary fibrosis (compared with , hospitalizations owing to chronic obstructive pulmonary disease and asthma). in japan, the mortality rate for ipf per , population was estimated to be . in men and . in women, with an overall rate of . in both sexes ( ). in the united kingdom, the annual number of deaths from ipf increased twofold between and . the age-adjusted rate of pulmonary fibrosis among deceased in the united states increased from . per , in to . per , in in males, and from . per , in to . per , in in females ( ). pulmonary fibrosis listed as a cause of death increased from % in to % in . in the united states, the age-adjusted mortality rates are highest in the western and southwestern states and lowest in the midwest and northeast. in the united kingdom, highest mortality rates are found in industrialized areas of england and wales ( , ). in case-control studies, smoking has been identified as a possible risk factor for ipf with an odds ratio (or) of . ( % confidence interval [ci] . - . ) for ever-smoking, and . ( % ci . - . ) for former-smokers ( , , ) . smokers of to pack-years have an or of . ( % ci . - . ) for pulmonary fibrosis ( ). in a recent study in japan, the adjusted odds ratio for cigarette smoking was estimated at . ( % ci . - . ) ( ). interestingly, three studies reported improved survival among current or former smokers with uip compared to never-smokers ( ) ( ) ( ) . however, others found no such effect ( ) ( ) ( ) . it is possible that the apparent protective effect of cigarette smoking may relate to the following: lead time bias; alterations in the balance of proteinases and antiproteinases that would influence net deposition of extracellular matrix in the lung; or inhibitory effects of cigarette smoke on lung fibroblast proliferation and chemotaxis ( , ). instillation of acid in several animal models results in aspiration-induced lung injury and pulmonary fibrosis ( ) . clinical data suggest that a high percentage of patients with ipf have clinically silent gastroesophageal reflux disease (gerd) ( , ) . small tracheobronchial aspirations of gastric acid may play a role in the pathogenesis of ipf; however, a causal relationship has not been established ( , ) . investigators at the university of washington medical center are conducting an ongoing prospective study of patients with ipf. interim results indicate that the prevalence of ipf patients with gerd is %, with only % of patients reporting symptoms ( ) . however, the perpherial pattern of uip in the lung would be unusual if gerd was truly the cause, as compared with an association. in one case-control study, ipf was associated with exposure to antidepressants with an or of . . - . ] ). these associations were independent of smoking and occupational dust exposure. the authors concluded that exposure to antidepressants may be responsible for approx % of cases of ipf seen in their population. no significant association was noted between ipf and the other drug groups tested (anticonvulsants, β-blockers, antibiotics, and nonsteroidal anti-inflammatory drugs [nsaids]) ( ). in a recent study, clinical and demographic data were extracted from medical records of consecutive patients with ipf admitted to a japanese hospital. ipf was associated with diabetes mellitus (dm) with and or of . ( % ci . - . ). the authors concluded that dm might be a risk factor for ipf ( ). the etiology of ipf is unknown, but environmental factors may play a causative role. metal and wood dust environments may be important risk factors for pulmonary fibrosis. in one study, metal dust exposure was identified as a risk factor with an odds ratio (or) of . ( % ci . - . ) , and wood dust exposure with an or of . ( % ci . - . ). in that study, metal and wood dust exposure may have caused up to % and % of pulmonary fibrosis cases, respectively. dust containing brass, lead, cobalt, aluminum, zinc, cadmium, mercury, and pine dusts were associated with pulmonary fibrosis ( ). certain occupations may predispose to pulmonary fibrosis. in one study, farming was identified as a potential risk factor with and or of . ( % ci . - . ) and exposure to livestock was associated with an or of . ( % ci . - . ). hairdressing was linked to pulmonary fibrosis with an or of . ( % ci . - . ), metal dust exposure with an or of . ( % ci . - . ), raising birds with an or of . ( % ci . - . ), stone cutting/polishing with an or of . ( % ci . - . ), and vegetable/animal dust exposure with an or of . ( % ci . - . ) ( ). a number of viruses have been associated with pulmonary fibrosis, but true cause-effect relationships remain unproven. a serological survey found an association between active epstein-barr virus (ebv) infection and ipf ( ). egan and colleagues reported immunohistochemical evidence of ebv-productive cycle antigens in type ii alveolar epithelial cells in ipf ( ). subsequently, these investigators detected ebv dna by polymerase chain reaction (pcr) in the lung tissue of patients with ipf ( ). further study demonstrated that productive ebv replication is common in ipf and it is not associated with immunosuppressive therapy ( ). tang in a recent study, human t-lymphtropic virus type i (htvl-i) positive ipf patients had more affected lung parenchyma, demonstrated traction bronchiectasis with honeycomb change, and exhibited increased levels of specific cytokines that correlated with activated t-cells in the bronchoalveolar lavage fluid (balf). these findings suggested that htlv-i infection might contribute to the development of ipf via activation of t-cells ( ). the latent nature together with episodic reactivation of many of these viruses may provide a scenario for the concept of "multiple hits" host defense followed by repair that these patients may experience during the course of their disease. the genetics of familial ipf have not been elucidated. an autosomal dominant trait with variable penetrance may account for approx % of cases; there is no clear mode of transmission in the remaining % ( , ). investigators have linked ipf to an increase in mz phenotype for α -antitrypsin inhibition on chromosome ( - ). using a candidate gene approach, researchers identified surfactant protein c gene mutations in large familial pulmonary fibrosis kindred, including adults with uip and children with nonspecific interstitial pneumonia (nsip) ( ). in a separate study, selman and co-workers demonstrated that surfactant protein a and b genetic variants predispose to ipf ( ). genetic polymorphisms for interleukin- receptor antagonist (il- ra) and tumor necrosis factor (tfn)-α appear to be important in determining risk ( ). in contrast, transforming growth factor (tgf)-β polymorphisms do not predispose to ipf, but these polymorphisms may affect the course of the disease ( ). it is unknown what proportion of ipf is familial, but it is estimated that . to . % of cases have a genetic basis ( ). thirty-eight families affected by pulmonary fibrosis have been identified and are currently under active investigation. the familial aggregation in those families is consistent with a genetic basis in at least a subset of patients with ipf ( ). ipf is a specific form of chronic fibrosing interstitial pneumonia limited to the lungs and associated with the histological pattern of uip on surgical lung biopsy ( ). many earlier studies included various other idiopathic interstitial pneumonias under the term idiopathic pulmonary fibrosis, but the clinical term ipf is now reserved to patients with idiopathic uip. the diagnostic approach to any patient with diffuse lung disease must include a thorough history and physical examination with attention to symptoms or signs suggestive of a connective tissue disease, occupational or environmental exposures, use of fibrogenic drugs, and family history of pulmonary fibrosis. patient age at disease onset is generally between and yr of age and ipf is more common in males than females. ipf typically presents insidiously, with gradual onset of a nonproductive cough and dyspnea ( ). patients are often treated for other conditions such as congestive heart failure, "walking pneumonia," bronchitis, or asthma before the diagnosis is made. the physical examination in most patients (> %) reveals fine bibasilar inspiratory crackles ("velcro rales"), and clubbing is noted in up to % of patients ( , ). signs of right heart failure are evident in advanced cases ( ). laboratory abnormalities are mild and nonspecific. one early study described "autoimmune factors" in blood of patients ( of whom had autoimmune-associated diseases) among patients with diffuse fibrosing alveolitis ( ). a positive rheumatoid factor occurred in of patients with unexplained pulmonary fibrosis and positive antinuclear factor in the serum (ana) ( ). a later study examined serum specimens from patients with ipf and compared them with specimens from age-and sex-matched controls; anas were present in % of patients with ipf and in % of the control subjects ( ). positive circulating anas or rheumatoid factor occur in % to % of patients with ipf, but titers are rarely high ( , , , ). an elevated erythrocyte sedimentation rate, lactate dehydrogenase, or hypergammaglobulinemia may be found in patients with ipf, but are nondiagnostic ( ). serological findings do not correlate with extent or severity of disease, and have no prognostic value ( , ). in the absence of symptoms of connective tissue disease, the presence of autoantibodies does not imply an underlying systemic disorder. recently, investigators reported the occurrence of low fasting triglyceride and high free fatty acid levels in patients with pulmonary fibrosis. because insulin-like growth factor (igf)-i is known to lower triglycerides and increase free fatty acids, the authors hypothesized that the reported increased production of igf-i in patients with ipf may explain such findings ( ). classic chest radiographic findings in ipf include a basal predominant reticular, or reticulonodular, pattern associated with decreased lung volumes, and in later stages, cystic areas representing honeycomb (hc) lung ( , - ). when a "confident" diagnosis of ipf is made on the basis of the chest radiograph, it is correct in to % of cases ( , , ). most patients with ipf will have an abnormal chest radiograph but, rarely, patients may present with a normal plain film ( ). it is important to review all previous chest films to assess the rate of change in disease activity. in addition, radiographs are indicated if clinical deterioration occurs in order to identify superimposed infection or malignancy ( , ). pleural effusions, upper lobe predominant disease, airbronchograms, or prominent lymphadenopathy should suggest an alternative diagnosis. typical high-resolution chest computed tomography (hrct) features of ipf/uip include patchy, predominantly peripheral, subpleural, and symmetrical bibasilar honeycombing, reticular abnormalities, and limited "groundglass" opacities (ggo) ( [ ] [ ] [ ] [ ] . several studies have shown that experienced radiologists can make a "confident" diagnosis of uip with specificity greater than %, provided ct features are typical ( , [ ] [ ] [ ] [ ] . although a characteristic hrct is highly specific for ipf/uip, "typical" hrct identifies only to % of patients with histological uip; therefore, a surgical lung biopsy (slb) is recommended when clinical and radiological information result in an uncertain diagnosis ( , , , ). one study evaluated the proficiency of physicians with expertise in interstitial lung diseases to identify accurately the hrct scans from patients with biopsy-proven ipf/uip. when these investigators made a "confident" diagnosis of ipf based on hrct scan and clinical data, they were right in more than % of the cases. however, more than half of the patients with ipf had an uncertain diagnosis on the basis of hrct and clinical assessment ( ). in a subsequent analysis of these data, investigators identified hrct features associated with a pathological diagnosis of uip. on multivariate analysis, lower lobe honeycombing (or, . ), and upper-lung irregular lines (or, . ) were the only independent predictors of uip. when they combined those two factors, a diagnosis of uip was established with a sensitivity of %, a specificity of %, and a positive predictive value of % ( ). interestingly, in that study, adenopathy was observed in % and % of patients with uip and without uip, respectively. this finding suggests that patients with ipf generate a marked lymphoproliferative response to an unknown antigen or antigens; we believe that this observation requires further investigation as it may provide important clues to further our understanding of the pathogenesis the disease. in a separate study, two radiologists independently assessed ct scans from a cohort of patients with either uip. ct features were "typical" for uip in only % patients, and all of them had histological uip on slb. typical ct features of uip are associated with advanced, latestage disease. among patients with earlier phases of uip, ct features may be atypical ( ) or indeterminate ( ). extensive ggo is not a major feature of uip, and suggests an alternative diagnosis such as desquamative interstitial pneumonia (dip), nsip, lymphocytic interstitial pneumonia (lip), cryptogenic organizing pneumonia (cop), hypersensitivity pneumonia (hp), or pulmonary alveolar proteinosis (pap) ( ). in contrast, honeycomb change is a cardinal feature of uip, and is rare in other iips ( , ). pulmonary function tests (pfts) characteristically reveal a restrictive ventilatory defect with impaired gas exchange; however, smokers may have preserved lung volumes or airflow obstruction in the initial stages of the disease ( , , ). impairments in gas exchange (i.e., carbon monoxide diffusing capasity [dl co ]) and oxygenation may be evident early in the course of the disease, even when spirometry and lung volumes are normal ( ). the most appropriate and simple tests are vital capacity and dl co ; these are most useful for assessing the extent and monitoring the progression of the disease ( ). cardiopulmonary exercise testing (cpet) demonstrates hypoxemia, widened a-a o gradient, submaximal exercise endurance, reduced oxygen consumption (vo ), high respiratory frequency, low tidal volume (v t ) breathing pattern, increased dead space (v d /v t ), increased minute ventilation for the level of vo , and a low o pulse ( - ). arterial desaturation and abnormal widening of a-a o gradient with exercise may be elicited with relatively simple tests, such as the -min walk test ( , ). balf may play a role in the diagnosis of inorganic dust diseases, suspected malignancy, infections, some hematological disorders, drug-induced diseases, pulmonary alveolar proteinosis, langerhans' cell histiocytosis, and alveolar hemorrhage ( ). balf is useful in research studies but of limited clinical application when evaluating iips ( ). increases in polymorphonuclear leukocytes, eosinophils, mast cells, alveolar macrophages, and countless cytokines are noted in balf from patients with ipf/uip; lymphocyte numbers are usually normal ( ). balf neutrophilia is present in to % of patients with ipf/cfa ( , ), but does not predict prognosis or therapeutic responsiveness. elevations in balf eosinophils were associated with more severe clinical impairment ( , ), but balf eosinophil counts do not correlate consistently with prognosis ( , ). by contrast, the presence of balf lymphocytosis, found in fewer than % of cases, was associated with a greater responsiveness to corticosteroid therapy, a more cellular biopsy, and less honeycombing ( , ). data compiled from two studies documented favorable responses to corticosteroids in of patients exhibiting balf lymphocytosis, but in only of without lymphocytosis ( , ). because the studies citing balf lymphocytosis in steroid-responsive patients with ipf ( ) or cfa ( ) antedated the description of nsip, it is possible that balf lymphocytosis reflects disorders distinct from uip (such as cellular nsip). nevertheless, in a recent study, researchers hypothesized that balf findings may distinguish between uip and nsip; balf total and differential cell counts were not different between the two groups, and in neither group, were balf findings predictive of survival or changes in lung function ( ). the american thoracic society (ats) and the european respiratory society (ers) in collaboration with american college of chest physicians (accp) published an international consensus statement on the diagnosis and treatment of ipf. this statement stated that the definite diagnosis of ipf requires an slb showing the uip pattern. however, an slb is not recommended in patients with suspected ipf in whom the clinical or radiographic information are stereotypical of ipf/uip. it has been suggested that, in the absence of an slb, the presence of all four major diagnostic criteria and at least three minor criteria increases the likelihood of an accurate diagnosis of ipf/uip ( ). however, these criteria have not been prospectively validated. an slb, preferably by video-assisted thoracoscopy (vats), is recommended in patients with suspected ipf in whom the clinical or radiographic information are not typical of ipf/uip ( ). given the patchy and heterogeneous nature of the uip lesion, a large piece of lung tissue is required and tbbx are used mainly to rule out other disorders that mimic ipf. however, emerging data suggest that tbbx findings may be more useful in diagnosing uip than previously recognized; characteristic histological features of uip (interstitial fibrosis with fibroblastic foci [ff] and/or hc change) can be appreciated even in a small sample obtained by tbbx; these findings in a patient with characteristic clinical and radiographic features may indicate a diagnosis of uip. however, these findings require prospective validation ( ). significant advances have been made in our understanding of the idiopathic interstitial pneumonias (iips). the most important advancement has been the greater appreciation of the clinical relevance of the different histopathological subgroups that make up the iips. until recently, inflammatory or fibrotic lung disorders of unknown etiology were "lumped" under the term ipf ( , , ). however, with the advent of vats lung biopsies and the greater availability and quality of surgical specimens, pathologists have recognized the heterogeneous nature of these disorders and described specific histopathological patterns that predict response to therapy and survival ( , , ). ipf/uip is the most common of the iips, comprised of to % of the cases ( , , , ). the uip lesion is characterized by temporal and geographic heterogeneity, with areas of old scar and hc change, admixed with granulation tissue and normal lung; the lesion has predilection for the subpleural and basilar regions of the lung, there is scant inflammation, and prominent aggregates of fibroblast and myofibroblasts, so-called "fibroblastic foci," which actively secreting extracellular matrix ( , , ). additional features include smooth muscle hypertrophy, metaplasia and hyperplasia of type ii pneumocytes, destroyed and disrupted alveolar architecture, traction bronchiectasis and bronchioloectasis, and secondary pulmonary hypertension changes ( , , ). other categories of iip that must be distinguished from ipf/uip include nsip, dip, respiratory bronchiolitis-associated interstitial lung disease (rbild), acute interstitial pneumonia (aip), cop, and lip ( ). nsip is observed in approx % of patients with iip ( ). this provisional category is used to describe a temporally homogeneous lesion with varying degrees of inflammation and fibrosis with favorable response to therapy and prognosis. nsip can be subdivided into nsip-cellular and nsip-fibrotic varieties depending on the degree of inflammation and fibrosis present in the surgical specimen ( ). this subclassification provides important prognostic information; patients with idiopathic nsip, cellular pattern have a better -and -yr survival than those with idiopathic nsip, fibrosing pattern ( % vs % and % vs %, respectively) ( ). in many patients, however, histological overlap between uip and nsip is evident. flaherty and co-workers reviewed slbs from patients with iip who had multiple lobes biopsied and reported histopathological variability between lobes in % of patients. importantly, in that study, uip in at least one lobe defined prognosis ( ). in a later study, the pathological findings in biopsy and subsequent explant specimens from patients with uip were reviewed to refine histological criteria and to assess the relationship between uip and nsip. the important new finding was that nsip-like areas were present in the majority of uip patients ( %) in both biopsy and explants specimens, and in some, these areas were extensive, making accurate diagnosis of uip difficult (cases were misdiagnosed as nsip). the most useful feature for diagnosing uip in difficult cases is the presence of a distinct "patchwork" or variegated pattern of parenchymal involvement ( ). rbild and dip comprise approx % of iips ( ) . these entities are thought to be smoking-related diseases and, like nsip, tend to be responsive to anti-inflammatory therapy. this is not surprising, as pathologically, these lesions are characterized by varying degrees of intra-alveolar and/or peribronchial pigmented macrophage infiltration with scant or no fibrosis. aip is characterized by active fibrosis consisting of proliferating fibroblasts and myofibroblasts with minimal collagen deposition resembling the organizing stage of diffuse alveolar damage (dad) ( ). finally within the iips, some include cop (previously termed bronchiolitis obliterans organizing pneumonia, or boop), and lip. both are relatively steroid-responsive lesions; pathologically, cop is characterized by the presence of intra-alveolar plugs of granulation tissue, and lip by lymphocytic infiltration of the alveolar walls. it should be noted, however, that many experts argue that lip should not be included within the iips because it is considered as lymphoproliferative disorder which, in turn, is rarely idiopathic and is mostly observed in association with infections (e.g., hiv) or collagen vascular diseases (cvds) ( ). the natural history of the pathogenesis of ipf is not known. the description of temporal heterogeneity for the histopathological entity of uip would suggest that this process occurs over a significant period of time within the same low-power microscopic field of the lung. moreover, the description supports the notion that the lesions are not homogeneous for both the timing of the orginal injury and the subsequent response to the injury and repair. in addition, the histopathological entity of uip is not unique to ipf, and can be found in patients with connective tissue diseases, end-stage asbestosis, and end-stage hypersensitivity pneumonia. therefore, uip may represent an end-stage of a "process," not the beginning, intermediate, and end-stage of a disease. the only insight into the natural history of this process comes from two recent studies that suggest the potential concept of a continuum of iips that may overlap in time. in a study of patients whom had multiple lobes biopsied, histological variability was evident in % of the patients. patients concordant for uip were older ( ± yr) than those discordant for uip ( ± yr) or with fibrotic nsip ( ± yr) or cellular nsip ( ± yr), suggesting that nsip may be an early lesion that progresses with time to uip ( ). in a separate study, investigators found discordant histological diagnoses between lobes in % of the patients. nsip-like reactions were evident in % of patients with uip, suggesting that nsip may evolve into uip ( ). in a genetic study, two different histopathological patterns of interstitial pneumonia were found to exist in members of a family who shared protein c gene mutations: adults with uip and children with nsip; this supports the notion that nsip may be a precursor lesion to uip ( ). it has been suggested that most patients with ipf progress in a relentless and insidious manner with a median survival of less than yr ( ). this concept was challenged in a recent study of subcutaneous interferon (ifn)-γ b ( μg thrice weekly) in patients with mild to moderate ipf (forced vital capacity [fvc] > % and dl co > %), where a trend toward lower mortality was seen in ifn-γ b-treated patients compared with placebo-treated patients ( ). interestingly, there were no significant differences in lung function or gas exchange between ifn-γ b-treated and placebo-treated patients at wk of follow-up. in both study groups, % of patients remained stable, % deteriorated, and the rest improved, suggesting that most patients with mild to moderate ipf remain stable for at least yr on no specific therapy. the socalled "ipf exacerbations" may explain the trend toward lower mortality seen in this study, but this requires further study. ipf exacerbations may be defined as an accelerated deterioration of ipf in the absence of apparent infectious agents and heart failure ( , ). it is often a terminal event, with features of dad or organizing pneumonia on lung biopsy or autopsy ( , ). this syndrome is indistinguishable from idiopathic aip ( ), and is similar to acute respiratory distress syndrome (ards). the factors responsible for this accelerated phase of ipf are unknown, but viral infections, high concentrations of oxygen, or drug reactions are plausible etiological factors ( ). only one study has addressed mechanism of mortality of patients with ipf. panos and colleagues ( ) found that most patients with ipf succumb to respiratory failure ( %), cardiovascular disease ( %), lung cancer ( - %), pulmonary embolism ( %), infection ( %), or other health problems ( %) ( ). although infection would appear unlikely as a cause of mortality in ipf patients, clinically we can only determine the micro-organism cause of community acquired pneumonia in % of all patients. therefore, we do not know the true incidence and prevalence of infection as a cause of mortality in patients with ipf, and perhaps a significant portion of the respiratory failure mortalities had infectious etiologies. with regard to cardiovascular disease, congestive heart failure and coronary artery disease (cad) account for % of deaths ( ). patients with ipf appear to be at increased risk of developing cad. in a cross-sectional study of patients referred for lung transplantation, fibrotic lung diseases were associated with an increased prevalence of cad compared with nonfibrotic diseases after adjustment for traditional risk factors (or . ; % ci, . - . ); the authors theorized that the fibroproliferative process may influence cells beyond the pulmonary compartment, and that mediator molecules produced in these disorders might promote atherogenesis ( ). pulmonary arterial hypertension occurs in % of patients with advanced ipf and its presence correlates with a vital capacity (vc) below % of predicted or a dl co under % of predicted ( ). left ventricular (lv) dysfunction occurs in less than % of patients and it is mostly ( %) a result of coexisting right heart failure. other causes of lv dysfunction include ischemic and hypertensive heart disease ( , ). six to % of patients with ipf develop bronchogenic carcinoma. lung cancer in patients with ipf typically presents as a peripheral squamous cell carcinoma in older male smokers ( ). predisposing factors include squamous metaplasia, atypical epithelial cells, or occupational exposures ( , , ) . hubbard and colleagues, in a population-based cohort in the united kingdom, studied patients with ipf and controls. the risk ratio for ipf and lung cancer was . ( % ci . - . ). importantly, adjusting for previous smoking had little effect on this ratio, suggesting that ipf is an independent risk factor for lung cancer ( ). pulmonary embolism occurs in approx to % of patients; inactivity, heart failure, bronchogenic carcinoma, and possibly corticosteroid therapy predispose patients to thrombosis ( ). pulmonary infection causes to % of deaths in patients with ipf; immunosuppressive therapy, traction bronchiectasis, and possibly gerd are predisposing factors ( ). pneumothorax occurs in up to % of patients with ipf and tends to be less responsive to tube thoracostomy, often necessitating surgical intervention ( ). corticosteroids (cs) can cause a myriad of side effects including myopathy, peptic ulcer disease, cataracts, osteoporosis, compression fractures, fluid and electrolyte abnormalities, adrenal insufficiency, and infection ( , ) . in a cross-sectional study in patients with asthma, chronic obstructive pulmonary disease, or "alveolitis" taking oral corticosteroids (n = ) vs controls (n = ), the or for bone fractures was . ( % ci . - . [vertebral fracture or , hip fracture or , and ribs or sternum fracture or . ]). patients tak-ing corticosteroids experienced more cataracts, used more antacids, had more muscle weakness, back pain, bruising, and oral candidiasis, and had fewer teeth compared with controls ( ). one prospective study included patients with ipf; received mg/d of prednisone for mo and received mg/d for mo followed by mg/d for mo. patients were monitored monthly for steroid-related side effects. all patients experienced at least one side effect. common side effects included insomnia ( %), cushingoid change ( %), weight gain ( %), irritability ( %), infection ( %), blurred vision ( %), abdominal bloating ( %), glucose intolerance ( %), and fractures or avascular necrosis ( %) ( ) . cytotoxic agents (cyclophosphamide [cp], azathioprine [aza]) can cause infections, bone marrow suppression, hepatitis, hemorrhagic cystitis (cp) and/ or malignancies ( , ) . in a prospective uncontrolled study, patients with biopsy-proven uip who were unresponsive or intolerant to cs therapy were treated with oral cp ( - mg/kg/d) for mo. nearly two-thirds of patients reported adverse effects, and % of patients discontinued therapy because of intolerable side effects. common side effects related to cp include nausea/ vomiting ( %), anorexia ( %), cytopenias ( %), weight loss ( %), alopecia ( %), infection (herpes zoster) ( %), and ovarian failure ( %) ( ). several factors have been shown to predict poor outcome in ipf. these include older age at presentation, male gender, severe dyspnea at presentation, history of cigarette smoking, severe loss of lung function, severity of reticular opacities or honeycomb change on hrct, characteristic hrct appearance, lack of response to conventional therapy, and histopathological findings showing prominent ff ( , , , , ) . investigators from the university of michigan evaluated the impact of histological diagnosis, baseline clinical, physiological, and radiographical factors on survival in patients with suspected iip. the presence of histological uip was the most important risk factor for mortality (risk ratio [rr] of . [ % ci . - ]), followed by the presence of honeycombing on hrct, a radiographic feature that was shown to be a good surrogate for histological uip (sensitivity of %, and a specificity of %) ( ). the same group evaluated the impact of hrct appearance on survival in patients with iip. patients with histological uip and stereotypical hrct appearance of uip had a shorter survival (median survival . yr) when compared with patients with histological uip and indeterminate hrct scans (median survival . yr) ( ). three studies have shown that a higher hrct-fibrosis score identify patients with worse prognosis. gay and colleagues did not find any measure of pulmo-nary function to be predictive of survival, but did find both the hrct-fibrosis score and the pathological fibrosis score to be useful in predicting survival ( ) . similarly, investigators from the united kingdom found that baseline percent-predicted dl co and hrct-fibrosis score were independent predictors of mortality ( ) . japanese investigators demonstrated that the baseline hc score and the rate of hc progression were both predictive of worse survival in patients with ipf ( ). histopathological findings showing prominent ff identify patients with poor outcome. nicholson and associates retrospectively studied ( ) patients with ipf/uip and analyzed the prognostic significance of four specific microscopic features of uip. multivariate analysis revealed that increasing ff and mononuclear cell infiltrate scores were associated with worsening lung function. higher profusion of ff and a lower dl co were independent predictors of mortality ( ). these results supported the findings by king and co-workers, who also demonstrated that an increase in the number of ff correlated highly with mortality in patients with ipf/uip ( ). in a separate study, expert pathologists reviewed slb from patients with idiopathic or cvd-associated uip and assigned a score for ff. patients with idiopathic uip had more ff and worse survival compared with patients with cvd-associated uip ( ). a number of composite scoring systems have been developed with which to predict survival in ipf. king and co-workers studied patients with ipf/ uip and derived a clinical-radiological-physiological (crp) scoring system using clinical (age, smoking status, clubbing), radiographical (extent of interstitial opacities, presence of pulmonary hypertension on chest radiographs), and physiological parameters (reduced lung volume, abnormal gas exchange during maximal exercise). these investigators demonstrated that the crp score correlated with important histopathological findings and was helpful in predicting survival in patients with ipf. a second abbreviated crp scoring system that excluded pa o during maximal exercise was inferior in predicting survival ( , ) . similarly, investigators from the brompton hospital devised a composite physiological index (cpi) using radiographical and physiological information that predicted mortality more accurately than individual pft in patients with ipf ( ). even though these composite scoring systems are accurate in their predictive ability, they are expensive and cumbersome to generate in clinical practice. with this in mind, the prognostic value of oxygen desaturation during a -min walking test was evaluated in patients with ipf. desaturation defined as a fall in oxygen saturation to % or less during the min walk test identified patients with higher mortality compared with patients who did not desaturate. the -yr survival rate of ipf patients who desaturated to that level was . % compared with . % in patients who did not desaturate ( ). predicting survival in ipf has been centered on baseline radiographical, pathological, and/or physiological testing. recently, researchers have focused on the association of serial changes in pulmonary function or radiographical features and prognosis. one study determined that a decrease in fvc (> % from baseline) during the initial mo of follow-up was associated with increased mortality (hazard ratio . ; ci . - . ) ( ). in a separate study, investigators concluded that at and mo of follow-up, serial pulmonary function trends (change in dl co , fvc, forced expiratory volume in s [fev ], and the cpi) provided important prognostic information in ipf ( ). a third study showed that assessment of changes in clinical and physiological variables (dyspnea score, total lung capacity, thoracic gas volume, fvc, fev , dl co , p o , oxygen saturation, and alveolar-arterial oxygen gradient) at and mo provide clinicians with more accurate prognostic information than baseline values alone ( ). serum markers and nuclear medicine testing may have a predictive role in ipf. greene in a prospective study, investigators analyzed the usefulness of inhaled mlabeled diethylenetriamine penta-acetic acid ([ m] tc-dtpa) aerosol clearance and survival in a cohort of patients with uip. multiple stepwise cox regression analysis identified fast clearance as an independent predictor of mortality ( ). conventional therapy (cs, aza, or cp) for ipf provides only marginal benefit. unfortunately, in many studies, diagnoses were not based on the findings of lung biopsies or were not classified by current pathological criteria; thus, there is uncertainty as to the nature of the disease being treated. two recent meta-analyses searched two large databases for randomized controlled trials (rct) and controlled clinical trials (cct) using cs or non-cs agents in patients with histological uip or who fulfilled all ats criteria for ipf; the authors could not find rcts or ccts evaluating cs alone in ipf and concluded that there are scant good-quality data regarding the efficacy of non-cs agents in ipf ( , ) . the following is a brief discussion of anti-inflammatory (conventional) therapy in the treatment of ipf. cs were the mainstay of therapy for more than four decades, but are of unproven efficacy, and are associated with significant toxicities ( , , ) . early studies of patients with ipf/cfa cited response rates of to % with cs (alone or combined with immunosuppressive agents), but complete or sustained remissions were rare ( , - ). more importantly, many responders likely had iips other than uip (e.g., nsip or rbild/dip). in recent studies, response rates to cs among patients with histological evidence for uip are low ( - %) ( , , , , ) . large retrospective studies of patients with ipf showed no survival benefit with cs ( ; , , ) . in one retrospective study from england, survival was worse among ipf patients treated with cs or cp, although this likely reflects a selection bias ( ). given the potential severe toxicities associated with cs ( , ), recent international consensus statements argue that high-dose cs should not be used to treat ipf ( , ) . however, because anecdotal responses to cs are occasionally noted in patients with ipf/uip ( ), these statements acknowledge that selected patients with clinical or physiological impairment or worsening pfts should be treated ( , ). both statements ( , ) advocate an individualized approach to treating ipf/uip. among patients requiring treatment, both statements recommend combining therapy with either oral aza or cp plus low-dose prednisone or prednisolone ( . mg/kg [lean body weight per d] for wk, then . mg/kg for wk, then . mg/kg). this represents a substantial departure from earlier regimens advocating high-dose prednisone (e.g., ≥ mg/kg/d for ≥ - wk) ( , , ) . combined therapy should be continued for mo in the absence of adverse effects. treatment should be continued beyond or mo or later time points only if patients improve or remain stable. it should be emphasized that these recommendations ( , ) reflect expert opinion, but have not been validated in clinical trials. we believe cs should not be given to patients at high risk for adverse effects (e.g., age > yr, osteoporosis, dm, extreme obesity, and so on). two prospective studies evaluated aza for ipf ( , ) . in both studies, aza was combined with prednisone. in the first study, patients with progressive ipf were initially treated with prednisone alone for mo ( ). at that point, aza ( mg/kg/d) was added and both agents were continued for an additional mo or longer. twelve patients ( %) responded. the independent effect of aza was difficult to assess, because all patients received prednisone concomitantly. in a second, double-blind trial, raghu and associates compared the effect of aza plus prednisone on lung function with that of prednisone alone in previously untreated patients with ipf (the study population may have included patients with iip other than uip). forty-three percent of patients randomly assigned to aza plus prednisone died during the -yr follow-up period, compared with % of patients randomly assigned to prednisone alone. the difference became statistically significant only after adjustment for age (p = . ) ( ). two randomized trials evaluated cp for ipf ( , ) . in one -mo trial, patients with "mid-course" ipf were randomized to prednisone alone (n = ); prednisone plus oral cp ( . mg/kg/d) (n = ); or cp alone (n = ) ( ) . mean balf neutrophil counts declined in the cohort receiving cp, but pfts did not change in any group. johnson and colleagues compared the effect of prednisolone alone with that of prednisolone plus cp on breathlessness, radiographic appearance, and lung function in patients with ipf (the study population included patients with cvd and with iip other than uip). initial improvement occurred in of the patients in the prednisolone-only group and in of the patients in the cp plus prednisolone group. however, at mo, only of the patients in the prednisolone-only group remained improved, and only of the patients in the cp-prednisolone group remained improved. life-table analysis suggested better survival in patients in the cp-prednisolone group, but this was not statistically significant ( ). in a prospective uncontrolled study, zisman and associates studied the efficacy of cp in patients with biopsyproven uip who were unresponsive or intolerant to cs therapy. only patient improved; remained stable, and deteriorated. nearly two-thirds of the patients developed drug-related side effects and one half of the patients discontinued therapy due to intolerable side effects ( ). intermittent, intravenous "pulse" cp, administered every to wk, has been tried for ipf refractory to cs in nonrandomized studies, but benefit was not convincing ( - ). lung transplantation should be considered for patients with ipf refractory to medical therapy ( , ) . two-year survival following single lung transplant (slt) ranges from to %; -yr survival is to % ( - ) . in one study, lung transplantation reduced the risk of death by % ( ) . in addition, patients surviving lung transplantation appear to achieve considerable improvement in most dimensions of health-related quality of life ( ) ( ) ( ) . unfortunately, owing to a shortage of donor organs, waiting time may be prolonged (up to - yr) and many patients with ipf die while awaiting transplantation ( , ) . one study evaluated baseline pft and hrct fibrosis scores and the relationship to -yr survival in patients with ipf younger than yr of age; the optimal points on the receiving operator characteristics (roc) curves for discriminating between survivors and nonsurvivors corresponded to a combination of dl co of % predicted with hrct-fibrosis score of . ( ) . in a separate study, investigators reviewed all transplant referrals for iip that were listed for lung transplantation at their center. the aim of the study was to determine a parameter that would discriminate between patients who survived and patients who died awaiting transplantation. the severity of hypoxemia at rest was the only significant difference between both groups ( ). unless contraindications exist, patients with severe functional impairment (e.g., fvc < % predicted, dl co < % predicted), oxygen dependency, and a deteriorating course refractory to medical therapy should be listed promptly for transplantation ( , ). historically, the fibrotic process in ipf has been thought to be preceded by a chronic inflammatory process that injures the lung and modulates fibrogenesis ( ). conventional management of ipf has been primarily based on the notion that suppressing inflammation may prevent progression to fibrosis. evidence against the notion that inflammation plays an important role in the pathogenesis of ipf comes from the lack of correlation of most markers of inflammation with disease stage or outcome, and the recognition that inflammation is not a prominent histopathological finding in uip ( , ) . additionally, emerging evidence suggests that inflammation is not required for the development of a fibrotic response ( ). in light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to the treatment of ipf are being pursued. the following is a brief discussion of antifibrotic therapy and other promising agents in the treatment of ipf. colchicine is an alkaloid derivative of the plant colchicum autumnale, which has been used in acute attacks of gout. it is known to bind microtubular proteins necessary for intracellular trafficking and cellular mitosis, thus adversely affecting secretion of proteins from cells and cellular proliferation ( , ) . its antifibrotic activity was described following the discovery that colchicine inhibits secretion of collagen and other important growth factors necessary for fibroblast proliferation ( ). however, further studies ( ) with or without additional therapeutic agents, such as steroids, failed to document efficacy of colchicine in the treatment of human pulmonary fibrosis. it is thus not currently recommended for use in therapy of ipf. the d-isomer of penicillamine has been extensively studied in animal models of fibrosis, in which it has been shown to prevent accumulation of collagen in the lung by interrupting cross-linking of collagen molecules ( ). this observation has led to its use in treating fibrotic lung disease associated with systemic sclerosis with good results ( ). however, its efficacy in the treatment of ipf has been disappointing ( ), and it is known to have toxic and significant adverse effects ( ). thus it is currently not recommended as therapy for ipf. pirfenidone is a novel agent with broad-spectrum antifibrotic activity. numerous in vitro and animal model studies have demonstrated its effectiveness as an antifibrotic agent. in vitro studies have shown that pirfenidone significantly reduced mrna levels of type i and type iii collagen, and may act at the transcriptional or translational level of collagen synthesis ( ). in vivo, it has been shown to inhibit tgf-β -induced collagen synthesis, decrease extracellular matrix deposition, and suppress the overexpression of tgf-β in the bleomycin model of pulmonary fibrosis ( , ) . because ipf is becoming increasingly recognized as primarily a fibrotic process, the potential role of pirfenidone as a therapeutic agent is being explored. in a prospective open-label study, raghu and colleagues ( ) treated ( biopsy-proven) consecutive patients with pirfenidone who were either unwilling to receive or unresponsive to conventional therapy. survival rates of % at yr and % at yr compared favorably with historical controls. in addition, % of patients discontinued prednisone therapy and the remaining % were able to reduce their daily dose. all patients treated with immunosuppressive therapy tolerated discontinuation of the drug. interestingly, patients whose lung function had deteriorated before enrollment appeared to stabilize after beginning pirfenidone. side effects were relatively common, with patients reporting nausea ( %), fatigue ( %), and photosensitivity ( %). despite these encouraging observations, the results of this study are difficult to interpret owing to the lack of appropriate controls, incomplete pre-entry and follow-up pulmonary function test data, a small study population, and a bias associated with survivorship effect (pulmonary function data of patients who died were not included in the analysis, and this could have biased the results). furthermore, the observed steroid-and immunosuppressive-sparing effects of pirfenidone may have simply reflected lack of efficacy of conventional therapy rather than a true effect of pirfenidone. in a second open-label trial, japanese investigators evaluated oral pirfenidone in eight patients with ipf and two with diffuse lung disease associated with systemic sclerosis; after yr of therapy, there was no change in chest radiographic scores and arterial oxygen tension; the drug was well tolerated ( ). early treatment with pirfenidone appears to slow the progression of pulmonary fibrosis in patients with hermansky-pudlak syndrome ( ). a randomized-controlled trial focusing on early treatment is warranted to test the efficacy and safety of this agent in ipf. ifns play an integral role in the regulation of fibroblast proliferation and collagen synthesis, but the mechanism by which they exert their effect is not clearly understood. recent observations have shown that ifn-γ has antiproliferative, immunomodulatory, and antifibrotic effects ( ), and thus may play a crucial role in the pathogenesis of ipf. ifn-γ decreases collagen content in the bleomycin model of lung fibrosis by inhibiting tgf-β transcription and subsequent procollagen mrna production ( ). in addition, ifn-γ inhibits fibroblast proliferation in cultures derived from normal and fibrotic human lung, making an argument that ifn-γ may have therapeutic applications ( ). lower levels of ifn-γ have been found in patients with ipf compared with patients with less fibrotic diseases such as pulmonary sarcoidosis ( ). kuroki and associates ( ) measured levels of type iii collagen in patients with progressive pulmonary fibrosis and found an inverse correlation with ifn-γ levels, particularly in patients with ipf. these studies suggest that patients with ipf may have a defect in ifn-γ production or function, which predisposes them to develop fibrosis following injury. however, the potential for developing fibrosis is not likely to be dependent on one factor; rather it is likely the result of a complex interplay of fibrotic mediators, differential gene expression, and feedback mechanisms. a study by shaw and colleagues ( ) showed that alveolar macrophages from patients with interstitial lung disease had increased production of platelet-derived growth factor, which is a potent mitogen for fibroblasts. this increase in platelet-derived growth factor was upregulated following treatment with ifn-γ, suggesting that ifn-γ may act to potentiate fibrosis in certain cellular environments. clearly, there is a complex regulatory mechanism in place with regard to whether fibrosis occurs or not, and conflicting in vitro studies must be interpreted with caution. a randomized, prospectively controlled trial was conducted in patients with ipf comparing ifn-γ b and low-dose prednisolone with prednisolone alone for mo ( ) . the results were remarkable in that patients with progressive pulmonary fibrosis treated with ifn-γ b plus lowdose prednisolone demonstrated improvement in pulmonary function, whereas those who received prednisolone alone experienced further decline in pulmo-nary function. the authors showed that all patients treated had almost undetectable levels of ifn-γ mrna, and increased levels of both tgf-β and connective tissue growth factor mrna in lung tissue. furthermore, after treatment with ifn-γ b, transcription of tgf-β and connective tissue growth factor were both significantly decreased. several concerns have been raised regarding the findings reported by ziesche and co-workers ( ), particularly the unexpectedly good results with ifn-γ b. to address some of the issues raised, an outside panel of experts reanalyzed the study data by reviewing each patient's lung function studies, ct scans, and slbs to assess the clinical course and diagnosis of ipf according to the international consensus statement ( , ) . fifteen of patients had either definite (n = ) or probable (n = ) ipf. the panel reanalyzed treatment response using published criteria and eliminated the patients who definitely did not have ipf. patients treated with ifn-γ b plus low-dose prednisolone demonstrated either stability or improvement in pulmonary function and gas exchange after yr of treatment, whereas treatment with prednisolone alone was associated with no improvement in all patients ( ) . the observed benefit of ifn-γ b on lung function has not been reproduced in subsequent studies. in one retrospective uncontrolled observation of patients with ipf treated with ifn-γ b, only one patient experienced objective improvement, discontinued therapy (owing to lack of perceived benefit), and died after mo of therapy ( ). in a separate study of five patients with ipf treated with ifn-γ b, only one patient improved, two discontinued treatment owing to adverse effects and decline in lung function, and one died after mo of therapy ( ). in a recent prospective, randomized, placebo-controlled, double-blind, multicenter phase iii clinical trial of subcutaneous ifn-γ b ( μg thrice weekly) in patients with mild to moderate idiopathic pulmonary fibrosis (fvc > % and dl co > %), a trend toward lower mortality was seen in ifn-γ b-treated patients compared with placebo-treated patients. however, there were no significant differences in lung function or gas exchange between ifn-γ -treated and placebo-treated patients after wk of therapy ( ). a prospective controlled multinational trial is planned to verify the possible survival benefit observed with ifn-γ b therapy in ipf. ifn-β is used for the treatment of chronic hepatitis c and multiple sclerosis. in vitro ifn-β a has been shown to reduce fibroblast proliferation ( ), inhibit collagen production by fibroblasts ( ), increase collagenase mrna ( ), decrease pro-collagen mrna ( ), and increase collagenase activity ( ). a multicenter randomized, double-blind clinical trial examining the efficacy of ifnβ- a was recently completed. patients were randomized into four groups: placebo or ifnβ- a at , , or μg intramuscularly twice per week for a minimum of mo and up to . yr. preliminary results suggest that ifnβ- a lacks significant efficacy ( ). with a dismal response to existing therapy and its accompanied toxicity, the search for additional therapies has intensified in the past decade. the following is an overview of other therapeutic approaches, most of which are undergoing investigation and have not been adequately studied in humans. the prior discussion has centered on fibroblast proliferation and collagen deposition as two areas of therapeutic intervention. it is becoming more apparent that the fibrotic process has multiple pathogenetic mechanisms. one of the fundamental hypotheses of pulmonary fibrosis involves an imbalanced response to injury, in which the capacity of the alveolar epithelium to repair itself is compromised, ultimately leading to fibrosis. some investigators propose that the alveolar epithelium itself has antifibrotic properties, and that chronic loss of alveolar epithelium leads to an environment conducive to the development of fibrosis ( ). support for this notion exists in the fact that induction of apoptosis of alveolar epithelium has been shown to occur following administration of bleomycin ( ). therapies that either inhibit epithelial injury or enhance repair may limit the fibrotic response. in this regard, captopril, an angiotensin-converting enzyme inhibitor widely used in clinical practice, may have a role in the treatment of ipf. in vitro, captopril inhibits fibroblast proliferation, and in models of bleomycin-induced pulmonary fibrosis, it has been shown to reduce alveolar epithelial cell apoptosis and fibroproliferation. in addition, captopril abrogates fas-induced apoptosis in human alveolar epithelial cells ( , ) . there is currently an ongoing clinical trial at the national institute of respiratory diseases in mexico testing the efficacy of captopril in patients with ipf ( ). another agent that may protect the alveolar epithelium is keratinocyte growth factor (kgf). this class of growth factor stimulates type ii cell proliferation with no direct effects on fibroblasts ( ). keratinocyte growth factor increases surfactant protein gene expression and sodium/potassium adenosine triphosphatase, factors that may protect the alveolar epithelium ( ). in vivo, kgf has been shown to protect animals from injury and subsequent development of fibrosis caused by a variety of insults ( ). there is evidence that an exaggerated oxidant stress may play a role in the pathogenesis of pulmonary fibrosis by injuring the alveolar epithelial cells. this oxidant burden is thought to be a consequence of both increased levels of reactive oxygen species and a defective antioxidant response. a major protector of oxidant-induced injury of the alveolar epithelium is glutathione, which has been shown to be deficient in the balf of patients with ipf ( ). moreover, in vitro studies have shown that n-acetylcysteine (nac), a precursor for glutathione synthesis, may augment the antioxidant defense system and protect the alveolar epithelium from free radical-induced injury ( ). in vivo, hagiwara and associates ( ) reported a significant inhibition of bleomycininduced lung fibrosis in mice following aerosolized nac during the early inflammatory phase of injury. whether this effect was secondary to nac inhibition of cellular inflammation, or its role as a scavenger of reactive oxygen species, is not clear. german investigators evaluated oral nac as a strategy to augment lung glutathione levels in patients with biopsy-proven ipf. following therapy with nac, glutathione levels in balf were significantly increased compared with pretreatment levels ( ). in a separate study, behr and colleagues ( ) prospectively studied patients with ipf and assessed the redox balance of the lung and changes in lung function following high-dose nac therapy for wk. they reported an increase in the total and reduced form of glutathione concentration in the balf, and significant improvement in pulmonary function. the authors suggest that nac may be considered as an adjunct in the treatment of ipf. currently, there is a clinical trial in europe to evaluate the potential benefits of nac in ipf. as mechanisms of fibrosis at the cellular and molecular level become elucidated, their application to the development of novel therapeutic strategies appears promising. given the temporal heterogeneity of the uip lesion, early histopathological abnormalities may be present even in patients with advanced ipf. if early cytokine release is relevant to the initiation of this pathogenic response, then the targeting of early cytokines such as tnf-α should be considered. tnf-α appears to be upregulated soon after bleomycin-induced injury and has been implicated in a variety of inflammatory processes ( ). sime and colleagues ( ) showed that transient overexpression of tnf-α in rat lung led to fibrosis associated with concomitant tgf-β expression and proliferation of myofibroblasts ( ). furthermore, upregulation of tnf-α expression has been shown to occur in inbred murine strains that are sensitive to bleomycin-induced lung fibrosis, with similar expression being absent in resistant strains ( ). in addition, ortiz and colleagues ( ) showed that tnf receptor-deficient mice did not develop pulmonary fibrosis following exposure to bleomycin despite increased tnf expression. studies of human lung biopsy specimens of patients with ipf have shown an upregulation of tnf-α mrna and protein ( ). these observations along with other studies in animal models demonstrating abrogation of pulmonary fibrosis following treatment with soluble tnf receptors suggest that tnf-α may play an important role in the pathogenesis of pulmonary fibrosis ( ). several agents that can block tnf-α are now available for human use ( ). there is currently an ongoing clinical trial evaluating the safety and efficacy of etanercept, a tnf-α receptor antagonist, in patients with ipf. the expression of tnf-α is inhibited by certain cytokines such as il- , which is produced by a variety of cells including t-helper (th) cells, monocytes, and alveolar macrophages ( , ) . it is conceivable that il- may be useful in blunting the action of increased tnf-α observed following bleomycin-induced lung injury, therefore possibly inhibiting progression to fibrosis. arai and colleagues ( ) investigated the possible inhibitory effects of il- by introducing the il- gene into mice exposed to bleomycin and found that bleomycin-induced pulmonary fibrosis was suppressed. these results suggest that treatment with il- during the early inflammatory phases of lung injury may be promising and requires further investigation. concerns regarding the role of this agent in treating pulmonary fibrosis exist in that il- is a type- th (th ) cytokine that could suppress ifn-γ expression and promote fibrogenesis ( ). a clinical trial to study the effect of this cytokine is now underway in the united states. the realization that th cell subsets could be categorized on the basis of cytokine profiles has helped clarify our understanding of chronic cell-mediated immune responses. the type- (th ) cytokines include ifn-γ, il- , il- , il- , and th cytokines include il- , il- , il- , and il- . analysis of subset populations of th cells within the interstitium of patients with ipf reveal a predominantly th -type pattern of cytokine production, suggesting that alterations in t-cell subpopulations of th and th cells and their associated pattern of cytokine production may contribute to progression of ipf ( ) . supporting evidence comes from studies demonstrating that ifn-γ (a th cytokine) has profound antifibrotic effects in ipf possibly because it shifts the balance away from a th -dependent profibrotic environment. thus, it seems reasonable to target therapy to correct the th imbalance by either favoring a th phenotype or abrogating the predominant th response (e.g., administration of il- to promote ifn-γ expression, or inhibition of il- , il- , and so on). tgf-β is a critical cytokine for the promotion of fibrosis. in bleomycininduced pulmonary fibrosis, passive immunization with neutralizing antibod-ies against tgf-β reduces collagen deposition ( ) . in addition, the overexpression of tgf-β results in a fibrogenic response resembling uip (i.e., abundant ff) ( ) . in patients with ipf, increased expression of tgf-β is localized to bronchiolar epithelial cells, epithelial cells of hc cysts, and hyperplastic type ii pneumocytes ( ) . it is possible that therapy with neutralizing antibodies against tgf-β , or utilization of a tgf-β inhibitor such as decorin, may become useful in the treatment of ipf ( ) . tgf-β signals through a receptor that activates transcription factors smad and smad promoting tgf-β gene transcription. interestingly, ifn-γ inhibits the activation of smad and induces the expression of smad , an antagonistic molecule that inhibits tgf-β expression. smad can be produced in the laboratory and may become a useful molecule in the treatment of ipf ( ) . monocyte chemoattractant protein (mcp)- is a member of the c-c subfamily of chemokines involved in monocyte/macrophage mediated inflammation ( , ) . in addition, mcp- has been shown to stimulate pulmonary fibroblasts, tgf-β synthesis, and collagen production ( ) . analysis of serum, balf, and lung biopsy specimens from patients with ipf reveal increased levels of this chemokine ( , , ) . furthermore, serum mcp- levels correlate with clinical course in patients with interstitial lung disease ( ) . further investigation into the clinical significance of mcp- and its contribution into the pathogenesis of ipf are necessary, and may provide the groundwork for novel therapies. another potential mediator of fibrosis produced in a variety of cells in the lung is the vasoactive peptide endothelin (et) - ( , ) . first thought to be primarily a vasoactive agent, et- has been shown to stimulate fibroblast proliferation, activate monocytes, induce collagen production, and regulate cytokine production ( ). mutsaers and colleagues ( ) revealed that et- levels are augmented following administration of bleomycin with increased localization of the agent in areas of fibrosis. with increases in et- synthesis following tnf-α and tgf-β stimulation, one may speculate that et- may play an important role in the cascade of events leading to pulmonary fibrosis ( , ) . additional support for its role in pulmonary fibrosis comes from studies in animals in which fibrosis was attenuated following treatment with bosentan, an et receptor antagonist ( ). et- has also been associated with pulmonary fibrosis in humans. in a study examining the expression of et- in patients with interstitial lung fibrosis, giaid and associates ( ) found a striking expression of et- in lung tissue that correlated with parameters of disease activity in patients with ipf. there is currently an ongoing clinical trial evaluating the safety and efficacy of bosentan in patients with ipf. some have hypothesized that inducing fibroblast apoptosis may curb progression of fibrosis. lovastatin is a pharmacological agent widely used in the treatment of hypercholesterolemia that inhibits -hydroxy- -methylglutarylcoenzyme a, therefore affecting many cellular functions essential for normal cell homeostasis including proliferation and cell survival. tan and associates showed that clinically achievable concentrations of lovastatin induced apoptosis of human lung fibroblasts in vitro, and in vivo reduced granulation tissue formation and induced fibroblast apoptosis in a guinea pig wound model of fibroproliferation ( ) . with its known safety profile and potential antifibrotic effect, lovastatin is an attractive candidate in the treatment of ipf. suramin is a sulfonated napthylurea that has been used to treat onchocerciasis, acquired immunodeficiency virus, and prostate cancer. in vitro, suramin antagonizes the effects of a number of growth factors that promote fibrogenesis such as tgf-β, insulin-like growth factor- , platelet-derived growth factor, epidermal-like growth factor, and fibroblast growth factor. in vivo, suramin has been shown to delay wound healing ( ). relaxin is a protein secreted by the gravid uterus responsible for remodeling of the interpubic ligament and cervix during the later phases of pregnancy. relaxin inhibits the tgf-β-mediated overexpression of extracellular matrix, stimulates the expression of collagenases by lung fibroblasts in vitro, and has been shown to block bleomycin-induced fibrosis in mice ( ). the eicosanoids are potential candidates for therapeutic intervention. the prostaglandin pge is a potent inhibitor of fibroblast proliferation and extracellular matrix deposition and may ameliorate the fibrotic process in ipf ( ). indomethacin, an inhibitor of cyclo-oxygenase, has been shown to decrease bleomycin-induced pulmonary fibrosis in an animal model but to our knowledge, it has not been evaluated in human ipf ( ). the profibrotic leukotriene b has been shown to be increased in balf and lung tissue of patients with ipf ( ). inhibition of leukotriene production may be an effective adjuvant therapy, and drugs are now available to block leukotriene synthesis. gene-specific antisense therapy against proteins known to be important in human lung fibroblast proliferation may become an effective approach in treating ipf patients. in vitro, chen and associates showed that gene-specific oligonucleotides (oligos) against c-ki-ras substantially inhibited the proliferation of human fibroblasts ( ). beractan is a natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins. in vitro, beractan pro-voked fibroblast apoptosis, induced collagenase- expression, and decreased type i collagen ( ). pulmonary fibrosis can be complicated by pulmonary hypertension limiting exercise tolerance and survival. german investigators performed a randomized-controlled, open-label trial in individuals with pulmonary hypertension secondary to pulmonary fibrosis. they compared oral sildenafil with inhaled nitric oxide and infused epoprostenol. a single dose of sildenafil reduced pulmonary vascular resistance by nearly one-third and increased the mean arterial blood oxygen tension by mmhg. the drug was well tolerated with no adverse effects on ventilation-perfusion matching ( ). a clinical trial evaluating sildenafil in patients with ipf and pulmonary hypertension will be conducted soon. in recent years, significant advances have been made in our understanding and management of ipf. however, in order to further our knowledge and make significant progress in the care of these patients, it is critical that we improve our understanding of the natural history and pathogenesis of ipf. in addition, we need to pursue novel imaging and diagnostic technologies to improve earlier diagnosis and we must also educate primary care physicians and pulmonologists to refer patients early to 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endothelin- in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist lovastatin induces fibroblast apoptosis in vitro and in vivo. a possible therapy for fibroproliferative disorders sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial key: cord- - sa ju authors: ko, jane p.; girvin, francis; moore, william; naidich, david p. title: approach to peribronchovascular disease on ct date: - - journal: semin ultrasound ct mr doi: . /j.sult. . . sha: doc_id: cord_uid: sa ju diseases that are predominantly peribronchovascular in distribution on computed tomography by definition involve the bronchi, adjacent vasculature, and associated lymphatics involving the central or axial lung interstitium. an understanding of diseases that can present with focal peribronchovascular findings is useful for establishing diagnoses and guiding patient management. this review will cover clinical and imaging features that may assist in differentiating amongst the various causes of primarily peribronchovascular disease. d iseases that are primarily peribronchovascular in distribution represent an identifiable pattern on computed tomography (ct) and include those entities that primarily localize either to the airways, vasculature and/or associated lymphatics within the central or axial interstitium. , to date, interstitial lung diseases have been approached through ct pattern recognition, for which algorithms have been proposed including those defined by diffuse nodular, reticular, or overall increased or diminished lung opacity, respectively. our discussion will concentrate upon peribronchovascular disease centered around and primarily affecting the axial interstitium. this involves diseases presenting as combinations of nodules, masses and/or focal ground-glass attenuation or air-space consolidation that have in common the resulting appearance of air-bronchograms. based on these characteristics, an algorithm is introduced that integrates characteristic ct findings and essential critical clinical features that provide a limited differential diagnosis. an understanding of the axial interstitium and its role in defining the ct appearance of peribronchovascular disease is the key to interpretation. the axial interstitium is comprised of a fine network of connective tissue that provides the lattice upon which the central airways, vasculature, and lymphatics course and extend from the hila throughout the lungs. although still of debate, recent publications have supported that the interstitium, rather than containing dense connective tissue only, also has spaces that are compressible and distensible and defined by the network of collagen fibers. through confocal microscopy, investigators have shown collagen bundles interspersed with spaces such as biliary submucosa. peribronchovascular diseases originate from the axial interstitium and bronchus-associated lymphoid tissue that surround the bronchi and extend into lung periphery. we will consider peribronchovascular abnormalities to be primarily within the inner two-thirds of the lung. the focus of this description will be on larger nodules and consolidations, rather than diffuse small nodules for which alternate diagnostic algorithms are available. cell neoplasms. this update reflects better understanding of the precursors of leukemia and lymphoma, which may undergo observation rather than treatment, and the underlying molecular causes. secondary involvement of the lung by lymphoma. secondary involvement occurs in both non-hodgkin and hodgkin lymphoma. less prevalent than non-hodgkin lymphoma, hodgkin disease patients have lung parenchymal involvement more than their counterparts with non-hodgkin lymphoma. , adenopathy in the mediastinum and hila is frequently present, such as in %- % of hodgkin lymphoma, while non-hodgkin lymphoma has %. a lymphangitic carcinomatosis pattern appears on ct as thickened interlobular septa around the secondary pulmonary nodule and centrilobular core regions, related to lymphoid tissue enlargement and lymphatic infiltration. nodularity is helpful for differentiating this from edema that occurs due to lymphatic obstruction in the hilar regions. lung masses and nodules can occur (fig. ) . the pleura can be affected, either by effusions or soft tissue. the degree of adenopathy in the mediastinum is a helpful feature for differentiating from primary pulmonary lymphoma. primary pulmonary lymphoma. primary pulmonary lymphoma is less common, comprising less than % of lymphoma diagnoses. primary pulmonary lymphoma comprises about %- % of extranodal lymphomas. primary pulmonary lymphoma represents a monoclonal proliferation of lymphoid tissue that arises from the lymph nodes around that bronchus and mucosa of the alveoli. other sites outside of the lung cannot be identified at the time of or within months of presentation. most commonly, pulmonary lymphoma derives from extranodal marginal zone lymphoma of mucosal associated lymphoid tissue (malt), reported in %- % of cases. , diffuse large b-cell lymphoma predominantly accounts for the remainder of primary pulmonary lymphoma. less common entities include lymphomatoid granulomatosis, primary pulmonary hodgkin's lymphoma, and plasmacytoma. other lymphoproliferative disorders affecting the lung and pleura also include nodular lymphoid hyperplasia and castleman's disease, which lack monoclonal proliferation, in addition to primary effusion lymphoma that affects pleural, pericardial, or peritoneal spaces in immunocompromised individuals such as with acquired immune deficiency syndrome (aids). malt lymphoma arises from tissues that typically lack malt tissue, yet develop malt lymphoma due to infections and inflammation, including autoimmune disease, such as in %. other organs affected by malt lymphoma are the gastrointestinal tract, thyroid gland, and salivary glands. the tumor is typically comprised of b-cells. marginal zone lymphomas other than malt include nodal marginal zone lymphoma and splenic marginal zone lymphoma. while helicobacter pylori is associated with developing malt lymphoma in the stomach, no conclusive organism has been identified for pulmonary malt lymphoma. pathology of malt lymphoma is that of small clonal lymphoid cells in the bronchiolar and alveolar epithelium with immunohistochemistry positive for cd and cd . approximately one-third of patients with malt lymphoma can be asymptomatic. patients have been described to have a mean age of - years, although ages can range from as young as years to a more elderly age such as years. , an association of malt lymphoma with autoimmune disease has been reported, with % of patients with pulmonary lymphoma having rheumatoid arthritis, sjogren's syndrome, or mixed connective disorder. possible mechanisms for developing lymphoma include antigenic stimulation and underlying genetic causes, such as translocations. diffuse large bcell lymphoma is diagnosed pathologically when large b cells in sheets are identified. individuals with diffuse large b-cell lymphoma are symptomatic with fever, weight loss, and pulmonary symptoms. imaging of primary pulmonary lymphoma has been described as mass-like consolidation in % and nodules in %, with air bronchograms reported in % (fig. ) . peribronchovascular thickening has been reported, , with peribronchovascular thickening identified in of patients in one investigation. attenuation of nodules can be ground glass. lesions are more commonly multiple, although can be solitary. , , halos of ground glass can occur around soft-tissue nodules. lymphomas of large cells are reported as more mass-like and with nodules lacking air bronchograms, compared to lymphomas of small cells. lymphadenopathy is not a major finding with malt lymphoma. king et al. describe % of their cohort of to have lymphadenopathy, of which with no more than nodes that were smaller than mm, while the others had less than mm nodes; another investigation by wislez et al. describe hilar nodes in two of patients. , cavitation and necrosis is seen in large diffuse b-cell lymphoma, and the tracheobronchial tree can be affected. pleural effusions are , the lactose dehydrogenase value, often considered to be elevated in lymphoma, can be normal in malt lymphoma. as mentioned, autoimmune disease is a predisposing factor. an association of aids with lymphoma is known, primarily diffuse large b-cell lymphoma. , diagnosis of primary pulmonary lymphoma is made by open surgical biopsy, and when multifocal disease is present, transthoracic needle core biopsy/ fine needle aspiration and transbronchial biopsy with ct navigation and cryobiopsy are potential methods to make diagnosis with increasing sensitivity. molecular testing of cells obtained from bronchoalveolar lavage fluid may aid in diagnosing malt lymphoma. lymphomatoid granulomatosis a rare entity, lymphomatoid granulomatosis is related to ebstein barr virus infection and comprised of large b cells. cells test positive for ebstein barr virus rna using epstein-barr encoding region in situ hybridization. histopathologically, the disease is centered around the vessels and characterized by a heterogeneous polymorphous group of lymphoreticular cells that exhibit necrosis and invasion of the vessels. , diagnosis by pathology of lymphomatoid granulomatosis can be challenging, and the criteria have evolved over time. therefore, cases considered lymphomatoid granulomatosis in the past may not satisfy current criteria and now are considered other lymphoproliferative disorders. clinically, patients can be immunocompromised, and their reported age ranges between and years, with a mild male predominance. , , the lungs are primarily involved in about % of cases. also, patients can have other organs involved, such as the brain in %, ear, nose and throat, skin and kidneys. , diagnosis is usually made by surgical lung biopsy, while bronchoscopic biopsy is not as diagnostic. sampling of other involved sites can provide a diagnosis, such as the skin. lymphomatoid granulomatosis appears on ct as peribronchovascular masses that spare the lung periphery and can have air bronchograms and cavitation (fig. ) . , , , in a series by chung et al., lesions size is - mm. also, ground-glass nodules can evolve to solid masses. groundglass opacity can occur around the nodules, creating a halo appearance, and a reversed-halo sign in which groundglass opacity centrally is surrounded by soft tissue is also a possible manifestation. lesions are hypermetabolic on fluorodeoxyglucose positron emission technology ct. small pleural effusions can occur. lymphocytic interstitial pneumonia and follicular bronchiolitis lymphocytic interstitial pneumonia (lip) and follicular bronchiolitis probably relate to a spectrum of disease, with overlap in features clinically and on histology, with a more bronchiolar association for follicular bronchiolitis, whereas lip has more diffuse infiltration of the interstitium. , follicular bronchiolitis is a polyclonal hyperplasia within the bronchus-associated nodal tissue. reactive germinal centers are present. idiopathic follicular bronchiolitis is rare, and secondary forms are associated with autoimmune diseases such as sjogren's syndrome, connective tissue disorders including rheumatoid arthritis, immunodeficiency that is either congenital or acquired, and interstitial lung disease. on ct imaging, poorly-defined centrilobular and subpleural nodules are more commonly seen around the bronchioles than bronchi. although frequently small, nodules can be large in size between and mm with ill-defined borders. , patchy ground-glass opacities and, less commonly, peribronchovascular consolidation can occur. , adenopathy is not a frequent feature. in lip, a benign polyclonal proliferation of lymphocytes and plasma cells in the pulmonary interstitium is seen. lip is also associated with patients who are immunocompromised, such as those with sjogren's and acquired-immunodeficiency syndrome, multicentric castleman's disease, and autoimmune diseases. lip on ct appears as small nodules and ground glass opacity. jokoh et al., in a series of patients, report ct findings comprising ill-defined centrilobular nodules in , ground glass opacity in , bronchovascular thickening in , subpleural nodules in , septal thickening in , cysts in ( - mm, mean . mm), and lymph node enlargement in . large nodules on the order of - cm and air-space consolidation are both described in % of their cohort, and enlarged lymph nodes seen in %. other less common entities reported are castleman's disease, also termed angiofollicular lymph node hyperplasia, which is associated with lip. the imaging manifestations on ct in the lung of castleman's disease may relate to concomitant lip. adenocarcinoma is now the most common subtype of lung carcinoma. the appearance of adenocarcinoma on ct ranges from pure ground-glass nodules to part-solid and solid nodules. lung cancer patients often have a smoking history; however, nonsmokers are affected by lung cancer, some of which have underlying molecular mutations and translocations. other risk factors for lung cancer include occupational and environmental exposures such as to asbestos and radon. patients with early stage lung cancer frequently present with a lesion that is incidentally detected on a chest radiograph or ct. often solitary, yet potentially multiple, lung cancer is considered in the differential diagnosis of peribronchovascular lesions (fig. ) . the presence of emphysema, bulla, and bronchial wall thickening may indicate an individual with a smoking history. subsolid nodules well demonstrate a peribronchovascular distribution, as internal air bronchograms can be seen. when adenopathy is present in the ipsilateral hilum and mediastinum in combination with a solitary lesion, lung cancer can be considered, as other peribronchovascular abnormalities are more typically multifocal. organizing pneumonia pathologically is characterized by fibromyxoid intra-alveolar plugs containing fibroblasts, myofibroblasts, and connective tissue matrix with foamy macrophages. , hyaline membranes, necrosis, vasculitis, eosinophilia or granulomatous response are lacking. a more recently described variant, acute fibrinous organizing pneumonia (afop) on histopathology has prominent fibrin deposition to a greater degree than with typical organizing pneumonia accompanied by with type ii pneumocyte hyperplasia. , afop has been described by beasley et al. and travis et al. in small cohorts of and , respectively. another form of organizing pneumonia termed granulomatous organizing pneumonia entails non-necrotizing granulomas that are poorly-formed and accompany organizing pneumonia. organizing pneumonia should be the major finding on histopathology if a diagnosis of organizing pneumonia is rendered as the primary disease. also, organizing pneumonia is often secondary to other disease processes and has been described in conjunction with infection, neoplasms, drug reaction, radiation therapy, and autoimmune disease. when no identifiable cause exists, organizing pneumonia is considered idiopathic and termed cryptogenic organizing pneumonia, which falls within the category of acute or subacute idiopathic interstitial pneumonias according to the american thoracic society multidisciplinary classification of interstitial pneumonias. the typical age group affected by organizing pneumonia is approximately - years, although the age of affected individuals can vary. , subacute cough, dyspnea, wheezing, and fatigue on the order of months or shorter are presenting features, with fever more common with afop. afop has been associated with a worse prognosis. organzing pneumonia is a common pattern on ct identified with immunotherapy for cancer. organizing pneumonia appears as consolidation and ground-glass opacities. a peribronchovascular and/ or subpleural distribution is reported in approximately %- % of patients with cryptogenic organizing pneumonia (fig. ) . , consolidation can be peripheral in %, as reported by chung et al. an atoll or reversed-halo sign can occur, seen as a nodule with central lower-attenuation ground-glass and peripheral soft-tissue opacity. in patients with organizing pneumonia, a reversed-halo sign was initially described in one-fifth of patients in a series. subsequently, a number of etiologies known to cause a reversed-halo sign and include infection such as zygomycosis, invasive apergillosis, tuberculosis, histoplasmosis, cryptococcosis, pneumocystis jirovecii pneumonia, paracoccidioidomycosis; infarct from pulmonary embolism; eosinophilic processes; post-lung ablation and stereotactic body radiation therapy changes; lung adenocarcinomas; granulomatosis with polyangiitis; lymphoproliferative disorders; and sarcoidosis. , pleural effusions are not frequent. , thus, integration with other clinical and imaging features is needed when seeing the reversed-halo sign. the relationship of cryptogenic organizing pneumonia to nonspecific interstitial pneumonitis (nsip) has been suggested by imaging investigations. lee et al. also evaluated the evolution of findings with complete resolution identified in %. a decrease was noted in % and no change was observed in patient ( %) in their cohort during the follow-up period. patients with unresolving parenchymal opacities have worse pulmonary function tests such as forced vital capacity and diffusion capacity; more diffuse consolidation; and longer treatment duration. , organizing pneumonia in some patients is shown to progress to fibrosis (progressive interstitial fibrosis) that resembles on histopathology nsip. imaging studies support the evolution of organizing pneumonia to persistent ct findings, with an appearance similar to fibrotic nsip. , in one investigation by chung et al., a nsip-like pattern is identified in % of patients with nonresolving organizing pneumonia. infection peribronchovascular consolidation and ground-glass opacities are seen in bacterial, viral, and fungal infections. [ ] [ ] [ ] [ ] parasitic infection such as schistosomiasis is another potential etiology. generally, infection derives from the large and small airways, affecting the adjacent alveoli. spread can occur to other areas of the lung. in terms of bacterial agents, a large number of organisms lead to bronchopneumonia, such as staphylococcus species and gram negative organisms that are either community or hospital-acquired. active tuberculosis also causes bronchopneumonia. viruses such as cytomegalovirus (cmv), adenovirus, herpes simplex virus, human metapneumovirus, human parainfluenza virus, respiratory syncytial virus, and influenza lead to pneumonia. , , clinical features of viral pneumonia include upper respiratory symptoms, fever, sore throat, and dyspnea and hypoxemia. patients who are immunocompromised such as due to steroids or organ and hematopoietic stem cell transplantation are highly susceptible to atypical viral infections. bone marrow transplant patients are vulnerable to cmv infections due to reactivation of cmv in previously infected patients, occurring most commonly in the early phase or less than days after transplantation ( %- %) but also in the late phase, reported in %. fungal infections can be opportunistic such as aspergillosis and mucormycosis, in addition to endemic in etiology including paracoccidiodomycosis, blastomycosis, coccidiodomycosis, and histoplasmosis. aspergillus infection affects immunocompromised patients, such as those on steroids, leukemia, and after bone marrow and organ transplantation, often in the form of angioinvasive aspergillosis (ang), although airway invasive aspergillus (aia) is another manifestation that is associated with peribronchial opacities. , in heart transplantation patients, the authors of one study report about % of invasive aspergillus infections to be related to aia, and patients have worse prognosis than counterparts with ang. mucormycosis also affects immunocompromised patients, with a higher incidence of rhinocerebral involvement than with invasive aspergillosis, and leads to peribronchial opacities on ct. paracoccidiodomycosis, also known as south american blastomycosis, is the most common endemic fungal infection in south america. funari et al. describe that % of their patients have peribronchovascular thickening and % ground-glass opacities with consolidations, cavitation, and nodules. on imaging, infection particularly with bacterial agents appears as a bronchopneumonia, with peribronchovascular consolidations and ground-glass opacity, given the dissemination via the airways (fig. ) . accompanying bronchiolitis is often present and seen on ct as small centrilobular tree-in-bud nodules that represent inflamed and infected small airways at the terminal respiratory bronchiole level. cavitation can occur particularly with bacterial and fungal infections. viral infections affect the lung interstitum and present on ct with centrilobular nodules, ground-glass opacity, consolidation, and bronchial wall thickening (fig. ) . commonly, viral infections are bilateral and diffuse with asymmetric distribution. some viruses are associated with pleural effusions. fungal infections are often multifocal, presenting with mass-like consolidations and large nodules, although can be solitary. in one study, aia is reported as having a higher number of patients with peribronchial distribution, while ang had more cavitary nodules. a halo of ground-glass opacity around a nodule is a sign of ang in the early phase. subsequent development of a crescent of air (air-crescent sign) occurs within the lesion often, once the immunity of the affected patient is restored and a white-cell response to the infection can occur. diagnosis of infection entails integration of clinical, laboratory, and imaging findings. a clinical suspicion of infection, typically indicated by fever, shortness of breath, and cough in an acute and subacute presentation, in conjunction with a peribronchovascular distribution raises suspicion for infection from bacterial, viral, and, particularly in immunocompromised patients or in an area where endemic fungal infections are prevalent, fungal etiologies. a more chronic clinical history raises question of mycobacteria and endemic fungal etiologies. when infection is suspected, noninvasive tests including sputum analysis for smear and culture can be performed in addition to other laboratory workup entailing a white blood count and differential. antigen urine testing for communityacquired pneumonia for streptococcus pneumoniae and legionella pneumophila are available; although, in conjunction with sputum analysis and two blood cultures, these tests are less than % sensitive. a number of rapid molecular testing options such as nucleic acid amplification tests and polymerase chain reaction (pcr) have been developed to improve the diagnosis of infection in patients who are critically ill. these new methods can be performed on nasal and nasopharyngeal swabs and sputum. agents such as staphylococcus aureus; streptococcus pneumoniae; a large number of viruses that include adenovirus, parainfluenza, respiratory syncytial virus, human metapneumovirus, coronavirus, rhinovirus; mycoplasma pneumoniae, and chlamydia pneumoniae can be assessed for using molecular testing. , the addition of molecular testing increases the diagnosis of pathogens causing severe community-acquired pneumonia to %- %. procalcitonin has been investigated as a method to detect and differentiate bacterial and mixed bacterial/viral infections from only viral infection, which does not have procalcitonin levels higher than . ng/ml. the combination of procalcitonin and viral pcr analysis can be used to identify patients with communityacquired pneumonia. however, caution is needed given procalcitonin levels can be negative for a few hours after bacterial invasion and be influenced by a number of factors, such as renal failure and dialysis. cmv infection is established when peripheral antigenemia for cmv is identified, or tissue that is sampled is positive for cmv. rapid nucleic acid amplification test techniques are also available for confirming active tuberculosis. galactomannan antigen assays from bronchoalveolar lavage and serum can be used to diagnose ang in the acute setting, with lower sensitivity when testing serum for chronic aspergillus infection. beta-d-glucan assays from serum can be used to diagnose a number of fungal infections including aspergillus, candida, and endemic fungi, although sensitivities vary and range between % and % depending on assay, population, and organism. , assays for immunoglobulin (ig) g that are specific for aspergillus are also used to aid in diagnosing infection. more invasive testing includes analysis of bronchoalveolar lavage samples for smear and culture and biopsy for verifying viral and fungal infections. lung parenchymal abnormalities can be caused by small and medium-vessel vasculitis and pulmonary hemorrhage. peribronchovascular abnormalities have been described in antineutrophil cytoplasmic antibody-associated vasculitides (anca) such as granulomatosis with polyangiitis (gpa), churg-strauss vasculitis, and microscopic polyangiitis (fig. ) . [ ] [ ] [ ] vasculitis can be due to: ( ) collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis, and sarcoid; ( ) a probable cause such as infection and drug reactions; ( ) pauci-immune pulmonary vasculitis; ( ) immune-complex small-vessel vasculitis such as goodpasture's syndrome (antiglomerular basement membrane disease), iga vasculitis, cryoglobulinemic vasculitis or hypocomplementemic urticarial vasculitis; and ( ) igg- related vasculitis. multisystem organ involvement is present often in vasculitis. idiopathic pulmonary hemosiderosis is a cause of pulmonary hemorrhage in the absence of vasculitis. gpa affects patients on the order of in , , primarily between and years of age, who can have upper and lower airway involvement and glomerulonephritis that are often acute. , limited gpa can occur, in which renal involvement is not present and mainly the upper airways are affected. upper airway abnormalities occur in %- % and include sinusitis, ear inflammation, and subglottic stenosis. patients may present with massive hemoptysis. on ct, multiple nodules and masses are present. although reported as predominantly subpleural in % of patients, nodules can occur in a peribronchovascular distribution in % (fig. ) . the halo sign is reported in the series by lee et al. in %. adenopathy is less common, on the order of %. tests for cytoplasmic anca are highly positive on the order of % and have a high positive predictive value for gpa. pleural effusions are reported in % and % and were small and bilateral. pleural effusions may relate to renal failure. eosinophilic granulomatosis with polyangiitis, also known as churg-strauss vasculitis, is characterized by asthma, sinus involvement, lung opacities, eosinophilia larger than figure human metapneumovirus pneumonia. -year-old man presented with wheezing and fever and was diagnosed by molecular testing. patchy ground-glass opacities in the right lower lobe are centered around the bronchovascular bundles, and mild clustered nodules are present. bilateral mild ground-glass opacities are present. . £ /l or % on white blood cell differential, mononeuropathy or polyneuropathy, skin rash, cardiac disease, and eosinophilic tissue with granulomatous inflammation. , three phases have been described, the first being asthma, followed by a second of peripheral and tissue eosinophilia, and the third a vasculitis phase. the eosinophilia of churg-strauss is higher than that of eosinophilic asthma, which is typically less than . £ /l. imaging studies report parenchymal consolidations and nodules. , in a study of ct histopathology correlation by kim et al., consolidation in churg-strauss patients correlates with eosinophils in the alveoli and alveolar walls. a peripheral distribution is more commonly identified. bronchial wall thickening and peribronchial thickening are identified in addition to peribronchial consolidation. in the study by kim et al., necrotizing granulomas and areas of necrotizing vasculitis on histopathology in churg-strauss are seen in the peribronchial intersititum. small centrilobular nodules also are present. interlobular septal thickening is reported to correlate with eosinophilia and fibrosis on pathology. , pleural effusions can occur. a newer diagnosis, igg -related lung disease can result in lung disease, although limited information currently exists pertaining to the imaging findings. igg -related lung disease entails lymphoplasmacytic infiltration with fibrosis. multiple other organs are involved such as the pancreas, salivary glands, kidneys, and aorta, followed by the lung. groundglass opacity with thickened bronchial walls/bronchovascular bundles are described (fig. ) . , , adenopathy can occur such as in % of patients in one study. microscopic polyangiitis, a small vessel vasculitis, presents with pulmonary hemorrhage. multiple organs are affected, including the kidneys, lung, and skin. also, hemorrhage that tracks along the hilar structures from the mediastinum and into the lung parenchyma along the peribronchovascular bundles can lead to peribronchial ground-glass opacity. eosinophilic lung disease can be idiopathic or secondary, such as from a drug reaction, parasites, and associated with vasculitis. idiopathic eosinophilic pneumonia can be categorized as simple, acute, or chronic. simple eosinophilic pneumonia is often transient and manifested by fleeting focal illdefined opacities and peripheral eosinophilia. acute eosinophilic pneumonia presents in an acute presentation with diffuse alveolar damage and diffuse ground-glass opacities that mimic acute respiratory distress syndrome on imaging. peripheral eosinophilia may be lacking although eosinophils identified on bronchoscopy. chronic eosinophilic pneumonia affects elderly patients, with greater preponderance for women. an association with asthma, a chronic clinical history of symptoms on the order of months, and peripheral eosinophilia are described. a predominantly peripheral consolidative process on ct, chronic eosinophilic pneumonia manifest as air-space nodular opacities. a peribronchial distribution is possible, such as in . % of patients, as reported by arakawa et al. (fig. ). pleural effusions are uncommon, on the order of %. sarcoidosis sarcoidosis, a granulomatous disease, can affect the lungs, appearing as a large number of small nodules in a perilymphatic distribution affecting the peribronchovascular and subpleural regions. consolidative opacities can result from confluent granulomas termed "alveolar sarcoid." the consolidative opacities, given the lymphatic involvement by the disease, are often peribronchovascular (fig. ) . individuals with sarcoid have bilateral, symmetric adenopathy in addition to calcified lymph nodes, which can be peripherally calcified. patients are often younger in age, on the order of - . skin involvement can be present. angiotension converting enzyme elevation occurs in approximately % of sarcoidosis although can be falsely positive. also elevated calcium levels can be identified. kaposi's sarcoma is a neoplasm that affects both humanimmunodeficiency virus (hiv) and non-hiv affected the ct imaging appearance represents the "alveolar" form of sarcoid, which are related to confluent interstitial granulomas. peripheral nodularity in the right upper lobe can be an indicator of an interstitial process that becomes coalescent. individuals. kaposi's sarcoma is categorized as classical, endemic or african, iatrogenic related to organ transplantation, and aids-associated or epidemic, or nonepidemic. the human herpes virus (hhv- ) causes kaposi's sarcoma and is termed the kaposi's sarcoma-associated herpesvirus. hhv- is also associated with multicentric castleman's disease and pleural effusion lymphoma. the prevalence of hhv- infection is very high in sub-saharan africa and the mediterranean region, affecting approximately % and %- %, respectively. the virus is believed to activate cellular oncogenes. skin lesions, disseminated or localized, are present regardless of the type of kaposi's sarcoma, and the oral cavity is affected also. visceral organ involvement, including the gastrointestinal tract and lungs, is particularly more aggressive in the endemic and aids-related forms, while the classic and nonepidemic form tends to be more indolent. the classic form presents in eastern european and south american older men, who have occasional visceral organ involvement and adenopathy. the endemic form occurs in younger patients, such as between and years and in children. the nonepidemic form has been more frequently described in younger men and limited to the skin. pathological diagnosis is made by the presence of spindle cells forming vascular spaces around a vessel and proliferation of spindle cells. staining for latency-associated nuclear antigen expressed in hhv- infected cells and pcr identification of the hhv- genome are also methods. thoracic involvement in kaposi's sarcoma has been primarily described in the aids-related kaposi's sarcoma. kaposi's sarcoma presents as peribronchovascular nodules, pleural effusion, lymphadenopathy, and interlobular septal thickening on chest radiography (fig. ). radiographic findings have been graded as isolated peribronchial cuffing (stage ); small nodules (stage ); and large nodules or areas of consolidation (stage ). nodules and less commonly masses are frequent, on the order of % being bronchovascular and perihilar in distribution. pleural effusions are described on ct. [ ] [ ] [ ] [ ] naidich et al. report bilateral pleural effusions in % and unilateral effusions in % of patients on chest radiograph, and on ct % had bilateral pleural effusions, with none unilateral. the lung parenchymal lesions are described as flame-shaped on ct. lymphadenopathy is described in approximately %- % on ct and tends not to be bulky. , imaging with positron emission technology ct reports high-metabolic activity to lesions in the lung and adenopathy, although hiv lymphadenopathy can have abnormal fluorodeoxyglucose uptake. lytic bone lesions, skin lesions, and chest wall involvement also can be identified on ct. cardiac involvement also occurs more with immunocompromised aids-related cases. , immune reconstitution has been described with kaposi's sarcoma, when aids patients who are newly placed on antiretroviral therapy have a flare in kaposi's sarcoma findings. pulmonary lymphangiomatosis is a rare entity, described to have smooth peribronchovascular thickening, nodules, ground glass, interlobular septal thickening, and consolidation can occur. the disease affects mainly young adult and pediatric populations. on pathology, lymphatic proliferation is greater than normal, occurring in areas where lymphatics are typically seen. lymphangectasia, on the other hand, pathologically entails dilated lymphatic spaces due to lymphatic obstruction. the integration of imaging and clinical findings is essential for organizing the differential diagnosis and patient diagnosis. when peribronchovascular findings are identified on ct, specific clinical information can aid in narrowing the differential diagnosis (table ) . a majority of the diseases tend to occur in patients who are younger than - years of age, although patients who are older can be affected, such as those with infection, organizing pneumonia, eosinophilic pneumonia, and lymphoma. infection is a major consideration for acute presentations of patients with peribronchovascular-predominant findings (fig. ) , and in this scenario, workup for infection would ensue with microbiology, hematology, and assays to identify a causative agent. in identifying a peribronchovascular pattern of consolidative and mass-like opacities is useful for developing a differential diagnosis. the peribronchovascular pattern derives from the lymphatics, airways, and pulmonary arteries in this region. diseases affecting the peribronchovascular interstitium: ct findings and pathologic correlation pulmonary parenchymal involvement of low-grade lymphoproliferative disorders high-resolution ct of the lung structure and distribution of an unrecognized interstitium in human tissues clinical impact of the update to the who lymphoma classification the revision of the world health organization classification of lymphoid neoplasms the radiological spectrum of pulmonary lymphoproliferative disease radiographic distribution of intrathoracic disease in previously untreated patients with hodgkin's disease and non-hodgkin's 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lymphomatoid granulomatosis: ct and fdg-pet findings case : lymphomatoid granulomatosis fatal lymphomatoid granulomatosis with primary cns-involvement in an immunocompetent -year-old woman lymphomatoid granulomatosis: two different phenotypes of computed tomography findings reversed halo sign on computed tomography: state-of-the-art review pet/ct characterization and monitoring of disease activity in lymphomatoid granulomatosis follicular bronchiolitis: thinsection ct and histologic findings lymphocytic interstitial pneumonia and other lymphoproliferative disorders in the lung granulomatous-lymphocytic interstitial lung disease as the first manifestation of common variable immunodeficiency primary pulmonary lymphoid lesions: radiologic and pathologic findings lymphocytic interstitial pneumonia: thin-section ct findings in patients international association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma yatabe y: egfr mutations and the terminal respiratory unit pathology-radiology correlation of common and uncommon computed tomographic patterns of organizing pneumonia a comparison of the pathological, clinical and radiographical, features of cryptogenic organising pneumonia, acute fibrinous and organising pneumonia and granulomatous organising pneumonia statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage cryptogenic organizing pneumonia: serial high-resolution ct findings in patients pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors cryptogenic organizing pneumonia: ct findings in patients serial chest ct in cryptogenic organizing pneumonia: evolutional changes and prognostic determinants reversed halo 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transplantation pseudomembranous aspergillus bronchitis in a double-lung transplanted patient: unusual radiographic and ct features invasive pulmonary aspergillosis in heart transplant recipients: two radiologic patterns with a different prognosis comparison of computed tomographic findings in pulmonary mucormycosis and invasive pulmonary aspergillosis chronic pulmonary paracoccidioidomycosis (south american blastomycosis): high-resolution ct findings in patients radiographic and ct features of viral pneumonia invasive pulmonary aspergillosis in acute leukemia: characteristic findings on ct, the ct halo sign, and the role of ct in early diagnosis role of procalcitonin in the management of infected patients in the intensive care unit a guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: update by the infectious diseases society of america and the diagnostic accuracy of xpert test in tuberculosis detection: a systematic review and metaanalysis recent 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sarcoma-associated herpesvirus infection cellular and viral oncogenes: the key to unlocking unknowns of kaposi's sarcoma-associated herpesvirus pathogenesis intrathoracic kaposi's sarcoma. ct findings ct appearances of intrathoracic kaposi's sarcoma in patients with aids kaposi's sarcoma. ct-radiographic correlation kaposi's sarcoma: imaging overview thoracic kaposi sarcoma in aids: ct findings demonstrations of aids-associated malignancies and infections at fdg pet-ct primary kaposi's sarcoma of the heart in non-immunodeficient patient: case report and literature review cardiac lesions in acquired immune deficiency syndrome (aids) imaging features of pulmonary kaposi sarcoma-associated immune reconstitution syndrome diffuse pulmonary lymphangiomatosis: ct findings key: cord- -s jp ej authors: menon, nithya; reed, mary jane title: respiratory diseases of pregnancy date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: s jp ej respiratory complaints in the gravid patient are often difficult to identify as a disease state, expected physiologic changes of pregnancy or both. understanding the underlying pulmonary physiologic changes that come with pregnancy as well as those conditions which are unique to the pregnant patient will help arrive at the correct diagnosis and management. recognizing that the gravid patient has other physiologic changes that contribute to decreased respiratory reserve, increased risk of aspiration, infection, and difficult airway can help in managing these patients acutely. consumption by almost %. however, the body compensates for this by increasing both respiratory rate and tidal volume, thereby increasing minute ventilation [ , ] . these changes make the partial pressure of oxygen slightly higher than normal on a blood gas, and would range from to mmhg. the partial pressure of carbon dioxide would be lower than normal for a nonpregnant patient and ranges from to mmhg [ ] . low pulmonary reserves that arise from reductions in functional residual capacity and increased oxygen consumption make pregnant women develop hypoxemia more rapidly [ ] . pulmonary edema can be broadly classified as cardiogenic or non-cardiogenic. cardiac output increases very early on and is the highest in the post-partum period. plasma volume expands due to sodium and water retention, thereby increasing preload, but afterload reduces due to vasodilation systemically [ ] . the most common causes of non-cardiogenic acute pulmonary edema in pregnancy are the use of tocolytic agents, fluid overload, preeclampsia, sepsis, trauma or following aspiration of gastric contents [ , ] . pre-eclampsia associated pulmonary edema -pulmonary edema is a frequently encountered complication in patients with pre-eclampsia with most cases occurring after delivery. initial management involves lowering the blood pressure urgently especially in patients who have severe elevations of blood pressure that persists longer than min. once pulmonary edema occurs, parenteral therapy is more effective, and nitroglycerine is the agent of choice as recommended by the european society of cardiology [ ] . diuretics should be instituted to promote pre load reduction recognizing that the preeclamptic patient may have complex fluid balance needs due to low oncotic pressure. when necessary, noninvasive ventilation is recommended, in patients with increased work of breathing or hypoxemia as it is known to improve these parameters and can decrease the need for invasive mechanical ventilation by [ ] . tocolytic induced pulmonary edema is relatively uncommon [ ] . tocolytics such as ritodrine and terbutaline are beta agonists that increase heart rate and stroke volume but cause peripheral vasodilation and decrease blood pressure. management involves firstly stopping the tocolytic therapy and treating pulmonary edema with diuretics. these patients tend to recover well and reported mortality is low [ ] . peripartum cardiomyopathy -these patients usually have no known prior heart disease and present with congestive heart failure typically in the last month of pregnancy and up to months post-partum. unfortunately, the mortality can be as high as - % [ , ] . ovarian hyperstimulation syndrome (ohss) is another uncommon cause of pulmonary edema with a prevalence of - %. mechanisms are not entirely clear but involve increased vascular permeability. treatment is supportive care [ ] . aspiration -certain factors such as an incompetent lower esophageal sphincter coupled with a decrease in stomach motility can increase the risk for aspiration. one must have a high index of suspicion as not all events are witnessed. treatment is usually supportive [ ] . pulmonary edema asthma is seen very frequently with prevalence in pregnancy ranging from to % [ ] . certain factors easily obtained by a good history can help you understand who is at increased risk of complications from asthma, these being history of exacerbations, intubations, and recent steroid use. most exacerbations are characterized by cough, wheezing, and dyspnea. the national asthma education and prevention (naep) group recommends obtaining a baseline peak expiratory flow in order to guide further management. if the patient is approaching less than half of what their baseline is, then treatment with supplemental oxygen to correct hypoxemia and bronchodilators such as a beta-agonist and anticholinergic agents are to be given. a target oxygen saturation above % with consideration for invasive mechanical ventilation in those who are in impending respiratory failure. a partial pressure of carbon dioxide within the normal range of - on an arterial blood gas can be a early sign of imment respiratory failure in the gravid patient. intravenous steroids also have to be instituted. care should be taken during mechanical ventilation to avoid a short expiratory time that can cause auto peep [ ] . intravenous magnesium sulfate may be beneficial in acute severe asthma in addition to bronchodilators especially in patients with coexistent hypertension or preterm uterine contractions [ , ] . large airway obstruction mostly arises due to a difficult intubation and the incidence is anywhere between . and . %. intubation may be difficult during pregnancy and the peripartum period due to upper airway edema, pharyngeal mucosal friability and diminished airway caliber, especially late in pregnancy. the gravid patient especially third trimester, should be considered a difficult airway patient with high risk of aspiration and decreased oxygen reserve. other causes of airway obstruction such as tumors, hematoma and laryngeal edema are rarely encountered [ , ] . increased upper airway resistance may occur in pregnancy as a result of pharyngeal edema and increased pharyngeal tone could potentially worsen osa in pregnant women. incidence of osa is estimated to be between . % in the first trimester and . % in the third trimester [ ] . maternal risks include increased morbidity from conditions that have been associated with osa and underlying obesity such as preeclampsia, eclampsia, gestational hypertension, cardiomyopathy and gestational diabetes [ ] . these patients are at higher risk for hypoxemia during labor, and continuous monitoring is necessary. cpap therapy remains the first line of therapy and women are instructed to bring in their device when they come during labor. varicella and influenza are the most common pathogens associated with viral pneumonia in pregnancy [ ] . estimated mortality rate amongst the h n pandemic ranged from . to . % [ ] . the risk of hospitalization is highest in the third trimester. mortality related to influenza is mostly due to secondary bacterial pneumonia, although the h n pandemic differed in this aspect with more patients dying primarily from the effects of h n virus. the most commonly implicated pathogens are s. pneumonia and staphylococcus aureus followed by h. influenza and it is reasonable to start empiric antibacterial agents at the time of presentation [ ] . streptococcus pneumonia followed by hemophilus influenza are the most commonly encountered agents [ ] . some of the risk factors for pneumonia in pregnancy include anemia, asthma, antepartum corticosteroids given to enhance fetal lung maturity, and the use of tocolytic agents to induce labor [ ] . oxygen supplementation is necessary with a goal of keeping the partial pressure of oxygen above mmhg. the penicillins, cephalosporins, and macrolides are considered safe to use in pregnancy [ ] . a history of contact with farm animals should raise suspicion for q fever and therapy with macrolides is preferred [ ] . central causes of respiratory failure such as drugs, tumors, hemorrhage, and infection should be treated for in a similar manner as the general population with treatment of the underlying cause and mechanical ventilation if necessary. conditions such as kyphoscoliosis may precipitate hypercapnic respiratory failure in pregnancy [ ] . these patients should be closely monitored with arterial blood gasses, vital capacity and maximal and minimal inspiratory pressures [ ] . magnesium sulfate which is used as a tocolytic and to prevent seizures in pre-eclampsia can cause respiratory depression at levels greater than , and respiratory arrest at levels of - . careful monitoring of magnesium sulfate dosing and infusion rates and monitoring maternal deep tendon reflexes and urine output with serum magnesium levels with precise infusion rates is necessary. pneumothorax may occur because of hyperemesis, pushing efforts in labor, underlying lung disease, and without obvious precipitating cause [ ] . hamman's syndrome of intrapartum subcutaneous emphysema, pneumomediastinum, or pneumothorax results from the forceful "pushing" efforts during labor and about cases have been reported worldwide before [ ] . the clinical presentation is usually chest pain with breathlessness and presence of crackles or 'hamman's sign 'in the left lateral decubitus position in systole. most cases resolve spontaneously, but emergent chest tube placement might be required in some cases. embolic events rank among the major causes of maternal mortality in modern obstetrics. risk factors include venous stasis, advanced age, sepsis, obesity and cesarean section. hypoxemia is common. with massive embolism, circulatory failure is more prominent. diagnosis is made by compression ultrasonography and if negative they will need perfusion study. if the diagnosis of pe is strongly considered, then treatment with unfractionated heparin should be started immediately unless a high risk or contraindication is present for the use of any anticoagulants. unfractionated heparin and low-molecular weight heparin are safe to use during pregnancy because they do not cross the placenta. tpa has also been used during pregnancy although there are no controlled trials [ , ] . cystic fibrosis is the most common congenital pulmonary disease encountered during pregnancy. it is a restrictive and obstructive disorder, with a predisposition to infection. bronchodilators and chest physiotherapy should be recommended, and chest infections should be treated aggressively [ ] . the critically ill pregnant patient requires a multidisciplinary approach and early inclusion of obstetrical expertise is paramount in managing these patients especially in the third trimester. pregnant women have hypocapnia due to hyperventilation at baseline. thus, the arterial carbon dioxide tension (paco ) tends to be lower in a pregnant woman, and a normal paco is a sign of impending respiratory failure. intubation may be difficult during pregnancy and the peripartum period due to upper airway edema and diminished airway caliber, especially late in pregnancy. the goal is to rest the fatigued respiratory muscles while providing suitable gas exchange. respiratory muscle rest involves institution of invasive or noninvasive mechanical support, and the ventilator must overcome pressures related to airway resistance and elastic properties of the lung to allow adequate ventilation and gas exchange. a trial of niv can be instituted early on in patients with pulmonary edema. favorable outcomes have been reported in case reports and series [ ] . low tidal ventilation strategy is recommended [ ] . peep improves oxygenation and should be used to provide a pao > mmhg while administering the least fio . the target paco is - mmhg since this is the normal level during pregnancy. marked respiratory alkalosis should be avoided because it may decrease uterine blood flow. maternal permissive hypercapnia may also be deleterious to the fetus because of resultant fetal respiratory acidosis although this mode of ventilation has been used safely in pregnant women in small trials. propofol remains the first choice for sedation in these patients and if paralytics are clinically of cisatracurium would be the preferred agent [ ] . this technique has been used a rescue therapy for refractory ards with reported maternal and fetal survival rates between % and %, respectively [ , ] . most of the published literature is from the h n influenza pandemic. early institution with careful patient selection and judicial management of anticoagulation might improve successful outcomes [ , ] . use of prone positioning in the third trimester has not been widely studied however case reports have appeared in the literature with apparently acceptable results. as in other severe ards patients, proning requires careful attention to inadvertent decannulation of lines or extubation. the pressure points especially eyes need to be protected and no hyperextension of joints. there needs to be adequate room for the abdomen to expand passively. this can be achieved by the use of appropriately sized bolsters at chest and hip level to help elevate the patient above the mattress. this also allows for anterior displacement of uterus off of the inferior vena cava which is necessary for adequate venous return after weeks gestation. close monitoring of mother and fetus including continuous fetal cardiotocography should be in place if fetus of viable age [ , ] . delivery of the fetus can improve the maternal condition in several obstetrical disease states. in ards, it appears perhaps to improve oxygenation and management of the mother but does not definitively improve maternal survival [ , ] . respiratory physiology in pregnancy normal cardiopulmonary physiology during pregnancy maternal blood-gases, pao --pao ), physiological shunt and vd/vt in normal pregnancy arterial oxygen tension during apnoea in parturient women studies of colloid osmotic pressure in pregnancy-induced hypertension acute lung injury and acute respiratory distress syndrome in pregnancy clinical characteristics and outcomes of obstetric patients requiring icu admission cardiovascular implications in preeclampsia: an overview acute pulmonary oedema in pregnant women ards associated with the use of sympathomimetics and glucocorticoids for the treatment of premature labor pulmonary edema in obstetric patients is rapidly resolved except in the presence of infection or of nitroglycerin tocolysis after open fetal surgery peripartum cardiomyopathy: national heart, lung and blood institute and office of rare diseases (national institutes of health) workshop recommendations and review acute pulmonary edema in pregnancy diagnosis, prevention and management of ovarian hyperstimulation syndrome pulmonary aspiration-a life-threatening complication in obstetrics asthma during pregnancy: mechanisms and treatment implications national asthma education program working group on asthma and pregnancy. national institutes of health, national heart, lung, and blood institute difficult and failed intubation: incident rates and maternal, obstetrical, and anesthetic predictors difficult intubation in pregnancy risk factors for sleep-disordered breathing in pregnancy maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and meta-analysis pneumonia in pregnancy pandemic influenza a(h n ) virus illness among pregnant women in the united states pulmonary infections complicating asian influenza pneumonia and pregnancy antepartum pneumonia in pregnancy pulmonary disease in pregnancy glob noninvasive ventilation for chest wall and neuromuscular disorders spontaneous subcutaneous emphysema and pneumomediastinum during second stage of labour pleural disease in pregnancy melton rd lj. trends in the incidence of venous thromboembolism during pregnancy or postpartum: a -year population-based study epidemiology of pregnancy-associated venous thromboembolism: a population-based study in canada pregnancy and the lungs successful use of noninvasive ventilation in pregnancy implications for the pregnant patient mechanical ventilation during pregnancy: sedation, analgesia, and paralysis systemic inflammatory response syndrome, organ failure, and outcome in critically ill obstetric patients treated in an icu extracorporeal membrane oxygenation for severe ards in pregnant and postpartum women during the h n pandemic modern use of extracorporeal life support in pregnancy and postpartum prone positioning for ards following blunt chest trauma in late pregnancy how safe is the prone position in acute respiratory distress syndrome at late pregnancy does delivery improve maternal condition in the respiratory-compromised gravida? key: cord- -g qaoub authors: lohan, rahul title: imaging of icu patients date: - - journal: thoracic imaging doi: . / - - - - _ sha: doc_id: cord_uid: g qaoub imaging in intensive care unit (icu) is integral to patient management. the portable chest radiograph is the most commonly requested imaging examination in icu, and, despite its limitations, it significantly contributes to the decision-making process. multidetector ct (mdct) is reserved for relatively complex and challenging clinical scenarios. bedside ultrasound is emerging as a promising imaging modality as it does not subject the patients to risks and resources involved in the transportation of these patients to the ct facility. ultrasound is an effective modality to triage patients and is being increasingly incorporated into the emergency and intensive care management algorithms. imaging in intensive care unit (icu) is integral to patient management. the portable chest radiograph is the most commonly requested imaging examination in icu, and, despite its limitations, it significantly contributes to the decisionmaking process. multidetector ct (mdct) is reserved for relatively complex and challenging clinical scenarios. bedside ultrasound is emerging as a promising imaging modality as it does not subject the patients to risks and resources involved in the transportation of these patients to the ct facility. ultrasound is an effective modality to triage patients and is being increasingly incorporated into the emergency and intensive care management algorithms. the commonly encountered disease states in icu setting are pulmonary parenchymal diseases, pulmonary thromboembolism, barotrauma, and pleural fluid. besides the evaluation of these conditions, imaging is routinely used for the assessment of various catheters and tubes commonly used in icus. the common pulmonary parenchymal disease processes in icu patients include hydrostatic pulmonary edema, acute respiratory distress syndrome (ards), atelectasis, pneumonia, aspiration, and pulmonary hemorrhage. pulmonary edema is an abnormal accumulation of fluid in the extravascular compartment of the lungs. the fluid accumulation depends on the capillary permeability and the oncotic pressure, as described by the starling equation, i.e., q = k (hpiv − hpev) − t(opiv − opev), where q represents the amount of fluid filtered and hp and op denote the hydrostatic and oncotic pressures of the intravascular (iv) and extravascular (ev) compartments. k represents the conductance of the capillary wall, determined by the resistance offered to the water flow by the capillary endothelial cell junctions [ ] . t represents the permeability of the capillary membranes to the macromolecules. lymphatic drainage is another pathway for handling excess water in the lungs. however, the lymphatic drainage needs time to be effective, and in the acute situation, it often fails to eliminate the excess fluid [ ] . classically grouped into cardiogenic and non-cardiogenic variants, the pulmonary edema can be divided into the following four types based on the pathophysiology [ ] ( almost all pulmonary edema presentations in critical care units are due to increased hydrostatic pressure or increased permeability with dad. the two common pathophysiological forms are further discussed. the two most common causes of increased hydrostatic pressure edema (hpe) in critical care units are left heart failure and fluid overload. besides renal and liver failure, overzealous hydration in settings of trauma and immediate postoperative care frequently contibutes to fluid overload. there are two distinct radiological phases of the pressure edema-the interstitial edema and the alveolar edema. the radiographic findings in the early interstitial phase include indistinctness of the intrapulmonary vasculature, peribronchial cuffing, and kerley lines. indistinctness of pulmonary vasculature is subtle but often the most useful radiographic sign of early interstitial edema in icu patients. with increasing intensity and duration of pressure gradient, edema extends into the alveolar spaces, resulting in nodular or acinar areas of increased opacity that coalesce into frank consolidation ( fig. . ). there is a good correlation between the increased pressure in the intravascular compartment as measured by the pulmonary capillary wedge pressure (pcwp) and radiographic appearances (table . ) [ ] . the vascular pedicle width is measured from the svc and azygos vein complex on the right to proximal descending thoracic aorta on the left. it can provide a reasonable estimate of intravascular volume status. increased width of vascular pedicle (> cm) thus may help in differentiating hydrostatic pulmonary edema from non-cardiogenic edema ( fig. . ) . the ct findings of hydrostatic pulmonary edema include smooth interlobular septal thickening, ground-glass opacities, consolidation, and pleural effusions ( fig. . ) . the distribution of densities often demonstrates gravity-based gradient, with abnormalities being most notable at the lung bases. atypical distribution or appearances similar to aspiration pneumonitis or pneumonia may be seen in presence of underlying chronic pulmonary disease, such as emphysema [ ] . acute respiratory distress syndrome (ards) represents the most severe form of permeability edema associated with dad [ , ] . in icu settings, the common primary pulmonary pathologies causing ards are pneumonia, aspiration, and pulmonary contusions. the common extrathoracic causes include drug toxicity, systemic inflammatory response syndrome, sepsis, shock, and abdominal trauma [ ] . clinically, ards is defined by recently created "berlin defi- (table . ) [ ] . ards involves three often overlapping and conflicting stages. the first or exudative stage is characterized by a rapidly progressing high protein content interstitial edema that quickly fills the alveoli and is associated with hemorrhage and hyaline membrane formation. the second or proliferative stage involves organization of the fibrinous exudate, regeneration of the alveolar lining, and thickening of the alveolar septa. the third or fibrotic stage manifests as varying degrees of scarring and formation of subpleural and intrapulmonary cysts. the radiographic findings in exudative phase are that of interstitial edema pattern, rapidly progressing to perihilar opacities and subsequently widespread alveolar consolidation ( fig. . ). in comparison to hydrostatic edema, . this gravitational distribution can be changed by patient's position (supine vs prone), suggesting a significant contribution from atelectasis [ ] . the atypical pattern comprises of dense consolidation in anterior (in supine position) nondependent locations. this may be seen in up to % of ards patients and is more common in ards with underlying primary pulmonary cause [ ] . "crazy paving," i.e., ground-glass opacities with superimposed inter-and intralobular septal thickening, may be seen [ ] . during the fibroproliferative stage, patchy heterogeneous areas of ground-glass opacification are seen with reticular changes. traction bronchiectasis and bronchiolectasis may be seen on ct. these findings early in the course of ards are associated with a poorer clinical outcome [ ] . subpleural and intrapulmonary cystic lesions may be observed in the fibrotic stage which can directly result in pneumothoraces [ ] . recurrent episodes of exudative phase in the proliferative and fibrotic stages often result in mixed radiologic findings. hrct of the patients recovered from ards on subsequent follow-up shows characteristic anterior lung fibrotic bands with sparing of posterior lungs. distinguishing imaging features between hpe and ards are described in table . . atelectasis, defined as a decrease in lung volume, is the commonest cause of radiographic parenchymal opacities in icu patients, particularly amongst the postoperative surgical icu patients. the atelectasis most commonly involves the left lower lobe ( %), followed by the right lower lobe ( %) and right a b to symmetrical central ground-glass opacities and bilateral pleural effusions at a later stage. note there is a gravity-based gradient of increasing density in the lungs upper lobe ( %) [ ] . obstructive atelectasis from impaired mucociliary clearance, increased secretions, and altered consciousness is often encountered in the icu patients. distal obstruction manifests as crowding of air bronchograms, whereas the proximal mucus plugging leads to lobar or even complete lung collapse ( fig. . ). compressive atelectasis from pleural effusion and cicatrization from fibrosis in later stages of ards are other forms of atelectasis seen in icu setting. the imaging findings include linear, band-like, or wedge-shaped opacities with signs of volume loss. mechanical ventilation and aspiration are two main risk factors for pneumonia in icu patients. ventilator-associated pneumonia can occur in up to % of patients after days of ventilation [ ] . the diagnosis of pneumonia in icu patients is often challenging as the airspace opacities seen on chest radiographs in these patients can be caused by atelectasis, aspiration, pulmonary hemorrhage, noninfectious lung inflammation (e.g., drug reaction), pulmonary edema, or ards [ ] . however, there are certain features that may favor pneumonia (table . ). air bronchograms typically associated with pneumonia result from the complete filling of the alveolar spaces around nonobstructed bronchi. however, when the airways get filled with mucus, air bronchograms are not seen on imaging which is often the case in critically ill patients (fig. . ). on ct, pneumonia can often be differentiated from atelectasis by lack of signs of volume loss. ct may provide additional clues to the possible causative agent of pneumonia. cavities, upper lobe or superior segment of lower lobe airspace disease, endobronchial spread (tree-in-bud densities), and findings of prior granulomatous disease point toward reactivation tuberculosis (tb). multiple peripheral lung nodules, solid as well as cavitary, in certain patients (long-term indwelling catheters, endocarditis, or history of iv drug abuse) suggest septic emboli [ ] . widespread bilateral predominantly central ground-glass opacities and cysts with or without spon-taneous pneumothorax in immunocompromised patients are features of pneumocystis jiroveci pneumonia (pcp), whereas focal areas of consolidation surrounded by a "halo" of groundglass suggest angioinvasive aspergillosis [ ] . intubation, diminished cough reflex, sedation, altered mental state, and enteric tube feeding predispose the icu patients to increased risk of aspiration. the different manifestations of the aspiration include chemical pneumonitis, pneumonia, and airway obstruction. aspiration of large amounts of severely acidic gastric contents can be fatal, resulting in a severe chemical pneumonitis and ards [ ] . aspiration is more common in the right lung, due to the vertical orientation of the right main bronchus. in the supine position, the frequently involved sites are the posterior segments of the upper lobes and superior segment of the lower lobe [ ] . the radiographic abnormalities commonly seen with aspiration are patchy ill-defined ground-glass opacities, nodular opacities, or consolidation in the dependent regions of the lungs (fig. . ). the opacities usually are seen over the first - days in aspiration pneumonitis demonstrating relatively rapid resolution on follow up radiographs. persisting opacities indicate progression to infectious pneumonia, and this is one important reason for following up the patients on radiographs. the ct better demonstrates the ground-glass changes or consolidation. areas of necrosis and cavitation can be seen when aspirates contain anaerobic organisms [ ] . tree-in-bud opacities present in the abovementioned dependent distribution are also frequently seen with aspiration [ ] . the pulmonary hemorrhage can be localized or diffuse. the localized form is often secondary to bronchiectasis, tumors, or some infections. the diffuse alveolar hemorrhage results from injury to the alveolar microcirculation leading to bleeding into the air spaces [ ] . this form is encountered in various autoimmune diseases, bleeding diathesis, vasculitis, certain drugs, and infections (invasive aspergillosis, mucormycosis). in icu patients, the culprit drugs often are systemic or catheter-directed thrombolytics (for myocardial infarction, pe, or stroke). the differentiation of pulmonary hemorrhage from pneumonia or pulmonary edema may be difficult. rapidly developing central and basilar predominant pulmonary parenchymal opacities sparing the costophrenic angles, along with drop in hemoglobin and hemoptysis (or blood in tracheal aspirate), should suggest the diagnosis of pulmonary hemorrhage. on ct scan, patchy ground-glass opacities, typically cloud-like opacities without significant interlobular septal thickening, are seen in the acute phase. in subacute phase, interlobular and intralobular interstitial thickening often develops [ ] . although the ct imaging features are nonspecific, the distribution of these findings, the temporal evolution of opacities, and the radiologic manifestations of predisposing disease (table . ) can help in arriving at the diagnosis [ , ] (fig. . ) . the prevalence of pulmonary embolism (pe) in critically ill patients is as high as % with only one-third of these cases being suspected clinically [ ] . besides the general risk factors for pe such as obesity, past history of venous thromboembolism, cancer, immobilization, trauma, and recent surgery; the icu patients are exposed to additional risk factors [ ] there are various radiographic signs (table . ) described for pe [ ] [ ] [ ] [ ] . although these signs are difficult to interpret, their timely recognition might alert the physician to the possibility of pe before it is suspected clinically (figs. . and . ). ct pulmonary angiography (ctpa) is now the reference standard for diagnosing pe in icu patients, with most icus moving away from the ventilation-perfusion scan and conventional invasive pulmonary angiography. ctpa not only detects pe by direct visualization of the thrombus in pulmonary arteries, it allows risk stratification by providing signs of right heart strain and quantification of thrombus burden. an rv/lv ratio > . - . has been shown to predict adverse outcomes similar to the echocardiographic measurements [ ] . newer ct techniques, such as dual-energy ct, can be used to assess functional lung perfusion [ ] as well as reduce contrast burden in icu patients who are prone to acute kidney injury [ ] . barotrauma, particularly the pneumothorax, remains a common icu complication despite continuously improving mechanical ventilation strategies of low tidal volumes and plateau pressures [ ] . the other forms of barotrauma are pneumomediastinum, pneumopericardium, pneumoperitoneum, subcutaneous emphysema, and interstitial emphysema. even a small pneumothorax can rapidly progress to tension pneumothorax in ventilated patients. the typical appearance of a thin curvilinear line, bordered by the lung on one side and pleural air space devoid of lung markings on the other, is often absent in the supine radiographs. in the supine position, air collects to the least dependent anteromedial pleural space (fig. . ) resulting in increased radiolucency at the bases and sharply elongated cardiophrenic and costophrenic sulci (the deep sulcus sign) [ ] . ct is useful for evaluation of loculated air collections and guides the proper placement of chest tube when pneumothorax persists. pneumomediastinum (fig. . ) in ventilated patients most commonly occurs from the rupture of the terminal airways. the pressure gradient between an alveolus and the interstitium directs the air from the ruptured alveolus to the perivascular and peribronchial fascial sheath. the fascial sheath at the lung root gives away letting the air escape into the mediastinum. with increasing severity, the air overflows into the subcutaneous tissues of the neck and into the retroperitoneum [ ] . pneumomediastinum can also be seen in tracheobronchial injury, following tracheostomy tube placement, asthma, and esophageal rupture. pleural effusion in icu patients is mostly transudative. despite being a common occurrence, it is difficult to detect small to moderate pleural fluid on the supine radiograph. in addition, differentiating it from other causes of lower zone opacities such as consolidation and atelectasis is often not possible. the costophrenic angle is often not blunted on the a b supine radiograph, and pleural fluid may only demonstrate diffuse hazy "veil-like" opacification from the layering of the pleural fluid (fig. . ). the apex is the most dependent location in supine patients and fluid may manifest as an apical cap [ ] . ct helps in differentiating pleural fluid from pulmonary parenchymal disease and better demonstrates the loculated pleural fluid collections. on ct, the thick enhancing visceral and parietal pleura suggests empyema often with a "split pleura" sign. hemothorax is suggested by increased attenuation of the pleural fluid, commonly - hu [ ] . ultrasound, readily available as a bedside imaging modality in most icus, is very useful in demonstrating loculations and in guiding fluid sampling as well a c b tubes, lines, and catheters are always present in icu radiographs. one major use of the radiographs in icu is to check their position and to evaluate any complications related to their insertion (table . ) . endotracheal tubes (ett) are used for short-term respiratory support with mechanical ventilation. the tip of endotracheal tube should be located about cm above the carina when the patient's head is in a neutral position [ ] . the neck flexion moves the tube inferiorly by up to cm, and the neck extension moves it superiorly by the same cm, hence the saying "the hose goes with the nose" [ ] . intubation of the main bronchi (most frequently right sided) may result in subsegmental atelectasis (fig. . ), segmental collapse, or complete collapse of the contralateral lung and puts the ipsilateral lung at risk of pneumothorax from overventilation. the too high a position of ett can lead to inadvertent extubation or damage to the larynx. overinflation of the endotracheal balloon cuff beyond the normal tracheal diameter chronically can lead to tracheal stenosis or may rarely result in acute rupture [ ] . the tracheal rupture however mostly occurs in the peri-intubation period, through the membranous trachea within cm of the carina [ ] . difficult intubation can occasionally result in hypopharyngeal injury (fig. . ). tracheostomy tubes are placed when long-term intubation is necessary. the tracheostomy tube tip should be approximately at mid-t level. the tracheostomy tube maintains its position during neck movements. pneumomediastinum can occur following an uncomplicated tracheostomy tube insertion. nasogastric tubes are the most commonly used for feeding, medication administration, and suctioning of gastric contents. the tip of a feeding tube should be ideally in the antrum of the stomach or distal to it (post-pyloric) to reduce the risk of aspiration. the proximal side hole of a nasogastric tube should extend beyond the gastroesophageal junction [ ] . the bedside chest radiograph is the most important investigation to detect tube malposition. the enteric tubes can coil within the pharynx or esophagus, resulting in high risk of aspiration, or very rarely esophageal perforations. the nasogastric tubes occasionally may terminate in the large airways ( fig. . ) where ectopic feeding can result in direct bronchopulmonary injury, pneumonia, pneumothorax, pulmonary laceration, and pulmonary contusion [ ] . the gastric feeding tubes are easier to insert than small bowel feeding tubes, allowing early initiation of enteral feeds, and are almost always placed at the time of icu admission. small bowel feeding tubes (nasojejunal or percutaneous jejunostomy) are reserved for patients who have high gastric residual volumes despite the use of prokinetics [ ] . the tip of the central venous catheter should be distal to the last venous valve, which is located at the junction of the internal jugular and the subclavian veins. on the cxr, the position of the valve corresponds to the inner aspect of the anterior first rib [ ] . a catheter is more likely to get blocked from thrombosis around it when its position is in proximal svc or at the thoracic inlet than in the distal svc or at the cavoatrial junction [ ] . the inferior border of bronchus intermedius serves as a good guide to the distal svc ( fig. . ) . on the cxr, the cavoatrial junction corresponds to the lower border of the bronchus intermedius, while the arch of azygos is located at the right tracheobronchial angle a b azygos location of a catheter tip can be identified by its characteristic orientation and position (fig. . c pulmonary artery catheters or swan-ganz catheters are placed primarily to measure pulmonary capillary wedge pressure, which helps to differentiate cardiogenic pulmonary edema from non-cardiogenic pulmonary edema. the catheter tip should lie in the main pulmonary arteries or the proximal lobar pulmonary artery (fig. . ) . the catheter tip should not extend beyond the pulmonary hilum on the chest radiograph [ ] . a further distal catheter tip increases the risk of arterial injury and pulmonary infarction. pulmonary infarcts may also occur secondary to persistent balloon occlusion or pericatheter thrombus. the proper position of the chest tube depends on the contents to be removed from the pleural cavity. the tip of the tube is directed toward the apex for pneumothorax and toward the lung base for fluid drainage (fig. . ). the side holes of the chest tube, identified on radiographs as interruptions of the tube's radiopaque line, should lie within the pleural space. an improper location of chest tube results in poor drainage and accumulation of air or fluid in the chest wall. the ineffective drainage may also result from tube kinking; blockage resulting from blood clots, pus, or debris in the tube; and apposition of the tip against the mediastinum [ ] . an intrafissural location of the tube may or may not affect its function; however, rarely it may result in herniation of lung parenchyma into the holes of chest tube leading to infarction [ ] . inadvertent parenchymal insertion of a chest tube (fig. . ) can lead to pulmonary laceration, hematoma, infarction, and bronchopleural fistula. besides the lung parenchyma, an inappropriately positioned chest tube can injure the heart, great vessels, diaphragm, liver, and spleen [ ] . interpretation of icu radiographs is a challenging task. important pearls for reporting icu chest radiographs are summarized in table . . on the absorption of fluids from the connective tissue spaces harrison's principles of internal medicine clinical and radiologic features of pulmonary edema revisiting signs, strengths and weaknesses of standard chest radiography in patients of acute dyspnea in the emergency department intensive care unit imaging acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative ct study crazy-paving" pattern at thin-section ct of the lungs: radiologic-pathologic overview prediction of prognosis for acute respiratory distress syndrome with thin-section ct: validation in cases lobar collapse in the surgical intensive care unit ventilator-associated pneumonia thoracic imaging in icu chest ct for suspected pulmonary complications of oncologic therapies: how i review and report the many faces of pulmonary aspiration diffuse pulmonary hemorrhage: clues to the diagnosis manifestations of systemic diseases on thoracic imaging venous thromboembolism prophylaxis in critically ill patients venous thromboembolic disease: an observational study in medical-surgical intensive care unit patients on the roentgen diagnosis of lung embolism roentgen diagnosis of pulmonary embolism pulmonary embolism: roentgenographic and angiographic considerations correlation of postmortem chest teleroentgenograms with autopsy findings with special reference to pulmonary embolism and infarction prognostic value of echocardiography and spiral computed tomography in patients with pulmonary embolism diagnosing pulmonary embolism: new computed tomography applications reduced iodine load at ct pulmonary angiography with dualenergy monochromatic imaging: comparison with standard ct pulmonary angiography -a prospective randomized trial distribution of pneumothorax in the supine and semirecumbent critically ill adult pneumomediastinum revisited imaging of the pleura complex disease of the pleural space: radiographic and ct evaluation stateof-the-art: radiological investigation of pleural disease radiographic evaluation of endotracheal tube position chest radiography in the icu: part , evaluation of airway, enteric, and pleural tubes early radiographic signs of tracheal rupture chest radiography in the icu: part , evaluation of cardiovascular lines and other devices gastric versus post-pyloric feeding: a systematic review to clot or not to clot? that is the question in central venous catheters lines, tubes, and devices lung entrapment and infarction by chest tube suction key: cord- -r axl w authors: porembskaya, olga; toropova, yana; tomson, vladimir; lobastov, kirill; laberko, leonid; kravchuk, viacheslav; saiganov, sergey; brill, alexander title: pulmonary artery thrombosis: a diagnosis that strives for its independence date: - - journal: int j mol sci doi: . /ijms sha: doc_id: cord_uid: r axl w according to a widespread theory, thrombotic masses are not formed in the pulmonary artery (pa) but result from migration of blood clots from the venous system. this concept has prevailed in clinical practice for more than a century. however, a new technologic era has brought forth more diagnostic possibilities, and it has been shown that thrombotic masses in the pa could, in many cases, be found without any obvious source of emboli. chronic obstructive pulmonary disease, asthma, sickle cell anemia, emergency and elective surgery, viral pneumonia, and other conditions could be complicated by pa thrombosis development without concomitant deep vein thrombosis (dvt). different pathologies have different causes for local pa thrombotic process. as evidenced by experimental results and clinical observations, endothelial and platelet activation are the crucial mechanisms of this process. endothelial dysfunction can impair antithrombotic function of the arterial wall through downregulation of endothelial nitric oxide synthase (enos) or via stimulation of adhesion receptor expression. hypoxia, proinflammatory cytokines, or genetic mutations may underlie the procoagulant phenotype of the pa endothelium. both endotheliocytes and platelets could be activated by protease mediated receptor (par)- and receptors for advanced glycation end (rage)-dependent mechanisms. hypoxia, in particular induced by high altitudes, could play a role in thrombotic complications as a trigger of platelet activity. in this review, we discuss potential mechanisms of pa thrombosis in situ. in the middle of the th century, rudolf virchow, studying pathophysiological aspects of venous thromboembolism (vte), put forward a theory that remained unshakable for a century and a half. virchow argued that thrombotic masses are not formed in the pulmonary artery (pa) but result from migration of blood clots from the peripheral venous system, causing secondary obstructions in the branches of the pa [ ] . since then, there have been attempts to match the morphological characteristics of thromboemboli with possible sources of their formation [ ] . since emboli were considered to be thrombotic casts from the veins, it was believed that blood clots with a large diameter originated from large veins, whereas smaller ones were from the crural or pelvic veins. if no thrombi could be discovered in the deep veins, transformation of a thrombus into an embolus by emptying of a vein was believed to be the cause of embolism [ ] . this mechanistic approach is still dominant in clinical practice. however, concurrent with the accumulation of clinical data on vte complications, the idea of embolism from thrombotic masses in the venous system as the only source of emboli in the branches of the pa started to become doubtful, since no initial thrombus was found in a large number of patients [ , ] . cases of thrombi discovered in the branches of the pa in the absence of concomitant deep vein thrombosis (dvt) cannot be justified only by the drawbacks of evaluation techniques that are used to diagnose thrombosis. magnetic resonance (mr) panphlebography assessment of the venous system of the whole body confirms the possibility of thrombosis in the pa with no thrombi in the deep veins. in a dutch study of patients with newly discovered symptoms of pulmonary embolism (pe), dvt was diagnosed by panphlebography in % of patients [ ] . no primary source of pe was identified in patients ( %) and the reliability of the results obtained in the study were confirmed by the high sensitivity ( %) and specificity ( %) of mr phlebography in the diagnostics of venous thrombosis [ , ] . development of thrombosis in the branches of the pa has been reported in pulmonological, hematological, surgical, and infectious patients ( figure ). incidence of thrombotic obstruction of pa branches in the registro informatizado de la enfermedad tromboembolica venosa (riete) study, which involved patients with chronic obstructive pulmonary disease (copd), was % [ ] . these included both patients with true pe and with isolated involvement of the pa and no dvt. however, follow-up of these patients for days and months showed that rethrombosis in the territory of the pa (without dvt), which predominates in this type of patients, is of greater importance in the structure of recurrent vte and mortality [ , ] . analysis of exacerbations of copd showed that low spo values, dyspnea, and disease severity increase the risk of pa thrombosis [ ] . studies evaluating incidences of local pa thrombosis separately from dvt+pe reported its development in - % of patients with copd [ , ] . computed tomographic (ct) angiography findings provide evidence of the most common involvement of segmental ( . %) and subsegmental ( . %) pa branches [ ] . thrombi in the pa trunk are diagnosed in . % of cases only [ ] . however, data on the incidence of pa branches involvement in patients with copd vary across different studies [ ] . a high risk of pa thrombotic complications is also typical for patients with asthma [ ] . the risk of pa thrombosis is significantly increased in patients with severe and moderate asthma, compared to the general population [ ] . at the same time, there is no association with the high risk of dvt in such patients [ ] . a high risk of pulmonary thrombosis is associated with episodes of aggravation in sickle cell anemia (sca) [ ] . a complication presented as acute thoracic syndrome (ats) during the period of aggravation in sca is caused by erythrocyte hemolysis, vasoconstriction, and platelet aggregation and may be accompanied by thrombosis of the pa branches. computed tomographic (ct) imaging performed within the first days of ats identifies pulmonary thrombosis without dvt in % of patients [ ] . thrombi are discovered mostly in the segmental branches of the pa ( %) and less commonly in its subsegmental branches ( %) [ ] . thrombi are also found in the lobar branches of the pa, although in a lesser number of cases ( %) [ ] . a typical ct finding is the opartial artery filling defect. thrombotic complications are registered both in patients with the newly developed ats and those with recurrent ats and in some cases during each exacerbation [ ] . studies evaluating incidences of local pa thrombosis separately from dvt+pe reported its development in - % of patients with copd [ , ] . computed tomographic (ct) angiography findings provide evidence of the most common involvement of segmental ( . %) and subsegmental ( . %) pa branches [ ] . thrombi in the pa trunk are diagnosed in . % of cases only [ ] . however, data on the incidence of pa branches involvement in patients with copd vary across different studies [ ] . a high incidence of pulmonary thrombotic events (reaching . %) is one of the complications of gunshot wounds and their associated injuries [ ] . in this cohort of patients, the combination of pa thrombosis with dvt was registered only in - % and primary pa thrombosis in more than % [ , ] . pa thrombosis is diagnosed in the first h following the moment of injury. the causes of "acute peritraumatic pulmonary thrombosis" may differ from those in other diseases and may be due to the local response of the pa to injury [ ] . formation of atelectasis, vascular constriction, blood stasis, and local hypoxia may be significant as well [ ] . the distribution of thrombi in "acute peritraumatic thrombosis" of the pa is registered in the segmental ( %) and subsegmental ( %) branches of the pa [ ] . thrombi can also be detected with high incidence in the large branches of the pa ( %) [ ] . it has been shown that pulmonary thrombosis can occur in the long-term postsurgical period of patients that have undergone a pneumonectomy or lobectomy [ ] . the average period of time between the surgical intervention and development of this complication is days. assessment of the degree of recanalization of thrombosed branches of the pa showed better results in patients with pe than in those with thrombosis of the pa. the degree of recanalization was % and %, respectively. based on the results of postmortem autopsy, the source of pe could not be detected in % of patients who died after emergency surgery and in % of patients after elective surgery [ ] . among patients who died in the non-surgical departments, thrombosis of the pa without dvt was found in . % [ ] . the data were obtained from the findings of autopsies of patients with pe being a confirmed cause of death. after excluding all cases where the source of embolism was identified, the cases were designated as pe with no primary source [ ] . thrombosis of the pa can develop as a complication in viral infections. in the multi environmental and genetic assessment (mega), with a case-control population study of patients with vte (pe +/− dvt), a high risk of pulmonary thrombosis was demonstrated in patients who had experienced viral pneumonia within a year prior to this event [ ] . at the same time, the risk of primary thrombosis of the pa increased . -fold ( %; . - . ), significantly exceeding that for dvt ( . ; %, . - . ). thrombosis of the pa without dvt could also be observed in patients with complicated severe viral pneumonia secondary to influenza [ , ] . studies of viral pneumonias caused by severe acute respiratory syndrome coronavirus (sars-cov- ) indicate that the development of pulmonary thrombosis is frequent and typical for this disease [ , , ] . a comparison of the incidence of pa thrombosis in severe pneumonias caused by sars-cov- and by the influenza virus demonstrates the higher risk for this complication in patients with covid- ( . % versus . %, respectively) [ ] . the combination of pa thrombosis with dvt is registered in only . % of patients with covid- , which suggests predominantly primary pa thrombosis. as a rule, bilateral thrombosis of the pa ( %) is described with predominant localization of thrombotic masses in the segmental branches of the pa ( %) [ ] . during the epidemic of viral pneumonias caused by the sars virus of the coronavirus family, there were also reports of venous thrombotic complications in patients with this disease [ , ] . in some patients, pulmonary thrombosis was primary and not associated with dvt [ ] . ct angiography showed localization of thrombi in the large branches of the pa [ ] . cases of cytomegalovirus infection accompanied by pa thrombosis have been described in patients without immunodeficiency [ ] . thrombosis is preceded by a vivid clinical presentation in the form of fever persisting for several days, lymphadenitis, and asthenia; diarrhea may also be observed [ , ] . giant basophilic lymphocytes are detected in the blood, thrombocytopenia is possible, and high c-reactive protein (crp) values are registered; an increase in hepatic transaminases levels is found in some patients [ , ] . development of sudden dyspnea, chest pain, and a nonproductive cough may be signs of primary pulmonary thrombosis in these patients [ ] . the mega population study evaluated specific features of the course of a first episode of vte, depending on the presence of either factor v leiden or the prothrombin gene a mutation [ ] . over the years of the study, pa thrombosis was diagnosed in patients, and dvt and dvt+pe in and patients, respectively. the presence of factor v leiden factor mutation increased the risk of isolated dvt -fold (odds ratio, or . %; . - . ) and the risk of isolated thrombosis of the pa only . -fold (or, . %; . - . ) compared to the patients without this mutation. this feature was called the leiden paradox. the discovered differences did not affect either the density of the thrombus or the rate of its formation in patients from the two groups. the presence of the prothrombin gene mutation equally increased both risks for development of dvt (or . %; . - . ) and pa thrombosis (or . %; . - . ) [ ] . the prolonged stay of a person at a high altitude above sea level is known to increase his/her risk of thrombotic events. the risk for development of vte in persons residing for months at an altitude of more than m above sea level increases -fold [ ] . unfortunately, there is no separate analysis of the groups of patients with pe and pulmonary thrombosis in the study. however, reviewing again the individual clinical cases could give the information about the isolated pa thrombosis with involvement of its large and segmental branches in patients from a high altitude [ ] . increased homocysteine content can become a provoking factor for thrombosis in large branches of the pa, with development of a vivid clinical presentation resembling pe symptoms: dyspnoe, productive cough with hemoptysis, and right sided pleuritic chest pain [ , ] . similar events may occur in cases where there is a combination of high homocysteine content with pernicious anemia and hereditary thrombophilia [ ] . flights lasting more than h and -h and longer driving trips can also provoke not only dvt but also primary pa thrombosis [ ] . pulmonary arterial endothelium is a complex, metabolically active system that fulfills a barrier function and is involved in gas exchange, the regulation of vascular tone, the coagulation system, leukocyte diapedesis, and vascular permeability [ ] . pa endothelium forms a monolayer due to intercellular interaction proteins, structural cellular proteins, and cytoskeletal proteins [ ] . among the structural proteins of endothelial cells, an important role is played by caveolin- that mediates regulation of nitric oxide (no) production and protein c effects on protease mediated receptor (par- ) [ ] . the properties of caveolin can be changed as a result of external causes, including oxidative stress [ ] . suppression of caveolin- causes endothelial dysfunction and becomes one of the mechanisms for the development of pulmonary hypertension, which carries the risk for pa thrombosis [ ] [ ] [ ] [ ] . endothelial nitric oxide synthase (enos) directly binds to caveolin- [ ] . this protein negatively regulates enos function and no production [ ] . the prominent role of no in antithrombotic mechanisms is the prevention of platelet adhesion to the vessel wall [ ] . it has been shown that infusion of no inhibitors increases platelet deposition in the vessels [ ] . protein c activation occurs by its interaction with thrombin coupled with thrombomodulin. activated protein c (apc) binds its own endothelial protein c receptor (epcr), which is associated with caveolin- on the membranes of endotheliocytes. the interaction with apc provides dissociation of epcr from the caveolin- and further epcr binding to par- , which blocks the effects of thrombin on vascular permeability [ ] . the epcr receptor is scattered throughout the pa endothelium from the large branches to the minor capillaries [ ] . mutant inactive protein c infusion deprives the complex with epcr of its protective function, but in an experimental setting, does not prevent the lethal effect of injected thrombin, since the death of mice still results from pa thrombosis [ , ] . suppression of protein c may result from the impact of tumor necrosis factor (tnfα) and reactive oxygen species (ros) [ , ] . the endothelial permeability regulation is only one of many different functions of par, which itself presents a molecular link between coagulation factors and immune cells involved in thrombosis [ ] . the par receptor family has four members. par- , , are activated by thrombin and par- and by the tf-viia and xa complex [ ] . thrombin binding to par receptors on the pa endothelium causes a number of effects: formation of thrombi, increase of vascular permeability, secretion of pro-inflammatory cytokines, chemoattractants and adhesion molecules, and upregulation of platelet aggregation and procollagen production [ , ] . the role of the thrombin-par- interaction in thrombosis was demonstrated by real-time tracking of probes labelled with fluorophores involved in this protease-activated thrombotic process [ ] . intravenous administration of non-lethal doses of thromboplastin accompanied with picomolar amounts of labelled probes to mice increased clotting activity in the pa. administration of a thrombin inhibitor, hirudin, reduced thrombus formation in the pa. an important factor that mediates homeostasis in the pa is the glycocalyx layer on the endotheliocytes. destruction of glycocalyx results in the loss of heparan sulfate and exposure on the surface of endothelial cells of adhesion molecules inter-cellular adhesion molecule (icam- ) and vascular cell adhesion molecule (vcam- ), which become accessible for circulating leukocytes involved in thrombosis [ , ] . one of the components of glycocalyx is the proteoglycan endocan [ ] . thus, expression of endocan is specific to the endothelium of the pulmonary and renal arteries [ ] . increase in blood endocan levels in patients with ct angiographic evidence of a pulmonary thrombotic event is associated with a more severe course of the disease [ ] . blood endocan levels rise with increased pa pressure and decreased partial oxygen tension. pa endothelial glycocalyx transmits mechanical signals from the endothelial surface to the cytoskeleton in response to varying shear stress and causes vessel contraction due to the interaction of actin with myosin [ , ] . increased contractions in the case of pa pressure fluctuations result in dissociation of cadherin membrane proteins, extension in intercellular spaces, and enhanced expression of adhesion molecules, leading to the recruitment of neutrophils and monocytes, which contribute to thrombosis [ , ] . the procoagulant shift of the pa endothelium can be mediated by a number of factors, such as vwf, p-selectin, tnf, ros, and modulation of the activity of enos and apc pkc and the function of glycocalyx. tnfα has been shown to activate pa endothelium in vitro [ ] . in human cultured pa endothelial cells, tnfα induces the procoagulant phenotype within h. this occurs in particular via increased expression of icam- , decreased expression of epcr, and suppressed thrombomodulin secretion. in addition, expression of tissue plasminogen activator (tpa) and urokinase-type (upa) is observed, accompanied by pai- upregulation. in clinical practice, there is a number of conditions accompanied by the production of pro-inflammatory cytokines, such as tnfα, including the postsurgical period, ulcerative colitis, injuries, sepsis, and others [ ] [ ] [ ] . endothelial activation can be induced by hypoxia, which provokes secretion of the ros and production of hypoxia inducible factors (hifs) and in the endothelial cells [ , ] . with a decrease in oxygen concentration, hifs accumulate in the cell nucleus and bind to the hypoxia-responsive element (hre) on the promoter or enhancer of targeted genes, which activates their transcription [ , ] . hifs induce synthesis of pro-inflammatory factors and adhesion receptors, including icam- , nuclear factor-kappab (nf-kb), tnfα, and interleukin- (il- ), as well as tissue factor (tf) and pai- , which promote blood coagulation [ ] . protein s and tissue factor pathway inhibitor (tfpi) expression is inhibited by hifs [ ] . in the setting of hypoxia, other signaling pathways are also activated, such as early growth response- (egr- ), which activate the pai- genes and thus contribute to the development of thrombosis [ ] . expression of hypoxia-induced genes is increased in persons residing at more than m above sea level and who have had dvt in the past [ ] . introduction of microspheres into the pa in an experiment showed that secretion of hif α and hif α occurs in response to hypoxia not only locally in the areas with occlusion of the blood vessel lumen, but also in adjacent segments where there is no obstruction [ ] . in patients with a prolonged history of smoking, combined with chronic bronchitis, there is a significant increase of hif α and vascular endothelial growth factor (vegf) in the vascular endothelium and smooth muscle cells (smcs), compared to the smokers without chronic bronchitis [ , ] . similar changes have been observed in patients with bronchial asthma [ ] . a different presentation is typical in patients with copd in whom the mechanisms of cell degradation prevail over the mechanisms induced by hypoxia. hif α and vegf levels in these patients are significantly reduced compared to those in smokers with no copd. this is combined with severe apoptosis of endothelial cells and vascular atrophy [ , ] . an increase in the activity of enzymes, including serpin family f member (serpinf , protease inhibitor), also results in the suppression of angiogenesis and the apoptosis of endotheliocytes [ , ] . endothelial atrophy causes loss of anti-adhesive and antithrombotic functions of the endothelium [ ] . ros enhance the risk of thrombus formation through several mechanisms. they increase expression of tf on endothelial cells and monocytes, inactivate protein c and its agonist thrombomodulin, and promote oxidation of fibrinogen, which increases its conversion to fibrin [ ] . free oxygen radicals in mitochondria in the setting of hypoxia activate par- and par- receptors, leading to tf secretion [ ] . in the context of hypoxia, par- activates the nuclear transcription factor nf-kb, which regulates secretion of pro-inflammatory cytokines and expression of neutrophil ligands on other cells [ , , ] . hydrogen peroxide produced in the endothelial mitochondria of pulmonary micro-vessels is involved in the upregulation of the pro-inflammatory response [ ] . increased pressure in the pulmonary capillaries contributes to increased production of mitochondrial ros, primarily hydrogen peroxide, provoking exocytosis of the weibel-palade body constituents, in particular p-selectin [ ] . genetic changes may underlie the procoagulant phenotype of the pa endothelium. hereditary factors play a role in the development of pulmonary hypertension, including a heterozygous mutation in the gene bone morphogenetic protein receptor type (bmpr ), found in - % of patients with familial pulmonary hypertension [ ] . the same mutation has been identified in - % of patients with idiopathic pulmonary hypertension. bmpr is expressed in a number of cell types; however, this heterozygous mutation is of the greatest importance, particularly in the pa endothelium, because of its role in pulmonary hypertension. in experiments with bmpr knockout mice, minor branches of the pa are partially or completely occluded by fibrin(ogen) positive thrombi in % of cases [ ] . this likely results from damage of the endothelial cells and apoptosis by bmpr signaling disregulation, which contributes to inflammation and thrombosis in pulmonary hypertension [ ] . endothelial damage can be caused by the immediate effect of a virus that destroys the cell. the ability of the influenza virus to penetrate cells has been shown in vitro in monolayers of endothelial cells [ ] . after h incubation, expression of tf was observed, which peaked at h [ ] . destruction of the endothelial cells was detected - h later. histological evaluation of the material collected from patients infected with sars-cov- demonstrates immediate damage to the endothelial cells from various vascular beds [ , ] . viral particles were found in the endothelium of the lungs, kidneys, and small bowel. signs of endotheliitis and endothelial edema were observed, and apoptotic bodies, lymphocytic and leukocytic infiltration, and platelets were discovered [ ] [ ] [ ] . apoptosis and pyroptosis may play a significant role in the death of endotheliocytes and the development of endotheliitis in covid- [ ] . the mechanism of penetration of coronavirus into the cell is based on its interaction with angiotensin converting enzyme ii (aceii) receptors [ , ] . expression of ace-ii is typical for pa endotheliocytes, making them a target for sars-cov- [ ] . this may explain the high prevalence of pa thrombosis in covid- infection and targeting ace-ii could potentially be beneficial to tackle this dangerous complication. activated platelets likely play a role in pa thrombosis. it has been shown in the warfarin and aspirin (warfasa) and aspirin to prevent recurrent venous thromboembolism (aspire) trails that the inhibition of platelet activity by antiplatelet drugs reduces the risk of recurrent pa thrombotic events after anticoagulant treatment is discontinued [ , ] . inhibition of platelet activation by a coumarin-derived compound, auraptene, or a mer tyrosine kinase (mertk) inhibitor, unc , protects animals from death caused by pa thrombosis in experiments [ , ] . there are several potential mechanisms of platelet activation possible in pa thrombosis, which are discussed below. in contrast to the endotheliocytes, only two types of par receptors are expressed on human platelets: par- and par- [ ] [ ] [ ] [ ] . par- has a greater affinity for thrombin and therefore requires lower thrombin concentrations for activation [ ] . engagement of par- induces rapid platelet activation in a ca + -dependent fashion [ ] . activated platelets induce expression of adhesion molecules, such as icam- , vcam- , vwf, and tf on the endothelial surface, thereby contributing to the migration of leukocytes, platelet adhesion to the endothelium, and blood clotting [ , , ] . binding of p-selectin on activated platelets to the p-selectin glycoprotein ligand (psgl- ) on leukocytes causes the formation of leukocyte-platelet complexes and results in leukocyte activation [ ] . the role of par receptor-mediated platelet activation in pa thrombosis has been shown in experiments with mice deficient in par- (an analogue of par- in humans) and par- . administration of thromboplastin into wild type par +/+ and par +/+ mice causes quick death of most of the animals because of the occlusion of the pa branches [ ] . a similar mortality level is observed in par +/and par +/mice. in contrast, most par −/− and par −/− mice survived. pulmonary artery perfusion and histological evaluation demonstrated much higher thrombosis prevalence in wild-type mice than in par −/− mice [ ] . a number of conditions are accompanied by the activation of platelets and leukocytes through the high-mobility group box (hmgb ), a protein bound to dna and released from the nucleus of dying or damaged cells, causing inflammation [ ] . hmgb binding to receptors for advanced glycation end (rage) products and toll-like receptor (tlr ) induces platelet activation and granule secretion [ ] . platelet activation can be induced not only by exogenous hmgb but also by secretion of intrinsic hmgb [ ] . this type of autocrine regulation promotes platelet aggregation during thrombosis formation [ ] . the oxidized form of hmgb activates leukocytes and induces secretion of pro-inflammatory cytokines [ ] . platelet-derived hmgb contributes to the recruitment of another important participant in thrombosis, monocytes, enhancing their production of tf [ ] . hmgb is present in pa thrombi and is also involved in the formation of neutrophil extracellular traps (nets), which may contribute to pa thrombosis [ ] . platelet activation by hmgb may be observed in cases of injury, sepsis, myocardial infarction, hemorrhagic shock, and dvt [ ] . on the first and second days after an injury, hmgb on patient platelets is increased [ ] . in an experiment with mice under conditions of multiple trauma and hemorrhagic shock, hmgb -dependent platelet aggregation occurs within the first min. this is accompanied by platelet sequestration to the arteries of the lungs and formation of thrombi in the minor branches of the pa, as evidenced by histology [ ] . in addition to the activation of platelets, this may be caused by the activation of the pa endothelium, which results from high concentrations of cytokines typical to multiple trauma [ ] . vasoconstriction of the pa branches, hypoxia due to constriction of the smaller pa branches, and shunting blood flow as a result of hemorrhagic shock aggravate activation of the pa endothelium, enhancing thrombosis [ ] . hypoxia causes platelet hyperreactivity [ ] . platelets from acute copd patients express higher levels of hif a than platelets from healthy people [ ] . in the patients with blood pao below mmhg, the levels of hif α and pai- in platelets are augmented [ ] . hypoxia induces shedding of extracellular vesicles from platelets, which is accompanied by increased expression of both hif α and pai- . moreover, platelets from the patients are primed to produce hif a in response to either hypoxia or activation with thrombin [ ] . in experiments on rats, high altitude hypoxia promoted platelet adhesion to collagen and fibrinogen [ ] . increases in secretion of dense granules reflects greater platelet activation [ ] . high values of soluble p-selectin remain in the blood plasma of patients after vte, residing at more than m above the sea level, and of patients with atherothrombotic vascular conditions, which indicates constant platelet activation [ , ] . enhanced levels of soluble cd l, p-selectin, and platelet factor- (pf- ) reflect platelet reactivity in high altitude hypoxia and could play a significant role in thrombotic complications [ ] . involvement of platelets in primary pa thrombosis may be due to their antiviral activity and involvement in the immune response. megakaryocytes with significant hyperchromasia and an atypia of the nucleus associated with activated platelets have been described among the pathological findings in patients infected with sars-cov- , who died of thrombosis in the small branches of the pa [ ] . these were located in the minor blood vessels and capillaries of the lungs. megakaryocytes in the lungs are a source of about % of platelets in the body [ ] . the encounter of megakaryocytes and platelets with an infectious agent results in the activation and initiation of the immune response. the signaling pathway, involving megakaryocytes and platelets in the immune response, may differ depending on the causative agent of the disease and may be mediated by the effects on interferon-induced transmembrane protein (ifitm ) receptors or through pattern recognition receptors (prr), which include different classes of tlr, c-type lectin receptor (clr), and nucleotide-binding and oligomerization domain (nod)-like receptors (nlrs) [ ] [ ] [ ] . as a result, thrombotic function of platelets is upregulated through several mechanisms, such as stimulation of the tlr- receptor, the tlr- -myd signaling pathway, or fcγrii [ ] [ ] [ ] [ ] . the result is secretion of the granule constituents, adhesion of the platelets and leukocytes to the endothelium, and release of nets, which, combined, cause an alveolar-capillary barrier disruption in the lungs and may lead to thrombosis in the pa branches [ ] [ ] [ ] . activation of pa endothelium and platelets can be mediated by rage receptors [ ] . their ligands and advanced glycation end products (ages), include hmgb , mac- , phosphatidylserines, and lipopolysaccharides (lps) [ , ] . pa endothelium contains at least two rage isoforms, and expression of these increases when stimulated with pro-inflammatory cytokines and erythrocytes during blood transfusion, resulting in the expression of adhesion molecules on the surface [ , ] . hmgb via interaction with rage activates platelets and makes them stimulate neutrophils to release nets [ ] . nets exert prothrombotic effects by promoting blood coagulation, adhesion and aggregation of platelets (mainly due to histones h and h ) and recruiting red blood cells [ , ] . blood coagulation is supported by nets ability to compartmentalize thrombus-associated tissue factor pathway inhibitor (tfpi) and facilitate its degradation by neutrophil-derived serine proteases [ ] . net components, including histones, myeloperoxidase, neutrophil elastase, and cathepsin g, cause a cytotoxic effect and contribute to pulmonary epithelium and endothelium damage [ ] . their immediate involvement in thrombosis has been shown both in dvt and in thrombosis of the coronary arteries [ , ] . nets have been identified in organized thrombi in the pa, where they are located extra-and intracellularly [ ] . evidence of nets with fibrin fibers and the involvement of neutrophils and cd monocytes has also been reported in patients with covid- with thrombosis in the minor branches of the pa [ ] . it has been shown that histones circulating in the blood after injuries, sepsis, and other abnormal conditions can become a source of damage to the pulmonary epithelium and endothelium [ ] . after severe injury, histone concentration in blood increases in h, reaches its peak by h, and still remains high h later [ ] . high concentrations of histones become toxic to the pa endothelium, and in one third of patients with toxic histone concentrations, lung injuries are diagnosed [ , ] . histones rapidly bind to endothelium but can be blocked by preincubation with an anti-histone antibody [ ] . prolonged incubation with histones causes endothelial death [ ] . administration of sublethal doses of histones to mice is accompanied by accumulation of neutrophils in alveolar micro-vessels, vacuolization of the pulmonary epithelium and endothelium, intra-alveolar hemorrhages, and formation of thrombi rich in fibrin and platelets [ ] . microparticles (mps) can play an important role in thrombotic pulmonary disease. their sources are platelets, endotheliocytes, and many other cells [ ] . microparticles retain the lipid bilayer of the parent cells and may contain their rna, enzymes, and mediators [ ] . in healthy people, circulating mps predominantly originate from platelets; a lesser number is derived from endothelial cells [ , ] . endothelial cells activated by mps secrete pro-inflammatory cytokines, including il- , il- , il- , and monocyte chemoattractant protein (mcp- ) [ ] . due to the high concentration of the tf and vwf on the surface of some mps, they can induce thrombin generation [ , , ] . tf-positive endothelial microparticles have adhesion molecules on their surface, which recruit monocytes and platelets, activate them, and transfer tf to their surface [ , ] . three-fold higher blood concentrations of platelet-derived and tf-positive mps are observed in patients with thrombosis of the pa branches rather than that in healthy individuals. this is accompanied by a -fold increase of chances for thrombosis [ , ] . the concentration of platelet mps and tf-positive mps remains fatally high during the first months after vte and later on it significantly drops [ ] . both clinical and experimental data indicate that different mechanisms can result in thrombus formation in the pa (figure ). histological evaluations of its thrombosed branches confirm the existing signs of endothelitis with edema, desquamation, apoptosis of endotheliocytes, and infiltration of the vascular wall with leukocytes, lymphocytes, and megakaryocytes. during activation, the endothelium loses its anticoagulant properties and acquires a procoagulant phenotype, which precedes thrombus formation. thus, a condition that could be designated as thrombotic angiopathy may underlie local thrombosis in the pa. phenotype, which precedes thrombus formation. thus, a condition that could be designated as thrombotic angiopathy may underlie local thrombosis in the pa. the most frequent initiating factor for pa thrombosis is an infectious agent or a systemic inflammatory process. hemodynamic factors may be less important for the initiation of pa thrombosis, but they do affect permeability of the vascular wall and can lead to the progression of thrombosis. recruitment of platelets, endothelium, and leukocytes, upregulation of the proinflammatory cytokine levels, and secretion of adhesion molecules, which collectively trigger the coagulation cascade and induce thrombosis, suggest that the term "immunothrombosis" is applicable to pa occlusion in situ. further studies are required to establish differential diagnostic criteria and peculiarities of the pathogenesis of the two conditions, pa thrombosis and pa thromboembolism, and this may become a basis for development of separate therapeutic approaches to treat these diseases. nets + h,nets (neutrophil extracellular traps and histones); hmgb +rage, interaction of hmgb and rage receptors; neutrophil (neu); microparticles (mps); tissue factor (tf); platelet (plt);von willebrand factor (vwf); p-selectin (p-sel); p-selectin glycoprotein ligand (psgl); interaction of neutrophil with icam- ; monocyte (mon); bone morphogenetic protein receptor type (bmpr ); par + platelet glycoprotein ibα (gpibα) + thrombin, interaction of thrombin with par and gpibα; virus (vir); hypoxia inducible factor (hif); par + thrombin, interaction of thrombin with par. the most frequent initiating factor for pa thrombosis is an infectious agent or a systemic inflammatory process. hemodynamic factors may be less important for the initiation of pa thrombosis, but they do affect permeability of the vascular wall and can lead to the progression of thrombosis. recruitment of platelets, endothelium, and leukocytes, upregulation of the proinflammatory cytokine levels, and secretion of adhesion molecules, which collectively trigger the coagulation cascade and induce thrombosis, suggest that the term "immunothrombosis" is applicable to pa occlusion in situ. further studies are required to establish differential diagnostic criteria and peculiarities of the pathogenesis of the two conditions, pa thrombosis and pa thromboembolism, and this may become a basis for development of separate therapeutic approaches to treat these diseases. nets + h,nets (neutrophil extracellular traps and histones); hmgb +rage, interaction of hmgb and rage receptors; neutrophil (neu); microparticles (mps); tissue factor (tf); platelet (plt); von willebrand factor (vwf); p-selectin (p-sel); p-selectin glycoprotein ligand (psgl); interaction of neutrophil with icam- ; monocyte (mon); bone morphogenetic protein receptor type (bmpr ); par + platelet glycoprotein ibα (gpibα) + thrombin, interaction of thrombin with par and gpibα; virus (vir); hypoxia inducible factor (hif); par + thrombin, interaction of thrombin with par. virchow's contribution to the understanding of thrombosis and cellular biology venous thrombosis and pulmonary embolism. a clinico-pathological study in injured and burned patients pulmonary embolism and deep venous thrombosis in trauma: are they related? the origin of fatal pulmonary emboli: a postmortem analysis of deaths from pulmonary embolism in trauma, surgical, and medical patients finding the origin of pulmonary emboli with a total-body magnetic resonance direct thrombus imaging technique magnetic resonance direct thrombus imaging: a novel technique for imaging venous thromboemboli pulmonary embolism 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influenza virus pathogenesis the role of extracellular histones in influenza virus pathogenesis the receptor for advanced glycation end products mediates lung endothelial activation by rbcs rage and icam- cooperate in mediating leukocyte recruitment during acute inflammation in vivo activated platelets present high mobility group box to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps extracellular dna traps promote thrombosis reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases circulating histones are mediators of trauma-associated lung injury extracellular histones are major mediators of death in sepsis antihistone properties of c esterase inhibitor protect against lung injury microparticles and acute lung injury effect of strenuous physical exercise on circulating cell-derived microparticles the many faces of endothelial microparticles phospholipid composition of in vitro endothelial microparticles and their in vivo thrombogenic properties interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation diagnostic value of platelet-derived microparticles in pulmonary thromboembolism: a population-based study circulating microparticles and risk of venous thromboembolism key: cord- -kb mez authors: calvillo batllés, p.; carreres polo, j.; sanz caballer, j.; salavert lletí, m.; compte torrero, l. title: hematologic neoplasms: interpreting lung findings in chest computed tomography() date: - - journal: nan doi: . /j.rxeng. . . sha: doc_id: cord_uid: kb mez lung disease is very common in patients with hematologic neoplasms and varies in function of the underlying disease and its treatment. lung involvement is associated with high morbidity and mortality, so it requires early appropriate treatment. chest computed tomography (ct) and the analysis of biologic specimens are the first line diagnostic tools in these patients, and sometimes invasive methods are necessary. interpreting the images requires an analysis of the clinical context, which is often complex. starting from the knowledge about the differential diagnosis of lung findings that radiologists acquire during training, this article aims to explain the key clinical and radiological aspects that make it possible to orient the diagnosis correctly and to understand the current role of ct in the treatment strategy for this group of patients. hematologic neoplasms (hn) are characterized by being frequently disseminated at the moment of diagnosis, with bone marrow affectation. they are especially sensitive to chemotherapy or radiotherapy, therefore the patients usually receive aggressive chemotherapy and, in certain cases, hematopoietic precursors transplantation (hpt). the disease per se and its treatments cause prolonged pancytopenias, predisposing to very serious infections that make up a diagnostic and therapeutic emergency. non-infectious pulmonary complications secondary to treatment are also frequent and determine prognosis. pulmonary tumor disease includes infiltration due to hn, pulmonary neoplasm and post-hpt lymphoma. chest computed tomography (ct) narrows down the differential diagnosis of these diseases. their indications are reviewed, as well as the main clinical information that should be recorded in the radiologic application and interpretation of the findings based on the clinical context. performing helical chest cts in patients with hn pursues two objectives: early detection of lesions not visible in the chest x-rays which require urgent treatment, and better characterization of the findings to outline diagnostic and therapeutic possibilities. reconstructions being < . mm cut thick and high resolution computed tomography (hrct) are required since many of the pulmonary complications kick in as interstitial patterns. the etiologic diagnosis of fever manifestations in patients with neutropenia and/or hpt requires the search for microorganisms and infectious markers. chest hrct plays a fundamental role---urgent when there are clinical signs of severity and early (< h) in the absence of a response to antibiotics therapy in --- h because treatment of a possible invasive fungal infection (ifi) requires an early administration, a determinant factor for prognosis. in patients clinically classified as being in high risk of ifi , antifungal drugs are administered empirically, while in subgroups of lower risk it is possible to delay treatment in cases of very likely clinical manifestations or early positive specific infection markers, which reduces the high costs and toxicity of these drugs. the markers usually used are the serum galactomannan test while the chest hrct is performed early in a serial way. , galactomannan, a component of the aspergillus cell membrane, is falling into disuse as a marker due to its loss of sensitivity associated to antifungal prophylaxis. the hrct gains more importance still as an urgent diagnostic test that allows starting an early therapy when pulmonary lesions characteristic of ifi are visualized. in addition, it can give rise to other etiologies and guide the acquisition of bronchoalveolar lavage (bal) through bronchoscopy, thus speeding up the diagnosis of germs not covered by the initial empirical therapy. in other respiratory manifestations hrct is necessary to identify and characterize non-infectious complications, relapse and secondary neoplasms that can go unnoticed in radiographic tests or show similar patterns. when studying the hrct of a patient with hn we need to know the clinical information and other fundamental data about the underlying condition as well as therapies and complications (table ) . patients with hodgkin lymphomas (hl) and non-hodgkin lymphomas (nhl) receive a less intense polychemotherapy than those with leukemias, with shorter neutropenias so if pulmonary lesions are seen the possibility of tumor affectation should be taken into consideration. it is not odd to find pulmonary neoplastic spread in autopsies of leukemias, but its radiologic manifestation is exceptional and the respiratory disease is mainly marked by infections. acute myeloid leukemia (aml) deserves special attention, since pulmonary manifestations occur in all the stages of the disease, and it is possible to observe added to infections, more cases of hemorrhages due to thrombocytopenia and toxicity due to chemotherapy. multiple myeloma (mm) occurs mainly with bacterial infections due to humoral immunity deficiency and hypoventilation due to bone affectation. pulmonary edema is very common while findings of pulmonary infiltration due to amyloids, plasma cells or light chain deposits are rare. chemotherapeutic drugs do not only depress immune function, but some of them are responsible for pulmonary toxicity, suspected by the radiologic pattern and its temporal relation with the treatment. other therapeutic agents used can cause respiratory failure, often with a radiologic expression similar to alveolar damage, edema or hemorrhage. in especially chemosensitive tumors (lymphomas and mm), the goal of autologous hpt is to allow the administration of high doses of chemotherapy with subsequent corticotherapy graft vs host disease (gvhd) (immunosuppressant therapy) actual infectious prophylaxis wide-spectrum antibiotics antifungal prophylaxis p jirovecii rescue of hematopoiesis thanks to the infusion of hematopoietic precursors obtained previously from the same patient. this prevents irreversible medullary failure and shortens the time of neutropenia. pulmonary complications will be fundamentally the consequence of intensive chemotherapy not the consequence of the transplant per se. the allogenic hpt is mainly used in patients with acute leukemias to re-establish hematopoietic and immunity functions. the cells are obtained from a family member with an identical hla (human leukocyte antigen) or else from someone unrelated but with a compatible hla and they may come from the bone marrow, peripheral blood or the umbilical cord. before the transplant the patient receives conditioning with high doses of chemotherapy, with or without full-body radiotherapy, to suppress the bone marrow, destroy the malignant cells and prevent the host's rejection against the graft cells. also a strong immunosuppressant treatment is later administered to avoid reverse rejection and when the hematopoietic function is reinstated the donor's cells recognize the recipient's tissues as foreign and they cause graft-versus-host disease (gvhd). yet despite of this some patients develop gvhd and require a more extended immunosuppressant therapy. all of this explains why the allogenic hpt recipient suffers from a deep and prolonged immune deficit that leads to death in nearly --- % of patients. based on at what specific moment in his history the patient is he will be included in one of these groups to approach diagnosis (tables and see tables and . in the onset of the disease, before treatment, infectious nodes are uncommon. they are usually bacterial or viral and exceptionally, at the very moment of the diagnosis of aml with severe cytopenia or iron overload they can be fungal. in severely immunologically depressed patients, the nodes can be fungal, viral or bacterial (fig. ) . filamentous fungi are common in prolonged deep neutropenias (over two weeks) especially during chemotherapy of an aml and in the early post-hpt period. in % of invasive aspergillosis it is possible to observe nodes that are usually multiple-bilateral and at least one > cm. the ground-glass attenuation halo distinguishes them from bacterial nodes , but it usually disappears during the first five days. mucormycosis is suspected before aspergillosis if nodes or more are observed as well as sinus affectation, pleural effusion and/or the inverted halo sign, especially if the antifungal therapy did not cover that fungus. the hrct is useful because there is no serological test available today for the diagnosis of mucormycosis. viral nodes often have poorly-defined edges and/or halos but they are distinguished by their small size (< cm) and the absence of cavitation. bacterial nodes usually have betterdefined edges. centrilobular nodes often represent unspecific infectious bronchiolitis, especially if accompanied by sprouting-tree images; however, diffuse symmetrical bilateral centrilobular nodes with predominance in upper fields and ground-glass attenuation, in the absence of other infectious findings, should lead to respiratory bronchiolitis by tobacco or pneumonitis due to hypersensitivity secondary to the treatment. in nhl and hl infiltration is observed more often in relapses, increasing due to the greater survival of the patients with the current therapies. it usually manifests itself as multiple pulmonary nodes < cm with irregular edges, consolidations and/or masses, which are more frequent in nhl and have worse prognosis. primary pulmonary lymphoma occurs in patients of --- years of age, it is usually non-hodgkin of the b malt type (mucosa-associated lymphoid tissue) and it shows as a nodule or peribronchovascular consolidation at the bronchogram test. these lesions can be single or multiple bilateral. , they are characterized by the absence of mediastinal adenopathies at the moment of diagnosis and up to months later, they grow slowly. identical presentations to those of lymphocytic interstitial pneumonia have also been described (fig. ) . myeloid leukemias and myelodysplastic syndromes can make up a blastic tumor called granulocytic sarcoma---extremely rare in the lung, where it can occur as a node, mass or consolidation. exceptionally, mm can present nodes and/or masses, associated with adenopathies that simulate a lymphoma or a pulmonary cancer with a bad prognosis. lymphomatoid granulomatosis is an extranodal lymphoproliferative process associated with the epstein---barr virus (ebv) mainly affecting the lung and the central nervous system. it occurs as multiple pulmonary nodes in more than % of the cases, they are variable in number and size, and of basal predominance. nodes can progress rapidly, coalesce and cavitate, as well as disappear spontaneously, migrate or evolve making up the sign of the inverted halo sign. , secondary neoplasms lung cancer has increased in survivors of hl, nhl and cll, and its etiopathogenesis is being studied. its appearance ranges from one to several years after the diagnosis of hn. patients receiving allogenic hpt can develop a posttransplant lymphoproliferative disorder (ptld), usually during the first six ( ) months, and up to a year, with a second peak at --- years. in ptld and the hiv-associated lymphoma (most attributed to ebv) pulmonary nodes are usually bilateral, well-defined, and may associate a halo. it is important not to take them for an ifi by taking into account the clinical context and the evolution of the lesions. ifi nodes typically cavitate --- weeks after the disease onset accompanying the recovery from neutropenia (neutrophiles > ), making up the growing air image (crescent moon). previously nodes can show low central attenuation (fig. ) . low attenuation nodes. invasive fungal infection (ifi) due to aspergillus. acute lymphoid leukemia and prolongued neutropenia. high-resolution computed tomography (ct). upper cut (upper side images) and lower cut (lower side images). the nodes low attenuation can be seen in images with filter while the mediastinal window (arrows in a and d) is very typical of ifi due to necrosis prior to cavitation seen two ( ) weeks later (c and f). serum gactolamannan was positive one ( ) month later. fungal and bacterial consolidations (especially staphylococcal or tuberculous ones) can also cavitate and less commonly nodes and consolidations due to lymphoma. the appearance of cavitated nodes corresponding to langerhans cell histiocytosis has been described in patients with hl and more rarely in leukemias; it is not known whether there is an actual association, but in any case tobacco plays a role in the etiopathogenesis. areas of attenuation in groud glass. consolidations (fig. ) see tables and infections at the disease onset and in the course of mm, it is possible to observe bacterial and viral bronchopneumonias similar to the rest of the population while in patients with severe immunodepression they are due to different germs (see tables and ) . segmental or lobar consolidations are most often bacterial. an ifi is suspected when they have a pleural base and halo, , but the most sensitive diagnostic sign ( %) is vascular occlusion in the sinus of the lesions shown through pulmonary angio-ct. patched bilateral ground-glass opacities, whose size is very variable, are more typical of viruses and they can be accompanied by small nodes and consolidations. --- in patients with hpt the paved pattern is of viral origin mainly and less commonly of a non-infectious cause. infection due to pneumocystis jirovecii causes perihilar bilateral ground-glass attenuation areas in upper fields, usually after the th day post-hpt---a moment in which prophylaxis is usually withdrawn. respiratory colonization due to candida is common in these patients, but pneumonia is exceptional except for in situations of spread candidiasis. emerging ''non-candida'' yeasts do cause infectious pulmonary consolidations and nodes. pulmonary edema is frequent in the course of mm (due to pet, cardiac and/or renal amyloidosis) and aml (mainly as a consequence of treatment). at the onset and in the course of aml it should be differentiated from diffuse alveolar hemorrhage (dah) due to thrombocytopenia and/or infection. secondary pulmonary lymphoid infiltration in leukemias is rare. it can be seen as ground-glass attenuation areas , or consolidations similar to an organizing pneumonia, , with adenopathies. in patients with cll of years of evolution and adenopathies, the appearance of peribronchovascular consolidations, even endobronchial occupations, and clinical worsening, will make us suspect transformation into a high-grade lymphoma. leukostasis (aggregation of blasts in pulmonary microvascularization) is exceptional and it will only be suspected in the diagnosis or relapse of an aml due to a rapid increase of the percentage of leucocytes in blood; it is characterized by respiratory and neurological failure kicking in with con pulmonary consolidations partly due to alveolar damage and hemorrhages due to plateletpenia. , in mm, consolidations due to pulmonary infiltration of plasmatic cells causing respiratory distress of poor prognosis have also been described. , noninfectious complications secondary to treatment in the h following the transfusion of blood products, the sudden appearance of consolidations simulating an edema and accompanying a respiratory failure usually reflect acute pulmonary damage (apd) called trali (transfusion-related alveolar lung injury) which associates high mortality rates. any courses of chemotherapy can cause pulmonary toxicity, although the most usual patterns are: organizing pneumonia (op), unspecific interstitial pneumonia (uip), pneumonitis due to hypersensitivity, eosinophilic pneumonia and diffuse alveolar damage. carmustine (used in lymphomas and mm), which usually gives a uip pattern ; cytarabine (administered in high doses for the treatment of aml), that can cause non-cardiogenic pulmonary edema and bleomycin (lymphoma treatment), causing diffuse alveolar damage and op are among the most common drugs used. expiration before-hpt rituximab is an anti-cd monoclonal antibody used in the treatment of lymphoproliferative b syndromes that have been associated to pulmonary disease due to a mechanism that has not been clarified yet after a median of four cycles and with a median time of appearance of weeks after the last infusion. the ground-glass areas or bilateral diffuse pulmonary consolidations appear in weeks or months, and less commonly in hours or days, and they correspond histologically to inflammatory and lymphocytic infiltrates, among others. most of them show hypoxemia of lethal evolution in %. the granulocyte colony-stimulation factor (g-csf) used in neutropenia recovery can rarely induce an apd during the first days of treatment displaying images similar to those of edemas or alveolar hemorrhages. all-trans retinoic acid (atra) and arsenic trioxide, used for the treatment of acute promyelocytic leukemia, can cause ( %) a ''differentiation syndrome'' consisting of respiratory failure manifestations during the following --- days probably due to the release of cytokines. pleural effusion, ground-glass areas and bronchial wall thickening due to edema and hemorrhage can be seen. the pre-graft early post-hpt period can become complicated with: • pulmonary edema-hydrostatic or due to increased patency (the most common non-infectious complication). • dah of multifactor etiology, characterized by large ground-glass attenuation areas that can evolve into paved patterns, in the absence of cardiomegalia and effusion; hemoptysis is only observed in % of the cases, but a drop in the levels of hemoglobin and the high rate of macrophages in bal help us in the diagnosis. • ''graft syndrome'' or pre-graft respiratory distress---the consequence of an endothelial damage possibly due to the release of pro-inflammatory cytokines; it is similar to edema but without cardiomegalia and with clinical manifestations of fever and cutaneous exanthem. • ''idiopathic pneumonia syndrome'' defined by the american thoracic society as an acute respiratory failure and diffuse alveolar damage in the absence of cardiac or renal disease, iatrogenesis and responsible microorganism. it is an exclusion diagnosis, probably of multifactor etiology or due to non-affiliated infections, such as it would happen with the recently discovered metapneumovirus. , in the late post-hpt period, peribronchovascular reticulation and ground-glass areas, and on occasion paved pattern ones, can represent an unclassifiable interstitial pneumonia, associated with rejection. histologically, it corresponds to a bronchioloalveolar lymphoplasmocytic infiltration that spreads toward peripheral regions and evolves into a fibrosis with traction and hive bronchiectasis. op can be secondary to infection, toxicity by drugs, radiotherapy or rejection; peripheral peribronchovascular and perilobular consolidations, and the inverted halo sign are characteristic findings in the appropriate clinical context. in a situation of neutropenia the inverted halo should lead us to consider mucormycosis in the first place which is different from the op in that the thickness of its ring is > cm and also presents internal reticulation (fig. ) . acute pneumonitis due to radiation can occur --- weeks after mediastinal lymphoma radiotherapy and cause clinical and radiologic manifestations similar to those of a pneumonia. it is located in the irradiated area with a marked delimitation of the healthy parenchyma; it evolves into paramediastinal fibrosis. acute pulmonary rejection to hpt and pulmonary alveolar proteinosis due to leukemic infiltration or lately to treatment are extremely rare. , these images represent bronchioles filled with mucous, liquid or pus; they usually correspond to an infectious bronchiolitis that can be due to many different germs. it can be due to unspecific respiratory infection, smoking, bronchiolitis obliterans, lymphoid infiltration or other bronchial conditions. liquid retention and inflammatory or tumor infiltration of perilymphatic distribution translate into thickening of the bronchovascular axes, interlobular septa and the subpleural interstice. the straight interstitial thickening can correspond to an interstitial pulmonary edema and a graft syndrome in the early post-graft period. in the --- months following the hpt, pulmonary veno-occlusive disease can be a rare complication leading to pulmonary hypertension with pulmonary congestion in the absence of left cardiac disease. secondary lymphatic tumor pulmonary infiltration can kick in as a straight or nodular thickening of the perilymphatic interstice , and make up peribronchial consolidations ( fig. a) . in most cases dissemination is retrograde from the hilar and mediastinal affectation, and can get to occlude the airways, especially in the cll. in mm, pulmonary amyloidosis can be seen radiologically as a septal interstitial thickening. chest computed tomography (ct) and mild mosaic patterns in expiration due to air entrapment (asterisks). heart failure and pleuropericardial effusion due to cardiac and serous amyloidosis. although the most frequent cause is pulmonary carcinoma we should not forget that they are a rare form of hl and nhl presentation. also in the course of cll, it is possible to see lymphoid growth in the lumen or bronchial wall making up obstructive endoluminal masses and cases of extra-osseous plasmacytoma as endoluminal masses have been published. it is a characteristic finding of bronchiolitis obliterans (bo), the most common ( --- %) and relevant complication --- months post-hpt. it is considered a chronic gvhd defined by functional criteria of airway obstruction in the absence of active respiratory infection and confirmed through transbronchial and/or surgical biopsy. the ''bo syndrome'' can be diagnosed without histology when there is air trapping and/or bronchiectasis in hrct and gvhd in at least one other organ. , the images in forced expiration show air entrapment in --- % of the cases; on the other hand and yet despite the fact that this is the finding with the most diagnostic sensitivity, it is not very useful for the detection of early preclinical stages. bronchiectasis appears in more advanced stages and its progression has been associated with the forced expiratory volume in one second. hrct is a very useful addition to rule out airway infection or tumor infiltration, which can alter respiratory tests. this disease causes slow functional worsening, especially if not detected early. its treatment with corticoids and immune depressants causes infectious complications that will be the main cause of death. it can be secondary to distress, toxicity, infection or radiotherapy (fig. ). in the late period after hpt it can correspond to an unclassifiable interstitial pneumonia or to a pleuroparenchymatous fibroelastosis likely as a consequence of chemotherapy, radiotherapy and gvhd. the history, distribution and evolution of the findings will guide the etiological diagnosis. they can be seen in a transitory way in the sinus of infectious consolidations and be due to organizing pneumonia. irreversible dilations (bronchiectasis) in areas of air entrapment are a characteristic finding of bronchiolitis obliterans unlike those observed in areas of fibrosis due to traction. interstitial pulmonary emphysema: air leak syndrome (fig. f) it is a typical complication of advanced post-hpt bo and a marker of poor prognosis. the increase of alveolar pressure leads both to its rupture and air leak around the ( ) week later (normal evolution not meaning non-responsiveness). (c) cavitation two ( ) weeks later coinciding with a recovering neutropenia, air crescent sign (arrows). (d---f) a different patient. consolidation (asterisk) with an initial halo (d); two ( ) weeks later (e) size increase and disappearance of the halo; further size decrease with persistence of peribronchovascular consolidation with bronchial dilations (f) without resolution. the resection of lesion to guarantee the control of the infection before the hematopoietic precursor transplantation (hpt) showed organized pneumonia without micro-organisms or malignant cells. bronchovascular axes due to retrograde dissection; it can reach the mediastinum, the subcutaneous tissue and the pleural cavity. the treatment is usually conservative except if the pneumothorax requires drainage. , pulmonary infiltration, radiotherapy and infection postulate as causes for a greater incidence of pneumothorax in hodgkin's disease (fig. ). in the absence of radiotherapy or infection, the possibility of pleura-pulmonary infiltration described in lymphomas and mm should be taken into consideration. , in the late post-hpt period, the air leak syndrome due to bo or the rupture of apical vesicles due to a pleuroparenchymatous fibroelastosis should be taken into consideration. small cysts in the upper fields can correspond to pneumatoceles due to infection by pneumocystis jirovecii. bilateral cysts, isolated or associated with nodes and adenopathies should make us think of the possibility of a pulmonary disease due light chains deposit disease in patients with mm or macroglobulinemia and obstructive functional pattern (fig. ) . in patients with a fever and active infection findings in the hrct it is recommended that the examination be repeated until resolution of the findings: a) in cases of good clinical response, it is possible to wait for several weeks and even for or months---the estimated time for the resolution of the findings. during the first week of treatment the ifi lesions can grow worse which does not mean poor evolution (fig. ) . also it is convenient to recognize in any infection an immune reconstruction syndrome not to be taken for an absence of response. it is an inflammatory exacerbation secondary to neutrophil recovery or to the withdrawal of immunosuppressant therapy which in turn translates into clinical worsening and lesion growth. b) if suspicion that there is not a good response (due to clinical and/or radiographic findings) it is important to repeat the diagnostic tests to rule out initially unidentified mixed infections. if nodes are detected without infectious clinical manifestations, they should be compared with previous images to find out whether they are residues of an infection that occurred during periods of immune suppression. indeterminate nodes can be followed up according to the recommendations made by the fleischner society, while the fnpa or the biopsy should be considered in lesions of suspected malignancy because of their characteristics, due to history of lymphoma and/or allogenic hpt, or because the lesions did not evolve as expected after therapy (fig. ). preferentially the sample will be obtained through cutaneous (guided by ct or ultrasound) or transbronchial access, and surgery will be considered as a last resort or preferably videothoracoscopy if available. the diffuse pulmonary disease of unclear etiology usually ends up requiring surgical or videothoracoscopic pulmonary biopsy due to its greater diagnostic yield. -fdg pet-ct is not only useful for the staging and follow up of metabolically-active lymphomas but also a pathological uptake in the absence of pulmonary findings in the hrct can raise early suspicion of drug toxicity , or leukemic infiltration and it can be useful to differentiate active lesion scarring (whether toxic, infectious or tumoral). in patients with hp the thoracic hrct helps us come close to the differential diagnosis of infectious and non-infectious pulmonary complications by integrating image findings and clinical data. the hrct needs to be performed in cases of acute clinical presentations and quickly when suspicion of ifi. it allows us to assess the response to treatment, detect malignancies and optimize the obtention of both the bal and the pulmonary biopsy. protection of people and animals. the authors declare that no experiments with human beings or animals have been performed while conducting this investigation. data confidentiality. the authors declare that in this article there are no data from patients. right to privacy and informed consent. the authors declare that in this article there are no data from patients. the authors declare no conflict of interests. manager of the integrity of the study study idea: pcb study design: pcb data mining data analysis and interpretation: - . statistical analysis pulmonary infections in the late period after allogeneic bone marrow transplantation: chest radiography versus computed tomography prevention of fungal infections in the immunocompromised host evidence-based approach to treatment of febrile neutropenia 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[ f]-fluorodeoxyglucose positron emission tomography combined with computed tomography detection of asymptomatic late pulmonary toxicity in patients with non-hodgkin lymphoma treated with rituximab-containing chemotherapy. leuk lymphoma the authors wish to thank ms. lucía flors, mr. carlos muñoz, ms. laura trilles, and mr. carles fonfría for their collaboration in the gathering of cases used to illustrate this article. key: cord- -ikq rm authors: rasmuson, j.; andersson, c.; norrman, e.; haney, m.; evander, m.; ahlm, c. title: time to revise the paradigm of hantavirus syndromes? hantavirus pulmonary syndrome caused by european hantavirus date: - - journal: eur j clin microbiol infect dis doi: . /s - - - sha: doc_id: cord_uid: ikq rm hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in eurasia, and hantavirus pulmonary syndrome (hps) in the americas. however, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. herein are presented three cases of severe european puumala hantavirus infection that meet the hps case definition. the clinical and pathological findings were similar to those found in american hantavirus patients. consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide. the present paradigm is that hantaviruses in the americas cause hantavirus pulmonary syndrome (hps), while hemorrhagic fever with renal syndrome (hfrs) is caused by hantaviruses present in eurasia [ ] [ ] [ ] . hantaviruses associated with hfrs and hps are primarily transmitted by inhalation of viral particles shed by infected rodents [ , ] . in both syndromes there is a local immune reaction in the lungs, mainly in terms of a cd + t lymphocyte response [ , , ] . another important feature is endothelial dysfunction and capillary leakage [ ] [ ] [ ] ] . after the prodromal phase, including fever, nausea, myalgia and headache, patients with hfrs commonly develop renal failure whereas in hps the kidneys are often spared and instead the patient frequently presents with severe cardiopulmonary dysfunction [ , , ] . although usually less severe and sometimes overlooked, pulmonary symptoms are common in european hfrs caused by puumala virus (puuv). frequent clinical findings include cough, dyspnoea, interstitial lung infiltrates, pleural effusion and impaired pulmonary function [ ] [ ] [ ] . pronounced lung involvement in hfrs has previously been reported [ ] [ ] [ ] [ ] . however, none of those reported patients had a fatal outcome that could be attributed to the acute infection, and there is no description of histopathological findings. our hypothesis is that also european hantaviruses can cause hps. the aim of this study was to investigate whether hfrs patients with severe cardiopulmonary distress fulfil hps criteria and have similar clinical and pathological features. in a prospective study, during the latest hantavirus outbreak in in the county of västerbotten, sweden [ ] , hfrs patients with cardiopulmonary failure and need of invasive assisted ventilation, i.e. intubation and mechanical ventilation, were selected. we identified three patients, two of which had fatal outcome and one survived. the two patients who died both underwent autopsy three days post-mortem. organ samples were investigated using immunohistochemistry to describe the immunological response and detect presence of viral antigen. quantitative real-time rt-pcr was used to detect viral rna in organ samples, plasma and bronchoalveolar lavage [ ] . for defining hps we used the case definition criteria published by the u.s. centers for disease control and prevention (cdc) [ ] . the project was approved by the research ethics committee of umeå university. informed consent was obtained either from the patient, or a close relative when not possible. a -year-old woman was admitted to the intensive care unit (icu) with acute respiratory distress. she was a lifelong non-smoker living with her husband in a rural area, and had a medical history of hypertension and type ii diabetes. the day prior to admission she fell ill with malaise and fever. nausea, vomiting and pronounced shortness of breath ensued. the initial findings at admission included fever, tachycardia, tachypnoea, hypoxia and somnolence. laboratory findings during hospitalisation indicated coagulopathy, elevated levels of lactate dehydrogenase (ldh), and development of renal failure (table ). there was release of cardiac enzyme troponin t (peak value . ; normal value < . μg/l), indicating myocardial tissue damage. lung computer tomography (ct) on admission revealed pronounced diffuse bilateral interstitial infiltrates with pulmonary oedema, dependant atelectasis, and moderate pleural effusions (fig. ) which were later drained (> ml). echocardiography showed inferior hypokinesia, moderate mitral valve insufficiency, normal sized left ventricle and atrium, and systolic pulmonary arterial pressure estimated at mm hg. despite non-invasive positive pressure respiratory support and furosemide, her respiratory distress progressed and she was intubated and mechanically ventilated on the first hospital day. the preliminary diagnosis was acute respiratory distress syndrome of uncertain cause, and she was treated with broad-spectrum antibiotics and corticosteroids without improvement. vasopressor and inotropic support was required to maintain adequate circulation. repeated echocardiogram showed no overt signs of cardiac failure, though several days into her illness the systolic pulmonary arterial pressure increased to > mm hg. maximal inspiratory pressures ( cm h o) were required to maintain minimally adequate oxygenation. she suffered a pneumothorax, and received a large bore thoracostomy with negative pressure drainage. the patient developed multiple organ dysfunction engaging the central nervous, respiratory, cardiovascular, renal and coagulatory systems, and she died after days of icu care. puuv serology was initially negative, but seroconversion occurred during the first week with development of positive immunoglobulin m (igm) and igg. no puuv rna could be detected in serum or bronchoalveolar lavage fluid, sampled two days after onset of disease. at autopsy puuv rna was detected in lung tissue, but not in samples from heart, brain, spleen and liver. sequencing of the puuv rna from lung tissue showed that it was homologous to puuv strains circulating in northern sweden. no puuv antigen could be detected in the tissue by immunohistochemistry using puuv specific monoclonal antibody. relevant bacterial cultures were all negative. notably, three weeks prior to icu admission the patient had sought medical treatment at our clinic for a urinary tract infection caused by e. coli. in the serum collected at that time puuv rna ( , copies/ml) was later detected. wbc white blood cell count (normal range . - . × /l), tpc thrombocyte particle count (normal range for women - and for men - autopsy revealed oedematous and atelectatic lungs with no normal aerated tissue. pulmonary histopathological features consisted of diffusely oedematous parenchyma with interstitial and intraalveolar fibrosis. the alveoli contained exudates of fibrinous fluid, high number of alveolar macrophages (cd + ), proliferative epithelial cells and thick septa but without characteristic hyaline membranes. interstitial mononuclear cell infiltrates were common, consisting mainly of cd + t lymphocytes whereof a vast majority was cd + . many mononuclear cells were expressing cytotoxic markers granzyme b and t cell restricted intracellular antigen- , tia- (fig. ) . in pulmonary vessels, focal thrombosis was evident. microscopy of the heart showed thrombosis in small vessels and focal massive infiltrates of granulocytes and macrophages. in the brain there was focal vasculitis, perivascular infiltration of cd + t lymphocytes and non-occlusive thrombosis. infarctions were seen in the brain, lungs and spleen. notably, the kidneys had no prominent inflammatory infiltrates. a -year-old woman was admitted to the icu with acute respiratory distress and circulation insufficiency. besides a history of waldenstrom's macroglobulinemia that had not required active treatment, she had no history of health problems, infections or recent hospitalisations. she was a lifelong non-smoker, lived in a rural home with her husband, and handled firewood for home heating. four days prior to admission the patient noted fever, chills, dyspnoea with dry cough and diarrhoea. on the day of admission, these symptoms were more severe, and an ambulance had been called because of syncope. her ability to oxygenate deteriorated progressively during the first hospital day, and she was intubated and mechanically ventilated. chest x-ray on admission showed bilateral diffuse lung infiltrates and signs of interstitial oedema. large bilateral pleural effusions were noted, and > ml were drained. echocardiographic examination identified normal left ventricular wall motion, and no signs of structural abnormalities or of pulmonary hypertension. thin-cut ct images of the lungs on the third icu day showed diffuse bilateral alveolar and interstitial infiltrates with dependent consolidation (fig. ) . the clinical course during the first seven days was dominated by respiratory insufficiency requiring maximal ventilatory support with high levels of inspired oxygen, as well as circulatory shock requiring treatment with vasopressor and inotropic infusions. other important clinical aspects included coagulopathy with diffusely spread petechiae, progression of renal failure with anuria requiring dialysis, and elevated levels of ldh (table ) . she was treated presumptively for bacterial pneumonia and sepsis with a series of broad spectrum antibiotics and corticosteroids, without apparent response. hantavirus infection was verified with the detection of puuv rna in plasma ( , copies/ml) on the day of admission, while igm and igg were negative. seroconversion with positive igm and igg occurred two and seven days later, respectively. consecutive plasma samples were analysed for puuv rna with declining viral copy numbers until negative days post onset of fig. chest ct-scans of two european patients with hantavirus pulmonary syndrome. the examination showed pronounced diffuse bilateral interstitial infiltrates with pulmonary oedema, together with bilateral dependent atelectasis and moderate pleural effusions in patient (a) and diffuse bilateral alveolar and interstitial infiltrates with dependent consolidation in patient (b) fig. immunohistochemistry results in lung sections from two fatal cases of hantavirus pulmonary syndrome. the findings were condensed oedematous pulmonary parenchyma with alveolar fibrinous exudate and infiltrates of mononuclear cells (a), whereof a vast majority were cd + t lymphocytes (b), and many were holding granules containing granzyme b (c) and t cell restricted antigen- , tia- (d); this immunophenotype is characteristic of activated cytotoxic t lymphocytes. in contrast, cd + helper t lymphocytes (e) were uncommon. viral antigen was detected in capillary vascular endothelium (f) and in mononuclear cells, here represented by a monocyte (f; inset), using puumala hantavirus nucleocapsid protein monoclonal antibody (a c , progen biotechnik gmbh, heidelberg, germany). for viral antigen, lung samples from two non-hantavirus patients were used as negative controls (data not shown). panels (patient in a-e; original magnification, x ; and patient in f; original magnification, x ) display lung sections from paraffin embedded material. staining was performed using hematoxylin and eosin (a), and immunoperoxidase technique (b-f) disease (data not shown). puuv rna was found in bronchoalveolar lavage fluid ( , copies/ml) nine days after onset of disease. bacterial cultures were all negative. the patient remained ventilator-dependent for days, but was finally extubated. she developed critical illness myopathy and needed six weeks in-hospital rehabilitation. at follow-up six months later, she complained of muscle ache during exercise and lowered general fitness, but was steadily improving. a -year-old male construction worker was admitted to the icu with acute respiratory distress, confusion and hypotension. he was a current and long-time smoker with a medical history of mild chronic obstructive pulmonary disease and hypertension. three days prior to admission he had fallen ill with fever, chills, diarrhoea, dry cough, and dyspnoea. in the emergency room, physical examination was notable for fever, somnolence, tachycardia and hypotension. arterial blood gas analysis on room air revealed hypoxia and respiratory alkalosis. the patient was taken to the icu and therapy was started with broad spectrum antibiotics due to suspicion of pneumonia and sepsis. as with the other patients, coagulopathy, increased ldh levels, and renal failure were detected (table ) . initial bedside chest x-ray showed no findings to explain the respiratory distress. during the two days icu course, the patient complained mostly of dyspnoea. he received supplemental oxygen and non-invasive ventilator support initially, but was eventually intubated and mechanically ventilated. ct findings which included only the lower lung lobes revealed bilateral pleural effusions and bibasilar atelectasis (data not shown). during the first day blood pressure was maintained with i.v. fluid, but on the second day his circulatory condition rapidly deteriorated. despite massive efforts with i.v. fluid, corticosteroids and vasoactive drugs, the patient died in refractory circulatory shock. puuv serology on the first hospital day was igm positive, while igg was negative. the patient had , copies of puuv rna/ml in plasma. bacterial cultures were all negative. at autopsy, puuv rna was detected in samples from lungs, heart, liver, kidney, brain and spleen. the organs were examined for viral antigen, which was found in the vascular endothelium and in mononuclear cells (fig. ) . post mortem examination showed that pulmonary architecture was preserved but with oedema and focal non-occlusive thrombosis. similar to patient , there were pulmonary infiltrates of lymphocytes with the same immunophenotype as described (data not shown). kidneys showed no prominent inflammation. growing evidence show that there are similarities between hfrs and hps, as both syndromes can give rise to hemorrhagia, renal impairment and cardiopulmonary dysfunction, which have been attributed to thrombocytopenia and capillary leakage [ , , , , , , ] . severe pulmonary involvement has not been generally perceived to be a significant feature of hfrs. previously, respiratory symptoms were commonly attributed to fluid overload as a result of renal failure. however, increasing evidence show that lung and heart involvement is common during the acute phase of hfrs [ , , , ] . concerning the cases of european hantavirus infection in our present report, there was only mild or no renal impairment at the time of admission, whereas the respiratory involvement was early and severe, consistent with acute respiratory distress syndrome (ards), fulfilling criteria of hps according to cdc case definition [ ] . as described in hps, the three reported patients suffered from cardiovascular dysfunction, requiring treatment with inotropic and vasopressor drugs [ ] . autopsy results support the cause of death to be cardiopulmonary distress due to hantavirus infection. the lungs of both the deceased patients were oedematous and contained mononuclear cell infiltrates with predominantly cd + t lymphocytes, as described in hps patients [ , ] . many cells expressed granzyme b and tia- , indicating a cytotoxic activity, which could further be supported by high levels of ldh. we chose to demonstrate the immune response in a non-smoker's lungs (patient ), but a similar picture was seen in patient . in the first two patients, the igm response was delayed, while the quantitative real-time rt-pcr for puuv rna was positive, suggesting it as a valuable tool to hasten the aetiological diagnosis [ ] . notably, in patient puuv rna was found in serum from three weeks prior to the acute onset of disease, that is, in incubation phase and consistent with hantavirus incubation time ranging from one to four weeks [ , ] . pulmonary involvement is well documented in european puumala hantavirus infection. from a single outbreak in our county, we report on three cases of life-threatening hantavirus pulmonary syndrome. arguably, additional cases are likely to either go undiagnosed or unreported. a clinical implication of this observation is that hantavirus infection should be included as a differential diagnosis for patients with febrile illness and acute respiratory distress of uncertain cause in endemic areas in eurasia. conflict of interest the authors declare that they have no conflict of interest. open access this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease. the hantavirus study group hantavirus pulmonary syndrome in the united states: a pathological description of a disease caused by a new agent hantavirus infections in europe shedding and intracage transmission of sin nombre hantavirus in the deer mouse (peromyscus maniculatus) model puumala hantavirus excretion kinetics in bank voles (myodes glareolus) local host response in the lower respiratory tract in nephropathia epidemica hantavirus pulmonary syndrome. pathogenesis of an emerging infectious disease hantavirus regulation of endothelial cell functions hantavirus infection induces a typical myocarditis that may be responsible for myocardial depression and shock in hantavirus pulmonary syndrome pulmonary involvement in nephropathia epidemica as demonstrated by computed tomography impaired pulmonary function in patients with hemorrhagic fever with renal syndrome pulmonary involvement in nephropathia epidemica: radiological findings and their clinical correlations hantavirus pulmonary syndrome in new england and europe puumala virus pulmonary syndrome in a romanian immigrant puumala virus rna in patient with multiorgan failure corticosteroids combined with continuous veno-venous hemodiafiltration for treatment of hantavirus pulmonary syndrome caused by puumala virus infection outbreak of puumala virus infection puumala hantavirus viremia diagnosed by real-time reverse transcriptase pcr using samples from patients with hemorrhagic fever and renal syndrome hantavirus pulmonary syndrome, case definition hantavirus pulmonary syndrome: the new american hemorrhagic fever outbreak of hantavirus pulmonary syndrome electrocardiographic changes in patients with haemorrhagic fever with renal syndrome more than half of the patients with acute puumala hantavirus infection have abnormal cardiac findings prospective evaluation of household contacts of persons with hantavirus cardiopulmonary syndrome in chile acknowledgements irene eriksson and ingrid gustafsson are greatly acknowledged for their skilled technical assistance. this work was supported with grants from the swedish heart lung foundation, the heart foundation of northern sweden, the county councils of northern sweden, the county council of västerbotten, and the medical faculty of umeå university. key: cord- -twwa djm authors: tomashefski, joseph f.; dail, david h. title: aspiration, bronchial obstruction, bronchiectasis, and related disorders date: journal: dail and hammar&#x ;s pulmonary pathology doi: . / - - - - _ sha: doc_id: cord_uid: twwa djm the conducting airways play a pivotal role in the spectrum of pulmonary pathology, not only as conduits for injurious agents to enter the lung, but also as an anatomic compartment that is affected by a diverse array of primary or secondary bronchocentric diseases. this chapter discusses aspiration and bronchial obstruction in detail, with emphasis on the aspiration of toxic, infective, or particulate matter. lung abscess, a frequent complication of obstruction or aspiration, is also reviewed. both aspiration and lung abscess are reconsidered within the context of pulmonary infectious disease mainly in chapter on bacterial infections, and to some extent in the chapters on mycobacterial (chapter ), fungal (chapter ), and parasitic diseases (chapter ). the conducting airways playa pivotal role in the spectrum of pulmonary pathology, not only as conduits for injurious agents to enter the lung, but also as an anatomic compartment that is affected by a diverse array of primary or secondary bronchocentric diseases. this chapter discusses aspiration and bronchial obstruction in detail, with emphasis on the aspiration of toxic, infective, or particulate matter. lung abscess, a frequent complication of obstruction or aspiration, is also reviewed. both aspiration and lung abscess are reconsidered within the context of pulmonary infectious disease mainly in chapter on bacterial infections, and to some extent in the chapters on mycobacterial (chapter ), fungal (chapter ), and parasitic diseases (chapter ) . bronchiectasis, which is frequently grouped with other forms of obstructive lung disease (see chapter ) , is discussed in this chapter as a major pathway of airway remodeling that may be of inflammatory, postobstructive, or congenital etiology, and is, itself, an important sequela of aspiration. the topic of bronchiectasis cannot be considered without reference to inflammatory lesions of the small airways, which may follow or precede the development of bronchiectasis (see chapter ) . the present chapter also discusses a variety of pulmonary disorders that may simulate, initiate, or complicate bronchiectasis. involvement of the large airways in systemic diseases such as amyloidosis (chapter ), sarcoidosis (chapter ), collagen vascular diseases, including relapsing polychondritis (chapter ), connective tissue disorders such as marfan's syndrome (chapter ), or as a complication of environmental dust exposures (chapter ) is reviewed in each of their respective chapters. an excellent review of bronchiectasis in systemic diseases is that by cohen and sahn.l a discussion of asthma and its related conditions of mucoid impaction, bronchocentric granulomatosis, and allergic bronchopulmonary aspergillosis can be found in chapter . unique congenital lesions of the airways in addition to the enigmatic intralobar sequestration are discussed respectively in chapters and on pediatric lung pathology. a variety of degenerative or so-called metabolic disorders that affect the large airways, such as tracheobronchopathia osteoplastica, are reviewed in chapter . finally, bronchial tumors are extensively covered throughout volume , which is devoted to pulmonary neoplasia. aspiration is the inhalation of liquid or solid materials into the lower respiratory tract, usually from the oral or nasal cavities, oropharynx, esophagus, or stomach. logically, the course of aspiration is determined by such laws of physics as inertia and gravity. larger, more solid materials, and finer more liquid materials, all follow the straightest and most dependent course after they enter the trachea. as explained in chapter , the right mainstem bronchus continues on a more direct course than the left ( to degrees compared to to degrees for the left mainstem bronchus); the wider angle of the left bronchus allows it to extend around the heart. larger, more solid objects that pass the larynx often lodge in the right mainstem bronchus, while smaller solid objects most frequently continue into the right lower lobe bronchus. this has been well demonstrated in the aspiration of foreign objects by children, generally in the age group of to years. , during this age range, children examine almost everything by placing items into their mouths. in both children and adults, larger objects are sometimes stopped at the larynx and may be expelled by strong coughing. in adults, sudden death due to laryngeal obstruction by aspirated food (most frequently meat) has been termed the cafe coronary.s more than % of aspirated foreign bodies occur in children, and among all age groups only % are spontaneously expectorated. , sharper objects may perforate a bronchus and cause bleeding, or even penetrate the pleural cavity and cause pneumothorax. a foreign body may migrate within the bronchi and cause wandering infiltra tes. young children most frequently aspirate peanuts, beads, and other fragments of wooden or plastic toys. peanuts and sunflower seeds lead the list in western countries, whereas in arabic countries children most often aspirate melon seeds. older children may inhale flowering grass fragments, which wedge themselves into more distal bronchi and resist expectoration. in any age group, teeth, fragments of bone ( fig. . ) , food, blood clots, tissue fragments, nasal pack components, lipids from oily nose drops or orally administered cathartics, bacterial fragments, and gastric content most commonly enter the lung. noguchi et a . reported a subacute reaction to mud aspiration in a victim of near-drowning, while aspiration of sand in children has been reported to cause a radiographic "sand bronchogram.,, drowning, often thought of as occurring in fresh or salt water, has also occurred in large vats of beer, wine, liquid chocolate, and other interesting concoctions. a literary example of this is shakespeare's richard iii, in which the duke of clarence is finally dispatched in a large vat of wine (the "malmsey butt,,). brock . in , beautifully illustrated the mechanics of aspiration with abscess formation, which most often followed the dependent course described. once within the lung, finer and more fluid ingredients flow into the first dependent orifices that are encountered. in the supine position, these are most often the posterior segment of the upper lobe and superior segment of the lower lobe ( fig. . ). in the more upright position, material flows preferentially into the basilar segments of the lower lobes. the basilar segments divide rather evenly, and localization within these segments is not as discrete as in other areas of the lung. when a person is in the lateral decubitus position, the axillary branches of the subsegments of apical and posterior upper lobe bronchi are favored. the more anterior portions of the lung are usually spared the effects of aspiration, unless aspiration occurs in the prone position, as in near-drowning. aspiration need not only be from external sources. rupture of large fluid-filled abscess cavities, tuberculous cavities, or other cysts might be followed by intrabronchial aspiration of infective or other types of material into dependent zones (see fig. . in chapter ). the most common conditions predisposing to aspiration include impaired consciousness, most frequently from alcohol, drugs, or anesthesia, followed by central nervous system disorders (e.g., epilepsy, stroke, dementia) or neuromuscular diseases. next in frequency is aspiration secondary to obstructing masses or other functional defects of the esophagus or stomach. episodes of aspiration are eventually confirmed in about % of children, but in only about % of adults. ,ls the difference in documentation is probably related to the altered level of consciousness in adults causing temporary amnesia. the common clinical manifestations of an aspirated foreign body constitute a triad of cough, wheezing or rhonchi, and decreased air entry. the wheezing that is sometimes associated with aspirated foreign bodies in children may be ameliorated with theophylline, leading to diagnostic confusion with asthma. early experimental animal studies showed that aspiration of material into the lungs regularly occurs when materials are placed in the nares or accessory sinuses during anesthesia. , myerson found blood immediately postoperatively in the tracheobronchial tree in % to % of humans who underwent tonsillectomy, including those under general or local anesthesia. several experimental studies have also proven that normal adults aspirate with some regularity. quinn and meyer in introduced lipiodal (iodinated poppy seed oil) into the noses of sleeping subjects and found the material often entered the lungs. amberson in reported placing barium in the mouths of normal subjects during sleep, with similar results. radiologists sometimes observe aspiration while performing upper gastrointestinal tract barium studies (see below). as reviewed by bartlett, various markers placed in the stomach the night prior to surgery have been identified in lungs sampled during surgery the next day in % to % of patients. • huxley and associates s refined these techniques by placing indium-ll chloride in the posterior nasopharynx periodically during sleep. on lung scanning, this tracer was found in the lungs of % of normal individuals and in % of those with some alteration of the central nervous system. those in the normal group who did not aspirate were fitful sleepers who tended not to enter deep sleep. the implication is that most normal people who enter deep sleep, aspirate. nasogastric and oropharyngeal tubes, including endoscopes and tracheostomy tubes, increase the risk of aspiration. normal individuals tend to clear such occult aspirations without difficulty or sequelae. an acute cough reflex is most important, but also valuable are intact mucociliary activity and alveolar macrophage response (see chapter ) . the pathologic effects of aspiration are dependent on the character, volume, and frequency of the aspirated components. in this chapter, food and medicinals, gastric acid, lighter hydrocarbons, and heavier oils are separately considered. aspirated bacteria are covered in the section on abscess formation. retained squamous if. tomashefski, jr. , and d.h. dail cells from meconium in newborns are a sign of in utero distress. squamous cells in the lungs of adults are an indicator of oral, oropharyngeal, or esophageal aspiration ( fig. . ). in the absence of other evidence of aspiration, finding mixed bacteria in lung tissue is very suggestive of aspiration of oral content. lung injury following aspiration has been subdivided by marik into aspiration pneumonitis and aspiration pneumonia. aspiration pneumonitis refers to acute chemical lung injury due to inhaled gastric acid with or without injury due to aspirated particulate matter, whereas aspiration pneumonia is an infectious process resulting from the inhalation of oropharyngeal secretions colonized by pathogenic bacteriay aspiration of gastric acid, a major cause of acute respiratory distress syndrome (ards), has been well studied in humans and in experimental animals. in experimental models, it has been suggested that a ph of . or lower and a significant quantity of acid (estimated to be to ml in an adult human or to mllkg in an experimental animal) are necessary to induce a chemical pneumonitis. when gastric acid with methylene blue was put into anesthetized dog tracheas, dye was visible on the pleural surface to seconds later. atelectasis oflung tissue was noted in minutes. human studies date from the classic study of mendelson in , and acute gastric acid aspiration is sometimes called the mendelson syndrome. mendelson studied cases of massive gastric aspiration in obstetric patients ( . % incidence) under ether anesthesia. respiratory distress occurred soon after aspiration, with accompanying cyanosis, tachypnea, and tachycardia. bronchospasm occurred in most of his patients. chest radiographs initially showed rather widespread mottled densities, most of which cleared by to days. only eight of patients became infected. this study was conducted before antibiotics were readily available, but other studies in humans with or without antibiotics or steroids have confirmed his findings. in general, later studies have found a lower incidence (about %) of bronchospasm, more frequent early temperature elevation, and increased mortality (in the range of % to %) despite therapy. hypotension and hypoxemia occurred more commonly than in mendelson's series. the combination of acid and particulate aspiration exacerbates alveolar capillary injury. bynum and pierce ! studied patients with welldocumented gastric acid aspiration. in their series, all these events followed altered consciousness, most often by a sedative drug overdose or a general anesthesia. as in mendelson's experience, respiratory symptoms developed rapidly and were very similar in all patients despite eventual outcome. three clinical outcomes were described: % died shortly after aspiration; % had rapid clinical and radiographic clearing on the average of . days; and % had rapid improvement followed by deterioration relating to bacterial infection. of this latter group % died, whereas % of the whole group died; death occurred between day and , averaging . days. these authors found initial steroid or antibiotic therapy did not affect eventual outcome. in both humans and animals, edema, congestion, hemorrhage, and degeneration of bronchiolar lining cells and alveolar type i and ii cells follows early in the course (fig. . ) . after hours alveoli are filled with polymorphonuclear neutrophils (pmns) and fibrin. hyaline membranes are formed by hours, providing a histologic picture of diffuse alveolar damage (dad) (see chapter ) . resolution begins at about hours and may either lead to figure . . gastric acid aspiration. acute effects show hemorrhagic necrosis of lung parenchyma. complete restoration of alveoli or leave some residual scarring. of course repeated aspiration may lead to combined acute, subacute, and chronic appearances. in his review, bartlett referred to this rapid and irreversible type of injury as comparable to a "flash burn," and noted that little can be done to prevent injury once acid has made contact with the lung (fig. . ). the reactions just described plus fluid extravasation help to dilute the acid, as do buffering components from serum and cell breakdown products, but these only occur after injury. more recent studies have indicated that the mechanism of lung injury following acid aspiration extends beyond the direct chemical effects of acid to involve various inflammatory mediators including tumor necrosis factora (tnf-a), interleukin- (il- ), adhesion molecules, and cyclooxygenase and lipoxygenase products. - the role of reactive oxygen species, and the adverse effect of oxygen administration after an episode of aspiration were demonstrated experimentally by nader-djalal et al. a primary role is currently placed on neutrophils and complement in mediating lung injury in this setting. , , . thus, aspiration pneumonitis represents a biphasic response composed of early-onset direct pulmonary injury due to acid, followed by delayed injury due to acute inflammation. , low-grade chronic aspiration of gastric content may escape easy detection. these occult aspirations may lead to interstitial fibrosis, and perhaps account for the % to % incidence of associated and unexplained pulmonary fibrosis in patients with esophageal abnormalities, most commonly hiatal hernia or simple reflux, , the role of reflux in asthma, chronic bronchitis, chronic cough, recurrent pneumonia, cystic fibrosis, and sudden infant death syndrome has been reviewed by allen et al. [see also section on cholesterol (endogenous lipid) pneumonia in this chapter]. children, particularly those aged to years, are likely to ingest various lighter hydrocarbons, mostly lighter volatile petroleum distillates. these products include kerosene, turpentine, and other paint thinners; furniture or shoe polish; lighter fluid; gasoline; dry cleaning fluids; and some insecticides. the toxicity is greater with those products that disperse most easily, specifically those that cause the greatest decrease in surface tension, or have the least viscosity or the highest volatility. although ingestion precedes aspiration, eade and associates nicely reviewed the reasons that aspiration is the most important toxic pathway of injury. symptoms develop rapidly and radiographs often show localized pulmonary infiltrates, often in the aspiration zones mentioned earlier. experimentally, the lethal dose by figure . . lentil bean. a. at top is thick outer coat; below, cotyledon compartments with starch cells. b. cellulose framework of legume cotyledon compartments is birefringent under ingestion alone is much higher than that usually ingested by persons who subsequently aspirate. sizable doses of distillates have been placed in the stomachs of experimental animals whose esophagi were ligated, and these animals did not suffer pulmonary toxicity. the pulmonary changes, almost identical to those of gastric acid aspiration, include diffuse congestion, hemorrhage, edema, hyaline membrane formation, and bronchopneumonia. atelectasis occurs early, apparently by direct toxic effect of these light hydrocarbons on s urfactan t. about % of affected children have abnormal chest radiographs, but only % to % have pulmonary signs or symptoms. , in the past, death has been reported in about % to % of cases, but in two large series death occurred in . % and %, respectively. a death usually occurs within hours of exposure. most survivors experience few sequelae. various food particles, such as skeletal muscle, fat tissue, or fragments of bone, may be aspirated and identified histologically in lung tissue. cooking or digestion may result in poorly defined particles that appear foreign but defy further definition. as was well demonstrated by knoblich and others, - portions of legume seeds are one of the better markers of food aspiration. the legumes most commonly eaten are various peas, beans, and peanuts; because they are relatively inexpensive and nutritious, they occur in many products. (the word lentil is sometimes used in these references, but it is also j.f. tomashefski, jr., and d.h. dail polarized light. c. degenerated aspirated vegetable material retains compartmental structure and stains strongly with gomori methenamine silver. the name of a specific type of bean). the legume seed ( fig. . ) consists of a thick cellulose outer coat, the cellulose walls of the inner food storage compartments, and the starch cells contained within these food compartments. cooking softens the outer shell and cell walls of the beans or peas and allows easy disruption of the content, with a resultant jelling effect of the starch particles (called "thickening" in cooking). the cellulose walls of the outer coat and starch compartments are more difficult to totally disrupt or digest, and therefore act as both a chronic irritant and a good marker of aspiration. aspiration of these fragments in both experimental animals and humans produces an acute exudative response within hours (fig. . ), followed by a foreignbody giant cell reaction ( fig. . ) . these cell wall fragments are gomori methenamine silver (gms) positive, and usually birefringent under polarized light (fig. . ). the glycogen compartments, when intact, are vividly periodic acid-schiff (pas) positive ( fig. . a) . starch cells may be mistaken histologically for parasite larvae (fig. . b ). at about days (experimentally) an organized granulomatous reaction occurs around the aspirated particles, and eventually the starch cells disappear, leaving only the cellulose fragments. the walls of carrots, onions, and most nonlegumes digest more readily and do not give rise to as much exuberant chronic reactions as seen with legumes. they do, however, undergo the same type of early changes if aspirated, and initiate acute and subacute pneumonia during digestion of the starch cells. some of the most offensive aspirated food fragments have undergone alterations in preparation, and some of the worst combinations are cooking oils and salts, as, for example, an aspirated potato chip ( fig. . b). eventually these areas become small fibrotic or fibrocalcific nodules, which may appear almost as degenerated parasites or as sclerosed blood vessels ( fig. . ). they may appear as small hyalinized granulomas or possibly as entrapped calcospherites, usually within a fibrous stroma. at times the conditions for aspiration are chronic, and recurrent aspiration leads to the acute and chronic changes together or in close proximity in the same specimen. respiratory bronchioles exhibit marked remodeling associated with proliferative bronchiolitis obliterans, foreign-body granulomas, and entrapped food particles. the macroscopic appearance is that of scattered yellow miliary nodules that are reminiscent of miliary figure . . chronic reaction from aspirated lentil beans. two hyalinized starch cells may be mistaken for fibrosed, obliterated blood vessels. matsuse and colleagues have designated this condition as diffuse aspiration bronchiolitis, which they observed in of consecutive autopsies ( . %). the mean age of patients with this condition was . years. affected individuals frequently were bed-ridden or had dysphagia due to underlying neurologic disorders. high-resolution computed tomography (hrct) may show a striking pattern of centrilobular miliary opacities. in chronically ill or hospitalized patients, aspirated medicinal products, such as intact or partially digested pharmaceutical tablets, may be associated with aspiration pneumonitis. inert tablet components such as microcrystalline cellulose, talc, and crospovidone may be identified histologically in conjunction with aspirated food, pneumonia, and foreign-body reaction (see chapter ) microcrystalline cellulose, like legume components, is brightly birefringent on polarization, and also positive with gms stain. it can be distinguished from vegetable particles, however, by its fiber-like, or "matchstick-like" appearance. aspirated tablet filler components, which reside within alveoli and bronchioles, usually can be discriminated from identical particles introduced by illicit intravenous injection of aqueous tablet suspensions, which localize within small pulmonary arteries or in a perivascular, interstitial distribution (see chapter ) . aspirated sodium (or calcium) polystyrene sulfonate (kayexalate), a potassium-binding cation exchange resin, has a distinctive histologic appearance characterized by large dark eosinophilic or basophilic, angulated, "glassy" particles, that sometimes appear striated ( fig. . ). [ ] [ ] [ ] [ ] duct. b. angulated, "glassy" kayexalate particles have elicited a foreign-body giant cell reaction. kayexalate particles are weakly birefringent, and positive with pas, acid-fast, and gram stains, but negative with von kossa stain. kayexalate has also been identified in tissue sections by infrared microspectrophotometry. l in humans and experimental animals, kayexalate has been shown to produce a necrotizing or organizing pneumonia. l , more frequently, kayexalate is a cause of mucosal ulcers of the gastrointestinal tract. , kayexalate histologically closely resembles the less frequently encountered material cholestyramine. cholestyramine, however, is more opaque and pink rather than red on acid-fast staining. the aspiration of an intact ferrous sulfate tablet may induce severe, potentially fatal, bronchial mucosal ulceration and hemoptysis. - the endoscopic appearance of the ulcerated bronchus typically is of a golden-brown discoloration ( fig. . a ). histologically, ulceration, necrosis, foreign-body reaction, and brown or yellow pigment that stains blue with prussian blue stain may be seen ( fig. . b ). the pathogenesis of this syndrome, colorfully termed "iron lung," is thought to be a chemical burn induced by oxidation of iron from the ferrous to the ferric form. the radiographic contrast material barium sulfate (bas ) is also readily visualized by chest x-ray in patients who aspirate this material. barium is a fairly inert white powder that tends to produce minimal functional lung impairment. grossly, following barium aspiration, lung parenchyma is chalky, tan-gray, and slightly indurated ( fig. . a ). histologically, fine, golden-tan, refractile, weakly birefringent particles of barium sulfate are present within the cytoplasm of alveolar macrophages. with chronicity, or upon repeated aspiration, barium-laden macrophages migrate into the interstitium (fig. . b ). inhalation of barium in the industrial setting (barytosis) is discussed in chapter . activated charcoal is sometimes given therapeutically for oral drug overdose. however, if the airway is not protected, charcoal may be aspirated in copious amounts, causing "charcoal lung," in which coarse black carbon particles obstruct small airways. oils that may be aspirated include mineral oils such as used in nose drops and cathartics, vegetable oils used in cooking, and animal oils such as cod liver oil or fat-soluble vitamin preparations. mineral oil, derived from petroleum products, is the most common agent of exogenous lipid pneumonia. oil aspiration was first described by laughlen in in a child who received oily oral and pharyngeal preparations for diphtheria; it was confirmed by him experimentally. the role of oil-based contrast media used for bronchoscopy was well reviewed by spencer. animal oils cause a more severe inflammatory reaction than mineral or vegetable oils, and this difference appears related to the number of free fatty acids and increased viscosity of animal oi . , . mineral oils are fairly inert, as they have no fatty acids, and are rapidly emulsified and consumed by pulmonary macrophages. vegetable oil droplets may remain in alveoli for months without eliciting significant reaction, but eventually, due to low-grade chronic irritation, they cause scarring. animal and mineral oils, but only rarely vegetable oils, may be seen in regional lymph nodes. aspiration of oils commonly occurs in older individuals, who may take oily nose drops or cathartics at bedtime. aspiration most frequently gravitates to the basilar segments of the lower lobes suggesting these patients usually sleep in a more upright position or experience aspiration before reclining. because of its weakly irritative nature, mineral oil can enter the tracheobronchial tree without stimulating glottic closure or cough reflex. only two of cases documenting exogenous lipid pneumonia at autopsy had reported significant clinical symptoms during life. because these oils float in the stomach, it is possible they also are aspirated via reflux from the stomach,z . in unselected autopsy series, oil aspiration has been documented in . % to . % of adults. . other oily products that have been incriminated as being aspirated in the lung include fragments of lip balm, burning fats (an occupational exposure), a rapid drying agent in spray enamel paint, oils applied to tobacco products (blackfat tobacco), and possibly hair spray. - children may aspirate oily medications if they are force-fed these while resisting and crying violently. atypical mycobacteria, particularly rapid growers such as mycobacterium jortuitum or m. chelonae, have been reported associated with oil aspiration pneumonia (see chapter ) . [ ] [ ] [ ] [ ] [ ] symptoms of lipid aspiration include fever ( % of patients), weight loss ( %), cough ( %), and dyspnea ( %), although in one large study lipid pneumonia was an incidental finding, without associated symptoms, in % of patients. lung function tests may indicate either obstructive or restrictive changes. computed tomography (ct) scans usually show alveolar consolidation or groundglass opacities in the lower lobes. subfissural clear zones may be interposed between densities, creating a "sandwich effect" on ct scan. grossly, lungs affected by oil aspiration are often gray to yellow and rather solid (fig. . a ). dense localized fibrotic lesions (paraffinomas) may grossly mimic cancer or complicated pneumoconiosis. , occasionally oily droplets exude from the cut surface. microscopically the lipid droplets are often dissolved by tissue processing. one exception is cod liver oil, which remains as salmoncolored droplets on hematoxylin and eosin stain after tissue processing. fats may be seen with rapid watersoluble or oil red stains on frozen section ( fig. . d); variably sized fat droplets and varying numbers of multinucleate giant cells are present ( fig. . a-c). when only a small amount of fat has been aspirated, the reaction may be contained in alveolar macrophages. this is most commonly seen in mild degrees of aspiration with a diluted fatty substance, as might be seen with milk aspiration. when larger doses of thicker and more toxic oils are aspirated or when oil aspiration is repeated, the areas become densely fibrotic with reduction of the background lung architecture ( fig. . a ). occasionally, cor pulmonale results, . transbronchial biopsies may provide enough tissue to make this diagnosis. precise identification of specific lipids can be determined by infrared spectrophotometry. in the differential diagnosis is artifactual collapse of lung around remnant air bubbles (see fig. . c in chapter ). exogenous lipid pneumonia can usually be distinguished histologically from endogenous lipid chronically ingested mineral oil as a laxative. note yellow oil layered on the surface of fluid. (cholesterol) pneumonia by subdivisions within fat droplets, coarse cytoplasmic vacuoles in macrophages, multinucleated foreign-body giant cell response, and, in more chronic cases, a greater degree of chronic inflammation and fibrosis with destruction of background lung parenchyma in exogenous lipid pneumonia ( fig. . ). at times some lipid is incorporated/entrapped in the interstitium ( fig. . c ), resembling a similar appearance in diffuse pan bronchiolitis and xanthomatous bronchiolitis obliterans (see below and chapter ). diffuse panbronchiolitis is centered more on terminalrespiratory bronchioles and is composed mostly of finely vacuolated fat. sputum cytology or cytologic aspiration specimens have been used to confirm lipid pneumonia. on bronchoalveolar lavage an oily layer is sometimes present on the surface of the collection tube ( fig. . b ). in , losner et al., using oil stains, found lipid-rich macrophages in of suspected cases in contrast to two of control patients. more recently, corwin and irwin restudied this situation using bronchoalveolar lavage in various lung diseases including aspiration, hemoptysis, cancer in the lung (either primary or secondary), bronchiectasis, interstitial fibrosis, and sarcoidosis. when compared to normal lungs, samples from diseased lungs in general contained increased fat-filled macrophages. these authors warned that the simple presence of fatty macrophages in cytology preparations is not diagnostic of lipid pneumonia; however, the quantity of lipid was more abundant in aspirators than in these other groups. their figure . . oil aspiration. a. subacute effects of oil aspiration show varyingly sized fat droplets, inflammation, lymphoid aggregates, and fibrosis. most of the lung architecture has been obliterated. b. higher power view shows foamy lipid-filled macrophages and multinucleate foreign-body cells. c. in the chronic state, oil droplets are still seen within the interstitium with "aspirator" group consisted mainly of patients with a history of upper gastrointestinal tract disease, including reflux in most. in young children the presence of numerous (> ) oil red o-positive lipid-laden macrophages on tracheal aspirate is highly specific for aspiration. corwin and irwin emphasized that the size of the fat droplets in lavage fluid cannot be used to distinguish endogenous from exogenous lipid pneumonia. wherever it occurs, an abscess is a localized accumulation of inflammatory cells, initially having abundant neutrophils, that is usually accompanied by tissue destruction. in the lungs, "cross-country" necrosis occurs during the formation of an abscess (figs. . bronchi, and arteries. in contrast, cavities that are more chronic and more slowly formed, such as tuberculous cavities, often leave remnants of fibrotic bronchopulmonary rays coursing through the cavity itself (see chapter ) . some more slowly forming nontuberculous abscesses can do this, but most of the abscesses in the lung have an acute initial phase that destroys most of the tissue in the area ( fig. . b ). bronchi frequently connect with abscess cavities, allowing drainage of the necrotic material, leaving an empty or partially empty cavity with or without an air/fluid level on chest radiograph (figs. . and . ). occasionally, inflammation seals off all such bronchial connections, resulting in a solid mass that may be suspected of being a tumor. adjacent organization in acute and subacute abscesses often accounts for an enlarged surrounding radiographic density (figs. . and . ). there are many etiologies for cavity formation in the lung, and abscess formation is but one of them. other pulmonary abscess formation, which were already well known by , were summarized in this review. by , a total of cases had been published. aspiration is the most common cause of lung abscess. other instigators of this type of damage include b. gross specimen. note cavity is mostly drained, with freshappearing, thin lining without fibrous wall. note also persistence of some trabeculae, presumed bronchopulmonary rays, and variable but narrow surrounding inflammatory reaction. penetrating trauma, postoperative states, obstruction, hemorrhage or infarction, necrotizing pneumonia, infected emboli, infection of a preexistent cyst or bulla, or extension from nearby infected areas in the mediastinum, chest wall, diaphragm, or infradiaphragmatic loca- tions. nonaspiration types of pulmonary abscesses of course do not follow the aspiration patterns of distribution, but occur as their coexistent factors dictate. for example, if there is an infarct or an obstructing tumor, infection would occur in the affected areas. septic emboli are hematogenously spread, and resultant abscesses are often multiple, small, and peripherally distributed (see fig. . in chapter ). as aspiration is the principal cause of pulmonary abscess formation, it is reasonable that conditions that favor abscess formation are identical to those favoring aspiration. the locations are similar; men are more frequently affected than women; and the right lung is involved twice as often as the left. - the posterior segments of the right upper lobe and superior segments of the right lower lobe are involved most frequently, followed by the corresponding segments on the left side. the single most commonly associated event is an alteration of consciousness; the second most frequent association is poor dental hygiene; and the third is an immunodeficient status. poor dental hygiene was noted in cases without other apparent causes of pulmonary abscess in the early studies between and . - the spectrum of bacteria involved in abscess formation is almost identical to that of endogenous oral flora. - moreover children and edentulous older people do not often develop lung abscesses.ll in children cases caused by aspiration must be separated from other cases of cavitary necrosis, such as pneumatoceles in primary staphylococcal pneumonia. - l anaerobic bacteria are the only organisms cultured in about one half to two thirds of lung abscesses; in the remaining cases either aerobic or facultative aerobic bacteria are isolated, or no bacteria are culturedys the anaerobic bacteria most frequently found are peptostreptococci (i.e., gram-positive anaerobic cocci), pigmented gram-negative bacilli (including bacteroides), and the fusobacteria. . l . spirochetes were described morphologically in earlier studies and seemed to be significant, as they were present in the growing rims of necrosis; however, they have not been mentioned much recently, perhaps because they are difficult to culture.los. about half of cultures with anaerobes also contained aerobic bacteria capable of necrosis, specifically staphylococcus, streptococcus, haemophilus, pseudomonas, klebsiella, and escherichia spp. patients with predominantly anaerobic pulmonary abscesses often present with indolent symptoms, in contrast to those with necrotizing aerobic abscesses. the latter may be more common in nosocomial-acquired lung abscess. s - immunocompromised patients often acquire gram-negative necrotizing pneumonias and vasoinvasive necrotizing fungal pneumonias, both of which may lead to cavitation. one clue to aspirated bacteria in lung abscesses is finding mixed-type organisms on smear gram stain, tissue gram stain, or culture. the oral cavity abounds with mixed bacteria and is estimated to contain some different types of organisms. this is one reason sputum cultures are notoriously difficult to interpret, and why even oral contamination of a bronchoscope interferes with most lung cultures. transtracheal and transthoracic needle aspirations, however, correlate well with blood culture results. i . the third most frequent factor in abscess formation is host response. factors that compromise normal host defenses include alcohol ingestion, diabetes mellitus, renal failure, malnutrition, malignancy, and other debilitations, along with treatment with immunosuppressive agents for any reason. patients with these factors do more poorly with pulmonary abscesses (and most other insults) than those without. [ ] [ ] [ ] pathologically, acute cavities have only a thin transition zone into the reactive adjacent lung parenchyma (see numbers of neutrophils and macrophages, along with tissue necrosis. the nearby lung parenchyma has variable findings depending on the rapidity of spread. rapidly growing cavities necrose nearby lung parenchyma, destroying any early attempts at organization. there may be adjacent hemorrhage, exudate, and fibrin extravasation. in those that are slightly more stable, beginning organization occurs in the surrounding lung parenchyma, sometimes chronic cavities heal with a thin fibrous border and may retain a coagulum of necrotic debris in their lumen. this apparently indicates that the nearby bronchi have been sealed off. chronic cavities may resolve by collapse and fibrosis, or may remain open. in the open variety they may become reepithelialized, first with a squamous lining and then with ciliated respiratory lining. in the latter case, the distinction from bronchiectasis or bronchocele may be somewhat confusing, but multiple bronchial connections in a chronic abscess cavity distinguish these entities. spontaneous healing may occur, but healing is greatly aided by appropriate antibiotic dosage. weiss l noted in appropriately treated and monitored cavities that % of cavities disappeared by weeks of therapy, % by weeks, % by weeks, and % by months. surgery is sometimes indicated for nonhealing cavities or when complications develop, such as hemoptysis, persistent sepsis, bronchopleural fistulas, or empyema. the incidence of abscess formation has greatly decreased during the past years, partly because antibiotics are available and frequently used early in pulmonary infections, and partly because factors leading to of fibrin ( ) resting on cellular granulation tissue ( ). b. wall of chronic abscess cavity composed of dense, fibrotic, mature granulation tissue. abscess formation are better understood; for example, surgery is avoided with the patient in the upright position or on patients with food in the stomach. in the pre antibiotic era approximately % of the patients treated either conservatively or by surgery died, and another one third had chronic residual lung disease. more recently the prognosis is much better, but the mortality associated with established abscess formation remains in the range of % ? although the term gangrene of the lung has been applied to necrotizing, sometimes putrid, pneumonia in any location, it has more recently been used more specifically to indicate massive necrosis and sloughing of lung associated with severe infection. this entity almost always involves the upper lobes, usually on the right side, and radiographically evolves through typical changes of diffuse infiltrate into multiple cystic spaces that become confluent, leaving a crescent of lung density compressed medially, or occasionally laterally, with a final walled-off area of pus and necrotic lung in an otherwise empty structureless space. curry and colleagues l and penner et a . attribute the first description of pulmonary gangrene to laennec in the s. phillips and rao,l l who reported four cases, refer to sir william osler's description of diseased lung "converted into a horribly offensive greenish, black mass, torn and ragged in the centre" (fig. . ) . the patients may cough up large pieces of necrotic lung, which in one case was therapeutic. these fragments histologically show ghosts of lung parenchyma and thrombosed vessels. vasculitis has been described in some reports. , assorted microorganisms cultured from these cases include klebsiella pneumoniae, pseudomonas aeruginosa, haemophilus injluenzae, staphylococcus aureus, streptococcus pneumoniae, and mucor species, anaerobic bacteria probably also playa significant role. in their reviews, phillips and rao l l and penner and colleagues note that similar predisposing factors as those with community-acquired pneumonia, such as aspiration and abscess formation, pertain to this entity, but the location helps distinguish it from the other typical sites of aspiration, when in the upper lobes, it appears to progress through necrotizing pneumonia with thrombosis of arteries (pulmonary and bronchial) and veins, [ ] [ ] [ ] although not strictly abiding by the foregoing definition (of localization in upper lobe), in one case total unilateral lung gangrene was attributed to hilar vessel involvement following treatment of a massive hilar recurrence of hodgkin's disease. pulmonary gangrene is life threatening, and surgical removal of necrotic lung tissue if. tomashefski, jr. , and d.h. dail figu re . . pulmonary gangrene, lung parenchyma is greenish-black, necrotic, and cavitated in this specimen from a patient with central bronchogenic carcinoma, bronchial obstruction, pulmonary artery invasion, and thrombotic occlusion. note hyperemic rim between necrotic lung and apical lung parenchyma. proteus, e coli, and enterococcus cultured, is often indicated since only a few patients survive with antibiotic therapy alone, an entire lung, or even one lobe, may rotate around the hilar structures and cause congestion, hemorrhage, or infarction, cases of torsion involving only single lobes most commonly occur postoperatively when a portion of ipsilateral lung has been removed, , torsion is an infrequent event. a review of the literature in by schamaun documented cases of postoperative torsion, five posttraumatic occurrences, and four spontaneous events. in a poll of british thoracic surgeons, however, of responders ( % ) had encountered at least one instance of torsion, torsion has also been documented to occur in transplanted lungs or as a result of pneumothorax or mass lesions. , due to the simultaneous compromise of pulmonary and bronchial arteries and the pulmonary vein, fatal gangrene may occur (see above), the entity of obstructive, golden, or endogenous lipid pneumonia is most commonly seen secondary to tumor obstruction of large airways, but any of the causes of obstruction can lead to obstructive pneumonia. the obstructive effect accounts for a much larger infiltrate on the usual chest radiograph than is caused by tumor alone. the involved area is primarily supplied by the affected bronchus, and the larger the obstructed bronchus, the greater the area involved. however, even when obstruction occurs in the smallest bronchioles, there may be secondary effects in the centriacinar regions. cholesterol pneumonia may also spread into the adjacent nonobstructed segment, and occasionally throughout the lobe. the latter pattern of disseminated spread is often associated with more poorly differentiated or cavitated carcinomas. the involved lung is reduced in size, but not to the extent expected in simple atelectasis. the difference is due to the infiltration by abundant inflammatory cells. the microscopic hallmark of obstructive pneumonia is flooding of air spaces initially by edema followed by fat-filled, finely vacuolated, so-called foamy alveolar macrophages (fig. . a golden-yellow color, hence the term golden pneumonia. obstructed secretions, increased cell breakdown products, and possibly leakage from vessels and interstitium, may give rise to the fat seen in this characteristic reaction. as these products are derived from the lung, this is called endogenous lipid pneumonia. early in its course the alveolar outlines are well defined though distended with foamy macrophages. if the pneumonia is rapidly reversed, lung function may return. gradually, permanent damage ensues, including fibrosis and vascular sclerosis, and it is then difficult to restore lung function even though the obstruction may eventually be reversed. some degree of intraalveolar organization may also be present in approximately % of cases. l features of superimposed infection, such as acute inflammation, necrosis, or abscesses are seen in a minority of cases. in contrast to exogenous (aspiration) lipid pneumonia, endogenous lipid pneumonia is characterized by finely vacuolated fat, absence of a foreign-body response, and minimal inflammation and fibrosis of the underlying lung architecture (figs. . and . b,c). sometimes there are changes that suggest pulmonary alveolar lipoproteinosis (see below). . at times parenchymal changes very similar to those just described may be present, although no obstruction of bronchus can be identified, so-called idiopathic cholesterol pneumonia. , in , robbins and sniffen described cases of chronic nonobstructive cholesterol pneumonia, of which ( %) occurred in men aged to years, the only female being a -year-old girl. in extent, five of their cases involved most of the lobe and six cases included a portion of one or more segments, often with pleural adhesions; some had small abscess cavities. the involved areas were wedge-shaped with their bases on the pleura and were described as bright yellow; they were accounted for histologically by abundant, finely vacuolated foamy macrophages, but otherwise these areas presented as mass effects. mucoid or mucopurulent exudate filled some bronchioles and bronchi, but no other cause of obstruction was present. bronchiectasis was absent, although focal necrotizing bronchitis was noted. the lobar distribution was not documented. these authors argued against aspiration as they noted the usual aspiration to be more diffuse, often multifocal, and more often seen in lower lobes. lawler able foreign material in ( %) and strongly suspected aspiration in another six for a total of % in this series. all except two cases ( %) of confirmed aspiration were solitary lesions. it seems reasonable that at least some of both chronic organizing pneumonia and idiopathic cholesterol pneumonia, even when not so confirmed, may be the result of aspiration, usually involving ingredients other than exogenous lipid. secondary chronic organizing pneumonia, involving large portions of a lobe or presenting as a mass lesion, is not to be confused with the distinctive form of interstitial lung disease termed cryptogenic organizing pneumonia (bronchiolitis obliteransorganizing pneumonia), which is further discussed in chapter . fisher et al. have described a series of patients (six children [< years of age] and two adults) with progressive diffuse interstitial lung disease having a combination of histologic features including endogenous lipid pneumonia, interstitial cholesterol granulomas, and patchy alveolar proteinosis (fig. . ). three patients in this study had severe combined immunodeficiency, two had pulmonary hypertension, and one each had cystic fibrosis (cf), trisomy q, and ventricular septal defect (vsd), or lysin uric protein intolerance. all patients exhibited delayed growth, five had digital clubbing, six had depressed appetite or anorexia, five were anemic, and three experienced hemoptysis. six of eight patients also had evidence of gastroesophageal reflux, which the authors suggest is important in the pathogenesis of this condition. pulmonary function tests in four patients showed either restrictive or mixed restrictive and obstructive physiology. chest x-rays predominantly showed nodular pulmonary opacities, while bronchiectasis and perihilar or mild hazy parenchymal infiltrates occurred in one patient each. the mechanism whereby gastroesophageal reflux might elicit this interesting triad of histologic findings is through recurrent micro aspiration of gastric content with associated bronchospasm (see discussion of alveolar proteinosis in chapter ). the differential diagnosis of cholesterol pneumonia also includes drug reactions, notably reactions to amiodarone. the clinical history and documentation of amiodarone therapy should facilitate the correct diagnosis (see chapter and fig. . ) . while the foamy macrophages in both of these disorders resemble each other histologically, electron microscopy demonstrates more abundant osmiophilic dense bodies and giant lamellar bodies in many different cell types in amiodarone toxicity compared to similar but smaller inclusions within macrophages in endogenous lipid pneumonia. . ~ compared to endogenous lipid pneumonia, amiodarone toxicity also encompasses a prominent inflammatory response that may include fibrosis, organizing pneumonia and diffuse alveolar damage (see chapter ) . other drugs that have been implicated as a cause of endogenous lipid cholesterol granulomas not only are associated with endogenous lipid pneumonia and pulmonary alveolar proteinosis, but also have been attributed to pulmonary hypertension, organizing hemorrhage, and a unique case of excessive consumption of apples. - kay and colleagues suggest that cholesterol granulomas in patients with pulmonary hypertension are more likely due to other concomitant processes characterized by type ii pneumocyte hyperplasia and degeneration. atelectasis is the collapse of aerated lung. most often it is caused by internal bronchial obstruction of the air flow (absorption atelectasis) (see fig. . in chapter ), but it may result from external compression of the lung, such as by empyema, mesothelioma, constrictive pleural fibrosis, or tumors, or by internal compression, secondary to a bulla, tumor, or other space-occupying lesions (compressive atelectasis). pneumothorax is an important cause of atelectasis in the ipsilateral lung. atelectasis may also be caused by a change in metabolism or surface-wetting balance such as with hyaline membrane disease, ards, infection, or gastric acid or other aspiration with loss of pulmonary surfactant. it may also have vascular causes as with embolism, postoperative splinting, obesity (e.g., pickwickian syndrome), or secondary to nerve or muscle dysfunction of diaphragm or chest wall. following complete airway obstruction, atelectasis occurs when alveolar oxygen and nitrogen are absorbed. atelectasis is also commonly seen around chronic inflammatory reactions such as bronchiectasis, and may be part of the sequence of events leading to bronchiectasis (see below). pathologists must be cautious, however, because most often, when observed histologically, atelectasis is artifactual. upon the release of negative pressure, air escapes from the lung when the thorax is opened or when lung tissue is excised, and this collapse may cause confusion with preexisting atelectasis (see fig. when bronchial obstruction is partial, it may easily lead to air trapping, as discussed in chapter (see asthma). obstruction of segmental bronchi usually does not cause atelectasis because of preserved collateral ventilation. a collapsed lung may be an isolated cause of fever, but is also a frequent site for superinfections, such as in postoperative patients. chronic atelectasis may lead to irreversible scarring. the special situation of rounded atelectasis is discussed in chapter on asbestos-related pathology. bronchiectasis simply defined refers to dilatation of bronchi. included in this broad definition are conditions such as traction bronchiectasis secondary to parenchymal scarring; airway dilatation accompanying parenchymal loss as in emphysema; or reversible dilatation, which may be seen radiographically in atelectasis or pneumonia. - a more selective definition of bronchiectasis, and the type usually understood by pathologists, is irreversible fixed airway dilatation associated with inflammation and destruction of bronchial matrix components. • bronchiectasis can be further categorized as localized or diffuse/multifocal. causes of localized bronchiectasis, the most important of which is airway obstruction, are listed in table . . localized bronchiectasis may also have an infectious etiology, most notably pulmonary tuberculosis (see fig. . in chapter ). obstructive bronchiectasis is most commonly seen beyond endobronchial tumors (fig. . ), but foreign bodies, concretions such as broncholiths, secretions such as inspissated mucus in mucoid impaction and allergic bronchopulmonary aspergillosis (see chapter ), strictures, or compression as by tumor or enlarged nodes may play a role. rarely, lack of cartilaginous support with airway collapse, bronchial atresia, or mucosal webs may be associated with bronchiectasis. obstructive bronchiectasis occurs anywhere obstruction occurs, but there are some localizing factors in a few of these conditions: the upper lobe in allergic aspergillosis or with primary epithelial tumors, which are more common in this site; the middle lobe with its tendency toward airway compression (middle lobe syndrome); and localized bronchiectasis governed by the usual routes of aspiration (covered earlier in this chapter). there are many exceptions, and bronchoscopy is usually indicated in both children and adults to diagnose the type of obstruction. localized bronchiectasis is often successfully treated by surgical resection or elimination of the cause of bronchial obstruction. diffuse or multi focal bronchiectasis is usually of the nonobstructive type, the major causes of which are listed in table . . it is this type that is more frequently a cause of significant chronic obstructive pulmonary disease (copd) and respiratory failure. nonobstructive bronchiectasis occurs most frequently in the basal segments of the lower lobes, often sparing the superior segment and the anterior basal segment. it is found more than twice as frequently in the left lower lobe as in the right. s -j next in frequency are the right middle lobe and its counterpart, the lingula. these areas of the lung may have the poorest drainage. the upper lobes may be involved but are usually not solely involved by nonobstructive bronchiectasis. tuberculosis more selectively causes bronchiectasis in the upper lobes, and cystic fibrosis should be considered in cases of upper lobe involvement without a definitive etiology. about one third of the cases of nonobstructive bronchiectasis have bilateral involvement. . , macroscopically bronchiectasis typically involves the second to the eighth order of segmental bronchi, sparing the larger, more proximal airways, which are protected by a firmly supporting cartilaginous network. - more distal airways are often obliterated or effaced as the number of bronchial divisions is reduced (fig. . ). , within a bronchopulmonary segment there may be patchy involvement (see fig. . in chapter ). there is also apparent loss of more distal lung parenchyma as the dilated airways approach the visceral pleura ( fig. . ) . , bronchiectasis has been divided into many different patterns grossly and radiographically. the most widely applied classification is that suggested by reid l : ( ) saccular (cystic), ( ) cylindrical (fusiform or tubular), and ( ) varicose. in the saccular form, the distal extensions of the bronchi are more dilated than proximal portions, described by reid as "globular ballooning." usually, the second-to fourth-order bronchi are involved. cylindrical bronchiectasis consists of evenly enlarged tubular dilatation of bronchi, usually involving the sixth-to eighthorder bronchi. is i on bronchograms dilated bronchi come to an abrupt, square-ended termination thought to be caused by impacted endobronchial secretion. the varicose type describes focal dilatation separated by more narrow areas (see fig. . in chapter ). these various gross patterns were previously best visualized by bronchography, and are not specific for any given etiology, although certain clinical-pathologic correlations have been made (see below). whitwell integrated histologic features into his classification of follicular, saccular, and atelectatic bronchiectasis. follicular bronchiectasis most frequently begins in childhood as the sequela of viral infections, most notably adenovirus. saccular bronchiectasis, in whitwell's series, was often found to be postinfective or idiopathic. the pathogenesis of atelectatic bronchiectasis was linked to lobar bronchial obstruction, often by enlarged lymph nodes. congenital bronchiectasis, purportedly due to cartilage deficiency in the bronchial walls, is a controversial entity discussed elsewhere in this chapter under the williams-campbell syndrome. , s , not to be confused with congenital bronchiectasis are those hereditary conditions, such as cystic fibrosis or primary ciliary dyskinesia, that predispose to the subsequent development of progressi ve bronchiectasis (see below). , patients with bronchiectasis typically present clinically with forceful cough, purulent sputum production, wheezing, and recurrent pneumonia in the bronchiectatic zones. wet bronchiectasis refers to abundant inflammation and mucus hypersecretion, whereas dry bronchiectasis refers to minimal sputum production. dry bronchiectasis is most common in the upper lobes, is often of the cylindrical type, and probably relates to better drainage in this zone. hemoptysis commonly presents as blood-streaked sputum, but may be massive and life-threatening. frequently purulent sinusitis accompanies bronchiectasis and may contribute to its development. the chest radiograph is usually abnormal in bronchiectasis, including specific features of ring-like shadows due to dilated airways seen on end, or of tram lines when the airways are visualized longitudinally. iss high-resolution ct scan is the best current modality for diagnosing bronchiectasis, revealing airways that are dilated relative to the adjacent blood vessels, lack of airway tapering, constrictions along the path of the airway, and terminal balloon-like cysts. is ,is pulmonary function tests show obstructive changes with reduced forced expiratory volume in second (fev )/ forced vital capacity (fvc) and frequently airway hyperresponsiveness. various theories have been proposed to explain nonobstructive bronchiectasis. inflammation seems to best account for the changes that are observed, including the fact that the involved zones of lung are those most difficult to drain. it was known even in the s and confirmed in subsequent decades that respiratory infection often preceded bronchiectasis. , , - usually older children and young adults have the well-developed disease pattern, but also have a history of infections before the age of or years, with recurrent respiratory problems dating from this time. many patients may appear stable and do well for some time, and then develop a progressive course of recurrent infections and systemic toxicity. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in approximately % of cases of bronchiectasis, however, a specific inciting factor is not identified-so-called idiopathic bronchiectasis . in these patients, childhood respiratory infections especially those likely to have produced bronchiolitis obliterans, are presumed to have initiated the process of bronchiectasis. , , viral infections may be important in many cases. , , - glauser and associates noted in an extensive review that measles and pertussis immunizations probably have played a significant role in decreasing the incidence of bronchiectasis. bacteria also playa significant role, both in primary infections (see following) and in superinfections or reinfections in areas of previous injury. aggressive treatment of pediatric pulmonary infections with antibiotics has helped to make bronchiectasis a disappearing disease. historically, the impact of immunizations and antibiotics on the declining incidence of bronchiectasis occurred at about the same time, and it is difficult to differentiate their effects; nonetheless, this association supports the role of early infection in initiating bronchiectasis. excluding cases of kartagener's syndrome, the concurrence of sinusitis and bronchiectasis is greater than expected. as early as , quinn and meyer noted a % incidence of chronic sinusitis in cases of bronchiectasis. aspiration of infective material from the sinuses may playa role. however, another study noted a % incidence of sinusitis in cases with less than years of symptoms of bronchiectasis compared to the % incidence in all cases of bronchiectasis. h. infiuenzae, a common pathogen of the upper respiratory tract, is also found with some regularity in lung cultures from patients with bronchiectasis. anaerobic bacteria, reflecting endogenous oral flora , may also be cultured from bronchial secretions. long-term antimicrobial treatment may be required for complete eradication of these organisms. the role of recurrent infection in perpetuating and aggravating bronchiectasis cannot be overemphasized. this has been documented in children and adults. the dilatations of the bronchial contours, their irregularities, their relative stenosis at the proximal end, altered secretions and exudate, surface mucosal ulcerations, and metaplasia all playa role in hampering adequate drainage. a vicious cycle ensues as the injured area perpetuates further injury, leading to increased damage and progressive bronchiectasis. necrotizing inflammation involves bronchial walls and adjacent parenchyma (fig. . ) . some scarring probably takes place in healing, with retraction of surrounding tissue. retraction occurs circumferentially, and bronchial dilatation results. as noted, the more distal bronchi and bronchioles are often destroyed. there is also general lung contracture due to atelectasis of involved zones, while nonaffected lobes may undergo compensatory hyperinflation (fig. . ) . the basic principles of fibrosis and contraction also apply to traction bronchiectasis seen in interstitial fibrosis and honeycombing. traction bronchiectasis is usually not as marked as primary bronchiectasis, and is localized and most severe in the peripheral subpleural zones where fibrosis is often most prominent (see chapter ) . grossly, the involved lung tissue is usually atelectatic, gray-blue, shrunken, and rubbery. there may be zones of golden or obstructive pneumonia, and sometimes these zones form layers around the dilated bronchial tubes. it may be difficult or impossible to adequately inflate such a chronically contracted specimen. the involved bronchi are dilated instead of following their smoothly contoured courses as they extend peripherally. these dilated bronchi almost reach the pleural surface and run in a somewhat parallel or radial fashion without interbronchial connections (figs. . and . ). partially or totally circumferential thin folds in the mucosa extend internally from the wall and are seen as transverse infolded pleats on the bronchial cast (see fig. . in chapter ). these give the appearance of webs or bands of mucosa. there are variably sized outpouchings, larger ones between the remnant bronchial cartilages, and dilated smaller pits that appear to be dilated submucosal glands. grossly, elastic fibers can be seen still running through the wall, but these are more widely separated than is normal because of the stretched diameter of the bronchus. in wet bronchiectasis there is thickening of the wall, and mucinous, granular, semisolid material accumulates within the lumen (fig. . ). occasionally this material hardens and even calcifies (see broncholithiasis, below). in dry bronchiectasis the wall is thin, almost translucent, and gray-pink without mural thickening. microscopically the respiratory mucosa may be intact, show squamous metaplasia, or be ulcerated or inflamed (fig. . ). the bronchial walls are usually chronically inflamed. submucosal glands and surface goblet cells are not prominent and may decrease, although they may occasionally increase. elastic tissue is preserved except in areas of necrosis (fig. . ). smooth muscle is usually present and often shows some degree of hypertrophy; occasionally this is atrophic. cartilage seems less obvious and occasionally is eroded, but most often appears normal histologically. in advanced saccular bronchiectasis cartilage is markedly reduced or absent. , , neutrophils, macrophages, and desquamated and mucinous debris are present in the bronchial lumen in wet bronchiectasis. acute inflammatory cells may infiltrate the bronchial wall or the adjacent lung parenchyma depending on the status of inflammation and active infection at the time of lung removal. as these patients are subject to recurrent infections, acute pneumonia may also be present. lymphocytes and plasma cells usually predominate in bronchial wall and surrounding lung tissue. in follicular bronchiectasis, hyperplastic lymphoid follicles may appear to constrict the bronchial lumens (fig. . ). there may be a degree of obstructive pneumonia correlating with the gross yellow color. small granulomas are present in a few cases, apparently as a reaction to inspissated material within the bronchi. if granulomas are extensive or present in the adjacent lung parenchyma, in more normally contoured segmental and subsegmental bronchi, or in lymph nodes, one must consider fungal or mycobacterial infections. if granulomas are confined to the injured areas, one must also consider aspiration. bronchioles are often constricted or obliterated beyond the dilated bronchi (fig. . ). other small airways may be dilated and sometimes mucus-filled probably because of their obstruction at the junction with the larger bronchi. foci of carcinoid atypical proliferation (tumorlets) occur with some frequency in bronchiectasis (see chapter ) . bronchial arteries respond to sustained inflammation, and may exceed mm in diameter. ulceration of these systemic arteries accounts for the bright-red appearance of hemoptysis. the right middle lobe and occasionally its left-sided counterpart the lingula, have lobar bronchi that branch from their parent supply at a more acute angle than most other dividing bronchi (see chapter ) . the middle lobe bronchus is relatively narrow, and there are frequently moderately prominent nodes in the angle of bifurcation that may compress and further constrict the bronchus. the subcarinal node may even approach this angle. several authors have also suggested there is less effective collateral ventilation in the middle, compared to the adjacent upper lobe. . because of these anatomic characteristics there is a greater tendency toward middle lobe and lingular atelectasis, inflammation, nonspecific scarring, broncholith formation, and bronchiectasis-collectively termed middle lobe syndrome (mls) . io in addition to peribronchial lymphadenopathy, mls can result from numerous disorders including asthma, tuberculosis, foreign bodies, cf, broncholiths, endobronchial silicosis, cardiovascular and of bronchiolar wall. white arrow indicates cross section of separate, obliterated airway (patient with cf) (elastic van gieson stain). bronchopulmonary malformations, and allergic bronchopulmonary aspergillosis. - the pathologic findings in resected lung specimens of patients with middle lobe syndrome have been comprehensively described most recently by kwon and colleagues, and are delineated in table . . although the histologic findings are nonspecific, a combination of bronchiectasis, bronchiolitis, and atelectasis is typical. in this series, a mechanical obstruction (broncholith) was identified in only one patient. as early as , culiner also recognized bronchial patency in most cases of middle lobe syndrome. the current understanding suggests that mls is due to recurrent infection related to poor lung drainage, possibly associated with intermittent obstruction of the precariously situated bronchi in the setting of reduced collateral ventilation of the middle lobe. . broncholiths represent calcified material in the airways. - they most commonly are calcified lymph nodes that compress bronchi and either partially or completely erode through the bronchial walls (fig. . ). . they then may be expectorated (lithopytsis) (fig. . ) calculus (scale equals cm). c. rare yeast-like organisms, consistent with histoplasma, were identified in the necrotic center of the broncholith (gomori methenamine silver stain). or aspirated and cause hemorrhage or obstructive changes, including cough, atelectasis, pneumonia, abscess formation, bronchiectasis, or air trapping. broncholiths form less often from chronic reaction to retained aspirated material or eroded fragments of calcified or ossified bronchial cartilage. o they may also occur with retained mucus as in bronchiectasis. historically, "spitting stones" dates back to descriptions by aretaeus, galen, and aristotle. although usually less than cm in diameter, a record-sized calculus of g c/ ib) occurred in a patient who also had produced multiple sand-like or melon-seed-sized calcified particles. the pathognomonic finding of lithoptysis is fairly rare and was seen in only two of ( %) cases by faber et al. and six of ( %) cases by schmidt et au the regional nodes usually calcify from old granulomatous disease, and tuberculosis is the most common etiology worldwide while histoplasmosis is the most common etiology in the united states. other infectious agents include coccidioides, cryptococcus, actinomyces, or no cardia. , o, , the latter two organisms probably represent superinfections of necrotic debris. silicotic lymph nodes may also cause a similar reaction. , men and women are about equally affected, and although calcified nodes may occur at any junction of the bronchial tree, they are to . times as common on the right side, and favor the anterior superior segment of the upper lobe and the bronchus intermedius, along with the right middle lobe bronchus, where they may produce the middle lobe syndrome. , , the superior segment of the lower lobe is also a site of occurrence. occasionally, erosive calcified nodes may cause bronchopleural fistulas and are the most common cause of bronchoesophageal fistulas, [ ] [ ] [ ] retraction diverticula of the esophagus may also occur secondary to peribronchial fibrosis and calcified mediastinallymph nodes associated with broncholiths. , calcified nodes have also been studied with ct scans. in the retrospective series by conces et al., of patients with ct-proven broncholiths, ( % ) had juxtabronchial calcified nodes identified on chest radiographs. calcified intraparenchymal nodules were seen radiographically in only four ( %) patients. bronchoscopy is less accurate in detecting calcifications, ranging from % to % of cases. rarely, calcifying tumors such as an ossifying bronchial carcinoid or endobronchial hamartoma can cause confusion (see chapters and ) . , histologically broncholiths appear similar to calcified fibrocaseous lymph node lesions. the outer surface of the often sharp-edged calculus may be coated with inflammatory exudate or, in cases of actinomyces superinfection, eosinophilic rays (splendore-hoeppli phenomenon). , the gms stain may disclose histoplasma yeast forms in the centrally necrotic area of the calculus (fig. . b) . , , the airway in which the calculus is lodged is typically stenotic, with mural fibrosis and chronic inflammation. within the chest, fistulas may be bronchopleural, bronchocutaneous, bronchomediastinal, or bronchoesophageal in their connections. an aortobronchial fistula is a rare (and often fatal) complication of previous aortic or cardiac surgery, bronchopleural fistulas are the most common form and often are secondary to surgery, such as from a leaking postoperative bronchial stump. other causes include necrotizing pneumonia or abscess, penetrating wounds, eroding granulomatous disease, penetrating broncholiths, or malignancies. see chapter for congenital causes. extrathoracic bronchial fistulas include connections with bile ducts, pancreas, and other assorted sites. bronchocele means one or more dilated bronchi filled with fluid, which may be mucinous (bronchomucele) or purulent (bronchopyocele ). this condition is caused by stenosis or occlusion of the proximal end of dilated sac(s), and therefore differs from bronchiectasis and mucoid impaction, in which proximal ends are generally still patent. it may be either congenital, or early or late acquired, usually of postinflammatory nature but sometimes of malignant nature. localized emphysema, which occurs around the bronchocele, may be caused either by inflammation early in lung growth with continued traction-type effects on nearby lung, or by sustained air-trapping due to airway obstruction. , . o many cases are reported as bronchial atresia. - bronchocele/ atresia may present in adults or children and typically affects the left upper lobe. a characteristic ct appearance is that of a branching mass surrounded by hyperlucency. an irregularly cylindrical (sometimes branched) thin-walled cyst (fig. , a) grossly and histologically resembles a bronchocele lined by respiratory or squamous epithelium. , o, occasionally a scar or intrabronchial web proximal to the lesion represents the remnant atretic or occluded bronchus. the adjacent bronchial arteries may appear hypertrophic, especially if there have been recurrent infections (fig. . b) , bronchocele may be a relative of saccular bronchiectasis and may be the etiology for some so-called intraparenchymal bronchogenic cysts (see below and chapter ). mucoid impaction may also be related to an allergic effect, often to noninvasive aspergillus (see chapter ), usually does not have proximal bronchial stenosisocclusion, and has more eosinophils and cellular debris in the mucus, in addition to intraluminal hyphae. bronchocele/atresia is distinguished from intralobar seques- bronchogenic cysts are closed sacs lined by respiratory mucosa, usually with bronchial glands, smooth muscle, and cartilage in their walls. they often represent congenital fragments that drop off or are remnants of the original budding of the lungs from the primitive endodermal canal. they are most common in the middle mediastinum where they account for % to % of all primary mediastinal masses but can be seen as isolated masse es) in the lung. within the lung, some may form as bronchoceles as discussed previously. a series of cases of bronchogenic cyst, with ( %) in the mediastinum and ( %) in the lung, was presented by st. georges et al. from montreal. a similar distribution was recorded in adult patients by patel and colleagues. of interest, % to % of those in the lung were symptomatic at the time of operation, most often because of infection or bronchial obstruction,z , although suspected, a preoperative diagnosis was not correctly made in any case in the large montreal series. the presence of bronchial epithelial cells on trans bronchial fine-needle aspiration (fna) was found not to be specific for the diagnosis of bronchogenic cyst. most occur in the lower lobes, but all lobes may be affected. -z the ct appearance is that of a well-defined hypertrophic bronchial arteries (ba). lumen of cyst is at top (movat stain). ovoid lesion, with surrounding mosaic and band-like linear attenuation consistent with emphysema and bronchiolar metaplasia/fibrosis. a bronchioloalveolar cell carcinoma arising in a bronchogenic cyst in a -year-old woman has been reported as a rare association. bronchogenic cysts are uncommon in adults and are further discussed in children in chapter . bronchorrhea is arbitrarily defined as production of more than ml of sputum per day. although it is a clinical symptom, pathologists may ponder the differential diagnosis if faced with this history on a specimen request card. bronchorrhea may be idiopathic, or secondary to chronic bronchitis, bronchiectasis, scleroderma, asthma, mucinous bronchioloalveolar carcinoma, metastatic mucinous adenocarcinoma, tuberculosis, or relapsing polychondritis. - cytology exams, cultures, or trans bronchial biopsies may help evaluate at least some of these possibilities. cystic fibrosis is a prototypic example of bronchocentric inflammation and bronchiectasis and the most common lethal genetic disease among caucasians, having a frequency of approximately in live births. - the molecular defect of this autosomal recessive disorder was discovered in to involve mutations in a amino acid polypeptide, the cystic fibrosis transmembrane conductance regulator (cftr), encoded by a gene on the long arm of chromosome . , over different mutations of the cftr gene have so far been identified, but the most frequent mutation worldwide and the most severe genetic lesion, is the deletion of phenylalanine at position of cftr (af ), accounting for over % of affected patients. o , cystic fibrosis transmembrane conductance regulator functions as a cell membrane-associated, cyclic adenosine monophosphate (camp)-regulated chloride channel, which also has regulatory activity on the absorption of sodium through a separate epithelial channel (enac). - the structure of cftr is schematically depicted in figure . . mutations in cftr have been grouped into six major types, each of which may present phenotypically as cf: ( ) lack of synthesis of cftr; ( ) defective processing of cftr such that it does not reach the cell membrane; ( ) aberrant regulation of ion transport due to dysfunctional cftr; ( ) abnormal conductance of chloride ions; ( ) partly defective production and processing; or ( ) accelerated turnover at the cell surface ( fig. . ) . , , , the af mutation is a type defect in which abnormal cftr is sequestered within cellular organelles leading to reduced insertion into the cell membrane, markedly limiting the ability of chloride to cross the membrane. in epithelial cells of bronchi, biliary tract, and intestine, impaired transport of intracellular chloride and its accompanying water molecules leads to dehydration of ductal and lumen secretions. o in bronchial epithelium there is also enhanced intracellular absorption of sodium ions, which further dehydrates secretions within the airway lumen. o , , in contrast, the uptake of extracellular chloride is inhibited in sweat ducts, causing an elevation of sweat chloride concentration, a key diagnostic indicator of cf. , the manifestations of cf are protean, involving nearly every organ system either directly or secondarily. the correlation between genotype and phenotypic expression is best exhibited for pancreatic function and is relatively poor for pulmonary manifestations. , , however, certain mutations such as a e or the ivs t allele are associated with relatively mild lung disease that may initially present in adults.m- a unifying feature of the pathophysiology of cf is impaction of viscid secretions in exocrine gland ducts leading to cardinal manifestations such as intestinal obstruction (e.g., meconium ileus); pancreatic acinar atrophy and fibrosis with consequent metabolic insufficiency (due to intestinal malabsorption); organ maldevelopment (e.g., congenital bilateral absence of the vas deferens); hepatic fibrosis (focal biliary cirrhosis); and infection associated with mucus stasis (e.g., infective bronchitis). o, pulmonary involvement is usually the lungs in cf are structurally normal at birth. dilatation of mucous gland ducts followed by intrabronchial mucus stasis are the earliest pulmonary lesions seen in infants. , , o it has long been recognized that patients with cf are predisposed to lung infection. . current hypotheses suggest that susceptibility to infection may be related not only to entrapment of bacteria in thick bronchial secretions, but also possibly to abnormal binding and reduced uptake of bacteria by epithelial cells, or impaired epithelial antimicrobial protection provided by defensins (natural antibiotics of the innate immunity system). . - even in infants without apparent infection, however, bronchoalveolar lavage studies document ongoing bronchial inflammation associated with increased levels of endobronchial il- , a potent cytokine that recruits neutrophils into the inflammatory response, and relatively decreased levels of il-lo, an inhibitor of proinflammatory cytokines. g- it is as yet undetermined whether or not intrinsically exaggerated inflammatory responses are the direct result of mutations in cftr. infection and inflammation stimulate bronchial mucus secretion leading to a vicious cycle of worsening airway infection and obstruction, progressing to chronic bronchitis, bronchiolitis obliterans, and bronchiectasis. the chronic pulmonary complications of cf evolve from the airway disease. hyperinflation or collapse is the direct result of bronchial obstruction. air trapping and postinflammatory cystic lesions underlie an increased susceptibility to recurrent pneumothorax. pulmonary hypertension and cor pulmonale derive from sustained hypoxia, while hemoptysis is a direct effect of bronchiectasis and bronchial artery hypertrophy. endobronchial infection tends to occur in sequential fashion, initiated by s. aureus, followed by h. injluenzae, and finally by p. aeruginosa (mucoid strains). . submucosal glands are enlarged and chronically inflamed behind ducts that are obstructed by dense, inspissated, eosinophilic secretion (a characteristic, but not pathognomonic feature of cf) (fig. . ). - although bronchial smooth muscle in individual patients may appear hypertrophic, its mean volume density is within the normal range. in patients with cf-associated lung disease, saccular bronchiectasis is usually present beyond months of age. r although all bronchopulmonary segments may be affected, bronchiectasis tends to be more severe in the upper lobes (fig. . ). . . blind-ended ectatic airways, devoid of cartilage, are surrounded by atelectatic, chronically inflamed, and fibrotic parenchyma (see fig. . ). bronchial mucosa is frequently denuded or ulcerated leaving the bronchial surface lined by highly vascular granulation tissue that is rich in histiocytes (see fig. . ). in severe disease, bronchi terminate in large, juxtapleural, thin-walled cavities that present radiographically as contiguous, bubble-like cysts. intrapleural blebs or emphysematous bullae are less common forms of cystic lesions, which contribute to an increased incidence of pneumothorax. . extensive acute and chronic bronchiolitis and bronchiolar mucoid impaction impart a finely nodular texture to the parenchymal surface and account for a micronodular radiographic appearance ( fig. . ). bronchiolitis obliterans, predominantly of the constrictive type, contributes importantly to airway obstruction, and likely precedes the development of bronchiectasis (see fig. . ). . occasionally, occlusion of respiratory bronchioles by polypoidal protrusions of fibroblastic tissue accompanies interstitial and organizing pneumonia? small airway density decreases with age and is most significantly reduced in patients with hypercapnia. . the lung parenchyma is grossly indurated by multifocal, bronchocentric chronic pneumonia and fibrosis, with features of both organizing pneumonia and endogenous lipid (cholesterol) pneumonia. a variable degree of acute bronchopneumonia may also be seen at autopsy. some patients who are colonized by burkholderia cepacia undergo an accelerated decline due to acute necrotizing pneumonia (see figs. . and . in chapter ). other patients colonized by burkholderia follow a more protracted course, similar to those colonized by p aeruginosa. [ ] [ ] [ ] fungi and nontuberculous mycobacteria may also colonize cf airways and contribute to lung destruction. , , bhargava and colleagues identified fungal organisms histologically in % of cf patients retrospectively studied at autopsy. the dilated, obstructed airways of cf patients are predisposed to fungal colonization, accounting for an increased prevalence of allergic bronchopulmonary aspergillosis (abpa) of approximately . %. infrequently the pathologic features of abpa, including bronchocentric granulomatosis, are superimposed on chronic cf-associated airways disease (see fig. . in chapter ). in cf patients with non tuberculous mycobacterial infections (often due to mycobacterium avium or rapidly growing strains like m. chelonae or m. abscessus), necrotizing fibrocaseous granulomas may be present. , , , pulmonary lesions are most likely to be found in patients with repeatedly positive sputum cultures for mycobacteria (see chapter ) . the pulmonary vascular changes of cf-associated lung disease are usually pronounced, chronic hypoxia and inflammatory changes contribute to pulmonary artery medial hypertrophy and intimal fibrosis of muscular pulmonary arteries and medial myxoid degeneration of elastic arteries. - postmortem arteriograms often show abnormally tapered arteries with a reduced background haze (see fig. . in chapter ). morphometric studies provide evidence of a decreased density of arteries, which correlates inversely with the degree of right ventricular cardiac hypertrophy, the dropout of arteries may be related to impaired postnatal growth or to vascular destruction secondary to chronic hypoxia or sustained inflammation. right ventricular cardiac hypertrophy, seen at autopsy in approximately % of cf patients older than years of age, is a direct consequence of pulmonary artery remodeling and associated pulmonary hypertension. bronchial arteries also undergo significant hypertrophy as a response to sustained bronchial inflammation, bronchiectasis, and bronchocentric abscesses (fig. . ). - the source of hemoptysis in cf patients is most frequently the delicate capillaries within airway granulation tissue (see fig. . ), , occasionally, mucosal ulcers erode into hypertrophied bronchial vessels leading to life-threatening massive hemoptysis (fig. . ). interventional bronchial artery embolization of metal coils, polyvinyl alcohol (ivalon), or gelfoam particles is undertaken to induce thrombosis and control bronchial artery bleeding. , degenerated remnants of embolized polyvinyl alcohol may surround stenotic or occluded bronchial arteries in patients who have undergone this procedure. bronchopulmonary arterial anastomoses may further allow the paradoxical entry of small embolized particles into the pulmonary arterial circuit (see fig. . in chapter ). other less frequently reported complications of cystic fibrosis include systemic amyloidosis, intralobar sequestration, and anaerobic lung abscess. - emphysema is usually a minor feature, localized to bronchiolocentric scars or as paraseptal emphysema in the upper lung zonesys, s, cystic fibrosis patients with indwelling venous access devices may surreptitiously inject aqueous suspensions of psychoactive pharmaceutical tablets leading to pulmonary artery obstruction due to embolized tablet filler materials (see chapter ). primary ciliary dyskinesia (pcd) is an autosomal recessive disorder, occurring in approximately of , to , persons, characterized by the absence or dysregulation of ciliary movement mainly due to ultrastructural defects in the ciliary axoneme. (see chapter )? - cilia on the respiratory epithelial surface play an important role in propelling mucus, bacteria, and inhaled particulate debris out of the lung (see chapter ). as a result of impaired clearance due to ciliary malfunction, patients with pcd are predisposed to chronic sinusitis, serous otitis, and recurrent bronchopulmonary infections beginning in early childhood. , primary ciliary dyskinesia has also been implicated as a cause of neonatal respiratory distress syndrome. , male patients are usually infertile due to poor flagellar motility of sperm. approximately % of patients with pcd also have situs inversus secondary to abnormal rotation of embryonic epithelia consequent to the lack of ciliary movement. the syndromic triad of situs inversus, sinusitis and bronchiectasis was first proposed by kartagener in , and is now designated kartagener's syndrome (fig. . ). . while pcd is an important cause of bronchiectasis, the prognosis is generally more favorable than that of cf. in afzelius and pedersen and mygind were among the first to recognize that ultrastructural abnormalities of ciliary dyne in arms were associated with kartagener's syndrome. originally termed immotile cilia syndrome by afzelius, it is now recognized that there are numerous structural variations that may contribute to if. tomashefski, jr., and d.h. dail pcd, and that cilia are not always immotile? when compared to normal (fig. . a) , the most commonly observed ultrastructural defects are the complete absence of dyne in arms or the selective absence of either inner or outer arms (fig. . b ). other derangements of the axoneme contributing to pcd include defective or absent radial spokes (fig. . d ), transposition of microtubules (fig. . c ) (well seen in longitudinal sections of cilia), central microtubular agenesis, absence of nexin links, agenesis of cilia, or rarely, bizarre cystic dilatation of ciliary shafts. - nonspecific findings such as ciliary blebs, megacilia, compound cilia, and displaced microtubules may accompany the more specific defects, but are also frequently present in inflammatory airway disease of diverse causes including infectious bronchitis, cf, or air pollution. - some patients with structurally normal cilia and a normal ciliary beat frequency may develop the clinical manifestations of pcd due to ciliary disorientation, resulting in uncoordinated ciliary motion (fig. . e ). , ciliary disorientation has also been described in individuals with infectious bronchitis (including cf), but the degree of disorientation is usually not as great as in those in whom the defect is primary, and the disorientation secondary to infection typically resolves after effective antibiotic treatment. the diagnosis of pcd is established by ultrastructural analysis of respiratory epithelium in conjunction with typical clinical manifestations, exclusion of other causes of chronic airway inflammation, and documentation of abnormal ciliary motion by phase contrast microscopy. . , mucosal samples obtained by endoscopic biopsy or brushing are examined by transmission electron microscopy. in patients with pcd, nasal mucosal samples are reflective of bronchial changes when most cilia are abnormal. when only few cilia are structurally abnormal in a patient in whom the diagnosis of pcd is highly suspected, a bronchial sample is required. abnormalities in sperm flagella may differ in type and quantity from those of respiratory cilia within the same patient, suggesting separate genetic control of axone mal structures at differing loci? the lung pathology in pcd is postinfective in appearance. both saccular and cylindrical bronchiectasis may be present with the predominant histologic pattern of follicular bronchiectasis. , , neither bronchial mucus stasis nor squamous metaplasia is prominent chronic interstitial pneumonitis, peribronchial fibrosis, and atelectasis accompany the bronchiectatic changes. , , studies to date suggest that pcd is a genetically heterogeneous disorder. the molecular basis of pcd has been localized in a few instances to mutations in the human dyne in axonemal heavy chain (dnah ) located on chromosome , or in the intermediate dynein chain gene (dnail) on chromosome , - a mutation in the dyne in axonemal heavy chain type (dnahll) has been associated with pcd and situs inversus, without evident ultrastructural ciliary changes, ongoing studies on genetically engineered knockout mice may uncover other genetic defects associated with pcn, , in donald young, a urologist, reported a series of patients with obstructive azoospermia, % of whom had associated respiratory conditions including bronchitis and bronchiectasis, this condition was initially designated as berry-perkins-young syndrome and later shortened to young's syndrome. patients, nearly all had chronic cough, sputum production, and recurrent pulmonary infections. bronchiectasis and chronic sinusitis were each present in about two thirds of patients. in one study it was estimated that young's syndrome accounted for approximately % of all patients who presented with bronchiectasis of unknown etiology (equivalent to the prevalence of cf and slightly greater than that of pcd). azoospermia in young's syndrome is the result of retention of semen in an enlarged epididymal head. motility studies have demonstrated impaired upper airway mucociliary transport; however, ciliary beat frequency and ultrastructure are normal. , , , in patients with young's syndrome, sweat chloride concentration and the electrical potential difference across the nasal epithelium are normal. the respiratory symptoms in young's syndrome have been suggested to be the result of altered viscoelastic properties of airway secretions, but the basic molecular defect is unknown. an association with mercury toxicity has been hypothesized. friedman and colleagues evaluated mutations of cftr in a cohort of patients with young's syndrome and found that the prevalence of mutations did not differ significantly from the expected carrier frequency in the general population. pulmonary involvement is generally less severe than in cf. bronchiectasis tends to occur at an early age and predominantly involves the lower lobes. pulmonary function tests indicate mild obstruction with decreased fev and increased residual volume, although a number of patients have undergone lung resections for bronchiectasis, the pathologic features of bronchiectasis in young's syndrome have not been well described, and it is uncertain if there are any distinctive histopathologic changes. from a diagnostic standpoint it is important to exclude cf and pcd, each of which may be clinically misclassified as young's syndrome? , the distinguishing characteristics among these three conditions are presented in table sa . williams-campbell syndrome is a rare disorder in which extensive loss of bronchial cartilage is associated with diffuse cystic bronchiectasis without other recognized predisposing factors. , the clinical presentation that commences in infancy may include cough, dyspnea on exertion, cyanosis, and clubbing. on chest radiograph large thin-walled cysts reside in hyperinflated lungs. highresolution ct scan characteristically shows central, cystic, thin-walled airways that collapse upon expiration. . the clinical course is one of recurrent pulmonary infections leading to respiratory failure. patients may survive into adulthood and require lung transplantation. as described in the original report by williams and campbell and substantiated in subsequent morphologic studies, the lungs grossly exhibit extreme saccular and cystic bronchiectasis (fig. . a ). - microscopically, dilated airways have very thin walls with minimal inflammation (fig. . b ). cartilage is absent or markedly deficient from the fourth to the eighth divisions of subsegmental bronchi. first-and second-order bronchi usually have a normal cartilage investment. pan acinar emphysema or emphysema localized to the peribronchial zone is usually also present. . bronchiolitis obliterans has also been reported. . the williams-campbell syndrome has been considered to be the result of a congenital absence of cartilage in the subsegmental airways. morphologic studies documenting absent cartilage and insignificant inflammation, and rare reports of familial occurrence have been used to support this view. . . however, given the propensity for cartilage loss in acquired saccular bronchiectasis of diverse etiologies, the williams-campbell syndrome remains a controversial entity, and its congenital origins have yet to be proven beyond question. . . . the williams-campbell syndrome has not been associated, nor is it to be confused, with congenital lobar emphysema, in which cartilage is focally deficient, usually in upper lobe bronchi, leading to bronchial collapse and air trapping (see also chapter ). tracheobronchomegaly (tbm) is a condition of marked dilatation of the trachea and major bronchi, often associated with recurrent respiratory infections. tbm can be congenital, or at least evident in early life, in which it is termed mounier-kuhn syndrome (see chapter ) . it has occurred in several cases of ehlers-danlos syndrome, suggesting it may be related to poor elastic support, or perhaps to loss of other matrix components as in chondromalacia. tracheobronchomegaly occurs in adults, mostly in men in their fourth and fifth decades, and can be an acquired condition secondary to sustained inflammation affecting the trachea, such as in chronic tracheo- bronchitis secondary to tobacco abuse, cystic fibrosis, trauma, emphysema, or pulmonary fibrosis. , a comprehensive review and an intriguing study of various pulmonary fibrotic reactions associated with this entity was reported by woodring et al. these investigators evaluated the tracheal diameter on plain chest radiography in a series of cases of fibrotic lung reactions, and found enlargement of the trachea in ( %). the associated lung diseases were idiopathic pulmonary fibrosis and sarcoidosis in four patients each, and progressive histoplasmosis in two patients. in seven of these patients as well as in nine of patients ( %) who did not meet initial radiographic criteria for tracheal dilatation, tracheomegaly developed or progressed over time, tracheobronchomegaly was usually associated with moderate-to-severe restrictive pulmonary defects, and it was proposed that shrinkage of the lung tissue retracts all adjacent spaces including the trachea in a manner similar to traction bronchiectasis. regardless of the cause oftbm, airway dilatation may extend distally, bronchomegaly simulates bronchiectasis, probably impairs lung clearance, and promotes recurrent bronchopulmonary infection, which paradoxically may induce secondary bronchiectasis. roditi and weir identified tracheobronchomegaly in % of patients with evidence of bronchiectasis on ct scan, thereby emphasizing the frequent association and possible causal connections between these two conditions. tracheobronchomegaly is predominantly a radiologic diagnosis, and its pathologic features have not been well characterized. associated radiographic features include marked tracheal wall thinning, scalloping due to mural infolding, bronchial diverticula, and collapse on expiration. . the diagnostic criteria of tbm by ct scan are a tracheal diameter of greater than cm (measured cm above the aortic arch) and diameters of . and . cm for the right and left main bronchi, respectively. al? tracheobronchomegaly must be distinguished from saber-sheath trachea, seen in some patients with emphysema, in which there is a decrease in tracheal coronal diameter and increased sagittal diameter. . patients with immune deficiency, especially hypogammaglobulinemia due to x-linked agammaglobulinemia or common variable immunodeficiency (cvid), are predisposed to develop bronchiectasis secondary to recurrent pulmonary infections. - chronic pulmonary disease is the most common long-term complication in patients with hypogammaglobulinemia. common variable immunodeficiency, a heterogeneous immunodeficiency syndrome characterized by depressed levels of serum immunoglobulin g (igg) and defective antibody response to antigen challenge, is associated with sinusitis, recurrent pneumonia, and chronic sputum production in up to % of patients. patients with cvid also have an increased incidence of autoimmune diseases, and as with other primary immunodeficiency syndromes, a tendency toward lymphoproliferative disorders (see chapter ) . , in this population there is a spectrum of lung abnormalities including interstitial fibrosis (> % of patients), pneumonia, lymphoid interstitial pneumonia (lip), sarcoidosis-like granulomatous disease ( %), lung abscess, and bronchiectasis. , bronchiectasis is the most common radiologic finding and may be identified in over % of patients by chest x-ray, and in up to % of patients by hrct. , by hrct bronchiectasis may be either focal or multilobar, and is of the cylindrical or rarely cystic type. , the lower and middle lobes tend to be predominantly involved. . although mucociliary clearance is impaired in these patients, ciliary ultrastructure is normal. there is little information on the histopathology of bronchiectasis in cvid. . hill and colleagues noted severe bronchiectasis, emphysema, fibrosis, and granulomas in the lung explant of a -year-old man with cvid. no unique features of bronchiectasis were described. patients with cvid are treated with immunoglobulin replacement therapy, which reduces the severity and frequency of respiratory infections. symptomatic bronchiectasis, identified by hrct scan, has also been reported in patients with hiv disease in whom it is associated with rapidly progressive airways obstruction. o , king and colleagues correlated airway dilatation on ct scan with increased neutrophils on bronchoalveolar lavage. a single report of a transbronchial biopsy showed only nonspecific lymphocytic peribronchiolitis. the pathogenesis of bronchiectasis in hiv patients is likely consequent to bronchial damage from recurrent pneumonia and bacterial bronchitis in this immunosuppressed population. . frequently cultured microorganisms include h. injluenzae, p. aeruginosa, and s. pneumoniae. , bronchiectasis also occurs as a complication of lung transplant-associated immunosuppression and bronchiolitis obliterans and is further discussed in chapter . . rheumatoid arthritis symptomatic bronchiectasis is estimated to occur in % to % of patients with rheumatoid arthritis (ra), although with hrct scan, up to % of patients with ra can be shown to have cylindrical bronchiectasis. . , early autopsy studies of patients with ra provided a prevalence of bronchiectasis of % to %. [ ] [ ] [ ] [ ] in some studies bronchiectasis typically preceded the development of arthritis, leading to the interesting hypothesis that chronic suppurative airway disease is involved in the pathogenesis of ra. - shadick and colleagues, however, reported patients with bronchiectasis and ra, of whom developed bronchiectasis as a late complication of severe ra. bronchiectasis may also be more frequent in patients with ra-associated sjogren's syndrome. a bronchiectasis associated with ra cannot be adequately ascribed to either traction bronchiectasis or therapeutic immunosuppression. , the morphologic features of ra-associated bronchiectasis are not well documented. by ct scan, cylindrical bronchiectasis primarily involves the middle and lower lung zones. a , bronchiectasis is part of the spectrum of lung involvement in patients with inflammatory bowel disease (ibd), ulcerative colitis more so than crohn's disease (see also chapter ) . , suppurative bronchiectasis may also develop after proctocolectomy for either of these conditions. , in the literature review of camus et al., bronchiectasis was identified in six patients with ulcerative colitis out of patients ( %) with ibd-associated lung disease histologically a dense cuff of lymphocytes typically occupies the submucosa, and squamous metaplasia replaces the overlying epithelium (fig. . ). the chronic inflammatory infiltrate involves bronchial glands and ducts; however, lymphoid germinal centers are usually absent, distinguishing ulcerative colitis-associated bronchiectasis from the usual pattern of follicular bronchiectasis (fig. . b). , neutrophils infiltrating the mucosa and spilling into the dilated bronchial lumen impart a suppurative appearance in some cases. -- direct immunofluorescence staining of bronchial biopsies in three patients with ulcerative colitis showed deposits of immunoglobulin and complement in bronchial structures. lung biopsy in patients with crohn's disease and bronchiectasis may show features of either granulomatous bronchiolitis or suppurative-appearing acute bronchiolitis (see fig. . in chapter ). inhaled steroids were of durable benefit in patients with ibd-associated chronic bronchitis, but less so in patients with bronchiectasis. speculations on the pathogenesis of bronchiectasis in ibd are presented in a provocative editorial by stockley. bronchiectasis is reported as a late sequela of heroinassociated pulmonary edema. the bronchographic features include diffuse or localized cylindrical and varicose bronchiectasis. itis are etiologic factors in some patients, and bronchial ulceration and foreign-body giant cells have been observed at autopsy. other cases of diffuse bronchiectasis in heroin users appear to be unrelated to aspiration. see chapter for other pathologic features of heroin toxicity. in adults, severe direct chemical injury such as ammonia gas inhalation or aspiration can cause bronchiectasis. - delayed-onset bronchiectasis has also been described 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patients with cystic fibrosis weir . the association of tracheomegaly and bronchiectasis using ct to diagnose nonneoplastic tracheal abnormalities: appearance of the tracheal wall a -year-old man with tracheomegaly, tracheal diverticulosis, and bronchiectasis mounier-kuhn syndrome): ct diagnosis sabre-sheath" trachea: relation to chronic obstructive pulmonary disease recurrent respiratory infections in a family with immunoglobulin a deficiency bronchiectasis in hypogammaglobulinaemia-a computed tomography assessment igg subclass deficiencies associated with bronchiectasis common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution ct scan findings pulmonary manifestations of hypogammaglobulinaemia respiratory disorders in common variable immunodeficiency pulmonary abnormalities in patients with primary hypogammaglobulinemia radiologic findings of adult primary immunodeficiency disorders. contribution of ct mucociliary clearance in patients with immunoglobulin deficiency respiratory dysfunction in patients with common variable hypogammaglobulinemia heart lung transplantation in a patient with end stage lung disease due to common variable immunodeficiency bronchiectasis in hiv disease accelerated obstructive pulmonary disease in hiv infected patients with bronchiectasis bronchial dilatation in patients with hiv infection: ct assessment and correlation with pulmonary function tests and findings at bronchoalveolar lavage bacterial bronchitis and bronchiectasis in human immunodeficiency virus infection pathologic pulmonary alterations in long-term human heart-lung transplantation postmortem findings in lung transplant recipients use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis airways involvement in rheumatoid arthritis. clinical, functional, and hrct findings visceral lesions associated with chronic infectious (rheumatoid) arthritis lung lesions in rheumatoid arthritis pulmonary disease associated with rheumatoid arthritis convalescent care in chronic arthritis bronchiectasis and rheumatoid arthritis: a clinical study pulmonary lesions and rheumatoid arthritis bronchiectasis. a late feature of severe rheumatoid arthritis high resolution computer tomography of the lung in lifelong nonsmoking patients with rheumatoid arthritis the lung in inflammatory bowel disease bronchiectasis following colectomy for crohn's disease chronic bronchial suppuration and inflammatory bowel disease unexplained bronchopulmonary disease with inflammatory bowel disease noninfectious lung pathology in patients with crohn's disease commentary: bronchiectasis and inflammatory bowel disease the impact of substance abuse on the respiratory system bronchiectasis: a cause of pulmonary symptoms in heroin addicts pulmonary complication of heroin intoxication. aspiration pneumonia and diffuse bronchiectasis bronchiectasis following ammonia burns of the respiratory tract: a review of two cases fatal anhydrous ammonia inhalation bronchiectasis following pulmonary ammonia burn said sl bronchiectasis and progressive respiratory failure following smoke inhalation acknowledgments. the authors are deeply appreciative to diane gillihan for expert secretarial assistance, vince messina for photography, and the staff of the brittingham memorial library for bibliographic support. key: cord- - btg w authors: golfieri, r.; giampalma, e.; morselli labate, a. m.; d'arienzo, p.; jovine, e.; grazi, g. l.; mazziotti, a.; maffei, m.; muzzi, c.; tancioni, s.; sama, c.; cavallari, a.; gavelli, g. title: pulmonary complications of liver transplantation: radiological appearance and statistical evaluation of risk factors in cases date: journal: eur radiol doi: . /s sha: doc_id: cord_uid: btg w the aim of this study was to evaluate the incidence, radiographic appearance, time of onset, outcome and risk factors of non-infectious and infectious pulmonary complications following liver transplantation. chest x-ray features of consecutive patients who had undergone liver transplants over an -year period were analysed: the type of pulmonary complication, the infecting pathogens and the mean time of their occurrence are described. the main risk factors for lung infections were quantified through univariate and multivariate statistical analysis. non-infectious pulmonary abnormalities (atelectasis and/or pleural effusion: . %) and pulmonary oedema ( . %) appeared during the first postoperative week. infectious pneumonia was observed in . %, with a mortality of . %. bacterial and viral pneumonia made up the bulk of infections ( . and . %, respectively) followed by fungal infiltrates ( . %). a fairly good correlation between radiological chest x-ray pattern, time of onset and the cultured microorganisms has been observed in all cases. in multivariate analysis, persistent non-infectious abnormalities and pulmonary oedema were identified as the major independent predictors of posttransplant pneumonia, followed by prolonged assisted mechanical ventilation and traditional caval anastomosis. a “pneumonia-risk score” was calculated: low-risk score ( < . ) predicts . % of probability of the onset of infections compared with . % of high-risk ( > . ) population. the “pneumonia-risk score” identifies a specific group of patients in whom closer radiographic monitoring is recommended. in addition, a highly significant correlation (p < . ) was observed between pneumonia-risk score and the expected survival, thus confirming pulmonary infections as a major cause of death in olt recipients. abstract. the aim of this study was to evaluate the incidence, radiographic appearance, time of onset, outcome and risk factors of non-infectious and infectious pulmonary complications following liver transplantation. chest x-ray features of consecutive patients who had undergone liver transplants over an year period were analysed: the type of pulmonary complication, the infecting pathogens and the mean time of their occurrence are described. the main risk factors for lung infections were quantified through univariate and multivariate statistical analysis. non-infectious pulmonary abnormalities (atelectasis and/or pleural effusion: . %) and pulmonary oedema ( . %) appeared during the first postoperative week. infectious pneumonia was observed in . %, with a mortality of . %. bacterial and viral pneumonia made up the bulk of infections ( . and . %, respectively) followed by fungal infiltrates ( . %) . a fairly good correlation between radiological chest x-ray pattern, time of onset and the cultured microorganisms has been observed in all cases. in multivariate analysis, persistent non-infectious abnormalities and pulmonary oedema were identified as the major independent predictors of posttransplant pneumonia, followed by prolonged assisted mechanical ventilation and traditional caval anastomosis. a ªpneumonia-risk scoreº was calculated: low-risk score ( < . ) predicts . % of probability of the onset of infections compared with . % of high-risk ( > . ) population. the ªpneumonia-risk scoreº identifies a specific group of patients in whom closer radiographic monitoring is recommended. in addition, a highly significant correlation (p < . ) was observed between pneumonia-risk score and the score), the technical quality of the transplant surgery, the type, intensity and duration of the immunosuppressive therapy and epidemiological exposure to environmental agents. because one or more of these factors are important at different points in the posttransplant course, it should be possible to predict which complications are most likely to occur at different moments [ ] : an accurate chest x-ray follow-up could therefore lead us to the type of pulmonary abnormality (infectious or non-infectious) and to the possible infecting agent, thus improving the final patient outcome. the aim of the present study was to: . describe the radiological pattern on chest x-ray film (crx) and prevalence of non-infectious and infectious pulmonary complications during the follow-up of olt . verify the type of infecting pathogens and the mean time of their occurrence . identify the main risk factors for lung infections, and their quantification through univariate and multivariate statistical analysis, in order to evaluate the likelihood of developing pneumonia. particular emphasis was placed on the predisposing factors for pneumonia occurring during the first posttransplant month, because this is considered to be the most critical period, when technical and clinical problems are associated with fatal infections [ , ] . many papers have been published previously on this topic [ , , , , , , , , , ] , but, to our knowledge, the present study represents the largest series to date of radiologically demonstrated pulmonary complications following liver transplantation involving a follow-up of over years. the first patients who underwent olt at the surgical department and transplant centre of the university of bologna, between september and september , were included in this retrospective study. among these, patients received only a single graft, cases were retransplanted and cases received three grafts for a total number of retransplantations ( due to vascular ischaemic events, for ªprimary non-functionº and for acute rejection). of the patients who needed retransplantation, only survived ( . %). the medical records of all patients were reviewed from the time immediately preceding olt until death or throughout the complete follow-up (maximum . years). the following clinical data were recorded and correlated to the onset of pulmonary infections and to the outcome: . the mean age of the present patient population was . years (sd . years), with females and males. mean follow-up after the transplant was . years (median . years; interquartile range . ± . years). two hundred fifteen olt recipients are still living ( . %). in addition to the six major indications listed in table , the ªotherº group included the following cases: wilson's disease; diffuse angiomatosis; giant hemangiomas; hemangio-endothelioma; hepatoblastoma; macronodular hyperplasia due to venocclusive disease; crigler-najjar disease; polycystic disease; amyloidosis; and different metabolic liver diseases. the patients' pre-operative clinical conditions, presented in table , were assessed according to the united network of organ sharing (unos) classification [ ] . orthotopic liver transplantation (olt) was carried out with two standard surgical techniques: the traditional technique, as first described by starlz [ ] in patients ( . %), and the ªpiggy-backº caval anastomosis technique [ ] in patients ( . %). in this population, piggy-back caval anastomosis was performed only once in each patient. selective bowel decontamination with colomycin, nystatine or gentamicin sulphate was routinely performed in the immediate pre-transplant period and continued for the weeks following olt. a standard triple immunosuppressive therapy [cyclosporine a (cya)-azatioprine-steroids] was routinely used. in non-responsive cases ( . %), monoclonal anti-t cells antibodies okt was administered, combined with steroids, antihistamines and lasix iv on the first day and immunoglobulins. in patients ( . %) as an alternative to okt (in steroid-refractory rejection episodes or in cases of neuro-/nephrotoxicity secondary to cya) fk (tacrolimus fuji, sawa, japan) alone, together with steroids and/or azatioprine was used. in cases fk was associated with okt . intensive care unit (icu) risk was considered to be duration of stay in icu and days of assisted mechanical ventilation (amv). data distribution is reported in table . rejection was histologically diagnosed after liver biopsy and its severity was graded from i to iv according to the current classification system (table ) [ ] : it was observed in patients ( . %) and needed retransplantation in cases ( . %). in all patients chest roentgenograms (cxr) were performed daily, as a bedside semi-erect film, in the immediate posttransplantation period and throughout the entire hospitalisation as an erect film; in the follow up, cxr was performed according to the study protocol: an erect cxr every months during the first months and every months during the following years. chest x-rays were independently reviewed by two radiologists (r. g. and e. g.) who were unaware of the clinical pa-rameters at that time: in every cxr the following parameters were evaluated and described according to the commonly used terminology, fleishner society nomenclature [ ] , and quantified as described below. atelectasis was classified as slight (involvement of less than one subsegment or discoid atelectasis), moderate (involving one or more segments or lobar hypoventilation) or severe (atelectasis of one or more lobes). pleural effusion was scored as slight (in the case of loss of the sharpness of costo-phrenic sulci and diaphragmatic profiles or subpulmonary effusion), moderate (effusion involving less than % of a hemithorax) or severe (involving more than %, including a massive effusion with mediastinal shift). for statistical analysis, normal pulmonary patterns were considered as score ; slight and moderate atelectasis and/or slight and moderate grades of pleural effusion were considered as score ; and severe atelectasis and/or severe effusion and/or when lasting > week were included in score . pulmonary oedema was classified as score (interstitial: localised, basal and/or diffuse) and score (alveolar: localised or diffuse). vascular pedicle width (vpw) was classified as normal when it was approximately cm. hydrostatic oedema, due to hyperhydration, was considered in all cases where a non-cardiogenic oedema with homogeneous pattern was associated with an increase in vpw diameters. adult respiratory distress syndrome (ards) was defined as the acute onset of a diffuse ªpatchyº alveolar oedema documented at cxr, with no enlargement of the vascular pedicle (no clinical evidence of cardiogenic pulmonary oedema), with reduced pulmonary compliance, needing assisted ventilation at fi o . and, when measurable, pulmonary artery occlusion pressure of less than mmhg [ , , ] . infectious pneumonia was classified according to three main radiological patterns: (a) focal pulmonary consolidation; (b) nodules or rapidly growing masses (with or without central cavitation); and (c) diffuse pulmonary infiltrates (interstitial or alveolar pattern) [ , ] . in order to identify early lung infections, control cultures from biological fluid specimens were obtained (bacteriology of sputum, bronchoscopy aspirates, pleural fluid, bile, blood) and serological samples were controlled daily. a pathogen or a potential pathogen obtained from a normally sterile site (sputum, specimen obtained through a bronchoscopy or pleural fluid) was considered responsible for pulmonary infection. the combination of a chest x-ray positive for a new or increasing infiltrate, clinical symptoms such as fever or dyspnoea, and positive cultures were considered to be pulmonary infection [ , ] . in order to limit our observations to ªmajorº infections only, febrile episodes with no positive cultures or isolated cultural positivities without clinical±radiological positivities were considered as ªminorº infections or ªcontaminationsº and were excluded [ , ] . when superimposed on ards, pneumonia could not be identified by cxr: the diagnosis could only be obtained by positive cultures from biological fluids. for the evaluation of the time of occurrence, in polymicrobial pneumonia, the most aggressive pathogen of the association was considered prevalent (e. g. bacterial vs viral and fungal over bacterial). the yates corrected chi-square was applied to compare proportions between different groups of patients. the putative risk factors for development of pneumonia after olt were tested by means of univariate and stepwise multivariate survival analysis based on the cox proportional hazard regression model [ ] . the exponentials of the coefficients calculated by these analyses (or) were reported to quantify the effect of each putative risk factor on the hazard function. these ors estimate the fractional increase of the risk of developing pneumonia either determined by the increase of one unit in the score of the putative risk factors or determined by the presence of dichotomous risk factors. the % confidence intervals (ci) of the ors were also evaluated. the same univariate and multivariate procedures were applied to analyse the mortality rate after olt. the product-limit estimate [ ] was used to plot both the time course of the appearance of pneumonia and the survival after olt. statistical analyses were performed by means of the bmdp statistical software [ ] running on a personal computer. a two-tailed p-value of less than . was used to define statistical significance. a summary of non-infectious pulmonary abnormalities is presented in table . in the early postoperative period, pulmonary non-inflammatory changes involved patients ( . %). atelectasis of different degrees was a common finding ( . %): it was lamellar or subsegmental and it accompanied pleural effusion in most cases ( of , . %), whereas only in cases did it prevail against effusion, appearing as lobar or multilobar atelectasis. in the majority of patients it resolved itself spontaneously within days on average: in of the cases of severe and prolonged right lobar atelectasis, a bacterial superinfection appeared (table ) . pleural effusion was very frequent ( . %) in the first week: in the majority of cases ( cases: . %) it was slight or moderate, situated mainly or exclusively at the base of the right lung, the site of surgical manipulation, with complete resolution within days on average (range ± days). only in cases did it last more than days and in of them ( . %) it was treated with thoracentesis. pulmonary oedema was very common in the early postoperative period. the interstitial involvement was prevalent ( . %). the cause was overhydration (hydrostatic oedema) in cases ( . %) and it regressed after ± days of diuretics and fluid restriction. a cardiomegaly was always absent. the radiographic pattern of interstitial pulmonary oedema was characterised by bilateral, diffuse or central ªground glassº opacities accompanied by kerley b lines. the vpw was always increased in hydrostatic oedema. in alveolar oedema a diffuse or basilar air-space consolidation was present, differing from the patchy focal opacities of interstitial pneumonia. in patients ( . %) a disseminate pattern of ards was observed in the final phase and al-ways superimposed on sepsis complicating a pulmonary infection: the ards mortality was %. the appearance of ards was characterised by an extensive patchy diffusion of air-space opacities (more extensively than the previous pneumonia infiltrates), with air bronchogram and without an increase in vpw diameters. the frequency of ards was significantly higher (p = . ) in retransplanted patients ( of , . %) than in single graft patients ( of , . %). of patients who received immunosuppressive therapy with okt ( due to hyperacute rejection and due to the onset of cya toxicity), developed acute pulmonary hydrostatic oedema with diffuse interstitial involvement. no okt -related alveolar oedema was observed. infectious pneumonia was observed in patients ( . %), and was fatal in ( . %). in patients a polymicrobial infection was present and in a single agent was isolated (a total of pathogens were isolated on biological fluids or confirmed by serological tests). in addition, in two bacterial abscesses the specific agent could not be identified. bacterial infections were the most common ( of , . %) followed by viral ( of , . %) and fungal ( of , . %) pneumonia: the most frequent agents were gram-negative (mainly represented by pseudomonas aeruginosa as a single or coinfecting agent) isolated in . % ( of ), cytomegalovirus (cmv) isolated in . % ( of ) and candida albicans observed in . % ( of ) of cases, respectively. in . % of cases, pulmonary infection was the cause of death ( with final ards). the majority of infections ( of cases, . %) had their onset within the first months (ªearly infectionsº). in cases ( . %) the pneumonia occurred during the first month, in cases ( . %) within the second month, and in only cases did the infection have later onset. all the lethal infections developed within the first months after olt, of which developed during the first month. twenty-seven of ªearly infectionsº had onset during the icu stay ( . % of the whole infections); among these, patients were still subjected to amv at the time of the onset of pulmonary infections and the causal agents were: pseudomonas in cases; staphylococcus aureus in cases; and coinfections of candida with pseudomonas and cmv in cases each. in all cases of infection solely by cmv, pre-olt serology was positive (high igg rate anti-cmv): of these had complete recovery. two of the cases of cmv pneumonia superinfected by candida were seronegative in pre-transplant screening, and both had lethal pneumonia: this confirms a more severe outcome of seronegative pre-olt patients. there was a general correlation between the type of radiographic pattern and the microorganism producing the pneumonia, since the radiological patterns observed in the lung infections were: . ) ; in cases of isolated cmv and cases of fungal superinfections the radiological findings were small multiple alveolar sub-segmental consolidations, associated with little pleural effusion, resembling those of bacterial pneumonia ( fig. b,c) . in all cmv infections, either isolated or coinfecting agent, a previous non-infectious pulmonary abnormality was present. the only case of herpes virus pneumonia showed a diffuse symmetrical reticular interstitial thickening, without pleural effusion at cxr (fig. ). fungal infections (candida, aspergillus) had late onset ± median day (range ± days). the radiological pattern in cases was as a single pulmonary infiltrate, and the six remnants showed multiple focal rapidly growing lesions, always associated with pleural effusion. in cases a central cavitation occurred, quickly evolving towards an ards syndrome with fatal outcome (figs. , a). in all fungal infections a previous non-infectious pulmonary abnormality had been present: of slightmoderate and of severe entity. mortality related to pneumocystis carinii pneumonia had onset on the twenty-eighth postoperative day: cxr showed an interstitial ªground glassº pattern, mainly in the perihilar or basal lung regions (fig. ) , which resolved after therapy in weeks. univariate analysis for infections demonstrated six risk factors associated with pneumonia, as reported in ta non-infectious pulmonary abnormalities are strong risk factors for pneumonia: the increase of one unit in the score scales of both atelectasis/effusion and pulmonary oedema elevates the pneumonia-risk by three times. atelectasis and pleural effusion were observed in . % of patients who developed pneumonia. pulmonary oedema preceded pneumonia in . % of cases. among the patients who developed infections, pulmonary oedema, especially with alveolar pattern, was observed significantly (p = . ) more frequently ( . %) when compared with uninfected cases ( . %). these findings indicate the pre-existing pulmonary abnormalities as a local risk factor predisposing to infection. the variables which entered the stepwise procedure are shown in table ; four independent risk factors for pneumonia were identified: pulmonary non-inflammatory abnormalities and oedema, both doubling the risk of pulmonary infections, and prolonged amv; on the contrary, piggy-back anastomosis reduces the risk of pneumonia as compared with traditional caval anastomosis. on the basis of the coefficients computed by the stepwise multivariate survival analysis and the pattern of the variables that entered into the procedure, a score for the risk of developing pulmonary infections was calculated for each patient: pneumonia-risk score = . (if no piggyback) + . ´amv + . ´pni + . ´ede, where amv, pni and ede represent the score values of mechanically assisted ventilation, pulmonary non-infectious abnormalities and oedema, respectively. patients with different risks of developing pulmonary infections were identified according to the tertile values of the pneumonia-risk score (low risk: score less than . ; medium risk: score from . to . ; high risk: score greater than . ). the time-course of the appearance of pulmonary infections (fig. ) shows that the cumulative -year incidence of pneumonia in high-risk patients was . %, . % in medium-risk patients, and . % in low-risk patients. in univariate analysis (table ) , a statistically significant higher risk was demonstrated in cases of ahf patients, retransplantation, immunosuppression with okt , prolonged stay in icu and amv and in protracted pulmonary oedema; instead, surgical piggyback caval anastomosis is a factor reducing hazard. multivariate analysis taking into account all the risk factors expressed in table , also including pneumonia and age, was performed. two of the four independent risk factors are represented by prolonged amv, which triples the risk, and pulmonary oedema, which doubles the risk (table ) , whereas the piggy-back technique and a prolonged icu stay both seem to constitute a relative ªprotectionº against fatal complications, since their or were significantly less than one ( . and . , respectively). a highly significant (p < . ; or = . , ci = . ± . ) correlation was also observed between the survival rate and the pneumonia-risk score in the same groups of patients: kaplan-meier curves depicting survival rates in pneumonia-risk scores groups are shown in fig. . the expected -year survival rate in low-, medium-and high-risk patients is . , . and . %, respectively. unlike the experience with respiratory disorders occurring after transplantation of organs such as the kidney, bone marrow, lung and heart [ , , , , , , , , ] , the majority of the pulmonary complications we identified following olt were non-infectious in origin. non-infectious pulmonary complications were re- [ ] , respectively, in % in a preliminary report of our institution [ ] and in . % of the present series. these complications are directly related to surgical manipulations for diaphragmatic dissection and to the type of technique and the surgical time spent in performing caval anastomosis: the right phrenic nerve is often injured during surgery. therefore, atelectasis due to diaphragmatic hypomobility in the early postoperative period is a common finding, involving one or more lung segments, mainly on the right side [ ] . reduced compliance of the pulmonary basis secondary to the increase of intravascular volume, retained secretions or compression from perioperative pleural effusion can also be responsible for postoperative atelectasis [ ] . usually the recovery is complete after intense respiratory therapy, with no need for bronchial aspiration. afessa et al. [ ] reported atelectasis in % of patients after olt (unilateral right in % and bilateral in % of cases) with spontaneous resolution in % of the cases after weeks. similarly, in our experience, atelectasis was observed in . %, bilateral ( . %) or right-sided ( . %), and it resolved itself spontaneously within days on average. a severe and prolonged right lobar atelectasis is rare [ , ] and a superimposed bacterial pneumonia should be suspected in these cases, as it was observed in of patients ( %) of the present series. pleural effusion is an expected consequence of olt, observed in ± % of patients in the first postoperative week [ , , , ] : mainly on the right side or bilateral, it is a transudate (as demonstrated by the performed thoracentesis) also named ªhepatic hydrothoraxº [ ] due to residual ascites or to surgical trauma. usually less than % of the effusions need thoracentesis [ , , , ] . in duran et al.'s series, pleural effusion was noted in . % of patients, . % of them requiring thoracic tube drainage [ ] . in the present series it was observed in . % of the cases, with spontaneous resolution within a week in the majority of cases and thoracentesis was required in only % of them. pulmonary oedema with hemodynamic or hydrostatic origin is a common non-infectious complication of cardiac, renal, bone marrow and liver transplant. in liver transplants pulmonary oedema is due mainly to overhydration from fluid infusion, excess or massive blood transfusion during surgery, to fluid retention related to preoperative renal dysfunction or to renal failure due to cya nephrotoxicity [ , ] . in the majority of cases, it regresses after diuretics. in our series pulmonary oedema was observed in . %, with interstitial involvement in the majority of them: the main cause was overhydration (hydrostatic oedema) and it regressed after ± days of diuretic therapy. ards has been reported in the literature in from . to . % of cases following olt [ , , ] . the rate of mortality approaches % and the onset is generally within the first postoperative week [ ] . multiple etiological factors have been described (peri-surgical events such as infraoperative hypotension, prolonged surgical time, haemorrhage and blood transfusions). despite the complexity and dura-tion of the olt surgical procedure, which often involves extensive blood transfusions, ards has rarely been described in the early postolt period. sepsis appears to be, in our and in other authors' experiences [ ] , the most common cause of ards in olt patients. the incidence of ards in our experience was . %. it was always associated with sepsis from pulmonary infections and had a fatal outcome in all cases due to toxic shock syndrome. similarly, in a recent report [ ] , ards was observed in . % of cases during the postolt course, sepsis was always the causal factor and, as in non-transplant patients, there was a very high mortality rate [ , ] . retransplantation is a significant risk factor for ards, as seen in a recent series in which ards occurred in % of the patients receiving multiple grafts as compared with . % of patients receiving one graft [ ] . accordingly, in our series, ards was observed in . % of second graft patients and in . % of the single graft cases (p = . ). pulmonary infections after olt have been observed in a range from to % [ , , , , , , , ] , with mortality around %. these prevalences are much higher than those observed after routine hepatic surgery, as shown in approximately % of cases [ ] . the . % prevalence of pneumonia (lethal in . %) in the olt population of this series was similar to some previous reports [ , , ] and lower in comparison with previously reported prevalences of . % of infectious events (fatal in %) [ ] . a wide variability among the reported experiences about rate of infections, prevalence and type of infecting agents in postolt follow-up is observed in table , depending mainly on bowel decontamination, patient selection criteria for olt, immunosuppressive therapy, percentage and type of environmental agents. during the first month after olt, the majority of bacterial pneumonia is reported by almost all series [ , , ] . the most frequent pathogens in our series were gram bacteria and viruses (cmv) followed by candida in cases. after olt, the majority of lung infections have onset within the first months of the posttransplant course. after the first month graft recipients have passed the major global risk of lethal infections (figs. , ) . in our experience, in the first month . % of the infections appeared. almost all the infections ( . %) and all the fatal infections appeared by the end the second month (fig. ) . the different opportunistic pathogens tend to appear at predictable times during the posttransplant course, following the timetables suggested by rubin [ ] after liver transplant and recently by leung [ ] after bone marrow transplant. the knowledge of the time lines of the different pathogens is helpful in the differential diagnosis. accordingly, in our series, during the first weeks, bacteria and fungi were the only agents observed; subsequently (days ± ), cmv and fungi were the most important pathogens, followed by p. carinii. the only difference in our data is the pcp onset, which is reported to occur, in the majority of cases, ± months after olt and which in the sole case of our series had onset approximately the twenty-eighth day. after the second month, there is no predominant patho-gen: bacterial pneumonia from the environment, viral infections from cmv and herpes simplex and p. carinii pneumonia are common [ ] . bacterial pneumonia is the most common pulmonary infection after liver, lung and cardiac transplants [ , , ] . in olt, bacterial pneumonia constituted up to % of pulmonary infections and arises during assisted ventilation: pre-transplant prolonged intubation, aspiration pneumonia or postoperative atelectasis and lengthy surgical procedure seems to represent promoting factors [ , , , , , ] . in our series, bacterial infections constituted . % of all pulmonary infections. the bacteria most frequently described are enterogenic gram-and particularly pseudomonas aeruginosa, as observed in . % of our series, as single or co-infecting microorganism. all but three bacterial infections had an onset within the first month, during assisted mechanical ventilation in . %. the radiographic findings of bacterial pneumonia are believed to be identical in immunocompetent and immunocompromised patients: in the present series they appeared as dense air-space consolidations with lobar, segmental, localised or patchy distribution, usually associated with a small amount of pleural effusion. the same characteristics were also observed in two cases of candida superinfection. in patients with sepsis and bacteraemia, fulminant disease with rapid progression to ards may occur, with a pattern changing into diffuse, irregular (patchy) air-space consolidation. cytomegalovirus pneumonia is reported to be the most frequent pulmonary infection after bone marrow transplantation [ ] and it has been described in up to % cardiac and kidney transplants and in more than % lung and lung-heart transplant recipients. in olt recipients the major cmv-infected organs are the liver, intestine and lung. a high prevalence of cmv pneumonia is, however, reported [ , , , ] and it is confirmed in our series, where it was second in frequency, with . % overall incidence. due to frequent superinfections (three candida superimpositions in our series), the prognosis is poor. coinfection with other opportunistic pathogens has been previously described [ ] , particularly with pneumocystis carinii, as observed in one case of the present series. strong antirejection therapy, such as antilymphocytic antibodies, such as okt , has been reported to be the highest risk factor of serious cmv infections [ , , ] . our experience excludes a specific cmv-promoting effect of okt . as predictors of cmv pneumonia have also been identified: the donor seropositivity and recipient seronegativity, advanced unos status, invasive fungal diseases, abdominal reinterventions and bacteraemia, all events reducing immunological defences [ ] . in our series, reactivation or reinfection mechanisms were present in the majority of seropositive recipients: preoperatively cmv-seropositive recipients have a higher percentage of reactivation infections, yet rarely develop severe infections, whereas cmv seronegative recipients have a higher risk of developing severe infections [ , , ] . furthermore, as the most significant effect of primary cmv infection, a broad-based depressant effect on the host defences is described, responsible for the onset of a great number of opportunistic infections, elevating the mortality rate [ , ] . moreover, in the present series, the immunodepressant effect of primary cmv infection and the frequent fungal superinfection was confirmed, as cases of primary cmv pneumonia were superinfected by candida and led to a fatal outcome. the chest radiographic findings of cmv have been variably described as consisting of a diffuse fine re- ticular or a haziness pattern of interstitial pneumonia, diffuse micronodular patterns, focal air-space consolidation resembling that of bacterial pneumonia [ ] or, eventually, with normal findings [ ] . the majority of our cases demonstrate diffuse parenchymal haziness and in cases we found a pattern of parenchymal consolidation distributed in the middle and lower lung zones, similarly to what has been observed in previous studies performed on bone marrow transplant recipients [ ] : in these cases the basilar predominance has been reported as related to hematogeneous cmvdissemination, with preferential distribution to the lower lung zones, due to their greater blood flow perfusion. candida superinfections appeared as nodular or focal airspace consolidations. herpes simplex pneumonia is rarely described in liver transplant recipients. it usually has a late onset, after the first month, and is due, like cmv, to the reactivation of a latent virus, as a result of immunosuppressive therapy. the only case of herpes pneumonia observed in our series showed the same radiological pattern of uncomplicated viral pneumonia, which consisted in all cases of diffuse interstitial infiltrates, having a grossly reticular pattern. pleural effusion was absent. fungal pneumonia in solid organ transplantations is less frequent than bacterial and viral (cmv) infections, but it is by far the most severe and it has the highest mortality rate. the two main agents are usually represented by candida or, more rarely, aspergillus. these infections are frequently observed within the first months [ ] . the starting point of candida infection is the gastroenteric tract, colonised by this fungal agent in ± % of the normal subjects, and the manipulations at the time of the transplant can cause the diffusion of the pathogens. surgical instrumentation and central catheters are the major source of aspergillus, criptococcus and mucor, which are non-endogenous agents, but are always acquired from the environment. as significant risks of postolt fungal infections, a surgical time > h, intratransplant transfusional requirements, bacterial infections within the first months after olt together with prolonged systemic antibiotic therapy, reinterventions and high dose immunosuppression have been cited [ , , ] . accordingly, a significant correlation has been observed in our population between okt immunosuppression and fungal pneumonia. the incidence of candida infections in the different olt series varies from to % according to the type of bowel decontamination and antifungal prophylaxis performed. the usual site of infection is abdominal. the mortality rate from fungal infection after olt ranges from to % and is higher in fungal superinfections of pre-existing infiltrates. accordingly, in the present series, the majority of candida pneumonia superinfected bacterial or viral infections and had a fatal outcome in % of the cases [ , ] . aspergillus infection most commonly appears as pneumonia or disseminated infection with mortality rates that approach %. the one observed case of aspergillosis in our series was present as an isolated pathogen with lethal pneumonia. the chest radiographic features of fungal infections consisted of multiple nodular opacities with intense alveolar infiltrates, with tendency to central cavitation and air bronchograms or nodules with hazy margins or clusters of fluffy nodules. the nodules of fungal pneumonia tended to be multiple rather than solitary, and a prevalent involvement of the upper lobes is frequently observed. pleural effusion and adenopathy may be seen [ ] . in the present study, the radiological pattern of candida infections or superinfections showed multifocal areas of air space consolidations, usually not associated with pleural effusion. in those cases which do not respond to therapy, the nodules may coalesce to larger regions of consolidation and, eventually, to the typical appearance of ards. in aspergillosis the nodules were rapid growing and showed a crescent-shaped area of hyperlucency (ªair crescent signº) representing cavitation around the pre-existing dense central nodule. pneumocystis carinii pneumonia (pcp) in organ transplants has a reported incidence of ± %, depending on the specific prophylaxis adopted [ , , , , , , , ] . usually pneumocystis pneumonia has a later onset as compared with the other agents, appearing between the third and sixth month: the mortality rate is between and % [ ] . it has rarely been observed in olt recipients ( % of cases) and more often is a coinfection with cmv infiltrates. in this case it is associated with a higher mortality rate [ ] . the radiological pattern is similar to viral pneumonia, with smooth interstitial reticular involvement or typically with central and bilateral perihilar linear processes, which progress to a homogeneous diffuse alveolar consolidation. pneumocystis carinii pneumonia sometimes appears with atypical infiltrates (focal and non-diffuse pattern) [ , ] . the sole cases observed in our series appeared late in the postolt course (twenty-eighth day) and showed a radiological pattern of diffuse interstitial impairment, ªground glassº appearance and mild symptoms (fever). there was a complete and rapid recovery after therapy. previously reported risk factors of pulmonary infections following olt [ , , , , ] included: poor preoperative unos status; technical quality and duration of the transplant surgery; surgical complications needing major surgery (retransplantation); the type, intensity and duration of the immunosuppressive therapy; infections due to immune-modulating viruses; metabolic disturbances and epidemiological exposure to environmental agents. in a previously published study on the first cases of olt [ ] , prolonged icu and amv, advanced unos status, okt immunosuppression and pulmonary oedema were identified as highly predictive risk factors for the onset of pulmonary infections. the present study, performed on a wider patient population, demonstrated, in univariate analysis, a significantly increased association of pulmonary infection with the following five risk factors: caval traditional anastomosis, retransplantation, okt immunosuppression, icu stay and amv duration, pulmonary non-inflammatory abnormalities, such as effusion and atelectasis, and oedema. in our multivariate analysis, the strongest independent risk factors for pneumonia were non-infectious abnormalities (atelectasis and pleural effusion) and pulmonary oedema, followed by prolonged amv, whereas piggy-back caval anastomosis is shown to be significant as a protection factor, preventing the onset of pneumonia, as compared with traditional caval anastomosis. in our experience, which differs from previous studies [ , , , ] , basal liver disease, unos score and graft rejection do not represent statistically significant risk factors for pneumonia. about surgically related risks, traditional caval anastomosis is demonstrated in our series to be more risky than the piggy-back technique. liver transplantation with preservation of the recipient vena cava (the piggyback technique), which avoids retrocaval dissection [ ] , reduces overall time of surgery, need of blood transfusions and postoperative renal failure, with earlier extubation, shorter icu and total hospital stay. due to these advantages, the follow-up of olts performed with the piggy-back technique showed, in the present study, non-infectious pulmonary abnormalities of a less severe degree, thus resulting in a significantly lower rate of pneumonia as compared with traditional caval anastomosis and a significantly reduced overall mortality rate. in multivariate analysis the piggy-back technique represents a significant factor preventing postoperative pneumonia and mortality. in accordance with the studies of the mayo clinic and other authors [ , ] , our results confirm a significantly higher percentage of major infections after retransplantation than in a single graft. retransplant also represents a significant risk of mortality. anti-t-cell antibody (okt ) immunosuppressive therapy has previously been described as a strong risk factor for serious infection in the weeks following treatment [ , ] . a significantly higher incidence of severe pneumonia with fatal outcome in the majority of cases has been also confirmed in our series. a further serious complication of okt is the onset of acute pulmonary oedema during the first days of treatment, which could predispose to superinfections. this usually appears in patients already overloaded with fluid prior to treatment. in of cases in our series, diffuse interstitial oedema was evident, with a slight increase in vpw: clear alveolar oedema was never observed due to diuretics routinely administered in the days before the injection of okt . a prolonged stay in icu has been reported as the only significant risk factor for the onset of infections in liver graft recipients [ ] . our statistical univariate analysis confirms this as one of the major risk factors for infection: of infections in our series ( . %) developed in icu, and in cases during amv ( . %). multivariate analysis, instead, demonstrates that the icu stay risk in the global population is paradoxically ªa protectionº against infection and mortality, and that it is only indirectly significant because it is related to the real ªmajorº risk for pneumonia and related mortality, represented by prolonged intubation and amv. protracted amv has been previously identified as a risk factor for developing nosocomial infection [ ] . the high percentage of pseudomonas pneumonia observed in the present series ( . %) was directly related to a longer duration of amv during the icu stay. prolonged intubation and amv were shown to be, in multivariate analysis, the greatest independent risk factors for mortality. among the variables studied, the pre-existing pulmonary abnormalities ± pleural effusion, atelectasis and pulmonary oedema ± were shown to be the greatest independent predictors of pneumonia in our olt population. persistent effusion, atelectasis and pulmonary oedema triple the risk of developing infectious complications. the vast majority of infections ( of ) were ipsilateral and superimposed on these previously non-infectious lesions, which constitute ªlocus minoris resistentiaeº especially in nosocomial bacterial infections (pseudomonas, staphylococcus). pulmonary oedema was demonstrated, in multivariate analysis, to be the second most important predictor for mortality. by associating the selected major risk factors for pneumonia and mortality, piggy-back anastomosis, prolonged amv and icu stay, pulmonary non-inflammatory abnormalities and pulmonary oedema, we defined a pneumonia-risk score in order to identify which patients needed closer cxr and clinical screening for pneumonia. the cumulative -year incidence of pneumonia was . % in the high-risk score, . % in the medium-risk score, and . % in the low-risk score. the time course of the appearance of pneumonia confirms that the majority of infections had their onset within the second month, but the time of onset is more protracted as the risk score increases. in low-risk patients, all pneumonia appeared by the twentieth day after olt, whereas the pneumonia risk period is prolonged in the high-risk group, in which a higher percentage of pneumonia can appear after the first month. clinical and radiological follow-up and intensified preventive measures should therefore be prolonged according to the risk score, in order to reduce morbidity and, consequently, mortality. previously published data [ , ] demonstrated that infections are the leading causes of death after olt. our study confirms that in all fatal infections the lung was the primary site of infection, as shown by the close correlation between pneumoniarisk score and survival: the expected -year survival rate differs significantly in low, medium and high pneumonia-risk populations, being . , . and . %, respectively. as previously reported [ ] , fungi constituted the pathogenic group most highly associated with mortality within days of diagnosis (mortality %) followed by bacteria ( %) and cmv ( %). in conclusion, in olt recipients, as in all immunocompromised patients, prophylaxis, when possible, per-sistent infection surveillance and an aggressive diagnostic and therapeutic approach help to reduce the potentially fatal impact of pulmonary abnormalities. bacteria were the most frequent ( . %) pathogenic group in our series, rarely fatal, followed by cmv ( . %) and fungi ( . %), the latter being associated with higher mortality rate. during the posttransplant course these agents show a predictable time of onset ± bacterial infections prevailing during the first weeks, fungal agents later (median days) and viral (mainly cmv) and p. carinii pneumonia appearing last. this knowledge could be an important aid to the radiological diagnosis in indicating the nature of the infiltrate and, therefore, in predisposing therapy, thus influencing the final clinical outcome. upon radiographic cxr features of the different agents, a fairly good correlation was found between the radiological cxr pattern and the microorganism, with an air-space consolidation pattern in bacterial, a nodular or focal consolidation pattern in fungal and a reticular interstitial pattern prevalent in viral and pcp pneumonia, with the only exception being cmv which could appear as focal alveolar consolidation in a minority. our study demonstrated three main independent risk factors for developing posttransplant pneumonia: prolonged amv/icu stay, pulmonary oedema and non-infectious abnormalities such as atelectasis and pleural effusion. the knowledge of the probability of the onset of infections based on the calculated pneumonia-risk score identifies the high-risk patient population, in whom closer, even daily radiographic monitoring is justified, in the early posttransplantation period, in order to control the pneumonia-risk factors. persistent or severe non-infectious pulmonary abnormalities, such as atelectasis and pleural effusions, triple the risk of pneumonia onset and therefore daily cxr monitoring is mandatory. pulmonary oedema, more frequently due to overhydration, should be surveyed and quantified by close cxr and clinically prevented, reducing postoperative water overload. furthermore, olt recipients having a high pneumonia-risk score are particularly at risk, since our data also confirms that pulmonary infections remain the leading cause of death after liver transplantation, as demonstrated by the close correlation between the pneumonia-risk score and mortality in the present series. very few studies have been done on the extensive employment of ct in early posttransplant follow-up. a recent report on ct studies of pulmonary complications after lung transplant [ ] , in which a comparison with histopathological studies has been carried out, demonstrated that ct findings were not helpful in differentiating between the different parenchymal complications. when matched with proper clinical data, close cxr monitoring could be of value in orienting the diagnosis of the different pulmonary abnormalities which complicate the postoperative course after olt. a precise knowledge of the probability of the onset of the different opportunistic agents of pneumonia which could superimpose on pulmonary non-infectious abnormalities at specific phases of the posttransplant course together with the consciousness of the differential risk of infection according to the calculated pneumonia-risk score is mandatory for whomever is involved with liver transplantation. infections complicating orthotopic liver transplantation early infections in kidney, heart, and liver transplant recipients on cyclosporine karchmer aw ( ) pulmonary complications of orthotopic liver transplantation infections after liver transplantation. an analysis of consecutive cases pulmonary complication and disease severity in adult liver transplant recipients infectious complications in liver transplantation ) incidence, distribution and outcome of episodes of infection in orthotopic liver transplantations early severe infections after liver transplantation pulmonary complications following orthotopic liver transplant: radiologic appearances and epidemiologic considerations in a series of cases pulmonary infections in liver transplant recipients receiving tacrolimus. changing pattern of microbial etiologies pulmonary complications following orthotopic liver transplant pulmonary complications of orthotopic liver transplantation pulmonary infections in the immunocompromised host pathologies pulmonaires dans la transplantation cardiaque, hØpatique et rØnale chez l'adulte state of the art: pulmonary considerations of organ transplantation infection in the organ transplant recipient diagnosis of pulmonary complications associated with lung transplantation in children: value of ct vs histopathologic studies infectious complications following isolated lung transplantation pulmonary complications after bone marrow transplantation pulmonary infections after bone marrow transplantation: clinical and radiographic findings the unos optn waiting list and donor registry: ± factors in the development of liver transplantation orthotopic liver transplantation with preservation of the inferior vena cava liver allograft rejection: an analysis of the use of biopsy in determining the outcome of rejection glossary of terms for thoracic radiology: recommendations of the nomenclature committee of the fleishner society regression models and life tables bmdp statistical software manual: to accompany the software release major liver resection: perioperative course and management the boston center for liver transplantation cmvig study group ( ) incidence and predictors of cytomegalovirus pneumonia in orthotopic liver transplant recipients a randomized trial comparing okt and steroids for treatment of hepatic allograft rejection cmv reinfection/reactivation after liver transplantation cytomegalovirus pneumonitis and lobar consolidation risk factors of invasive candida and non-candida fungal infections after liver transplantation pulmonary complications from monoclonal antibody (okt ) immunosuppresion in patients who have undergone an orthotopic liver transplant key: cord- - eutz xy authors: roumy, aurélien; liaudet, lucas; rusca, marco; marcucci, carlo; kirsch, matthias title: pulmonary complications associated with veno-arterial extra-corporeal membrane oxygenation: a comprehensive review date: - - journal: crit care doi: . /s - - -z sha: doc_id: cord_uid: eutz xy veno-arterial extracorporeal membrane oxygenation (va-ecmo) is a life-saving technology that provides transient respiratory and circulatory support for patients with profound cardiogenic shock or refractory cardiac arrest. among its potential complications, va-ecmo may adversely affect lung function through various pathophysiological mechanisms. the interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response which may increase pulmonary vascular permeability and promote the sequestration of polymorphonuclear neutrophils within the lung parenchyma. also, va-ecmo increases the afterload of the left ventricle (lv) through reverse flow within the thoracic aorta, resulting in increased lv filling pressure and pulmonary congestion. furthermore, va-ecmo may result in long-standing pulmonary hypoxia, due to partial shunting of the pulmonary circulation and to reduced pulsatile blood flow within the bronchial circulation. ultimately, these different abnormalities may result in a state of persisting lung inflammation and fibrotic changes with concomitant functional impairment, which may compromise weaning from va-ecmo and could possibly result in long-term lung dysfunction. this review presents the mechanisms of lung damage and dysfunction under va-ecmo and discusses potential strategies to prevent and treat such alterations. veno-arterial extracorporeal membrane oxygenation (va-ecmo) is a life-saving technology providing respiratory and circulatory support in patients with refractory cardiogenic shock or cardiac arrest [ ] and which may give time to plan future therapeutic decisions such as the insertion of long-term cardiac assist devices or heart transplantation (htx) [ ] . notwithstanding its potential benefits, va-ecmo remains associated with significant morbidity and mortality [ ] . this is partly due to the patients' critical condition, but also to complications related to va-ecmo, notably renal failure, sepsis, bleeding, thromboembolism, limb ischemia, and multiorgan failure [ , ] . va-ecmo-induced pulmonary complications are much less recognized, except from the pulmonary congestion related to left ventricle pressure overload induced by retrograde va-ecmo flow within the thoracic aorta [ ] . beside this particular aspect, several additional mechanisms may contribute to lung damage and dysfunction in the setting of va-ecmo. the latter may be assimilated to a simplified cardiopulmonary bypass (cpb) circuit, and both techniques share common pitfalls with respect to lung physiology. cpb may alter pulmonary function after cardiac surgery by promoting an inflammatory response via biomaterial-dependent and biomaterial-independent factors, the collapse of lungs during the procedure, the shunting of pulmonary circulation, and the phenomenon of lung reperfusion injury which takes place once cpb is weaned [ ] . during va-ecmo, although such processes are attenuated, they still occur at different stages of support and at various degrees, and they may persist for days or weeks. in such conditions, the combination of a chronic inflammatory response, pulmonary congestion, and lung ischemia could foster a wealth of morphological and functional alterations which could interfere with patient's recovery and compromise the overall planned therapeutic strategy. in this review, we discuss the pathophysiological mechanisms and potential clinical implications of the pulmonary complications associated with va-ecmo. the induction of a systemic inflammatory response syndrome (sirs) by the contact of blood with biomaterial is a typical consequence of extracorporeal circulation [ ] . while extensively studied in the field of cpb, this is also witnessed during va-ecmo, as recently reviewed [ ] . in addition, patients undergoing va-ecmo are critically ill and suffer from profound cardiogenic shock, which by themselves contribute to the development of sirs [ ] . the lung is a major target of inflammatory injury in the context of sirs, owing to its extensive capillary bed and the presence of abundant immune cells within the lung parenchyma. therefore, the occurrence of sirs in the context of ecmo provides a highly favorable environment for the development of acute lung injury [ , ] . the main mechanisms triggering the inflammatory response to biomaterials are presented below. blood contact with va-ecmo circuitry activates the contact system (cs) and the complement system ( fig. ) . cs generates kallikrein [ ] , which activates monocytes fig. main va-ecmo-induced mechanisms of lung damage and dysfunction. left side: sirs is initiated by the blood contact with the circuitry surface. it activates humoral cascades, platelets, and leukocytes, leading eventually to ec injury and activated pmn sequestration into the lung parenchyma. right side: ec injury favors fluid infiltration into both alveolar space and lung parenchyma, leading to pulmonary edema, which is aggravated by the increase of pulmonary vein pressure. alveolar edema and decreased pulmonary artery perfusion lead to lung parenchymal ischemia which in turn maintains chronic inflammation and promotes neoangiogenesis and fibrosis generation and polymorphonuclear cells (pmns), and triggers the intrinsic coagulation cascade, resulting in the rapid generation of thrombin and fibrin within the systemic circulation [ ] . thrombin activates platelets and endothelial cells (ecs) and induces the secretion of pro-inflammatory mediators and growth factors, such as interleukin- (il- ), interleukin- (il- ), or platelet-derived growth factor (pdgf) [ ] . the extrinsic coagulation pathway is activated to a lesser extent, mainly through the release of tissue factor (tf) by activated monocytes and ecs. cs also generates bradykinine [ ] , which activates ecs and leukocytes, and elicits hemodynamic alterations including systemic vasodilation and pulmonary vasoconstriction [ ] . complement activation occurs via the alternative pathway, generating the anaphylatoxins c a and c a, which activate ecs. c a is also a potent mediator of leukocyte chemotaxis. a peak of complement activation occurs within - h of ecmo onset, followed by a progressive decreases over the next to days [ ] . the humoral response triggered by blood-biomaterial interaction comprises the release of multiple cytokines [ ] . whereas a balance between pro-and anti-inflammatory cytokines is reached several hours after va-ecmo initiation [ ] , an initial imbalance in favor of pro-inflammatory tnf-α, il- β, and il- leads to the activation of ecs and promotes the release of multiple inflammatory proteins by the liver such as fibrinogen, complement, and c-reactive protein. tnf-α plays a major role in the amplification of the early inflammatory response, by upregulating proinflammatory cytokines and prostaglandin synthesis, activating pmns and ecs, and stimulating reactive oxygen species (ros) production [ , ] . platelets are activated by contact with the tubing surface and by thrombin and complement. activated platelets foster the generation of pro-inflammatory cytokines, thromboxane a (txa ), platelet-activating factor (paf), pselectin, and serotonin. txa induces ecs activation and local vasoconstriction, while serotonin and p-selectin promote pmn-endothelial interactions [ ] . platelet activation is maximal at the initiation of va-ecmo and progressively decreases over hours to days but remains persistent [ ] . ec activation leads to their detachment from the basal membrane and disassembly of tight junctions, increasing vascular permeability with the development of sub-endothelial edema [ ] . moreover, activated ecs display an upregulated expression of adhesion molecules favoring pmn adhesion and transendothelial migration [ ] , and they also release cytokines, tissue factor, and ros. circulating pmns, monocytes, and macrophages are spontaneously activated by tubing surfaces [ ] . furthermore, pmns are activated by complement, histamine, serotonin, and paf, which facilitate their adhesion to ecs, diapedesis, tissue infiltration [ ] , and the release of cytotoxic mediators, including proteases, cytokines, and ros. at variance with cpb, va-ecmo is generally maintained over several days. the initial significant sirs gradually decreases [ , ] , mostly through the progressive build-up of counter-regulatory mechanisms leading to compensatory anti-inflammatory response and of possible biomaterial inactivation [ ] . still, a delayed persisting inflammatory response can be observed several days after va-ecmo implementation, whose underlying mechanisms may involve the presence of low concentration of endotoxin within the circulation, which may sustain complement activation, cytokine release, and ros generation, to elicit a sepsis-like inflammation [ , ] . the low-level inflammatory response induced by pulmonary low flow is another potential mechanism (see below). some potential therapies have been proposed to downregulate inflammation and possibly improve lung outcome in this setting. the replacement of a silicon oxygenator by a poly-methyl pentene oxygenator has been associated with reduced radiological signs of pulmonary inflammation on chest x-ray [ ] , while the administration of steroids in patients undergoing va-ecmo has been associated with shortened mechanical ventilation time, although without any survival benefit [ ] . pathophysiology peripheral (femoro-femoral) va-ecmo provides a non-physiological blood flow promoting significant hemodynamic perturbations (fig. ). the retrograde reinjection of blood into the thoracic aorta increases lv afterload and impedes aortic valve opening, while increasing myocardial oxygen demand [ ] . in the setting of cardiogenic shock, these disturbances may worsen lv performance and dramatically reduce lv stroke volume [ , ] . in addition, if lv residual function is insufficient to permit aortic valve opening, progressive lv distension will occur, due to persisting venous return through pulmonary and bronchial veins into the left atrium and through thebesian veins into the lv, with concomitant increase of lv end-diastolic pressure. at worst, stagnation of blood within dilated left cardiac chambers may favor the formation of clots and induce pulmonary vein thrombosis [ ] . pulmonary congestion develops consecutively to the passive upstream transmission of elevated lv pressure [ ] . lung extravascular water accumulation is potentiated by the increased vascular permeability in the context of va-ecmo-induced sirs. the magnitude of afterload increase, lv distension, and pulmonary congestion is dependent on several parameters, including va-ecmo flow, systemic vascular resistance, and lv residual function [ , ] . pulmonary congestion may jeopardize lung parenchymal cell oxygenation through two mechanisms. firstly, interstitial edema increases the thickness of the alveolarcapillary barrier, hence the diffusion distance for oxygen between alveoli and parenchymal cells, whose oxygenation primarily depends on oxygen diffusing from alveolar spaces [ ] . secondly, alveolar edema results in a marked reduction of local alveolar po (pao ). alveolar epithelial cells, normally exposed to pao above mmhg, are sensitive to hypoxia from pao below mmhg, which may occur in alveoli flooded by pulmonary edema [ ] . alveolar hypoxia can destabilize intercellular junctions, impair barrier permeability, impede alveolar fluid clearance and surfactant production by pneumocytes, induce local vasoconstriction and neoangiogenesis, and finally trigger local and systemic inflammation [ ] [ ] [ ] . therefore, pulmonary congestion during va-ecmo creates a vicious circle in which va-ecmoinduced sirs and lv pressure overload promote pulmonary edema, leading to alveolar hypoxia which maintains sirs [ ] . alveolar hemorrhages are another frequent consequence of the combination of pulmonary congestion and the requirement of anticoagulation during ecls. even if massive hemoptysis is rare [ ] , local alveolar hemorrhages are frequent and sustain local inflammatory changes [ , ] . chest x-ray is the simplest exam to assess pulmonary congestion, although its interpretation is complicated by frequently associated abnormalities, such as pneumonia, atelectasis, or alveolar hemorrhages. chest ultrasound is an effective and reliable alternative method to assess interstitial edema, pleural effusion, and parenchymal consolidation [ ] . echocardiographic examination is mandatory, as it may show left heart dilation and indirect signs of cardiac congestion, such as spontaneous contrast echoes or the presence of "sludge" in heart chambers, as well as the absence of aortic valve opening [ ] . hemodynamic monitoring using pulmonary artery catheter (pac) has been associated with improved survival in cardiogenic shock [ ] , notably in the context of mechanical cardiac support. pac is particularly helpful to identify patients with cardiac distension, by demonstrating elevated left-sided filling pressure [ ] . it has been shown that combining a value of pulmonary artery diastolic pressure > mmhg (as a surrogate of pulmonary capillary wedge pressure) with evidence of pulmonary edema on chest x-ray could identify patients with subclinical lv distension [ ] . although these data need further validation, pac is now advocated by most experts to help manage patients under va-ecmo [ ] . severe pulmonary congestion during va-ecmo is associated with a dismal prognosis, and its treatment is mandatory [ , ] . inotropic agents increase cardiac contractility, promote aortic valve opening, and reduce lv dilation and filling pressure. reducing va-ecmo flow to decrease lv afterload, as long as residual lv ejection is present and peripheral perfusion maintained, should also be considered. the insertion of an intra-aortic balloon pump (iapb) is a further option to decrease lv afterload. as demonstrated by bréchot et al., iabp in combination with va-ecmo versus va-ecmo alone is independently associated with less frequent hydrostatic pulmonary edema and a shorter duration of mechanical ventilation [ ] . a recent meta-analysis found concomitant iabp to reduce in-hospital death and length of stay [ ] . if previous steps fail to reduce pulmonary edema, the left heart chambers must be directly unloaded ("vented"), either by percutaneous atrial transseptal approach or by using a venting cannula inserted into the left atrium or the lv apex by surgical or trans-aortic approach [ ] . in addition, the catheter-mounted microaxial pump impella® (abiomed, danvers, ma) may represent a further efficient device to permit lv unloading [ ] . eliet et al. have recently observed that impella® not only decreases lv diastolic diameter but also increases pulmonary flow [ ] . these different modalities of cardiac unloading during va-ecmo have been the matter of several extensive recent reviews [ , ] . the lung is characterized by a dual circulation, comprising the pulmonary circulation, which supplies the alveoli for gas exchange, and the bronchial circulation, which conveys oxygen and nutrients to the airways, but not alveoli, whose oxygen supply is almost exclusively provided by direct diffusion from the alveolar spaces [ ] . bronchopulmonary anastomoses allow collateralization between these two circulations. in case of chronic decrease of pulmonary blood flow (e.g., in chronic thromboembolic disease or pulmonary stenosis), the bronchial flow may increase from to % of the cardiac output, permitting to compensate this decrease and participate to gas exchange, providing a kind of "rescue flow" to the ischemic areas [ , ] . as depicted in fig. , venous blood during va-ecmo is derived from the vena cava and the right atrium through the venous canula, resulting in a reduction of right ventricle (rv) filling, pulmonary blood flow, and pulmonary arterial pulsatility [ ] . in a porcine model, vardi et al. demonstrated that the pulmonary capillary blood flow decreases dramatically as the va-ecmo flow increases [ ] . moreover, in case of pulmonary congestion (see above), the upstream transmission of increased left atrial pressure reduces the transpulmonary perfusion gradient. ventilation with high positive end-expiratory pressure (peep) might also impede pulmonary blood flow by compression of alveolar vessels [ ] . several additional mechanisms, including alveolar hypoxia, reduction of local no production, and the actions of inflammatory mediators can promote vasoconstriction and the subsequent increase of pulmonary vascular resistance, with a reduction of pulmonary blood flow [ ] . it is also noteworthy that blood flow through the bronchial arteries (bas) is also reduced during va-ecmo, due to attenuated pulsatility of the systemic circulation (which supplies the bas). this can further limit blood supply to ischemic areas within the congested lung [ ] . eventually, these various hemodynamic changes may lead to hypoperfusion of the entire pulmonary vasculature, which, superimposed to alveolar hypoxia, can promote a state of global, persistent lung ischemia. the best way to overcome such alterations is, of course, the withdrawal of va-ecmo. if this is not possible, va-ecmo flow may be reduced to maintain partial pulmonary perfusion. in early experimental studies in pigs, prolonged ( h) ecmo at full support (with no residual pulmonary blood flow) promoted massive pulmonary parenchymal damage [ ] , which was not observed at a residual pulmonary blood flow reaching % of the systemic cardiac output [ ] . an additional strategy relies in the upgrading of va-ecmo to a hybrid system of veno-veno-arterial support, with an additional cannula inserted into the jugular vein, which provides oxygenated blood within the pulmonary arteries. this approach is sometimes used to treat the harlequin syndrome (see below), but has not yet been evaluated to prevent lung injury during va-ecmo. although no dedicated study has specifically focused on pulmonary histological consequences of va-ecmo, data from animal models and small human necropsy series have reported several pathological alterations. koul et al. maintained pigs under total cpb for h before weaning. all the animals died within the next h, and on histological examination, more than % of the pulmonary parenchyma displayed edema, hyaline membranes, alveolar hemorrhages, thrombi, and focal necrotic changes [ ] . in another experimental study exploring the effects of long-term va-ecmo without anticoagulation, mizuno et al. succeeded to maintain a goat up to months under va-ecmo with a pulmonary blood flow reduced to %. at autopsy, diffuse interstitial fibrosis and swelling of endothelial cells with thickening of their basal membrane were noted [ ] . in humans, ratliff et al. reported postmortem findings in patients undergoing va-ecmo for to days. in two patients, diffuse lung fibrosis was noted, together with liquefaction necrosis of the lower lobes. the authors hypothesized that the combination of an increase in metabolically active cell mass together with partial pulmonary shunting concurred to establish ischemic areas with subsequent necrosis [ ] . in an autopsy series of infants supported by va-ecmo, chou et al. reported hyaline membrane formation, interstitial and intra-alveolar hemorrhages, and reactive hyperplasia of epithelial and smooth muscle cells, developing already after to days of va-ecmo support, whereas interstitial fibrosis was noted beyond days [ ] . to sum up, va-ecmo appears mostly associated with signs of protein-rich edema, alveolar hemorrhages, tissue necrosis, and fibrosis, which are reminiscent of the damage noted in the acute respiratory distress syndrome. these changes are likely the result of the combination of inflammatory injury, pulmonary congestion, and hypoxia, with the progressive development of epithelialendothelial injury, increased vascular permeability, and interstitial collagen deposition [ ] . furthermore, some degree of angiogenesis and vascular remodeling may also play some role, as alveolar hypoxia and chronic ischemia (typical of long-lasting va-ecmo) can activate several pro-angiogenic cascades in alveolar cells, relying on the hypoxia-inducible factor family or the resistin-like molecule-α [ ] . such alterations could result in longterm changes in pulmonary vascular physiology, with possible detrimental consequences on the right ventricle. pulmonary dysfunction during va-ecmo the impaired pulmonary function induced by va-ecmo may require long-lasting mechanical ventilation (mv) which may further alter the lung through ventilatorinduced lung injury (vili). although there is presently no consensus regarding optimal ventilator settings for mv during va-ecmo, the principles of lung-protective ventilation should be applied [ ] . furthermore, prolonged mv increases the risk of ventilator-associated pneumonia (vap), which occurs in up to % of patients under ecmo, as recently reviewed [ ] , with risk factors including an age > years, a higher sofa score on admission, and a history of copd or hypertension [ ] . causative microorganisms comprise primarily gram-negative bacilli, with pseudomonas aeruginosa isolated in - % of cases [ ] . diagnosis of vap may be particularly troublesome, as the usual criteria of vap are difficult to interpret in the setting of ecmo, and a high clinical index of suspicion coupled to early microbiological sampling are major clues to diagnosis [ ] . treatment of vap on ecmo is challenging, notably because of the alterations of antibiotic pharmacokinetics occurring in this setting, and frequent therapeutic drug monitoring is therefore recommended [ ] . preventive measures to reduce the risk of vap include primarily the reduction of mv duration. in this regard, a strategy of early extubation and awake ecmo support is emerging as a promising strategy [ ] . in properly selected patients, such strategy not only significantly reduces the incidence of vap [ ] , but also permits active mobilization, reduces the overall rate of complications, and increases survival [ ] . the prototypical consequence of va-ecmodependent impairment of lung function is the development of the "harlequin syndrome," reflecting the opposing flows from the heart (antegrade, poorly oxygenated blood flow) and from the peripheral ecmo (retrograde, highly oxygenated blood flow), resulting in differential hypoxia (upper body hypoxemia, lower body normo/ hyperoxemia). the level of mixing of the two flows within the aorta is termed the "watershed," which can be identified in contrast-enhanced ct scan of the chest (fig. ) . the harlequin syndrome may be treated by increasing va-ecmo flow or adding a venous injection cannula either as a hybrid ecmo (veno-veno-arterial ecmo, fig. ) or as pure veno-venous ecmo if the function of the heart allows withdrawal of the arterial cannula. another option consists of switching the arterial cannulation site from femoral to axillary or central (aorta) location, in order to avoid the retrograde flow from the peripheral femoral cannula [ ] . finally, bronchoscopy with bronchial hygiene may be considered routinely in order to maximize chances of successful weaning from va-ecmo when cardiac function recovers [ ] . pulmonary dysfunction after weaning from va-ecmo va-ecmo-induced lung alterations may only appear after weaning and the restoration of physiological pulmonary artery blood flow. in a series of patients who underwent long-term mechanical assist device implantation under va-ecmo (l-vad, bi-vad, or total artificial heart), boulate et al. noticed that % of patients develop acute lung injury (ali) few hours after restoration of pulmonary blood flow, with a significant impact on mortality. the authors hypothesized that chronic lung ischemia during va-ecmo support could promote alveolar frailty and that the sudden restoration of an antegrade pulsatile pulmonary blood flow creates a massive pulmonary bed overload responsible of ali [ ] . accordingly, one of the identified risk factors of ali in this study was the occurrence of a pulmonary edema during the week preceding the implantation of the mechanical device, featuring a preexisting lung frailty. this form of ali is reminiscent of reperfusion pulmonary edema, a well-known and described condition that occurs after reperfusion of a chronic low pulmonary blood flow situation, as in correction of tetralogy of fallot [ ] or pulmonary endarteriectomy for chronic embolism [ ] . such reperfusion pulmonary edema relies both on ischemia-induced chronic inflammation and reperfusion injury that involves similar mechanisms than those described above [ ] . fig. the watershed. a axial. b sagittal. contrast in the aorta indicates blood flow from the va-ecmo arterial cannula, whereas absence of contrast within the ascending aorta indicates blood flow from the native heart. the level of blood mixing in the thoracic aorta represents the va-ecmo watershed (arrows) in order to help the decision-making process in patients under va-ecmo, chen et al. developed a risk factorcalling score (rfss) to select patients eligible for l-vad or htx. the rfss has items and points, of which are allocated to pulmonary dysfunction. a rfss > predicted a poor outcome, which emphasizes the relative burden of pulmonary dysfunction in the outcome of patients under va-ecmo in a bridge strategy [ ] . it is currently unknown whether lung damage and dysfunction induced by va-ecmo have an impact on long-term outcome, the more so that many unrelated factors may interfere with such outcome, such as prolonged icu stay, previous health condition, or reduced lv ejection fraction. a few studies focused on long-term health-related quality of life (hrql) in va-ecmo survivors after cardiogenic shock. combes et al. questioned va-ecmo survivors about their hrql via the short-form questionnaire (sf- ). mean va-ecmo duration and follow-up were respectively days ( to ) and months ( to ). in comparison to sex-and agematched controls, va-ecmo survivors disclosed significantly lower role-physical score and a trend to a lower physical function, even though most patients recovered a good cardiac function with mean lvef % or underwent htx [ ] . these results were confirmed by other studies showing lower sf- values of physical functioning and role-physical scores in va-ecmo survivors compared to standard population [ , ] . these data however do not give any information with respect to the potential long-term burden of pulmonary alterations associated with va-ecmo, and future studies should be designed to address this issue, for example by performing delayed lung functional tests in long-term survivors of va-ecmo. va-ecmo elicits several pathophysiological disturbances which may significantly impact on lung integrity and function. first, the rapid development of a systemic inflammatory response with pulmonary involvement is an unavoidable consequence of the artificial va-ecmo circuitry. second, due to retrograde blood flow within the thoracic aorta, peripheral va-ecmo has the propensity to increase lv afterload, which may favor the congestion of alveoli already affected by the ongoing inflammation. third, persistent lung ischemia due to the partial shunting of the pulmonary circulation and reduced pulsatility of the bronchial circulation may elicit further cytotoxicity within the whole lung parenchyma. limited evidence from human observational studies and animal models indicates that va-ecmo support for more than a few days may lead to severe structural changes of the lung parenchyma and interstitial fibrosis, which could result in long-term functional limitation. clinicians in charge of va-ecmo patients should be aware of its effects on lung physiology and should take all measures to limit such consequences, including the maintenance of fig. veno-veno-arterial ecmo. oxygenated blood is propelled through both the femoral arterial cannula and the additional jugular cannula providing oxygenated blood directly into the right-heart chambers and consequently into the left atrium. this setting permits to wean progressively the arterial cannula in order to switch to veno-venous ecmo va-ecmo support as short as possible, the early diagnosis and treatment of cardiac overload and pulmonary congestion, and the application of lungprotective ventilation. future studies specifically addressing the issue of the pulmonary consequences of va-ecmo are warranted. extracorporeal life support during cardiac arrest and cardiogenic shock: a systematic review and meta-analysis ecmo as a bridge to decision: recovery, vad, or heart transplantation? use of extracorporeal membrane oxygenation in adults a meta-analysis of complications and mortality of extracorporeal membrane oxygenation pulmonary congestion (white lungs) on va ecmo. the vad pulmonary complications of cardiopulmonary bypass inflammatory response and extracorporeal circulation the inflammatory response to 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retrospective study awake and fully mobile patients on cardiac extracorporeal life support unconventional cannulation strategy in peripheral extracorporeal membrane oxygenation to achieve central perfusion and prevent differential hypoxia veno-arterial ecmo weaning failure in the operating room: have you considered preweaning bronchoscopy? acute lung injury after mechanical circulatory support implantation in patients on extracorporeal life support: an unrecognized problem reperfusion pulmonary edema in children with tetralogy of fallot, pulmonary atresia, and major aortopulmonary collateral arteries undergoing unifocalization procedures: a pilot study examining potential pathophysiologic mechanisms and clinical significance techniques and outcomes of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension lung ischemia reperfusion injury: a bench-to-bedside review risk factor screening scale to optimize treatment for potential heart transplant candidates under extracorporeal membrane oxygenation outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock survival, quality of life and impact of right heart failure in patients with acute cardiogenic shock treated with ecmo health related quality of life after extracorporeal cardiopulmonary resuscitation in refractory cardiac arrest publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. authors' contributions ar and mk designed and conceived the paper. ar wrote the manuscript. ll provided figures and was a major contributor in writing manuscript. all authors contributed to the content of this paper and critically reviewed the final manuscript. ar edited individual contributions and finalized the manuscript. all authors read and approved the final manuscript. lucas liaudet is supported by a grant from the swiss national fund for scientific research (nr _ ).availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare they have no competing interests. key: cord- -ehxpdavo authors: lee, joyce s.; collard, harold r. title: acute exacerbation of idiopathic pulmonary fibrosis date: - - journal: idiopathic pulmonary fibrosis doi: . / - - - - _ sha: doc_id: cord_uid: ehxpdavo acute exacerbation of idiopathic pulmonary fibrosis (ipf) is a clinically important complication of ipf that carries a high morbidity and mortality. in the last decade, we have learned much about this event, but there are many remaining questions: what is it? why does it happen? how can we prevent it? how can we treat it? this chapter attempts to summarize our current understanding of the epidemiology, etiology, and management of acute exacerbation of ipf and point out areas where additional data are sorely needed. predicted and a diffusing capacity for carbon monoxide of % predicted. his highresolution computed tomography (hrct) scan demonstrated peripheral, subpleural predominant reticulation and traction bronchiectasis without honeycombing. he was referred for surgical lung biopsy and had a video-assisted thoracic surgery procedure with biopsies obtained from the right lung. his perioperative course was uncomplicated. his pathology was reviewed and was consistent with a usual interstitial pneumonia (uip) pattern, confi rming the diagnosis of ipf. his initial postoperative course was uncomplicated, but approximately days postoperatively, he developed increased dyspnea and cough with occasional production of clear sputum. he had new-onset hypoxemia ( % on room air) with diffuse crackles to auscultation that were more prominent in the left chest. a repeat hrct demonstrated new ground-glass opacities in the left lung ( fig. . ). all microbiologic data were negative, and there was no evidence of cardiac dysfunction or ischemia. this case was thought to be due to an acute exacerbation (aex) of ipf triggered by surgical lung biopsy possibly due to single lung ventilation of the left lung. unfortunately, the patient progressively worsened despite supportive care and subsequently died from his aex of ipf. our view of the natural history of ipf has changed over the last decade with the recognition that there are several distinct clinical courses that patients may follow [ ] . although most patients with ipf experience a steady decline in lung function over time, some will decline quickly, while others seem stable for many years. increasingly, we recognize that some patients may also have a more unpredictable course [ ] . these patients experience periods of relative stability followed by acute episodes of worsening in their respiratory status [ ] . episodes of acute respiratory decline in ipf can be secondary to complications such as infection, pulmonary [ , ] . such episodes of acute respiratory deterioration have been termed aex of ipf when the cause for the acute worsening cannot be identifi ed. acute exacerbations likely comprise almost % of these acute respiratory events, and the clinical characteristics and prognosis are indistinguishable from acute exacerbations of known cause. this chapter will discuss only aex of ipf. the phenomenon of aex has been recognized since the late s, when it was initially reported in the japanese literature [ - ] . a survey of providers in the usa suggests that most clinicians believe aex to be somewhat or very common [ ] . the true incidence of aex remains unknown, and the incidence may vary by country due to different genetic and environmental factors. largely due to differences in case defi nition, patient population, sample size, and duration of follow-up, the range of aex incidence in clinical studies ranges anywhere from % to % [ , ] . the largest and probably most robust study of patients with ipf that were followed longitudinally over years found a -and -year incidence of . % and . %, respectively [ ] . the clinical presentation of aex is generally quite dramatic and characterized by acute to subacute worsening of dyspnea over days to weeks [ ] . some patients experience symptoms of worsening cough, sputum production, and fever mimicking a respiratory tract infection [ , ] . most reported cases of aex have required unscheduled medical attention (emergency room or hospital care), but there may well be less severe cases that do not get noted by patients and providers and, therefore, are not documented. the occurrence of aex is unpredictable and can sometimes be the presenting manifestation of ipf [ - ] . a few risk factors have been identifi ed, including lower baseline forced vital capacity (fvc) % predicted and having been a nonsmoker [ ] . it seems likely that patients with more severe ipf are more likely to develop clinically signifi cant aex of disease, and this perception is supported by the increased incidence of aex that was observed in the only study of advanced disease reported in the literature to date, namely, step-ipf [ ] . precipitating factors such as surgical lung biopsy and bronchoalveolar lavage (bal) have also been reported [ , - ] . the occurrence of aex after videoscopic-assisted surgical lung biopsy is particularly intriguing, as the exacerbation appears to be more pronounced in the lung that was ventilated (i.e., the nonsurgical side receiving single lung ventilation) [ ] . however, the precise relationship between these precipitating factors and aex remains unclear. acute exacerbations have also been described in non-ipf ild, including nonspecifi c interstitial pneumonia (nsip) [ ] , connective tissue disease-associated ild [ - ] , and hypersensitivity pneumonitis [ , ] . compared to ipf aex, patients with an underlying nsip pattern appeared to have a better prognosis following their aex [ ] . a uip pattern may be a risk factor for aex in the context of connective tissue disease-associated ild and hypersensitivity pneumonitis, as the presence of a uip pattern appeared to be a risk factor in some case series [ , ] . whether aex of non-ipf forms of ild shares a similar pathobiology as aex of ipf is unknown. the etiology of aex of ipf remains unknown. several hypotheses have been proposed, including the following: ( ) aex of ipf represents an abrupt acceleration of the patients underlying disease; ( ) aex is a collection of occult, pathobiologically distinct conditions (e.g., infection, heart failure); or ( ) aex is a combination of both processes that can serve as an occult trigger that leads to acceleration of the underlying fi broproliferative process. occult aspiration of gastric contents has been suggested as a possible trigger or cause of aex of ipf. ger is nearly universal in patients with ipf [ , ] and is thought to be a risk factor for aspiration [ , ] . bal pepsin levels, a biomarker for aspiration of gastric secretions, were shown to be elevated in a subset of patients with aex of ipf [ ] . in addition, patients with asymmetric ipf on hrct scan had a higher rate of ger and aex compared to patients with non-asymmetric disease, suggesting a role for ger and occult aspiration in a subset of patients with ipf [ ] . infection has also been suggested as a cause of aex of ipf. data in support of this hypothesis include animal studies [ ] as well as some human studies [ , ] . in one case series, . % of aex cases occurred between december and may [ ] , lending further support to occult infection as a cause of aex. however, in a prospective study of aex of ipf ( n = ), acute viral infection, as determined by the most current genomics-based methodologies, was found in only % of this cohort [ ] . while some cases may well have been missed (i.e., the virus had come and gone by the time testing was obtained), these data suggest that there are many cases of aex that are not primarily due to occult infection. an alternative explanation is that aex of ipf is caused by an inherent acceleration of the pathobiology of ipf [ ] . there is indirect evidence for this in several studies that evaluated serum biomarkers and gene expression in aex. serum biomarkers of alveolar epithelial cell injury/proliferation have been shown to be increased in aex, in a pattern that is qualitatively distinct from what is seen in acute lung injury (table . ) . gene expression studies performed in patients with aex of ipf [ ] have shown that patients have increased expression of genes encoding proteins involved in epithelial injury and proliferation including ccna and alpha-defensins. interestingly, there was no evidence from the same study for upregulation of genes commonly expressed in viral infection. there are no specifi c laboratory tests that aid in the evaluation and diagnosis of aex of ipf. often, patients are found to have impaired gas exchange with a decrease in sp-d marker of alveolar type ii cell injury and/or proliferation plasma levels higher in aex compared to stable [ ] thrombomodulin membrane protein expressed on the surface of endothelial cells which serves as a receptor for thrombin plasma levels higher in aex compared to stable and log change in thrombomodulin was predictive of survival [ ] von willebrand factor marker of endothelial cell injury and is involved in hemostasis higher plasma % in aex compared to stable [ ] aex acute exacerbation, ipf idiopathic pulmonary fi brosis, kl- krebs von den lungen- , pai- plasminogen activator inhibitor- , rage receptor for advanced glycation end products, nf-kb nuclear factor-kb, st , sp-d surfactant protein d their arterial oxygen tension [ ] . in patients that can tolerate bronchoscopy with lavage, an increase in bal neutrophils has been reported [ , ] . nonspecifi c elevations in serum lactate dehydrogenase (ldh) and c-reactive protein (crp) have also been observed [ ] . serial levels of serum kl- and baseline thrombomodulin may help identify patients at increased risk for death from aex [ , ] . although many experimental biomarkers have been investigated, as shown in table . , none are routinely used in clinical practice. high-resolution ct scans are often obtained during aex of ipf. the fi ndings include new, generally bilateral, ground-glass opacities and/or consolidation superimposed on the underlying uip pattern [ ] . the pattern of ground-glass changes during an aex may have prognostic signifi cance, with more diffuse abnormality correlating with worse outcomes [ ] . surgical lung biopsy is not frequently obtained during aex of ipf. a small case series of seven patients who had a surgical lung biopsy during their aex demonstrated primarily diffuse alveolar damage (dad) associated with underlying changes typical for uip ( fig. . ) [ ] . one case had organizing pneumonia and uip and another case had dad without underlying uip. autopsy series and other case series have demonstrated similar fi ndings [ , , , - ] . several defi nitions have been used over the last decade to defi ne aex of ipf [ , , ] . in order to standardize these criteria, a consensus defi nition was proposed by the national institutes of health-funded us ipf network (ipfnet) in (table . ) [ ] . other defi nitions that have been described are generally similar; however, they often include a reduction in pao as one of their criteria as well as bilateral chest x-ray abnormalities (instead of a hrct scan) [ , ] . the ipfnet criteria have helped to standardize the defi nition of aex of ipf, but satisfaction of all criteria is quite diffi cult to achieve in many clinical settings. specifi cally, it is not infrequent that in patients who appear to have aex of ipf, microbiologic data and occasionally radiologic data are not collected due to the severity of illness or because the clinician does not feel the tests will change clinical management. by maximizing specifi city at the cost of sensitivity, these criteria (along with the selection of only mild to moderate patients for enrollment) have likely contributed to the low prevalence of aex observed in recent clinical trials [ - ] . the choice of defi nition has signifi cant implications for outcome analyses in clinical trials and should be a focus for further discussion among clinical trialists. there is no known effective treatment for preventing or improving outcomes in aex of ipf. previous or concurrent diagnosis of idiopathic pulmonary fi brosis unexplained development or worsening of dyspnea within days high-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage exclusion of alternative causes, including left heart failure, pulmonary embolism, and other identifi able causes of acute lung injury a patients who do not meet all fi ve criteria should be termed "suspected acute exacerbation" while there are no data to support effi cacy, vaccination and treatment of comorbidities like heart disease and ger seem prudent as measures that could prevent episodes of acute decline in respiratory function due to known causes such as infection, heart failure, and aspiration. some novel therapies have suggested a reduction in aex in clinical trials; these include warfarin [ ] , pirfenidone [ ] , and, most recently, bibf [ ] . unfortunately, both warfarin and pirfenidone have subsequently been shown to have no impact on the rate of aex, suggesting that the initial observations were inaccurate [ , ] . although commonly prescribed for the treatment of aex of ipf, there have been no controlled trials assessing the effi cacy of high-dose corticosteroids. recent international guidelines on ipf management suggested that the majority of ipf patients with aex could be treated with corticosteroids [ ] ; however, approaches to dosing, route, and duration of therapy were not provided. although most clinicians would treat patients who develop an aex of ipf with high-dose corticosteroids, the effi cacy of this treatment is unclear. perhaps we should be more critical of the use of corticosteroids to treat aex of ipf. there are two distinct viewpoints regarding the role of corticosteroids in aex of ipf. the fi rst viewpoint is that aex of ipf is histopathologically similar to acute respiratory distress syndrome (ards) characterized by dad and acute lung injury [ ] and should, therefore, be treated similarly to ards. in the ards literature, the mortality benefi t of corticosteroids is unclear [ - ] . in one study, increased mortality was observed in ards patients treated with delayed corticosteroids (after days) [ ] . if we were to follow the ards paradigm, most clinicians would not use corticosteroids in the treatment of aex of ipf. a second viewpoint for the role of corticosteroids in ipf is that some patients with aex of ipf have organizing pneumonia on biopsy [ ] . organizing pneumonia is generally thought to be steroid responsive, and it may be that the pathobiology is different enough between ards and aex of ipf to warrant continued use of corticosteroids. there remains equipoise on the effi cacy of corticosteroids in aex of ipf, and this treatment intervention should be studied more carefully [ ] . the use of another immunosuppressant, cyclosporine a, to treat aex of ipf has been reported. these studies suggest some benefi t to the use of cyclosporine a plus corticosteroids [ - ] . however, conclusions that can be made from these data are limited by problems with study design and small sample size, and benefi t has not yet been validated in a randomized controlled trial. other experimental therapies that have reported possible effi cacy to treat aex of ipf include tacrolimus [ ] , hemoperfusion with polymyxin b-immobilized fi ber column [ - ] , and sivelestat [ ] . these investigations were all limited by small numbers and suboptimal study design. supportive therapy is the standard of care in aex of ipf. supportive care for respiratory failure almost always requires higher oxygen supplementation and consideration of additional means of ventilatory support, including mechanical ventilation (see discussion below) and noninvasive positive-pressure ventilation (nippv). yokoyama et al. described the outcomes of patients with aex of ipf treated with nippv to avoid intubation in acute respiratory failure [ ] . in this retrospective case series of patients, patients failed a nippv trial and went subsequently succumbed to respiratory failure. the other fi ve patients survived more than months after the onset of their aex. however, the use of ventilatory support in aex (both mechanical ventilation and nippv) has never been studied in a randomized controlled trial. a few select centers have experience with emergent transplantation for aex of ipf [ - ] . these critically ill ipf patients have generally been bridged to lung transplant with extracorporeal membrane oxygenation (ecmo) and/or mechanical ventilation [ ] . outcomes of patients who have undergone emergent transplantation have been mixed [ , ] . emergent lung transplantation requires careful patient selection and is not done at all transplant centers. the prognosis of aex of ipf is poor, with most case series reporting very high short-term mortality rates [ , - ] . this is particularly true for those patients requiring mechanical ventilation. a systematic review of mechanical ventilation in ipf and respiratory failure ( n = ), including aex, reported a hospital mortality of % [ ] . short-term mortality (within months of hospital discharge) was %. the routine use of mechanical ventilation in patients with aex of ipf is not recommended in the international consensus guidelines because of its low likelihood of benefi t and high risk of complications and further suffering [ ] . careful consideration regarding intubation and goals of care must be made, given the poor prognosis associated with this condition. ideally, a discussion concerning end-of-life issues should be held between the patient and their provider in the outpatient setting with the inclusion of the patient's family, if applicable. acute exacerbation of ipf is responsible for substantial morbidity and mortality in patients with ipf. we suggest that aex of ipf represents an acute acceleration of the fi broproliferative process (i.e., the underlying pathobiology of ipf) that is triggered by some generally occult stress or insult to the lung (e.g., infection, aspiration, mechanical stretch from ventilation or lavage, high inspired oxygen concentration during surgery). as many patients with aex of ipf will not meet the current consensus criteria due to missing data, it may be more useful clinically to defi ne aex by less stringent criteria. it seems likely that the prevention and treatment of aex of ipf must focus on both disease-specifi c (e.g., anti-fi brotic 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presentation of the disease risk factors of acute exacerbation of idiopathic pulmonary fi brosis a controlled trial of sildenafi l in advanced idiopathic pulmonary fi brosis videothoracoscopic lung biopsy in diffuse infi ltrative lung diseases: a -year surgical experience acute exacerbation of interstitial fi brosis after pulmonary resection high short-term mortality following lung biopsy for usual interstitial pneumonia pulmonary fi brosis and lung cancer: risk and benefi t analysis of pulmonary resection acute exacerbation of interstitial pneumonia following surgical lung biopsy bronchoalveolar lavage as a possible cause of acute exacerbation in idiopathic pulmonary fi brosis patients acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fi brosis clinical features and outcome of acute exacerbation of interstitial pneumonia: collagen vascular diseases-related versus idiopathic acute exacerbation of interstitial pneumonia associated with collagen vascular diseases acute exacerbations of fi brotic hypersensitivity pneumonitis: a case series clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis increased prevalence of gastroesophageal refl ux in patients with idiopathic pulmonary fi brosis high prevalence of abnormal acid gastro-oesophageal refl ux in idiopathic pulmonary fi brosis aspiration pneumonitis and aspiration pneumonia does chronic microaspiration cause idiopathic pulmonary fi brosis? bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fi brosis progression of idiopathic pulmonary fi brosis: lessons from asymmetrical disease exacerbation of established pulmonary fi brosis in a murine model by gammaherpesvirus acute exacerbation of idiopathic pulmonary fi brosis: role of chlamydophila pneumoniae infection a detailed evaluation of acute respiratory decline in patients with fi brotic lung disease: aetiology and outcomes viral infection in acute exacerbation of idiopathic pulmonary fi brosis raised plasma concentrations of alpha-defensins in patients with idiopathic pulmonary fi brosis gene expression profi les of acute exacerbations of idiopathic pulmonary fi brosis identifi cation of annexin as a novel autoantigen in acute exacerbation of idiopathic pulmonary fi brosis circulating fi brocytes are an indicator of poor prognosis in idiopathic pulmonary fi brosis gradual increase of high mobility group protein b in the lungs after the onset of acute exacerbation of idiopathic pulmonary fi brosis reduction in serum high mobility group box- level by polymyxin b-immobilized fi ber column in patients with idiopathic pulmonary fi brosis with acute exacerbation plasma biomarker profi les in acute exacerbation of idiopathic pulmonary fi brosis circulating kl- predicts the outcome of rapidly progressive idiopathic pulmonary fi brosis the increase in serum soluble st protein upon acute exacerbation of idiopathic pulmonary fi brosis acute exacerbation of idiopathic pulmonary fi brosis: report of a series computed tomography fi ndings in acute exacerbation of idiopathic pulmonary fi brosis histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fi brosis undergoing surgical lung biopsy terminal diffuse alveolar damage in relation to interstitial pneumonias. an autopsy study acute exacerbation (acute lung injury of unknown cause) in uip and other forms of fi brotic interstitial pneumonias ct fi ndings during phase of accelerated deterioration in patients with idiopathic pulmonary fi brosis pirfenidone in patients with idiopathic pulmonary fi brosis (capacity): two randomised trials build- : a randomized, controlled trial of bosentan in idiopathic pulmonary fi brosis incidence, prevalence, and clinical course of idiopathic pulmonary fi brosis: a populationbased study anticoagulant therapy for idiopathic pulmonary fi brosis double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fi brosis effi cacy of a tyrosine kinase inhibitor in idiopathic pulmonary fi brosis a placebocontrolled randomized trial of warfarin in idiopathic pulmonary fi brosis an offi cial ats/ers/ jrs/alat statement: idiopathic pulmonary fi brosis: evidence-based guidelines for diagnosis and management the acute respiratory distress syndrome snyder rd wh. early steroid therapy for respiratory failure corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ards) in adults: meta-analysis methylprednisolone infusion in early severe ards: results of a randomized controlled trial ineffectiveness of highdose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock high-dose corticosteroids in patients with the adult respiratory distress syndrome effi cacy and safety of corticosteroids for persistent acute respiratory distress syndrome cyclosporin a in the treatment of acute exacerbation of idiopathic pulmonary fi brosis cyclosporin a followed by the treatment of acute exacerbation of idiopathic pulmonary fi brosis with corticosteroid cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia tacrolimus and steroid treatment for acute exacerbation of idiopathic pulmonary fi brosis benefi cial effect of polymyxin b-immobilized fi ber column (pmx) hemoperfusion treatment on acute exacerbation of idiopathic pulmonary fi brosis effect of direct hemoperfusion with a polymyxin b immobilized fi ber column in acute exacerbation of interstitial pneumonia and serum indicators possible therapeutic effect of direct haemoperfusion with a polymyxin b immobilized fi bre column (pmx-dhp) on pulmonary oxygenation in acute exacerbations of interstitial pneumonia outcome of patients with acute exacerbation of idiopathic interstitial fi brosis (ipf) treated with sivelestat and the prognostic value of serum kl- noninvasive ventilation in acute exacerbation of idiopathic pulmonary fi brosis outcome of critically ill lung transplant candidates on invasive respiratory support extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation one-year experience with high-emergency lung transplantation in france extracorporeal membrane oxygenation as a bridge to lung transplant: midterm outcomes outcome of patients with idiopathic pulmonary fi brosis admitted to the intensive care unit mechanical ventilation in patients with end-stage idiopathic pulmonary fi brosis outcome of patients with idiopathic pulmonary fi brosis (ipf) ventilated in intensive care unit outcome of patients with idiopathic pulmonary fi brosis admitted to the icu for respiratory failure prognosis of patients with advanced idiopathic pulmonary fi brosis requiring mechanical ventilation for acute respiratory failure key: cord- -jck zq authors: cheung, oi-yee; graziano, paolo; smith, maxwell l. title: acute lung injury date: - - journal: practical pulmonary pathology: a diagnostic approach doi: . /b - - - - . - sha: doc_id: cord_uid: jck zq a wide variety of insults can produce acute lung damage, inclusive of those that injure the lungs directly. the clinical syndrome of acute onset respiratory distress, dyspnea, and bilateral infiltrates is referred to as acute respiratory distress syndrome. the histologic counterpart of acute respiratory distress syndrome is diffuse alveolar damage, classically characterized by hyaline membranes. other histologic features of acute lung injury include intraalveolar fibrin, organization, interstitial edema, and reactive pneumocytes. diffuse alveolar damage and other histologic features of acute lung injury are nonspecific as to etiology, and once identified require the pathologist to search the biopsy for further features that may help identify a specific etiology. this chapter reviews the temporal sequence of acute lung injury and explores the large variety of specific etiologic causes with emphasis on helpful histologic features to identify. resultant endothelial and alveolar epithelial cell injury is attended by fluid and cellular exudation. subsequent reparative fibroblastic proliferation is accompanied by type ii pneumocyte hyperplasia. , the microscopic appearance depends on the time interval between insult and biopsy and on the severity and extent of the injury. dad is the usual pathologic manifestation of ards and is the best-characterized prototype of acute lung injury. from studies of ards, the pathologic changes appear to proceed consistently through discrete but overlapping phases ( fig. . )-an early exudative (acute) phase ( fig. . a and b) , a subacute proliferative (organizing) phase ( fig. . c) , and a late fibrotic phase ( fig. . ). , , , , the exudative phase is most prominent in the first week of injury. the earliest changes include interstitial and intraalveolar edema with variable amounts of hemorrhage and fibrin deposition ( fig. . ). hyaline membranes (fig. . ), the histologic hallmark of the exudative phase of ards, are most prominent at to days after injury (eslide . ). minimal interstitial mononuclear inflammatory infiltrates ( fig. . ) and fibrin thrombi in small pulmonary arteries (fig. . ) also are seen. type ii pneumocyte hyperplasia ( fig. . ) begins by the end of this phase and persists through the proliferative phase. the reactive type ii pneumocytes may demonstrate marked nuclear atypia, with numerous mitotic figures (fig. . ). the proliferative phase begins at week after the injury and is characterized by fibroblastic proliferation, seen mainly within the interstitium but also focally in the alveolar spaces ( fig. . ). the fibrosis consists of loose aggregates of fibroblasts admixed with scattered inflammatory cells, reminiscent of organizing pneumonia acute interstitial pneumonia (hamman- in experimental ards, the exact time of injury is known, and the entire lung proceeds through the phases at the same time. in a patient who develops diffuse alveolar damage from any cause, the acute lung injury may begin in different areas at different times, so a biopsy specimen may demonstrate injury at various phases in this sequence. ( in ards the inciting event is frequently extrathoracic, and lung injury is therefore superimposed on normal preexisting structure. a b figure . acute respiratory distress syndrome: fibrin thrombi in arteries. acute lung injury results in local conditions that lead to arterial thrombosis. thrombi in various stages of organization may be seen (larger pulmonary artery in part a, smaller pulmonary artery in part b). ( fig. . ); collagen deposition is minimal. reactive type ii pneumocytes persist. immature squamous metaplasia may occur ( fig. . ) in and around terminal bronchioles. the degree of cytologic atypia in this squamous epithelium can be so severe as to mimic malignancy ( fig. . ). the hyaline membranes are mostly resorbed by the late proliferative stage, but a few remnants may be observed along alveolar septa. some cases of dad resolve completely, with few residual morphologic effects, but in other cases, fibrosis may progress to extensive structural remodeling and honeycomb lung. as might be expected, a review of outcomes for survivors of ards revealed persistent functional disability at year after discharge from intensive care. by definition, ards has a known inciting event. the foregoing description is based on a model of ards due to oxygen toxicity, wherein the evolution of histopathologic abnormalities can be studied over a defined time period. , in practice, lung biopsy most often is performed in patients without a known cause or specific time of onset of injury. moreover, with some causes of acute lung injury, the damage evolves over a protracted period of time, or the lung may be injured in repetitive fashion (e.g., with drug toxicity). in such circumstances, the pathologic changes do not necessarily progress sequentially through defined stages as in ards, so both acute and organizing phases may be encountered in the same biopsy specimen. the basic histopathologic elements of acute lung injury are presented in box . . acute fibrinous and organizing pneumonia (afop) is a histologic pattern of acute lung injury with a clinical presentation similar to that of classic dad, in terms of both potential etiologic disorders and outcome. it differs from dad in that hyaline membranes are absent. the dominant feature is intraalveolar fibrin balls or aggregates, typically in a patchy distribution. organizing pneumonia in the form of luminal loose fibroblastic tissue is present surrounding the fibrin (eslide . ). the alveolar septa adjacent to areas of fibrin deposition show a variety of changes similar to those of dad, such as septal edema, type ii pneumocyte hyperplasia, and acute and chronic inflammatory infiltrates. the intervening lung shows minimal histologic changes. afop may represent a fibrinous variant of dad. in some patients, both dad and afop disease patterns may be present simultaneously. , specific causes of acute lung injury infection infection is one of the most common causes of acute lung injury. if the lung injury pattern is accompanied by a significant increase in neutrophils, areas of necrosis, viral cytopathic effect, and/or granulomas, infection should lead the differential diagnosis. among infectious organisms, viruses most consistently produce dad. , occasionally, fungi (e.g., pneumocystis) and bacteria (e.g., legionella) also can cause infections manifesting as dad. some of the organisms that are well known to cause acute lung injury with characteristic histopathologic changes are discussed next. considerable structural remodeling may take place after ards as these atelectatic spaces fuse to form consolidated areas of lung parenchyma at the microscopic level. influenza is a common cause of viral pneumonia. the histopathology ranges from mild organizing acute lung injury (resembling organizing pneumonia) in nonfatal cases to severe dad with necrotizing tracheobronchitis ( fig. . ) in fatal cases. , specific viral cytopathic effects are not identifiable by light microscopy. on ultrastructural examination, intranuclear fibrillary inclusions may be seen in epithelial and endothelial cells. the coronavirus responsible for severe acute respiratory syndrome produces the acute lung injury associated with this disorder. , [ ] [ ] [ ] both dad and afop patterns have been identified in affected patients. on ultrastructural examination, involved lung tissue revealed numerous to moderate numbers of cytoplasmic viral particles in pneumocytes, many within membrane-bound vesicles. [ ] [ ] [ ] the virus particles were spherical and enveloped, with spikelike projections on the surface and coarse clumps of electron-dense material in the center. most had sizes ranging from to nm in diameter, but some were as large as nm. measles virus produces a mild pneumonia in the normal host but can cause serious pneumonia in immunocompromised children. adenovirus is an important cause of lower respiratory tract disease in children, , although adults (particularly those who are immunocompromised) and military recruits also are occasionally affected. the lung shows necrotizing bronchitis, or bronchiolitis, accompanied by dad. the pathologic changes are more severe in bronchi, bronchioles, and peribronchiolar regions ( fig. . a ). two types of inclusions can be observed in lung epithelial cells: an eosinophilic intranuclear inclusion with a halo usually is less conspicuous than the more readily identifiable "smudge cells" (see fig. . b). these latter cells are larger than normal and entirely basophilic, with no defined inclusion or halo evident by light microscopy. on ultrastructural examination, smudge cell inclusions are represented by arrays of hexagonal particles. herpes simplex virus is mainly a cause of respiratory infection in the immunocompromised host. two patterns of infection are recognized: airway spread resulting in necrotizing tracheobronchitis ( fig. . ) and bronchitis and bronchiolitis, and dad. the characteristic histologic feature is the presence of multinucleated giant cells (fig. . a) with characteristic eosinophilic intranuclear and intracytoplasmic inclusions. [ ] [ ] [ ] [ ] [ ] these cells are found in the alveolar spaces and within alveolar septa (fig. . b ). viral inclusions are seen on ultrastructural examination as tightly packed tubules. interstitial (alveolar septal) edema fibroblastic proliferation in alveolar septa alveolar edema alveolar fibrin and cellular debris, with or without hyaline membranes reactive type ii pneumocytes blood-borne dissemination producing miliary necrotic parenchymal nodules. dad and hemorrhage can occur in both forms. , characteristic inclusions may be seen in bronchial and alveolar epithelial cells ( fig. . ). the more obvious type is an intranuclear eosinophilic inclusion surrounded by clear halo (cowdry a inclusion), and the other is represented by a basophilic to amphophilic ground-glass nucleus (cowdry b inclusion). rounded viral particles with double membranes are seen under the electron microscope. , varicella-zoster virus causes disease predominantly in children and is the agent of chickenpox. pulmonary complications of chickenpox are rare in children with normal immunity (accounting for less than % of the cases). by contrast, pneumonia develops in % of adults with chickenpox; immunocompetent and immunocompromised persons are equally affected. , the histopathologic picture in varicella pneumonia ( fig. . ) is similar to that in herpes simplex. although identical intranuclear inclusions are reported to occur, , these can be considerably more difficult to identify in chickenpox pneumonia. cytomegalovirus is an important cause of symptomatic pneumonia in immunocompromised persons, especially those who have received bone marrow or solid organ transplants, and in patients with human immunodeficiency virus infection. [ ] [ ] [ ] the histopathologic findings range from little or no inflammatory response to hemorrhagic nodules with necrosis ( fig. . a) and dad. the diagnostic histopathologic b a with many organisms (see fig. . b). , however, in the mildly immunocompromised patient this feature is not observed or the pathologic changes may be subtle. in such cases, several "atypical" manifestations have been described. , , dad is the most dramatic of these atypical presentations ( fig. . a), with the organisms present within hyaline membranes ( fig. . b) and in isolated intraalveolar fibrin deposits. the grocott methenamine silver (gms) method is routinely used to stain the organisms, which typically are seen in small groups and clusters (figs. . b and . b). , , bacterial infection common bacterial pneumonias rarely cause dad; however, this lung injury pattern has been described in legionnaires' disease, mycoplasma pneumonia, and rickettsial infection. [ ] [ ] [ ] [ ] [ ] pattern, seen in endothelial cells, macrophages, and epithelial cells, consists of cellular enlargement, a prominent intranuclear inclusion, and an intracytoplasmic basophilic inclusion ( fig. . b). hantavirus is a rare cause of acute lung injury. [ ] [ ] [ ] the infection produces alveolar edema, hyaline membranes, and atypical interstitial mononuclear inflammatory infiltrates (fig. . ). [ ] [ ] [ ] spherical membrane-bound viral particles have been found in the cytoplasm of endothelial cells by electron microscopy. pneumocystis jiroveci (previously known as pneumocystis carinii) is the most common fungus to cause dad. [ ] [ ] [ ] the histopathology of pneumocystis infection in the setting of profound immunodeficiency is one of frothy intraalveolar exudates ( [afb] stains or gms or warthin-starry silver stain, etc.) on every lung biopsy specimen exhibiting dad. systemic connective tissue disorders are a well-known cause of diffuse lung disease. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in some cases, lung involvement may be the first manifestation of the systemic disease, even without identifiable serologic evidence. histologic clues that suggest the acute lung injury is secondary to connective tissue disease include associated bronchiolitis (especially if it is follicular bronchiolitis), pleuritis, capillaritis, hemorrhage, and legionella is a fastidious gram-negative bacillus that causes acute respiratory infection in older adults and immunodeficient individuals. , , the histopathologic pattern is that of a pyogenic necrotizing bronchopneumonia ( fig. . a) affecting the respiratory bronchioles, alveolar ducts, and adjacent alveolar spaces. dad is common. , , the rod-shaped organisms (fig. . b) can be identified by dieterle silver stain. of note, in immunocompromised patients, any type of infection can cause dad, with pneumocystis pneumonia being the most common. for this reason, it is essential to use special stains (acid-fast bacilli and small vessel vasculitis ( fig. . b), and pulmonary edema also may be observed. , , immunofluorescence studies demonstrate immune complexes in lung parenchyma, and both immune complexes and tubuloreticular inclusions may be seen on ultrastructural examination. , , rheumatoid arthritis a significant percentage of patients with rheumatoid arthritis have lung disease. , , [ ] [ ] [ ] [ ] many different morphologic patterns of lung disease in rheumatoid arthritis have been described, , , with the rheumatoid nodule being the most specific. acute lung injury has been reported ( fig. . ), referred to as acute interstitial pneumonia in some publications and as dad in others. a cellular lymphoplasmacytic infiltrate. acute lung injury has been reported to occur in the following connective tissue diseases. pulmonary involvement in systemic lupus erythematosus (sle) may manifest as pleural disease, acute or chronic diffuse inflammatory lung disease, airway disease, or vascular disease (vasculitis and thromboembolic lesions). acute lupus pneumonitis (alp) is a form of fulminant interstitial disease (fig. . a) with a high mortality rate. patients present with severe dyspnea, tachypnea, fever, and arterial hypoxemia. alp represents the first manifestation of sle in approximately % of affected persons. , the most common histopathologic feature of this acute disease is dad (eslide . ). alveolar hemorrhage, with capillaritis b a polymyositis/dermatomyositis, a systemic connective tissue disorder, is well known to be associated with interstitial lung disease. , three main clinical presentations are recognized: ( ) acute fulminant respiratory distress resembling the so-called hamman-rich syndrome, ( ) slowly progressive dyspnea, and ( ) an asymptomatic form with abnormalities on radiologic and pulmonary function studies. three major histopathologic patterns have been observed: dad (fig. . a), organizing pneumonia ( fig. . b) , and chronic fibrosis (fig. . c )-the so-called usual interstitial pneumonia (uip) pattern. the rapidly progressive clinical presentation is associated with a dad histopathologic pattern on lung biopsy studies and carries the worst prognosis. dad associated with scleroderma and mixed connective disease also has been described. , many patients with connective tissue disease receive drug therapy during the course of their illness. a large number of drugs, including cytotoxic agents used for immunosuppression, are known to cause dad. in addition, as a desired result of therapy, patients may be immunosuppressed, making the exclusion of infection a high priority in the case of acute clinical lung disease. drugs can produce a wide range of pathologic lung manifestations, and the causative agents are numerous. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the spectrum of drug-induced lung disease runs the entire gamut from dad to fibrosis. between these two extremes, subacute clinical manifestations may include organizing pneumonia, chronic interstitial pneumonia, eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, pulmonary edema, pulmonary hypertension, venoocclusive disease, and granulomatous interstitial pneumonia. , , dad is a common and dramatic manifestation of pulmonary drug toxicity. many drugs are known to cause dad. a few of the more common ones are discussed next. (drug-related lung disease is also discussed in chapter .) as a generalization, marked cytologic atypia and numerous foamy macrophages in the airspaces are histologic harbingers of possible drug reaction. dad frequently is caused by cytotoxic drugs, and the commonly implicated ones include bleomycin (fig. . ), busulfan ( fig. . ) , and carmustine. , , patients usually present with dyspnea, cough, and diffuse pulmonary infiltrates. [ ] [ ] [ ] [ ] [ ] the histologic pattern most commonly is one of nonspecific acute lung injury with hyaline membranes, but some changes may be present to at least suggest a causative agent. for example, the presence of acute lung injury with associated atypical type ii pneumocytes with markedly enlarged pleomorphic nuclei and prominent nucleoli (see fig. . ) is characteristic for busulfan-induced pulmonary toxicity, and, on ultrastructural examination, intranuclear tubular structures have been found in type ii pneumocytes in association with administration of busulfan and bleomycin. [ ] [ ] [ ] [ ] in most cases, the possibility that a drug is the cause of dad can only be inferred from the clinical history. considerations in the differential diagnosis typically include other treatment-related injury or complication of therapy (e.g., concomitant irradiation or infection). for example, oxygen therapy is a well-recognized cause of dad (fig. . ) and also may exacerbate bleomycin-induced lung injury. methotrexate (fig. . ) is another commonly used cytotoxic drug that can cause acute and organizing dad. methotrexate also produces other distinctive patterns, such as granulomatous interstitial pneumonia (see chapter ) that is seldom seen in association with other commonly used chemotherapeutic agents. to complicate matters further, methotrexate also is used in the treatment of rheumatoid arthritis, a disease known to produce dad independently as one of its pulmonary manifestations. , epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be associated with dad. , the increasing use of targeted therapy drugs in cancer patients warrants a notice of this category as a potential cause. amiodarone is a highly effective antiarrhythmic drug that is increasingly recognized as a cause of pulmonary toxicity. , - because patients taking amiodarone have known cardiac disease, the clinical presentation often is complicated, with several superimposed processes potentially affecting the lungs in various ways. clinical and radiologic considerations typically include congestive heart failure, pulmonary emboli, and acute lung injury from other causes. , distinctive features may be present on chest computed tomography scans. the lung biopsy commonly shows acute and organizing lung injury (fig. . a and eslide . ). other patterns include chronic interstitial pneumonitis with fibrosis and organizing pneumonia. characteristically, type ii pneumocytes and alveolar macrophages show finely vacuolated cytoplasm in response to amiodarone therapy (see fig. . b), but these changes alone are not evidence of toxicity because they also may be seen in patients taking amiodarone who do not have evidence of lung toxicity. methotrexate and gold, common agents for treatment of rheumatoid arthritis, are frequently implicated in lung toxicity. methotrexate is discussed earlier in this chapter. organizing dad (fig. . ) and chronic interstitial pneumonia are commonly described pulmonary manifestations of so-called gold toxicity. , , acute eosinophilic pneumonia acute eosinophilic pneumonia was first described in and is characterized by acute respiratory failure, fever of days' to weeks' duration, diffuse pulmonary infiltrates on radiologic studies, and eosinophilia in bronchoalveolar lavage fluid or lung biopsy specimens in the absence of infection, atopy, and asthma. peripheral eosinophilia frequently is described but is not a consistent finding at initial presentation. , acute eosinophilic pneumonia is easily confused with acute interstitial pneumonia because both manifest as acute respiratory distress without an obvious underlying cause. histologically, the disease is characterized by acute and organizing lung injury showing classic features (fig. . ) of ( ) alveolar septal edema, ( ) eosinophilic airspace macrophages, ( ) tissue and airspace eosinophils in variable numbers, and ( ) marked reactive atypia of alveolar type ii cells (eslide . ). intraalveolar fibroblastic proliferation (patchy organizing pneumonia) and inflammatory cells are present to a variable degree. hyaline membranes and organizing intraalveolar fibrin also may be present (fig. . ) . the most significant feature is the presence of interstitial and alveolar eosinophils. infiltration of small blood vessels by eosinophils also may be seen. it is important of special stains applied to tissue sections or cytologic preparations (e.g., afb, gms, or warthin-starry silver stain) also is essential to rule out infectious organisms in this setting. so-called pulmonary hemorrhage syndromes may feature the histopathologic changes of acute lung injury, in addition to the characteristic alveolar hemorrhage and hemosiderin-laden macrophages. in some patients, dad may be the dominant histopathologic pattern. in a study by lombard et al. in patients with goodpasture syndrome, all showed acute lung injury ranging in distribution from focal to diffuse lung involvement. histopathologic examination demonstrated typical acute and organizing dad, with widened and edematous alveolar septa, fibroblastic proliferation, reactive type ii pneumocytes, and, rarely, even hyaline membranes (figs. . and . ). alveolar hemorrhage, either focal or diffuse, was present in all cases. capillaritis, an important finding indicating true alveolar hemorrhage, also was seen, as evidenced by marked septal neutrophilic infiltration. capillaritis was absent in one case for which dad was the dominant histopathologic pattern. microscopic polyangiitis can manifest as an acute interstitial pneumonia both clinically and histopathologically. affected patients have vasculitis as the known cause of acute lung injury. alveolar hemorrhage with arteritis, capillaritis ( fig. . ) , and venulitis may be seen in some cases. polyarteritis nodosa and vasculitis associated with systemic connective tissue disease (notably sle and rheumatoid arthritis) can also show acute lung injury with alveolar hemorrhage as the dominant histopathologic finding. , cryoglobulinemia is a rare cause of acute lung injury and alveolar hemorrhage. [ ] [ ] [ ] radiation can produce both acute and chronic damage to the lung, manifesting as acute radiation pneumonitis and chronic progressive fibrosis, respectively. the effect is dependent on radiation dosage, total time of irradiation, and tissue volume irradiated. concomitant chemotherapy and infections, which in themselves are causes of dad, may potentiate the effect of radiation injury. , , , acute radiation pneumonitis manifests to months after radiation therapy. , with traditional external beam radiation the pneumonitis is typically confined to the radiation field. however, more diffuse radiation pneumonitis can be seen following yttrium -impregnated microsphere chemoembolization for nonoperable hepatic tumors. clinical findings include dyspnea, cough, pleuritic pain, fever, and chest infiltrates. the lung biopsy specimen shows acute and organizing dad. , markedly atypical type ii pneumocytes with enlarged hyperchromatic nuclei and vacuolated cytoplasm constitute a hallmark of the disease (fig. . a) , and increased numbers of alveolar macrophages are seen. foamy cells are present in the intima and media of pulmonary blood vessels in some cases, and thrombosis ( fig. . b) , with or without transmural fibrinoid necrosis, is common. , [ ] [ ] [ ] disease presenting as classic acute respiratory distress syndrome by definition, ards must be associated with an identifiable inciting event. the histopathologic pattern is that of classic dad. the histopathologic changes should be consistent with those expected for the time interval from the onset of clinical disease (see later). in many cases the ards may be caused by a combination of factors, each potentiating the other. for the purposes of illustration, a few thoroughly studied causes are discussed next. to distinguish acute eosinophilic pneumonia from other causes of dad because patients typically benefit from systemic corticosteroid treatment, with prompt recovery. however, before initiation of immunosuppressive therapy, infection should be rigorously excluded by culture and special stains because parasitic and fungal infections also can manifest as tissue eosinophilia. treatment with steroids prior to the biopsy can make the number of eosinophils less impressive. acute interstitial pneumonia, also commonly referred to as hamman-rich syndrome, is a fulminant lung disease of unknown etiology occurring in previously healthy patients. [ ] [ ] [ ] acute interstitial pneumonia is one of the major idiopathic interstitial pneumonias included in the most recent classification scheme for diffuse interstitial pneumonia. patients usually report a prodromal illness simulating viral infection of the upper respiratory tract, followed by rapidly progressive respiratory failure. the mortality rate is high, with death occurring weeks or months after the acute onset. , the classic histopathologic pattern is that of acute and organizing dad, , with septal edema and hyaline membranes in the early phase and septal fibroblastic proliferation with reactive type ii pneumocytes prominent in the organizing phase. in practice, a combination of acute and organizing changes ( fig. . ) often is seen in the lung at the time of biopsy. a variable degree of airspace organization, mononuclear inflammatory infiltrates, thrombi in small pulmonary arteries, and reparative peribronchiolar squamous metaplasia also are seen in most cases. because acute interstitial pneumonia is idiopathic, other specific causes of acute lung injury must be excluded before making this diagnosis. considerations in the differential diagnosis include infection, connective tissue disease, acute exacerbation of idiopathic pulmonary fibrosis (ipf), drug effect, and other causes of dad. most cases of dad are not acute interstitial pneumonia, and detailed clinical information, radiologic findings (localized vs. diffuse disease), serologic data, and microbiologic results will often point to or rule out a specific etiologic condition. use figure . acute interstitial pneumonia (aip). idiopathic aip may take the form of every possible morphologic manifestation of acute respiratory distress syndrome, depending on the timing of biopsy relative to the onset of symptoms. here, a classic pattern of diffuse alveolar damage (dad) with hyaline membranes of variable cellularity is seen (midproliferative phase). interstitial fibroblastic proliferation may be more or less prominent from case to case and should not serve as a qualifying morphologic finding for the diagnosis. aip is nothing more than dad of unknown causation. oxygen is a well-known cause of ards and a useful model for all types of dad. , , oxygen toxicity also is important in that it is widely used in the care of patients, often in the setting of other injuries that can potentially cause ards, such as sepsis, shock, and trauma. exposure to high concentrations of oxygen for prolonged periods can lead to characteristic pulmonary damage. in pratt first noted pulmonary changes due to high concentrations of inspired oxygen. in nash et al. described the sequential histopathologic changes of this injury, later reemphasized by pratt. in neonates receiving oxygen for hyaline membrane disease, bronchopulmonary dysplasia was reported to occur. as might be expected, the features of hyaline membrane disease in neonates and oxygen-induced dad in adults are indistinguishable (see fig. . ). other inhalants such as chlorine gas, mercury vapor, carbon dioxide in high concentrations, and nitrogen mustard all have been reported to cause ards. , , massive extrapulmonary trauma and shock first became recognized as causes of unexplained respiratory failure during the wars of the second half of the th century. a variety of names were assigned to this wartime condition, including shock lung, congestive atelectasis, traumatic wet lung, da nang lung, respiratory insufficiency syndrome, posttraumatic pulmonary insufficiency, and progressive pulmonary consolidation. it which can be performed even on autopsy specimens. other ingested toxins (e.g., kerosene, rapeseed oil) also have been reported to cause ards. pathologist approach to the differential diagnosis of acute lung injury the histologic spectrum encountered in acute lung injury is broad. very early cases may look nearly normal with only mild interstitial and alveolar edema. other more advanced cases are clearly abnormal with fibrin, inflammation, and organization. the basic elements of the acute injury pattern include interstitial edema, alveolar edema, fibrin, hyaline membranes, reactive pneumocytes, and organization (see box . ). acute lung injury is a pathologic pattern and by itself is a nonspecific finding. from a practical perspective, after an acute lung injury pattern is became clear that shock of any cause (e.g., hypovolemia due to hemorrhage, cardiogenic shock, sepsis) could cause ards, and that in most cases, a number of factors come into play. in the typical presentation, dyspnea of rapid onset is accompanied by development of diffuse chest infiltrates several hours to days after an episode of shock. after ards begins, the mortality rate is high. , , paraquat is a potent herbicide that causes the release of hydrogen peroxide and superoxide free radicals, resulting in damage to cell membranes. [ ] [ ] [ ] oropharyngitis is the initial sign of poisoning, followed by impaired renal and liver function. approximately days later, ards develops. the histopathologic pattern in most cases is one of organizing dad (fig. . ). the diagnosis is confirmed by tissue analysis for paraquat, b a raise consideration of immunologically mediated pulmonary hemorrhage. care must be taken not to interpret the pigmented macrophages seen in the lungs of cigarette smokers as evidence of hemorrhage. the hemosiderin in macrophages related to true hemorrhage in the lung (from any cause) is globular, often slightly refractile, and golden-brown in color. , [ ] [ ] [ ] presence of atypical cells. viral infections often produce cytopathic effects, including intracellular inclusions (see chapter ) . examples of intracellular inclusions are the cowdry a and b inclusions seen in herpesvirus infection, cytomegaly with intranuclear and intracytoplasmic inclusions of cytomegalovirus, the multinucleated giant cells of measles virus and respiratory syncytial virus, and the smudged cells of adenovirus infection. , , , , chemotherapeutic drugs such as busulfan and bleomycin often are associated with markedly atypical type ii pneumocytes, which may have enlarged pleomorphic nuclei and prominent nucleoli. , markedly atypical type ii pneumocytes that may be suggestive of a viropathic effect also are seen in radiation pneumonitis. , , presence of foamy cells. alveolar lining cells with vacuolated cytoplasm accompanied by intraalveolar foamy macrophages are characteristic features seen in patients taking amiodarone, and amiodarone toxicity may lead to acute lung injury changes. [ ] [ ] [ ] in some cases of radiation pneumonitis, foam cells are seen in the intima and media of blood vessels. , presence of foreign material. foreign material in the spaces in the form of vegetable matter or other food elements is indicative of aspiration. massive aspiration events may cause dad. other foreign material, such as radiation impregnated beads may also be encountered. presence of advanced interstitial fibrosis. clinical ipf is associated with the changes of uip on pathologic examination (see chapter ), with advanced lung remodeling. of interest, ipf undergoes episodic exacerbation, and on occasion such exacerbation may be overwhelming, with resultant dad. it is prudent to examine lung biopsy sections for the presence of dense fibrosis with structural remodeling (microscopic honeycombing) in cases of dad, to identify the rare case of ipf that manifests for the first time as an acute episode of exacerbation. because the morphologic manifestations of acute diffuse lung disease may be relatively stereotypical, clinicopathologic correlation is often helpful in arriving at a specific diagnosis. a summary of the more important history and laboratory data pertinent to this correlation is presented in box . . identified, careful search for the following additional features often help to narrow the list of possible causes (summarized in immune status acuity of onset radiologic distribution and character of abnormalities history of inciting event (e.g., shock) history of lung disease (e.g., usual interstitial pneumonia with current acute exacerbation) history of systemic disease (e.g., connective tissue disease, heart disease) history of medication use or drug abuse history of other recent treatment (e.g., radiotherapy for malignancy) results of serologic studies: erythrocyte sedimentation rate determination, assays for autoimmune antibodies (e.g., ana, rf, anca, scl- , jo- ) results of microbiology studies one of the first questions to be addressed is whether or not a known inciting event was identified clinically (i.e., is this ards?). next, the results of any sampling procedures to identify infection should be checked, along with application of special stains to the tissue sections, to exclude infection. finally, data regarding related disease, such as infection, autoimmune disease, underlying lung disease, are needed. for example, if the patient is immunosuppressed, infection should always be the leading consideration in the differential diagnosis. another point to keep in mind is that patients with certain diseases may be taking medications with the potential to cause dad (e.g., amiodarone for cardiac arrhythmia). moreover, laboratory studies may reveal antibodies related to connective tissue disease (e.g., antineutrophil antibody, rheumatoid factor, jo- , scl- , antifibrillarin, anti-mpp , ss-a, ss-b). regarding the pathologist's role and responsibility in biopsy cases of acute lung injury, use of special stains for organisms (at a minimum, methenamine silver and acid-fast stains) is indicated. additional stains (auramine-rhodamine, dieterle or warthin-starry silver stain, immunohistochemical stains for specific organisms, or molecular probes) may be used, especially in patients known to be immunocompromised from any cause. the pathology in immunocompromised patients may not show necrosis, neutrophils, or granulomas, all features favoring an infectious etiology. self-assessment questions and cases related to this chapter can be found online at expertconsult.com. acute and fibrinous organizing pneumonia (eslide . ) a. history-a -year-old female presented with acute onset dyspnea. her past medical history was significant for rheumatoid arthritis for which she had recently begun methotrexate. imaging studies show bilateral ground-glass infiltrates in upper and lower lobes. a surgical lung biopsy was performed. b. pathologic findings-from scanning magnification, the lung architecture appears preserved without significant fibrosis. at higher power there is an extensive airspace filling process. many airspaces are filled with fibrin and scattered inflammatory cells. in other areas there is light pink material suggestive of edema. finally, some early fibroblastic polyps of organization are present. the interstitium shows diffuse alveolar damage with hyaline membranes (eslide . ) a. history-a -year-old male without significant past medical history presented to the emergency room with acute shortness of breath and cough. a week prior he participated in a half marathon without difficulty. he was taking no medications and had no exposures. his oxygen saturation was % on room air. he progressed to respiratory failure after being admitted to the intensive care unit. a surgical lung biopsy was performed. b. pathologic findings-from scanning magnification the biopsy shows preserved lung parenchyma without significant scarring. however, there is a diffuse process that gives the biopsy a "pink" appearance from low power. at higher power, the histologic features of diffuse alveolar damage (dad) are recognized including alveolar wall edema, reactive type-ii pneumocytes, and hyaline membranes. a few foci of organization are also present. a significant inflammatory cell infiltrate is not recognized. there is no pleuritis, hemosiderosis, granulomas, or necrosis. c. diagnosis-diffuse alveolar damage. d. discussion-features of acute lung injury are readily apparent, and the numerous hyaline membranes support a diagnosis of diffuse alveolar hemorrhage. the biopsy is negative for numerous eosinophils, foamy macrophages, alveolar hemorrhage, foreign material, neutrophils, necrosis, and granulomas. therefore the histology does not suggest a particular etiology on this case. acid-fast and fungal stains were negative. extensive serologic screening studies were negative, and cultures are negative to date. because the additional work-up is negative, this case is best categorized as acute 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tissue have been associated with: a. cri du chat syndrome b. holoprosencephaly c. beckwith-wiedemann syndrome d. down syndrome e. cornelia de lange syndrome answer: d acinar pulmonary dysplasia: a. features cystic change and enlargement of all lobes b. accounts for one of the most common surgical specimens in pediatric lung pathology hyperplasia: a. refers to an increased number of alveoli relative to the corresponding conducting airways which of the following is not in the macroscopic differential diagnosis of cystic lung lesions in children? a. adenomatoid malformation b. intralobar sequestration c. congenital lobar overinflation d. lymphangioleiomyomatosis e. pneumatocele answer: d . pulmonary sequestration is characterized by: a. communication with second-order bronchial lumina b. solely systemic vascular supply c. exclusive extralobar localization d. densely apposed, atelectatic airspaces e. multifocal aggregates of eosinophils answer: b . extralobar pulmonary sequestrations may occasionally contain which one of the following heterotopic tissues? a. bone b. glial nodules c. hepatoid anlage d. striated muscle e. enteric-type epithelium answer: d . congenital malformations of the pulmonary airways: a. are most often seen in stillborns or newborns b. represent malformations of each bronchopulmonary segment c. may be difficult to subclassify in fetal lungs d. must be distinguished from pleuropulmonary blastoma e. all of the above answer: e . which one of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways? a. striated muscle b. cartilage c. mucinous epithelium d. embryonic-type mesenchymal tissue e. lymphoid aggregates answer: c .e . which one of the following storage disorders does not usually involve the lung parenchyma? a. niemann-pick disease b. gaucher disease c obliterative bronchiolitis in children can be associated with all of the following except: a. adenovirus b. influenza c. stevens-johnson syndrome d. paragonimiasis e. graft-versus-host disease answer: d acute eosinophilic pneumonia (eslide . ) a. history-a previously healthy -year-old female presented to the emergency room with acute-onset shortness of breath and cough. she was initially evaluated and admitted to the medicine floor for presumed pneumonia. however, she quickly deteriorated and was transferred to the medical intensive care unit and required intubation. imaging studies showed bilateral ground-glass opacities without lobar distribution. additional history obtained from the patient's roommate revealed the patient was recently treated with sulfamethoxazole and trimethoprim for a urinary tract infection. b. pathologic findings-the overall architecture of the lung appears intact, but there is a diffuse acute lung injury pattern including alveolar wall edema, airspace fibrin, organization, and scattered hyaline membranes. pneumocytes show marked reactive atypia. there are numerous eosinophils in the airspaces, embedded within the fibrin, and within the interstitium. numerous airspace macrophages are also present. no necrosis or granulomas are identified. c. diagnosis-acute eosinophilic pneumonia. d. there are four key histologic features in acute eosinophilic pneumonia, all of which are satisfied in this case. i. alveolar septal edema ii. eosinophilic airspace macrophages iii. tissue and airspace eosinophils iv. reactive atypia of type-ii pneumocytes there is a differential diagnosis for the acute eosinophilic pneumonia pattern of injury including drug reaction, infection, connective tissue disease, smoking related, and idiopathic. rigorous exclusion of infection is imperative and requires both infectious stains on the tissue blocks and culture studies. recognition of this injury pattern is of particular importance as these patients typically respond dramatically to high-dose steroids and have a better prognosis than that of diffuse alveolar damage. in this patient the exposure to a sulfa drug in the days prior to presentation was the likely etiology. she was treated with steroids, dramatically improved, and was discharged in days. amiodarone-induced diffuse alveolar damage (eslide . ) a. history-a -year-old male presented to the emergency room with acute shortness of breath first noted the evening prior. his past history was significant for a deceased donor renal transplant days prior to presentation for end-stage renal disease secondary to diabetes. he also had a history of hypertension and atrial fibrillation. imaging studies showed bilateral ground-glass opacities in the upper and lower lobes. b. pathologic findings-from scanning magnification there is preserved architecture without significant fibrosis. there is diffuse alveolar wall thickening, mostly by edema. overlying pneumocytes show reactive epithelial changes. numerous hyaline membranes and focal fibrin in airspaces are present. some airspaces are filled with numerous macrophages showing finely vacuolated cytoplasm. some acute lupus pneumonitis (eslide . )a. history-a -year-old african-american female presented with the emergency room with cough and shortness of breath. upon further questioning, she reported some blood-tinged sputum. the patient was febrile, and chest imaging studies showed bilateral ground-glass infiltrates without lobar distribution. serologic studies revealed an elevated erythrocyte sedimentation rate and c-reactive protein and positive antinuclear antibodies and anti-double-stranded dna antibodies. a surgical lung biopsy was performed. b. pathologic findings-the biopsy shows preserved lung architecture with a diffuse abnormality from scanning magnification. there is extensive alveolar wall edema with numerous foci of hyaline membranes. patchy organization is present, along with a relatively diffuse lymphoplasmacytic interstitial infiltrate. c. diagnosis-acute lupus pneumonitis. d. discussion-based on the histologic features alone, this biopsy is diagnostic of diffuse alveolar damage. however, the clinical history is required to arrive are a more specific diagnosis of acute lupus pneumonitis. the biopsy does show a mild increase in lymphoplasmacytic interstitial inflammation that would be unusual for most cases of idiopathic acute respiratory distress syndrome.edema and a mixed lymphoplasmacytic infiltrate. no hemorrhage, necrosis, or hyaline membranes are present. c. diagnosis-acute fibrinous and organizing pneumonia (afop). d. discussion-afop presents in the same fashion as diffuse alveolar damage (dad) and the differential diagnosis for afop and dad is the same, including drug reaction, toxin exposure, connective tissue disease, infection, and as an idiopathic reaction. they both represent forms of acute lung injury. in this case the degree of lymphoplasmacytic inflammation in the interstitium raises the possibility of a background connective tissue disease. additional history revealed she had recently cut her methotrexate dose in half to save money. she had also recently experienced inflammatory flares in her joints. all of these factors support a diagnosis of afop related to rheumatoid arthritis. a definitive etiology for afop is identified in a minority of patients.pneumocytes show similar cytoplasmic vacuolization. there is no necrosis, neutrophils, or hemorrhage. c. diagnosis-diffuse alveolar damage (dad) with foamy macrophages.a drug reaction leads the differential diagnosis. d. discussion-based on the presence of the patchy but marked cytoplasmic vacuolization in the macrophages and pneumocytes, a drug reaction is the most likely etiology for the dad pattern. in particular, amiodarone is a commonly used drug that causes this cytoplasmic vacuolization, even in the absence of associated lung injury. this was communicated to the clinical services who identified the patient was indeed taking amiodarone, even on the day of transplant. amiodarone-induced lung injury is associated with prolonged use of the drug and with an inciting event (such as a major operation). this patient had been on amiodarone for several years. following clinicopathologic correlation, this case is best diagnosed as amiodarone-induced dad. the patient was treated with pulse high-dose steroids and eventually had a full recovery. key: cord- -anrzcsrt authors: nan title: . jahrestagung der Österreichischen gesellschaft für pneumologie date: - - journal: wien klin wochenschr doi: . /s - - - sha: doc_id: cord_uid: anrzcsrt nan patientencharakteristik, anamnese, symptome: eine -jährige patientin wurde nach plötzlichem auftreten von dyspnoe, tachypnoe und rechtsthorakalen schmerzen mit ausstrahlung in den rechten oberbauch vorstellig. die anamnese bezüglich traumas oder chronischen vorerkrankungen war unauffällig. diagnostik und diagnose: die blutgasanalyse zeigte eine hypoxie. laborchemisch fand sich lediglich eine isolierte, milde leukozytose. die thoraxauskultation ergab rechtsseitig verminderte atemgeräusche. die computertomografie des thorax wies einen rechtsseitigen hinteren zwerchfelldefekt mit intrathorakaler hernierung des kolon ascendens und rechtsseitigen pneumothorax mit mediastinalshift nach links aus. bildgebend bestand mithin der verdacht auf eine kolonperforation und eine bochdalek-hernie. differentialdiagnostik: obwohl bochdalek-hernien bei erwachsenen selten sind, müssen sie differentialdiagnostisch bei patienten mit dyspnoe berücksichtigt werden. eine intrathorakale kontamination nach bakterieller translokation oder hohlorganperforation kann zur entwicklung von pleuraempyemen führen. die sorgfältige intraoperative lavage und drainage der thoraxhöhle hat deshalb in diesen fällen große bedeutung. therapie: es erfolgte eine notfalllaparotomie, welche die diagnose bestätigte. ein cm langer zwerchfelldefekt mit inkarzeriertem und perforiertem kolon ascendens wurde erkannt. unter erweiterung der bruchpforte konnte das kolon nach intraabdominell reponiert werden. aufgrund von ischämischen veränderungen sowie der kolonperforation wurde eine rechtsseitige hemikolektomie mit anlage einer seit-zu-seit ileotransversostomie erforderlich. nach ausgedehnter abdomineller und transdiaphragmaler thorakaler lavage wurde eine bülaudrainage platziert, zwerchfelldefekt und bauchdecke wurden mittels naht verschlossen. am . postoperativen tag wurde aufgrund eines rechtsseitigen pleuraempyems nach diagnostischer vats eine anterolaterale thorakotomie mit anschließender pleuradekortikation zur sanierung erforderlich. die patientin erholte sich letztlich gut und wurde am . postoperativen tag nach hause entlassen. patientencharakteristik, anamnese, symptome: im juli wird eine -jährige patientin vom niedergelassenen pneumologen an unsere abteilung überwiesen. die aufnahme erfolgt aufgrund einer vor ca. zwei wochen suspizierten pneumonie, welche mit amoxicillin-clavulansäure behandelt wurde. im aufnahmegespräch berichtet die patientin über deutliche abgeschlagenheit und belastungsdyspnoe (stiegen steigen) bei bisher altersentsprechend sehr guter leistungsfähigkeit. in der anamnese sind eine atypische pneumonie vor einem jahr, eine primär biliäre cholangitis (ed im rahmen der pneumonie) und eine substituierte hypothyreose auffällig. in den von uns initial erhobenen laborbefunden zeigen sich moderat erhöhte entzündungsparameter (crp , mg/ dl, leukozyten , g/l), woraufhin die antibiotische therapie auf azithromycin mg umgestellt wird. eine durchgeführte computertomographie des thorax zeigt bipulmonale fleckige milchglastrübungen, peribronchovaskuläre verdichtungen mit teils positivem pneumobronchogramm und hiläre sowie mediastinale lymphadenopathie. zur abklärung der dementsprechend im raum stehenden differenzialdiagnosen einer sarkoidose, vaskulitis bzw. eines lymphoms werden eine bronchoskopie mit transbronchialer lymphknotenbiopsie (lk l, lk r, lk und lk r) und detaillierte laborchemische untersuchungen durchgeführt. diagnostik und diagnose: im verlauf kommt es zu einer verschlechterung der nierenfunktion (creatinin , mg/dl) und einer proteinurie ( , g/l), ansteigenden entzündungsparametern (crp, leukozyten, bsg) und einem positiven ergebnis für mpo-anca ( iu/ml). die histopathologische aufarbeitung der lymphknotenbiopsien zeigt ausgeprägte reaktive zell-und kernveränderungen ohne hinweis für eine infiltration mit malignen zellen. die erhobenen befunde erhärten den verdacht auf eine mpa-anca-assoziierte vaskulitis mit pulmonaler und renaler beteiligung. die patientin wird an die universitätsklinik für nephrologie transferiert, wo komplikationslos eine nierenbiopsie durchgeführt wird. hierbei zeigt sich das histologische bild einer pauci-immunen glomerulonephritis mit halbmondbildungen und schlingennekrosen in % der glomeruli, vereinbar mit der diagnose einer mpo-ancaassoziierte vaskulitis. therapie: nach entsprechender aufklärung der patientin beginnen wir mit der therapie mit rituximab mg (aktuell zwei gaben erhalten, dritte gabe geplant) sowie methylpred-therapie: im rahmen einer rechtsseitigen thorakotomie erfolgte eine offene wedge-resektion des oberlappen sowie mittellappens rechts, wobei sich intraoperativ histologisch der verdacht einer lymphominfiltration ergab. die fistulierung zur speiseröhre wurde mittels vena azygos-patch gedeckt und übernäht. eine protektive endoluminale vac-anlage konnte bereits am . postoperativen tag entfernt werden. histologisch bestätige sich ein aggressives non-hodgkin-lymphom der b-zellreihe, speziell eines diffusen großzelligen b-zell-lymphoms (zentroblastisch-polymorph), nicht-keimzentrumstyp nach hans-klassifikator. von onkologischer seite wurde einer therapie mittels r-chop initiiert bei postoperativ chirurgisch unauffälligem status. allergie mit biss background: lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (clad). the mechanisms leading to clad remain elusive due to insufficient understanding of the complex post-transplant adaptation processes. here, we aimed to better understand the processes preceding clad, and investigate their association with future changes in allograft function. methods: we performed an exploratory cohort study in patients, including broncho-alveolar lavage samples from lung donors and recipients (after transplantation). we analyzed the alveolar microbiome using s rrna sequencing, the cellular composition using flow-cytometry, and conducted metabolome and lipidome profiling. results: we established distinct temporal dynamics for each of the analyzed data sets. comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. we further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. a decline in forced expiratory volume during the first second (fev ) is a major characteristic of lung allograft dysfunction in transplant recipients. by using a machine learning approach, we could accurately predict future changes in fev from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. conclusions: broncho-alveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. the lung microbiome can predict future changes in lung function with high precision. über eine anterolaterale thorakotomie rechts im . icr inklusive adäquate onkologische lymphadenektomie position rechts bis i the authors marked with an asterisk (*) are the corresponding authors. abstracts Ögp conclusions: patients with copd are insufficiently evaluated for cad due to overlapping symptoms. current cad risk scores for stable chest pain appear inappropriate for patients with copd. background: oncologic patients are regarded the population most at risk of developing a severe course of covid- due to the fact that malignant diseases and chemotherapy often weaken the immune system. in the face of the ongoing sars-cov- pandemic, how particular patients deal with this infection remains an important question. in the period between the th and th of april , a total of patients were tested in one of seven oncologic outpatient clinics for sars-cov- , regardless of symptoms, employing rt-qpcr using bgi real-time fluorescent rt-pcr kit for detecting -ncov on applied bioscience abi instruments. results: of patients, seventy-eight ( . %) were tested positive of sars-cov- . only one of the patients who tested positive developed a severe form of covid- with pneumonia (curb- score of ), and two patients showed mild symptoms. fourteen out of asymptomatic but positively tested patients received chemotherapy or chemo-immunotherapy according to their regular therapy algorithm (+/- weeks of sars-cov- test), and of ( . %) positive tested patients received glucocorticoids as co-medication. none of the asymptomatic p current symptom-based risk scores for stable coronary artery disease evaluation are not applicable in copd patients background: cardiovascular diseases are arguably the most important comorbidity in patients with chronic obstructive pulmonary disease (copd). despite an increased prevalence of coronary artery disease (cad) in copd patients, there are no dedicated diagnostic recommendations. we investigated whether copd patients receive adequate primary evaluation of cad despite overlapping symptoms. methods: patients with copd, who underwent invasive coronary angiography (ica), were retrospectively matched (for age, bmi and cardiovascular risk factors) with patients without functional lung diseases. quality and onset of symptoms prior to ica were documented and individual patients' pre-test probabilities according to esc guidelines were calculated. endpoints were delay of ica referral after symptom onset and clinical outcome, defined as subsequent revascularization. results: mean delay between symptom onset and ica was . ± . months in copd patients compared to . ± . months in the control group (p < . ). copd patients had a lower rate of typical chest pain ( . % vs. . %, p = . ), and dyspnoea only ( . % vs. . %, p = . ). sub-analysis of gold grades revealed an incremental delay with increasing copd severity: gold : . ± . months; gold : . ± . months; gold : . ± . months and gold : . ± . months. furthermore, the revascularization rate increased with higher pre-test probability for the control group, but not for patients with copd gold - . abstracts background: chronic thromboembolic pulmonary hypertension (cteph) is characterized by severe pulmonary artery hypertension and presence of sleep-disordered breathing (sdb) with associated hypoxemia which could further contribute to the severity of hypertension adversely affecting the outcome. limited data are available on the prevalence of sdb in cteph and so far, the effect of balloon pulmonary angioplasty (bpa) on sdb has not been evaluated. we hypothesized that subjects with cteph have a high prevalence of sdb, both obstructive and central sleep apnea with associated hypoxemia, which could improve with bpa. methods: consecutive patients with cteph underwent treatment-naïve and post-bpa polygraphy (nasal-pressure-sensor, thermistor, thoracoabdominal-excursion-sensors, pulse oximeter; alice pdx, philipps®) and hemodynamic and echocardiographic assessments. results: before bpa, prevalence of sdb (defined as an apnea-hypopnea index (ahi) > per hour) was %: patients infected patients showed unexpected complications due to the sars-cov- infection during the cancer treatment. conclusions: these data clearly contrast the view that patients with an oncologic disease are particularly vulnerable to sars-cov- and suggest that compromising therapies could be continued or started despite the ongoing pandemic. moreover, the relatively low appearance of symptoms due to covid- among patients on chemotherapy and other immunosuppressive co-medication like glucocorticoids indicate that suppressing the response capacity of the immune system reduces disease severity. background: for the further crisis management of the corona pandemic and the socio-economic impact on society, a strategy that allows selective isolation measures is particularly important. so far, it has been assumed that patients suffering from covid- develop antibodies that provide immunity and are thus protected from a reinfection with sars-cov- . this also forms the basis of the assumption that rapid vaccine development will lead to rapid control of the pandemic. in the present study, we analyzed the antibody development of oncology patients days after positive rt-qpcr testing for sars cov . methods: rt-qpcr and anti-sars-cov -antibody methods from bgi (mgieasy magnetic beads virus dna/rna extraction kit) and roche (elecsys anti-sars-cov- immunoassay) were used, respectively, according to the manufacturers' specifications. results: surprisingly, in only of individuals with a confirmed history of covid- antibody development was detected. despite of multiple testing, these patients did not develop antibodies in subsequent tests. conclusions: first analyses indicate that patients may benefit from inpatient pr after hospitalization due to covid- . symptoms of dyspnea, cough, depression, and anxiety decreased significantly over the course of the pr, whereas quality of life significantly increased. pr could therefore play an important role in dealing with the pandemic. follow-up assessments three and six months after the pr are currently ongoing. background: fatigue is among the most common symptoms in covid- patients and about % still suffer from persistent fatigue months later [ ] . some studies discuss a possible link to obstructive sleep apnea syndrome (osas) [ ] , however, no studies have been published in covid- patients after discharge. therefore, we examined covid- patients for the presence of osas within weeks after acute hospital discharge during inpatient pulmonary rehabilitation. methods: from may until july we screened all eligible covid- patients for osas using polygraphy. if the screening revealed an apnea-hypopnea index (ahi) of ≥ , further diagnostics using polysomnography were conducted. furthermore, we assessed the sleepiness using the epworth sleepiness scale (ess) and the body-mass-index (bmi). results: patients were eligible for the study, of which were willing to participate. mean age was . (range: - ), % were female, and mean bmi was . (range: . - . ). only four patients had an ahi < , whereas eleven fulfilled the criteria for an at least moderately severe osas (ahi ≥ ). the ahi was significantly correlated with the bmi (r = . , p < . ) but not with the ess (r = - . , p = . ). a positive airway pressure therapy was indicated in eight patients ( %); five agreed to the therapy ( %). conclusions: according to our data, rates of osas are extraordinarily high in patients after hospitalization due to covid- . this could be an explanation for frequently mentioned symptoms of tiredness and attention deficit. yet, further studies are needed to examine a possible causal association and correlations to other common symptoms, such as cognitive impairment or sleep disturbances. ( %) without sdb, ( %) with predominantly obstructive sleep apnea (osa; ahi = ), and ( %) with predominantly central sleep apnea (csa; ahi = ). osa was associated with male-gender, obesity and overnight fluid-shifts, whereas csa with worse right ventricular end-diastolic diameter. patients with sdb had significantly higher oxygen-desaturation index (odi) and tendency for worse desaturation than those without sdb. after bpa, mean ahi and odi decreased by % (p = . ) and % (p = . ). in osa patients, ahi decreased from to (p = . ) and in csa patients from to (p = . ). along with improvement in sdb, nocturnal desaturation decreased (time-below- % from % to % of time-in-bed, p = . ). conclusions: this is the first study of the effects of bpa on sdb in cteph. we found high prevalence of sdb, both osa and csa, in consecutive subjects underdoing bpa, and report that bpa significantly improved sleep-disordered breathing and nocturnal desaturations. future randomized controlled trials are needed to determine if effective treatment of sdb improves central hemodynamics, morbidity and mortality of patients with cteph. pulmonary rehabilitation following covid- -first short-term results regarding symptoms, quality of life, and psychological burden of disease background: even though many studies have been published on covid- within the last months, little is known about the results of pulmonary rehabilitation (pr) following a severe infection. therefore, the current study examines the changes of wellbeing through inpatient pr after covid- . methods: we surveyed patients at the beginning (t ) and the end (t ) of inpatient pr following hospitalization due to covid- . we assessed respiratory symptoms (dyspnea, cough, and phlegm expectoration) and pain with symptom rating scales, fatigue with the brief fatigue inventory (bfi), quality of life with the euroqol-questionnaire (eq- d-sl), and symptoms of depression and anxiety with the patient health questionnaire (phq-d). results: from the beginning of may until the end of june , patients were eligible, of which patients could be included in the study and completed all t and t assessments (mean age: . ; . % female; . % after invasive ventilation). at t the participants were heavily burdened and dyspnea on exertion was by far the most common and burdensome impairment. over the course of the pr (mean treatment duration: days; range: - days), the data revealed improvements in all mentioned outcomes. dependent samples t-tests revealed statistical significance in all variables, except for pain (p = . ) and phlegm expectoration (p = . ). effect sizes ranged from small (d = . , p < . for dyspnea at rest) to large abstracts background: patients with repaired congenital diaphragmatic hernia (cdh) often suffer from obstructive airway disease. nitrogen multiple breath washout (n -mbw) is a sensitive method to detect ventilation inhomogeneity and peripheral airway pathology with higher sensitivity than conventional spirometry. we set out to obtain detailed information about peripheral airway pathology by n -mbw in addition to conventional lung function testing. methods: we prospectively compared school-aged children following cdh repair and healthy controls using spirometry, body plethysmography and n -mbw. group analyses were made using t-test and mann-whitney-u test, as appropriate. matching criteria included age, gender and level of physical activity. results: (median [iqr] age [ - ] years, f:m = : ) former patients and matched healthy controls ( [ - ] years, f:m = : ) were included. mean lung clearance index (lci) was highly similar in both groups ( . vs. . ; p = . ). slope of conducting airways (scond) was significantly higher ( . vs. . ; p = . ) in cdh patients. fev ( vs. %pred; p = . ), mef ( vs. %pred; p = . ), mef ( vs. %pred; p = . ) and fef - ( vs. %pred; p = . ) were significantly lower in cdh patients. rv ( vs. %pred; p = . ), rv/tlc ratio ( vs. %pred; p = . ) and airway resistance (reff ) ( vs. %pred; p = . ) were significantly higher in cdh patients, whereas there was no significant difference in tlc ( vs. %pred; p = . ) and fvc ( vs. %pred; p = . ). three cdh patients had lci and eight scond values above the upper limit of normal (healthy controls: two and three, respectively). according to conventional lung function testing, / former patients showed an obstructive, none a restrictive pattern and six had normal lung function. fev % correlated significantly positively with mef %, mef % and fef - % and negatively with rv/tlc ratio. conclusions: we found significant airway obstruction in both central and peripheral airways and hyperinflation in patients with congenital diaphragmatic hernia compared to healthy controls. central sleep apnea in pacing-induced cardiomyopathy background: sleep disordered breathing, in particular central sleep apnea (csa) is common in heart failure patients, but its role in pacing induced cardiomyopathy has not been studied yet. in this study entitled upgrade, we set out to evaluate the effect on sleep architecture and sleep disordered breathing in picm patients receiving biventricular pacing. methods: presence of csa was assessed by single-night polysomnography (psg) in picm patients within one month after left ventricular lead implantation (with biventricular stimulation still not activated). csa was diagnosed in half of patients (n = ). patients with moderate or severe csa were randomized to cardiac resynchronisation therapy (crt) versus right ventricular pacing (rvp) in a double-blinded cross-over design and re-scheduled for a follow up psg - months, after repeated assessment of sleep and crossing-over another psg was conducted - months later. results: crt led to a significant increase in left ventricular ejection fraction and significant reduction in left ventricular end systolic volumes and n-terminal pro brain natriuretic peptide plasma levels, whereas no significant effect was observed with ongoing rvp. csa was significantly improved after . ( . - . ) months of crt: apnea hypopnea index (ahi) decreased from . ( . - . ) events per hour at baseline to . /h ( . - . ) by crt (p < . ). central apnea index decreased from . /h ( . - . ) at baseline to . /h ( . - . ) after crt activation (p < . ). ongoing rvp yielded only a minor improvement in ahi and central apnea index. pre-existent csa did not affect structural response rate and had no impact on mid-term follow up (median . years). conclusions: csa is highly prevalent in patients with picm. crt upgrading significantly improves csa leading to a similar outcome in picm patients without pre-existent csa. upgrade is an investigator-initiated independent clinical trial, supported by the Önb jubiläumsfondsprojekt nr. . this study was further supported by an unlimited scientific grant from the boston scientific investigator sponsored research , named severe acute respiratory syndrome coronavirus (sars-cov- ), was observed in wuhan (china) for the first time and subsequently spread rapidly across the globe. the lung is the virus' primary target organ, but many other organs are affected, too. in consequence, therapy focuses on both, pulmonary and systemic symptoms. at present, there is no established pharmacological treatment for covid- available, however, many studies are currently on their way. treatment is based on local (i. e. inhalation) and systemic therapy, often in ventilated patients. prerequisites for inhalation therapy are measures to prevent infection of health care personnel, use of adequate systems for drug administration and compounds suitable for pulmonary delivery. we reviewed publications on covid- treatment for strategies for save inhalation therapy of ventilated/non-ventilated patients and compounds used in clinical studies. strategies for inhalation administration differ in respect of disease severity and use of personnel protective equipment is essential. in mild-disease patients, asthma/copd treatment is preferred by pmdis/dpis, if necessary. jet/mesh nebulizers can be used with mouth pieces/nasal cannulas (no face masks to avoid aerosol spread) and one-way filters/valves. in ventilated patients, mesh nebulizers with filters should be used. physical therapy/suctioning should not be combined with aerosol therapy (avoidance aerosol spread). numerous compounds/biomolecules are under study for inhalation treatment of covid- , e. g. interferons (with/without systemic administration of antivirals, such as ribavirin, lopinavir, ritonavir), sargramostim (gm-csf), aviptadil (synthetic vasoactive intestinal polypeptide), das (recombinant sialidase), pul (immunostimulant, tlr / / agonist), budesonide, nitrogen oxide and hydrogen. in summary, inhalation therapy is important for treatment of pulmonary symptoms of covid- . strategies for pulmonary drug delivery differ in respect to disease severity (e. g. mild symptom patients vs. ventilated patients). various pharmacological compounds/biomolecules are under study. however, up to now there is no established inhalation treatment of covid- . ual basis. recent studies show that hs can improve health even in cf babies. methods: the surveys provide information about acceptance, reason and frequency of - % hs application using a jet or vibrating membrane nebuliser (vmn; eflow®rapid) in children ≤ years. the online questionnaires address healthcare professionals in paediatric cf centres in the uk and german speaking countries (dach). in the uk and in dach paediatric cf centres participated in the survey. from both regions, a total of healthcare professionals responsible for almost cf children ≤ years of age responded. results: secretolysis by hs in children ≤ y is rated excellent, very good, or good by . % in uk and by % in dach. the tolerability is reported excellent to good by . % (uk)/ % (dach). in both surveys approx. % of caregivers declare to use vmn in cf patients ≤ y and less than % in infants ≤ y. caregivers satisfaction regarding the ease of inhalation with vmn in infants ≤ y is rated excellent to good by . % (uk)/ % (dach) and in the group - y by % (uk and dach). conclusions: the results of the survey reveal that in children ≤ years nebulized hs for secretolytic therapy is general practice and well tolerated by this age group. they are consistent with the latest recommendations in the official cf guidelines for children, which confirm the benefits of using hs. in addition, the data also reflect the trend in the uk, where the annual report of the uk cf registry refers that the use of hs in young children is increasing every year. expression patterns of heat shock protein in patients with thymic epithelial tumors regarding the world health organization classification background: thymic epithelial tumors (tets) are rare malignancies with unique association to the paraneoplastic syndrome myasthenia gravis (mg). heat shock protein (hsp ) harbour great potential as cancer biomarker and hsp inhibitors approach clinical cancer therapy. methods: to investigate hsp tissue expression patterns, we analysed tumor tissues of completely resected tet patients (n = ; thymomas and thymic carcinomas (tcs)), regular thymic tissue of six mg patients, and four patients without mg, background: pulmonary hemodynamics during exercise may help to identify early pulmonary vascular disease in systemic sclerosis (ssc). whether they are of prognostic relevance in this subset of patients is unknown. we tested the association between pulmonary heamodynamics at rest and peak exercise with all-cause mortality in patients with ssc. methods: all ssc patients with resting mpap < mm hg and at least -year follow-up data who underwent symptomlimited exercise right heart catheterization between april and december , were analyzed. age-adjusted cox-regression analyses were performed to assess the association between pulmonary hemodynamics and mortality. ]) turned out as age-independent predictors of mortality. in contrast, resting pulmonary hemodynamics (mpap, pulmonary arterial wedge pressure, co, pvr and tpr) were not associated with age-adjusted mortality. conclusions: in this study assessing the prognostic relevance of pulmonary exercise hemodynamics in patients with systemic sclerosis, pvr and tpr at peak exercise as well as mpap/co-slope and tpg/co-slope turned out as age-independent predictors of all-cause mortality. clinical survey with hypertonic saline ( - %) and the eflow®rapid in cf children below years of age mnt: % a: % ab: % b : . % and b : . b : % tc: . %). we detected hsp expression in centroblasts, but not centrocytes, of germinal centres in % of mg patients with fth. all lymphoid follicles of myasthenic patients expressed hsp protein. hassall's corpuscles showed no hsp expression in every tissue sample. we did not detect thymic hsp expression in four patients with regular thymic morphology or five patients with tth. conclusions: hsp expression data propose high potential for hsp as an additional immunohistochemical marker for mnt, who-b thymoma, and tc or as a possible candidate molecule for targeted therapy. caution is warranted in tet patients with mg overexpressing hsp . later-line treatment with lorlatinib in alkand ros -rearrangement-positive nsclc: a retrospective, multicenter analysis background: anti-fibrotic medication is effective in progressive fibrosing interstitial lung diseases (ild), but a subgroup of fibrotic ild patients also benefits from immunomodulatory therapies. additional to high-resolution computed tomography (hrct), blood and broncho-alveolar lavage (bal) biomarkers could help to identify such phenotypes. methods: hrct of subsequent single-center ildboard patients (mean age (standard deviation ) years, % male), were evaluated for radiological findings considered noninflammatory (reticulation including honeycombing (ret), traction bronchiectasis (tbr), emphysema (emp)) or active inflammatory (consolidations (con), ground glass opacities (ggo), noduli (ndl), mosaic attenuation (mos)) in distinct lung regions. each resulting score was further graded as minimal ( - regions involved), medium ( - ) and extensive ( - ). associations between blood and bal biomarkers and radiological finding scores were evaluated using spearman correlation coefficients, kruskal-wallis tests were used for significance testing between the graded subgroups. results: blood neutrophil, lymphocyte and eosinophil fraction, neutrophil-lymphocyte ratio (nlr) and bal lymphocyte fraction consistently showed opposite correlations for inflammatory versus non-inflammatory hrct finding scores. blood lymphocyte fraction significantly differed by the graded extent of ggo (p = . ) and con (p = . ), eosinophil count by tbr (p = . ) and nlr by con (p = . ). c-reactive protein significantly related to ggo (p = . ) and con (p = . ), while ldh showed multiple significant positive associations with ret (p = . ), tbr (p < . ), ggo (p = . ) and mos (p = . ). in bal fluid, lymphocyte fraction had a significant interaction with ggo (p = . ). conclusions: biomarkers from peripheral blood and bal may have the potential to differentiate predominantly noninflammatory or fibrotic from active inflammatory radiological ild patterns. the german severe asthma registry: obesity is associated with asthma parameters abstracts (sgrq-c) was used. furthermore, we asked, independent from each other, the patient as well as the treating physician to estimate the global health status of the patient (excellent, good, fair, poor, very poor). inclusion criteria were a physician's diagnosis of copd and age ≥ years. subjects with a history of lung surgery, lung cancer or copd exacerbation within the last four weeks were excluded. results: pulmonologists and general practitioners participated and enrolled , copd patients. of those patients did not fulfill the gold criteria for copd (fev / fvc ≥ . ) and were excluded due to missing data. finally, patients ( . % men; mean age . ± . (se) years; mean fev %pred. . ± . (se)) were analyzed. in . % of study participants, patients and physicians disagreed on the global health status. in . % it was estimated better by the physician than by the patient (overrated patients), and in . % it was underrated. multivariate regression analysis indicated that overrated patients had a statistically significant better lung function (fev ), less exacerbations and a lower total sgrq-c score compared to underrated patients. conclusions: in stable copd outpatients, treated by pulmonologists and general practitioners, the global health status, most likely indicating the burden of copd, tends to be overestimated by physicians in patients with milder airway obstruction and less exacerbations and underestimated in patients with more severe airway obstruction and frequent exacerbations. this discordant perception of global health might severely affect treatment options. lowering of mean pulmonary artery pressure is a prognostic marker in pulmonary hypertension background: treprostinil (tre), a prostacyclin analog, is effective for the treatment of pulmonary arterial hypertension and non-operable chronic thromboembolic pulmonary hypertension (cteph). we hypothesized that a greater change of hemodynamics is of prognostic value. therefore, we evaluated effects of first-line subcutaneous (sc) tre in patients with severe pulmonary hypertension (ph) and analyzed the prognostic value of hemodynamic response at year on treatment. methods: data was prospectively collected from patients with pre-capillary ph in who functional class iii or iv, mean right atrial pressure of mm hg, and/or cardiac index ≤ . liters/min/m . patients received first-line sctre. dose adjustments were performed individually according to clinical symptoms and side effects. results: between and patients were treated with first-line sctre. all patients were classified as non-lowrisk at baseline ( mwd > , who functional class i or ii, right atrial pressure < mm hg and cardiac index ≥ . l/min/m ). ( %) patients underwent double lung transplantation, and ( . %) died of any cause. overall survival rates at , , , and years were %, %, % and %. the strongest predictor of outcome was change in mpap after one year of sctre. change in mpap - . ± . mm hg (p = . ) was associated with the best subsequent survival of . ± . years. obesity is a risk factor for asthma severity. this study aims to evaluate associations of obesity with severe asthma parameters in the german severe asthma registry including patients ( ± yrs, % female, bmi ± kg/m², % obese (bmi ≥ kg/m²)), treated with anti-ige-and with anti-il (r) antibodies. the same proportion of obese patients received biologics as non-obese patients, but obese patients were more frequently on lama therapy ( % vs. % p = . ), had more exacerbations ( . ± /y vs. . ± /y, p = . ), worse quality of life and more often uncontrolled asthma ( % vs. %, p < . ), as reflected by worse acq ( . ± . vs. . ± . ), act ( ± vs. ± ) and maqlq scores ( . ± . vs. . ± . ; all p < . ). obesity was associated with less blood eosinophils ( % vs. %, p < . ), more neutrophils ( . ± . g/l vs. . ± . g/l, p = . ) and lower lung function parameters: fev ( . ± . l vs. ± . l, p = . ) and fvc ( . ± l vs. . ± l, p < . ). non-obese patients were more often non-smokers ( % in non-obese vs. % in obese, p < . ). conclusions: in our severe asthma cohort, obesity represents a specific phenotype of severe asthma that is significantly associated with exacerbations, worse quality of life, lower blood eosinophil numbers, as well as lower fev , and fvc. discordant perception of global health between copd outpatients and their physicians -real world data from the clara project of pulmonary exercise hemodynamics with all-cause mortality in patients with normal or mildly elevated pulmonary arterial pressure (pap) at rest. methods: patients with unexplained dyspnea and/or suspected pvd undergoing exercise right heart catheter (rhc) at our ph-clinic were retrospectively analysed. exercise rhc was performed in case of a resting mpap < mm hg. in a first step, dichotomized resting-, submaximal-and maximal exercise hemodynamic variables were analysed using multivariate cox regression, adjusted for sex and age, to identify prognostic cut-offs. best cut-off for each variable was defined as the cut-off score with the smallest p-value. in a second step, the relevance of cut-offs, derived from the first model, was assessed using a multivariate model also accounting for age, sex, cardiopulmonary comorbidities, smoking history, and pulmonary resting hemodynamics. results: patients were included ( % female, age: ± yr, mpap: ± mm hg). median observational-time was . yr (iqr: . - . ) with n = ( %) mortality events. mpap/ cardiac ouput (co)-slope, transpulmonary gradient (tpg)/coslope and pulmonary arterial wedge pressure (pawp)/co-slope turned out as sex and age independent predictors of mortality. best cut-offs were found at . mm hg/l/min (mpap/coslope), . mm hg/l/min (tpg/co-slope) and . mm hg/l/ min (pawp/co-slope). in the second model, correcting for age, sex, cardiopulmonary comorbidities, smoking history and pulmonary resting hemodynamics, mpap/co-slope (hr: . , %ci: . - . ; p = . ), tpg/co-slope (hr: . , %ci: . - . ; p = . ) and pawp/co-slope (hr: . , %ci: . - . ; p = . ) remained significant predictors of allcause mortality. conclusions: in patients with normal or mildly elevated pap at rest, pulmonary pressure/co-slopes are predictors of allcause mortality, independent from age, sex, cardiopulmonary comorbidities and resting pulmonary hemodynamics. of the annual average of insured patients . to . % claimed an ao medication. distribution of the age groups - , - , - and > years was . , . , . and . %, respectively. based on diagnoses (hospital and sick leave data), age (< years) and drug patterns an asthma cohort was selected ( % of patients with ao). annual relative prevalence of selected drug groups is presented in fig. . from to the reduction in reliever drugs is associated with an increase in controller medication, in particular, combinations of inhaled corticosteroids (ics) and formoterol (f). subgroup analyses show that this pattern is consistent in differently defined asthma cohorts, not present in a copd cohort and more marked in asthma patients seen by a respiratory specialist. two large studies on the single inhaler treatment (sit) concept were presented and in sit was introduced in the gina report. conclusions: change in asthma treatment recommendation was effectively translated into practice in burgenland. pulmonary pressure/flow slopes during exercise as independent predictors of mortality in patients at risk for pulmonary hypertension philipp douschan* , , vasile foris , , alexander avian , teresa sassmann , , horst olschewski , , gabor kovacs , background: patients with early pulmonary vascular disease (pvd) typically show an abnormal hemodynamic response to exercise. however, it is unknown whether pulmonary exercise hemodynamics are of prognostic relevance in patients with early pvd, independent from pulmonary resting hemodynamics. the aim of this study was to assess the association fig. | p abstracts of extrafine beclomethasone-dipropionate, formoterol-fumarate and glycopyrronium (bdp/ff/ g, trimbow® / / µg) in patients with copd. methods: a prospective, multicenter nis was conducted over weeks in pulmonary and general practices in austria in / . eligible patients with copd had an indication for treatment with bdp/ff/g according to the summary of product characteristics. in addition to tolerability, lung function, exacerbation rate, symptom scores and copd assessment test (cat) were recorded. results: patients (male %, mean age years) with moderate to very severe airflow limitation (gold grade - : . %) and persistent symptoms (gold b: . %, gold d: %) according to the gold report were included. by end of weeks, lung function parameters (fev , fev %, and fvc; p < . ) and symptoms (cough, sputum and shortness of breath; p < . ) improved significantly compared to baseline. a clinically-relevant improvement from baseline in cat score was observed at week and persisted at week in gold b (from . to . points; p < . ) and gold d (from . to . points; p < . ) patients. a significant reduction of moderate and severe exacerbations over the study period was also observed ( . % and . % respectively; p < . ). by end of weeks, . % continued on the treatment. there were adverse reactions reported, of which were non-serious (e. g. oral mycosis) and five were serious, but none of which were deemed drug-related. conclusions: results of this study support the tolerability and effectiveness of bdp/ff/g in patients with copd in a realworld setting. patients treated with extrafine bdp/ff/g experienced an improvement in lung function, symptom control and reduction in exacerbations. tests for diagnostics of covid- -principles and approvals of commercially available tests rüdiger siekmeier* , tanja grammer , winfried märz , , in december an unknown viral infection was firstly described in a local fish and wild animal market in wuhan/ china which was identified as a novel coronavirus infection by the chinese center for disease control and prevention (ccdc) on jan. th and announced as -new coronavirus disease ( -ncov, now covid- ) by the world health organization (who) on feb. th . rapidly spreading across the globe up to begin of august at least million of infections and deaths were reported worldwide. therefore, there was an urgent need of laboratory tests. in our analysis we looked for commercially available covid- tests. at july th at least commercially available tests were described (https:// www. dx.com/coronavirus-test-tracker-launched-covid- -tests). of these, are based on pcr methods (mostly pcr, qpcr) (with federal drug agency (fda; very most) or center of disease control (cdc; few) emergency use authorization background: patients with acute exacerbations of copd do not only suffer from physical symptoms but also from psychological distress and stress. as pharmacological interventions showed only limited effectiveness in targeting the latter, a need for alternative treatment options emerges. in other chronic conditions, mindfulness interventions are effective in reducing psychological distress and stress. however, research on mindfulness interventions in copd is still scarce and not focusing on exacerbations. therefore, the present study reviewed the existing literature and explored the acceptability, feasibility, and implementation of mindfulness interventions focusing on exacerbations in copd patients. methods: firstly, literature examining mindfulness interventions in copd patients was reviewed. secondly, a qualitative and explorative study using semi-structured interviews was conducted. the sample consisted of copd patients ( % women; m = . years, sd = . ) hospitalised after an acute exacerbation. data were analysed using thematic analysis. results: the literature review yielded eight studies, providing preliminary evidence for the feasibility and effectiveness of mindfulness interventions in copd patients. the qualitative analysis revealed five main findings: ( ) patients express an openness and need for new treatment approaches. ( ) mindfulness is difficult to differentiate from other mind-body concepts. ( ) implementation conditions are crucial for patient's interest. ( ) limitations of the application of interventions must be considered. ( ) not interested patients differ from interested ones. conclusions: hospitalized copd patients showed a strong interest in new treatment approaches like mindfulness interventions. focusing on mindfulness interventions during exacerbations seem acceptable and feasible. future studies investigating those are needed and should consider implementation conditions, patients' needs and physical limitations. background: systemic sclerosis is a chronic autoimmune disease characterized by inflammation and tissue remodelling. increases in the expression and of the ap- transcription factor fra- has been shown in the skin of these patients. in mice ectopic overexpression of fra- leads to a systemic sclerosis phenotype, strongly affecting the skin and lung. fra- transgenic mice show pronounced pulmonary inflammation, vascular remodelling and lung fibrosis. although, the role of several immune cells such as macrophages, b and t lymphocytes has been investigated, the contribution of innate lymphoid cells (ilc) to disease pathogenesis remains elusive. the focus of this study was to determine the development and function of ilc and their role in scleroderma. methods: multi-colour flow cytometry was used to evaluate the inflammatory cell landscape in fra- transgenic mice in a time dependent manner. primary cells were isolated and functional assays e. g. apoptosis (caspase activation) and proliferation (ki staining and cell counts) were performed in vitro. results: pronounced changes in the inflammatory profile of the lung were observed in a time dependent manner, with increased numbers of t cells and eosinophils and reduced ilc. similar changes were also reflected in the blood, spleen and liver. isolated ilc exhibited decreased proliferation and functional activity. importantly, reduced numbers and function of ilc was already observed before the first signs of lung fibrosis, as assessed by collagen deposition and lung function measurements. conclusions: this early dysregulation suggests that ilc play an important role in the development of lung fibrosis in scleroderma and restoration of ilc could prevent the progression of the disease. (eua)/with ce-mark/with eua and ce-mark: ( pending)/ / ) serving as gold standard for virus diagnostics after sampling of nasal/throat swabs in acute infection or other molecular methods (isothermal amplification ( / / ), crispr ( / / ), sequencing ( / / ) and others ( / / ). more tests ( / / ) are based on immunological antigen detection of virus peptides after sampling of nasal/throat swabs in acute infection which are typically poct tests based e. g. on immunofluorescence-based lateral flow technology or chromatographic digital immunoassay providing results in a few minutes. tests ( ( pending, revoked)/ / ) allow measurement of immunoglobulines igm, iga and igg alone/in combination in blood samples and provide information on the immune status after convalescence. analytical principles of these are different and some (e. g. lateral flow assays) serve for rapid diagnostics. in summary, number and quality of tests rapidly increased. recent development is based on regulatory guidelines (e. g. https://www.gov.uk/government/publications/how-testsand-testing-kits-for-coronavirus-covid- -work) and includes also combined tests for discrimination against other diseases (e. g. influenza). serum tumor maker dynamics as predictive biomarkers in nsclc chemo-immunotherapy and mono-immunotherapy maintenance -a retrospective cohort study department of pulmonology, johannes kepler university linz, linz, austria objectives: to evaluate serum tumor markers (stm) as biomarkers for treatment, monitoring and prognosis in advanced non-small cell lung cancer (nsclc) treated with chemoimmunotherapy. methods: patients having received platinum-based doublet chemotherapy (cht) and pd- /pd-l -directed immune checkpoint inhibitor (ici) combination therapy were retrospectively followed. carcinoembryonic antigen (cea), carbohydrate antigen - (ca - ), cytokeratin- fragments (cyfra - ) and neuron specific enolase (nse) were routinely measured at nsclc diagnosis. the marker with the highest relative elevation was defined "leading stm", its change was assessed between cht-ici initiation as well as first mono-ici maintenance therapy and the respective subsequent restaging. corresponding computed tomography (ct) evaluations were analyzed according to response evaluation criteria in solid tumors (recist). for both cht-ici and ici-maintenance phase, stm and recist response were evaluated regarding progression-free (pfs) and overall survival (os) in kaplan-meier analyses. results: among cht-ici patients ( % women, mean age years), median pfs was months (m; , ) and median os was m ( ,/). pfs was significantly (p = . ) longer, when stm concomitantly decreased ( m ( , ; n = )) vs. m ( , ; n = ). in the ( . %) patients who received mono-ici maintenance, stm decrease was associated with significantly (p < . ) longer pfs ( m ( ,/; n = ) vs. . m ( , ; n = )). median os was not reached in most subgroups in both treatment phases. patients with radiologically stable or progressive disease and concomitant stm decrease vs. increase had similar pfs in the cht-ici setting ( m ( , ; n = ) vs. . ( , ; n = )), but longer pfs in the mono-ici maintenance setting ( m ( , ; n = ) vs. m ( , ; n = )). employing a retrospective approach, we collected and analyzed data of all patients with advanced non-small-cell lung cancer who received ici monotherapy with atezolizumab, nivolumab or pembrolizumab at the kepler university hospital linz between may and december . kaplan-meier analyses were used to evaluate pfs and os. uni-and multivariate cox-regression analyses were calculated to show the impact of influencing variables. results: of patients, persons died ( . %). regarding to the male patients, died ( . %). for female patients it was out of ( . %). kaplan-meier analyses showed no significant difference for pfs (median length , months, p = . ) or os (median length months, p = . ) between men and women. with regards to gender related predictors of outcome like pd-l expression or ecog-score, we observed considerable differences: pd-l expression could be shown a significant predictor for pfs and ecog status predicted os in men. however, we could not verify any significant predictors for female patients. conclusions: in our retrospective research covering participants, we could not verify the higher chance of survival among male patients, frequently mentioned in previous studies. the finding that we could not verify any significant predictors for female patients shows the necessity for further research in that field especially in women. background: endothelial cells (ec) represent a key cell type in the homeostatic regulation of vascular and lung function, including vasoreactivity, coagulation, immune processes and barrier function. disturbances in ec function have been associated with development and progression of pulmonary hypertension, both in its idiopathic form or associated with interstitial lung disease. however, it is not clear whether these functional changes are associated with altered ec composition. methods: we performed single cell rna sequencing on pulmonary arteries isolated from donors and pulmonary hypertension patients. bioinformatics analysis was conducted to gain unbiased insight into ec heterogeneity at the single cell level. multiplex immunofluorescence staining was combined with confocal imaging of lung tissue samples to assess the spatial heterogeneity of pulmonary artery ec. results: our data revealed that ec in adult human pulmonary arteries are composed of three major populations. each population was characterized by enrichment in a specific set of biological processes determining their distinct functional roles. background: systemic sclerosis (ssc) is an autoimmune disorder leading to fibrosis of skin and other internal organs. one ssc hallmark is severe vasculopathy with impaired vascular permeability and tone as an early disease manifestation. pulmonary complications are the main cause of mortality in patients, but treatment options are still limited. pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis (ipf), however its effectiveness in ssc-pf is still unknown. here, we investigated the effectiveness of pirfenidone in a preclinical ssc-pf model, the fra- transgenic (tg) mouse. methods: fra- tg and wild-type (wt) control mice received either standard or pirfenidone supplemented diet. pulmonary function testing, fibrosis quantification, inflammatory cell profiling of bronchoalveolar lavage (bal) and lung tissue as well as transcriptome analysis of lung homogenates was performed. using in vitro electric cell impedance sensing measurements pirfenidone effects on endothelial cell permeability were analysed. results: compared to wt mice, tg mice had decreased lung function and elevated levels of inflammatory cells in bal and lung. pirfenidone exacerbated this phenotype further by increasing collagen deposition and worsening lung function. these functional and structural changes were associated with significantly higher lung tissue and bal inflammation, characterized by predominant eosinophilic infiltration in pirfenidone-treated tg mice. of note, pirfenidone did not alter lung function, collagen deposition or inflammation in wt mice. transcriptomic profiling indicated the activation of inflammatory cell recruitment and extravasation pathways with significant downregulation of the endothelial cell barrier protein ve-cadherin. further, pirfenidone led to decreased resistance of pulmonary microvascular endothelial cell monolayers in vitro. conclusions: pirfenidone was associated with significant deterioration of lung function and elevated inflammatory infiltrates in the lungs of ssc mice. our study shows that this effect might be due to disturbances of endothelial cell integrity upon pirfenidone treatment especially in diseases with a predisposed vasculature such as ssc. background: there is a growing interest in metabolic profiling of pulmonary arterial hypertension (pah) due to current findings suggesting significant metabolic changes causing pulmonary arterial remodeling and linking pah to insulin resistance. such findings may have major impact on future diagnostic and therapeutic strategies for pah. however, most of the studies have enrolled patients with severe disease whose reduced physical activity may have a profound effect on insulin sensitivity. we aimed to directly measure insulin sensitivity in ipah patients by applying the gold standard method botnia-clamp. methods: we assessed insulin sensitivity in five non-diabetic, normal weight patients with severe idiopathic pah and preserved physical activity in comparison to their age-, sex-, and body composition matched non-diabetic healthy controls. for assessing insulin sensitivity, the hyperinsulinemic-euglycemic (botnia) clamp was performed in a simultaneous pairwise matched-control manner. results: in this study we detected no indication of insulin resistance in patients characterized by manifest ipah but no major limitations in their daily physical activity. both ipah and control groups displayed normal efficacy of glycemic control. the botnia clamp measurements showed no differences in insulin response or insulin sensitivity in any of the ipah patients when compared to their healthy controls and also the comparison of the groups showed no significant differences. in ipah, the whole-body glucose disposal capacity in response to insulin infusion showed the same characteristics as in healthy controls. conclusions: this study does not support insulin resistance to be a primary cause of pulmonary vascular remodeling in ipah. multiplex imaging analysis confirmed in situ relative frequencies of ec populations and revealed their characteristic spatial distribution throughout the pulmonary artery tree. arteries in pulmonary hypertension patients displayed altered composition of ec population characterized by the diminished presence of one cell cluster. conclusions: in this study, we have revealed ec heterogeneity in the human pulmonary arteries at a single cell resolution and uncovered evidence for their distinct functional specification. cellular therapy aimed at restoration of the affected cluster or expression of their key genes could serve as a potential therapeutic option in treatment of pulmonary hypertension. clinical relevance of exercise hemodynamics and right ventricular function in copd patients asthma may have consulted the internet for self-medication advice. methods: on july , we queried google trends for the terms "coronavirus asthma", "-copd", "-hypertension", "-diabetes" and "-cancer", all representing pre-existing conditions constituting a major risk for covid- . when further exploring the health-seeking behavior of patients affected by asthma and/ or copd during the covid- outbreak, we focused on those therapeutic approaches with the highest rsv world-wide and thus comparable. results: we observed highest rsv for "coronavirus asthma" followed by "coronavirus diabetes" and "coronavirus cancer", "coronavirus hypertension" ranked fourth together with "coronavirus copd". paralleling the world-wide covid- outbreak, highest rsv was seen for the topics "salbutamol", "montelukast", "ipratropium bromide", "beclometasone", and "flucticasone propionate", encompassing mainly relievers, followed by inhaled corticosteroids (ics). conclusions: despite other risk factors like hypertension having been largely debated in the media, our analysis revealed highest search volumes for asthma. considering the gina guidelines in which the authors explicitly state that asthma treatment should no longer be based solely on short-acting bronchodilators, our data clearly indicates a fail in reaching asthma patients with respective fundamental changes in therapy. even more alarming is the high search volume for montelukast, since the fda released a boxed warning for montelukast in march because of serious neuropsychiatric side-effects. our findings emphasize the urgent need of spreading guidelines and respective updates in a timely manner more intensively in order to reach the general public-especially in a world with an ongoing, potentially life-threatening pandemic. is there a difference in local disease control between a vats and thoracotomy approach? most studies suggest a similar outcome, but nodal upstaging as a quality parameter is frequently reported to be higher in thoracotomy patients. if more positive lymph nodes are missed by vats, pn in these patients should result in a higher failure rate of local disease control. in this study we analyze the difference of vats to open thoracotomy regarding above mentioned parameters. methods: the institutional database was queried. exclusion criteria were pathologic nodal positive status, metastatic disease, tumour size > cm, adjuvant/neoadjuvant therapy. patients were included. the vats cohort included patients, the thoracotomy cohort patients. results: a vats approach in patients with pathologic n disease did not show a significantly higher rate for local or lymph node recurrence compared to thoracotomy ( . % vs. . %; p = . ). there was no difference in disease-free and overall survival comparing the two groups. comparing the location of recurrence, thoracotomy patients showed a significantly higher rate of metastatic disease ( . % vs. . %; p = . ), beneficial effects of multidisciplinary rehabilitation in post-acute covid- tionnaire related to covid- specific symptoms was filled out by all participants. results: , subjects participated ( , lead participants, , household members). the projected number of cases according to age and sex for vienna is , cases ( . %). the cumulative number of positive tested cases in vienna until may th was , . hence, the projected number is . to . times larger than the observed cases. the relative risk of seropositivity by age was highest for children aged - years [rr . (ci . - . )] and lowest for subjects years and older [rr . (ci . - . )]. half of the infected subjects developed no or mild symptoms. in a multivariate analysis (fig. ) taste and smell disturbances were most strongly related to sars-cov- -specific antibody positivity. the infection probability within households with one confirmed sars-cov- -specific antibody-positive person was %, about times higher than the general ambulatory infection risk. conclusions: prevalence rates in vienna are low ( . %) with the highest seroprevalence in young children and lowest in older (≥ years) inhabitants. taste and smell disturbances are very prevalent in covid- infected persons and can guide clinicians in diagnosis-and decision making of covid- . distribution and prognostic significance of gluconeogenic and glycolytic phenotypes in nonsmall cell lung cancer background: skin prick test (spt) is a minimal invasive diagnostic test, identifying type-i-sensitization, which is associated with symptoms as wheezing, atopic dermatitis and rhinitis. prevalence data vary between countries from . %- . %. data about the prevalence in austria are scarce. moreover, associated factors for positive spt have only been investigated in specific age-(e. g. children or adults only) and subgroups (e.g asthmatics).therefore, our aim was to investigate the prevalence of positive spt in a general austrian population, to define associated factors and compare the prevalence and associated factors between childhood and adulthood. methods: data was obtained from the lead study, an observational, population-based cohort. we included . participants with a valid spt and analyzed two age groups separately: childhood ( - yrs; n = ) and adulthood ( - yrs, n = ). multivariate regression model was used to identify factors associated with positive spt including socioeconomic status, allergic and/or respiratory diseases, lung function, body composition, lifestyle habits, smoking exposure, pet exposure, and family history. results: in our study the overall prevalence of a positive spt is . % and is higher in male compared to female in all age pins (fig. ) . house dust mite and grasses mix are the most prevalent allergens. factors positively associated with positive spt in childhood are doctor's diagnosed allergy or asthma and diagnosed parental allergy; in adulthood are doctor's diagnosed allergy or asthma, diagnosed parental allergy, and high socioeconomic status. smoking (current, former and secondhand) is ally, glycolytic and gluconeogenic gene expression was inferred from the cancer genome atlas (tcga) datasets. results: pck was preferentially expressed in the lung adenocarcinoma subtype, while glut expression was higher in squamous cell carcinoma. glut and pck were inversely correlated, glut showing preferential expression in larger tumors while pck was highest in smaller tumors. however, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. in lung adenocarcinoma, pck expression was associated with significantly improved overall survival compared to glycolytic or mixed tumors, while the opposite was found for glut . pck / expression was enhanced in metastases compared to primary tumors. the metabolic tumor microenvironment and the -dimensional context play an important role in modulating both pathways, since pck expression preferentially occurred at the tumor margin and hypoxia differentially regulated glycolysis and gluconeogenesis in nsclc cells in vitro. conclusions: glycolysis and gluconeogenesis are activated in nsclc in a tumor size and oxygenation dependent manner and show a differential correlation with outcome. the frequent co-activation of gluconeogenesis and glycolysis in nsclc should be considered in potential future therapeutic strategies targeting cancer cell metabolism. abstracts assays showed significantly reduced migration of rgs -/-neutrophils towards chemokines with preserved intra-cellular calcium signaling. importantly, the attenuated neutrophil migration was associated with activated rhoa, suggesting rhoa as a predominant negative regulator of neutrophil transmigration. conclusions: our findings demonstrate the efficacy of silenced rgs for suppressing neutrophilic hyperinflammation in two different animal models. the specific effects of rgs loss might provide an option for a novel therapeutic intervention in inflammatory lung diseases with recurrent exacerbations, without compromising infection defense mechanisms. endothelial dysfunction following enhanced tmem a activity in human pulmonary arteries background: endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (pah). ion channelome changes have long been connected to vascular remodelling in pah, yet only recently the focus shifted towards ca +-activated cl-channels (cacc). the most prominent member of the cacc tmem a has been shown to contribute to the pathogenesis of idiopathic pah (ipah) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (paecs) and in the development of endothelial dysfunction remains underrepresented. methods: using healthy donor (n = ) and ipah (n = ) lungs, we analysed the expression of tmem a in primary human paecs. ipah was mimicked with selective adenoviral overexpression encoding tmem a tagged with mcherry. tmem a activity was investigated by patch clamp. live cell ca + imaging was applied to detect changes in ca + homeostasis. paec proliferation, apoptosis, tube-formation, wound healing assay, no production and measurements of paecs metabolic state addressed functional consequences of increased tmem a activity. the role of endothelial tmem a in the tone of pulmonary arteries ex vivo was investigated by wire myography. results: here we report enhanced tmem a activity in ipah paecs. upon tmem a overexpression in healthy primary human paecs in vitro and in human pulmonary arteries negatively associated with positive spt in adulthood, but not in childhood. conclusions: our study in an austrian general population identified that . positive spt is highly prevalent, . is more prevalent in male, . the main allergens observed are grasses mix and house dust mite, and . there is a difference in factors associated with spt in childhood vs adulthood. neutrophil recruitment in the acute inflammatory phase of interstitial lung disease is determined by rgs methods: data was obtained from the austrian lead study, an observational, population-based cohort study. adults aged - years with valid lf and metabolic data, including waist circumference (wc) for central obesity, and dxa scan for vat (n = . ) were included in this analysis. lf was assessed by spirometry pre-and post-bronchodilation (bd). abnormal lf was defined as fev pre bd<lln (gli) and further divided into obstructive (fev pre<lln + fev /fvc post<lln) and restrictive (fev pre<lln + fev /fvc post≥lln + fvc post<lln) pattern. regression models were performed analysing the association between mets components (idf ) and abnormal, obstructive, and restrictive lf pattern (corrected for age, sex, smoking status). results: fig. shows odds ratios of mets components and vat associated with impaired lf pattern. increased vat was associated with both, obstructive (or . [ . - . ]) and restrictive (or . [ . - . ]) lf pattern, while increased wc was not. conclusions: vat showed a consistent association with lf impairment independent of the type of impairment, in contrast to the different components of the mets. in december an unknown viral infection was firstly described in a local fish/animal market in wuhan/china. it was identified as a novel coronavirus infection by the chinese center for disease control and prevention (ccdc) on jan. th and announced as -new coronavirus disease ( -ncov, now covid- ) by the world health organization (who) on feb. th . the disease rapidly spreads across the globe (begin of august at least million of infections and deaths reported worldwide) and until now no specific treatment has been described. therefore, measures for disease prevention (e. g. vaccines, rapid testing, control of viral transmission by masks/face shields, gloves, digital monitoring/social ex vivo, we demonstrate the functional consequences of the augmented tmem a activity: alterations of ca + dynamics and enos activity as well as decreased no production, paecs proliferation, wound healing, tube-formation and acetylcholine-mediated relaxation of human pulmonary arteries. we propose, that erk / pathway is specifically affected by elevated tmem a activity, leading to these pathological changes. conclusions: with this work we introduce increased tmem a activity in the outer cell membrane of human paecs important for the development of endothelial dysfunction in ipah. metabolic syndrome and visceral adipose tissue (vat) are associated with obstructive and restrictive lung function impairment background: malignant pleural mesothelioma (mpm) is a highly aggressive tumor with dismal outcome and thus, investigating reproducible pretreatment parameters to assess benefit from treatment modalities and to estimate survival is of outmost importance. this study aims to identify potential serum prognostic biomarkers in a large retrospective cohort of a high-volume institution. methods: we performed a retrospective analysis of the clinical records, serum parameters at diagnosis, and longterm outcome of patients with pathologically diagnosed mpm between and . previously published prognostic serum biomarkers were tested and validated and, in consequence, the prognostic value of an inflammatory serum marker score (vmis-vienna mesothelioma inflammation score) was investigated. results: in total, patients ( male, . %) were included. median age was years (iqr - ). median overall survival (os) for all cases was months ( % ci; . - . ). survival was % at year, % at years, and % at years. median os and disease-free survival (dfs) of patients undergoing multimodality treatment including surgery was months ( % ci; . - . ) and months ( % ci; . - . ), respectively. the optimal cut-off values for pretreatment neutrophil-to-lymphocyte ratio (nlr), serum fibrinogen and crp were . , . mg/dl and . mg/dl, respectively. univariate analysis revealed that age (p = . ), ecog status (p = . ), tumor stage (p = . ), histologic subtype (p = . ), type of treatment (p < . ), nlr (p < . ), fibrinogen (p < . ) and crp (p < . ) were significantly associated with os. accordingly, the vmis (consisting of pretreatment nlr, fibrinogen and crp) was highly associated with os (score vs. , hr . , p = . ; score vs , hr . , p < . ). in multivariate analysis, vmis (p = . ), histologic subtype (p = . ), and the type of treatment (p = . ) were independently associated with os. conclusions: vmis was found to be an independent prognostic score in mpm helping to stratify patients into different treatment groups. methods: we performed a retrospective analysis of all inpatients aged < years, who were admitted to our department between january and december for suspected or confirmed tuberculosis (tb) infection, for the presence of otb. results: we were able to identify four paediatric cases with otb (cohort: inpatients, . %) (fig. ) . three patients suffered from posterior ( fig. ) and one from anterior uveitis associated with tb. two patients were diagnosed with pulmonary ultra wide-field fundus photography of the right eye shows two (one at the temporal inferior and one at the nasal superior vessel arcades) yellowish choroidal granulomas with ill-defined borders and substrantial elevation. there seems to be a serous retinal detachment around the granulomas (case # ) abstracts tb after being referred by the ophthalmologist, the remaining showed ocular involvement in the setting of disseminated tb. all patients were treated with systemic corticosteroids and anti-tuberculosis therapy (att). patients received topical steroids additionally, one of whom (case # ) also received steroids intravitreally once for persisting macular oedema. visual acuity remained normal in two patients. conclusions: despite a higher incidence of extrapulmonary tb in the paediatric age group in general ( ), otb was uncommon in our cohort. when disseminated disease is suspected or ocular symptoms are noted in paediatric tb patients, a detailed ophthalmological examination is imperative. lung transplantation for acute respiratory distress syndrome patients: a single center experience background: acute respiratory distress syndrome (ards) is a rapidly progressive lung disease with a high mortality rate. although lung transplantation (ltx) remains the only lifesaving option for certain end-stage pulmonary diseases, ards as indication for ltx is discussed controversially and only limited data are available. for example, in the eurotransplant region, only patients transplanted for ards are documented. since we have followed a liberal approach of accepting ards patients for ltx, we reviewed retrospectively the outcome of this particular patient cohort in our center. methods: from / to / at total of patients transplanted for ards were identified. demographic and clinical data of these patients were collected and analysed. results: eight/ patients were listed and transplanted while on extracorporeal membrane oxygenation (ecmo). the remaining patients could be initially successfully weaned from ecmo but remained respirator dependent. the median mechanical ventilation time and median length of ecmo was . ( . - . ) and . ( - ) days before ltx. primary graft dysfunction (pgd) grades at hrs were % (n = ), two patients were classified as pgd ungradable (due to prophylactically prolonged ecmo). length of icu and hospital stay was ( . - ) and ( . - ) days. the -day mortality was % and -year survival rate was calculated as . % (fig. ) . one patient developed chronic lung allograft dysfunction (clad) and received re-transplantation years after the primary procedure. the median follow up time was ( . - ) days. conclusions: lung transplantation is feasible in carefully selected ards patients. given the lack of alternative treatment options it provides acceptable long-term results. investigating prognosis in malignant pleural mesothelioma: the vienna mesothelioma inflammation score (vmis) including pretreatment neutrophil-to-lymphocyte ratio, fibrinogen, and crp is independently associated with overall survival background: malignant pleural mesothelioma (mpm) is a highly aggressive tumor with dismal outcome and thus, investigating reproducible pretreatment parameters to assess benefit from treatment modalities and to estimate survival is of outmost importance. this study aims to identify potential serum prognostic biomarkers in a large retrospective cohort of a high-volume institution. methods: we performed a retrospective analysis of the clinical records, serum parameters at diagnosis, and longterm outcome of patients with pathologically diagnosed mpm between and . previously published prognostic serum biomarkers were tested and validated and, in consequence, the prognostic value of an inflammatory serum marker score (vmis-vienna mesothelioma inflammation score) was investigated. results: in total, patients ( male, . %) were included. median age was years (iqr - ). median overall survival (os) for all cases was months ( % ci; . - . ). survival was % at year, % at years, and % at years. median os and disease free survival (dfs) of patients undergoing multimodality treatment including surgery was months ( % ci; . - . ) and months ( % ci; . - . ), respectively. the optimal cut-off values for pretreatment neutrophil-to-lymphocyte ratio (nlr), serum fibrinogen and crp were . , . mg/dl and . mg/dl, respectively. univariate analysis revealed that age (p = . ), ecog status (p = . ), tumor stage (p = . ), histologic subtype (p = . ), type of treatment (p < . ), nlr (p < . ), fibrinogen (p < . ) and crp (p < . ) were significantly associated with os. accordingly, the vmis (consisting of pretreatment nlr, fibrinogen and crp) was highly associated with os (score vs. , hr . , fig. | v survival curve from - (n = ) abstracts Ögp p = . ; score vs , hr . , p < . ). in multivariate analysis, vmis (p = . ), histologic subtype (p = . ), and the type of treatment (p = . ) were independently associated with os. conclusions: vmis was found to be an independent prognostic score in mpm helping to stratify patients into different treatment groups. surgical management and risk analysis of primary malignant pulmonary and chest wall sarcomasretrospective results from a high-volume center katharina sinn , berta mosleh , richard hritcu , györgy lang , jose matilla , konrad hoetzenecker , shahrokh taghavi , walter klepetko , thomas klikovits , mir alireza hoda Ögp background: postoperative pain management after videoassisted thoracoscopic surgery (vats) is still a heavily debated topic, which may affect patients' pain, need of opioids, and postoperative length of stay (los). this study aims to analyse the effects of an additional intercostal catheter (icc) in comparison to a single shot intraoperative intercostal nerve block (ssinb) alone. methods: all patients receiving an anatomic vats resection from / - / were analysed. icc placement at our department was initiated in september . patients with misplacement of the icc were analysed in the ssinb group. exclusion criteria for analysis was a prolonged los because of postoperative complications not related to pain-management protocol (one hiatal hernia with oesophageal perforation, one hematologic comorbidity requiring further workup). the icc cohort included patients, the ssinb cohort patients. results: pain scores on the first postoperative day, after chest drain removal and highest pain score measured did not differ between the two groups (p = . / . / . ). in four patients ( . %), icc showed a primary non-function. the overall amount of opioids (piritramide, . mg vs. . mg; p = . ) as well as the duration of opioid usage ( . days vs. . days; p = . ) was significantly less in the icc cohort. the icc cohort showed a significantly shorter postoperative los of . (mean, range - ) days in comparison to . (mean, range - ) days (p = . ). chest drain duration was significantly shorter in the icc cohort ( . days vs. . days; p = . ). there was no difference in comorbidities (coronary artery disease, diabetes mellitus, copd; p = . / . / . ), age, gender or postoperative complications (p = . / . / . ). conclusions: pain management with icc reduces the amount of opioids and number of days with opioids patients' require to achieve sufficient analgesia while at the same time reduces the postoperative los and chest drain duration. in conclusion, icc is an effective tool in postoperative pain management. analysis of pain management after anatomic vats resection in austrian thoracic surgery departments persistent symptoms in patients after acute covid- covid- and obstructive sleep apnea sars-cov- -specific antibody seroprevalence in a general population -the viennese lead covid- study background: pulmonary hypertension (ph) is a frequent complication of copd and is associated with poor survival. however, pulmonary and right ventricular hemodynamics and their association with physical capacity in copd patients with out-of-proportion dyspnea is unknown. in this study we hypothesized that copd patients show abnormal hemodynamics during exercise, associated with impaired exercise capacity.methods: out of outpatients with unexplained dyspnea, copd patients with mpap < mm hg and age and sex matched controls without copd and mpap < mm hg, who underwent right heart catheterization at rest and during symptom-limited ergometer exercise, were compared.results: we analyzed copd patients ( ± yr, fev : ± %) and controls ( ± yr, fev : ± %). in copd, resting mpap and pvr were slightly elevated (median: (iqr: - ) vs. ( - ) mm hg, p = . and . ( . - . ) vs. . ( . - . ) wu, p = . ). at peak exercise, mpap and pvr were markedly elevated ( ( - ) vs. ( - ) mm hg, p = . and . ( . - . ) vs. . ( . - . ) wu, p = . ), whereas pulmonary vascular compliance (pvc) and right ventricular output reserve ( . ( . - . ) vs. . ( . - . ) mm hg, p = . and ( . ( . - . ) vs. . ( . - . ) ml/mm hg, p = . ) were significantly reduced. mpap/co-slope ( . ( . - . ) vs. . ( . - . ) mm hg/l/min, p = . ) and transpulmonary gradient (tpg)/co-slope ( . ( . - . ) vs. . ( . - . ) mm hg/l/ min, p = . ) were significantly steeper in copd. compared to controls, copd patients had worse exercise performance (peak oxygen uptake (vo ) ( ( - ) vs. ( - ) %predicted, p < . ). moreover, peak vo was significantly correlated with peak exercise mpap (p = . , r = - . ), pvr (p = . , r = - . ), pvc (p = . , r = . ), pulmonary arterial stiffness index (p < . , r = - . ), rv output reserve (p = . , r = . ), mpap/co-slope (p = . , r = - . ) and tpg/coslope (p = . , r = - . ).conclusions: in copd, pulmonary and right ventricular hemodynamics are markedly changed as compared to patients without copd. these findings are strongly associated with exer-abstracts backgroud: the corona virus disease (covid- ) pandemic increases the demand for post-acute care in patients after a severe disease course. various longterm sequelae are expected and physical and rehabilitation medicine (prm) is challenged to support the recovery both physically and mentally. the aim of this study was to explore dysfunctions and outcome of covid- survivors after early post-acute rehabilitation.methods: this study analysed the rehabilitative outcomes of a subgroup of patients included in a prospective observational multicenter study to investigate long-term sequelae in patients hospitalized for sars-cov- infection.results: a total of subjects discharged after severe to critical covid- infection underwent an individualized, multiprofessional treatment plan. despite a high proportion of patients requiring mechanical ventilation with consequent symptoms of post intensive care syndrome, indices of performance status and pulmonary parameters improved significantly.conclusions: covid- survivors show varying degrees of physical and psychological dysfunctions in the early period of recovery after hospital discharge. in this phase, patients strikingly benefit from multidiscinplinary inpatient rehabilitation, but the course of residual impairments remains unclear. assessing self-medication for obstructive airway disease during covid- using google trends background: inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (pepck), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. however, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood.methods: we analyzed the expression of glut , the prime glucose transporter, and of pck and pck , the cytoplasmic and mitochondrial isoforms of pepck, in samples of nonsmall cell lung cancer (nsclc) and in nsclc metastases using tissue microarrays and whole tumor sections. spatial distribution was assessed by automated image analysis. addition-most likely due to a longer follow-up time. other clinical factors did not differ between groups.conclusions: vats lobectomy does not result in a higher rate of local disease recurrence, suggesting adequate lymph node dissection with this approach. other factors than the surgical technique might be responsible for nodal upstaging, therefore nodal upstaging should no longer be used as a quality marker for lymph node dissection.background: acute exacerbation of interstitial lung disease (ild) is associated with a poor prognosis and high mortality. the regulator of g protein signaling (rgs ) is present in the lung as well as in neutrophils. however, the potential of rgs to limit neutrophilic hyperinflammation and thus disease progression in acute exacerbation has not been explored so far.methods: to investigate the functional relevance of rgs invivo, we examined the acute inflammatory bleomycin response phase of pulmonary fibrosis utilizing rgs knock out (rgs -/-) and wild type (wt) mice at age - weeks (equivalent to adult age in humans). the lipopolysaccharide (lps)-induced acute lung injury model was used as a second model. the in-vivo studies were extended with analysis of the chemokine levels in the lung, the migratory behavior of the neutrophils obtained from wt and rgs -/-animals and the downstream pathways in-vitro.results: in the acute phase of pulmonary fibrosis, rgs -/mice had preserved lung function as compared with wt mice which showed significant combined ventilatory disorders. analysis of specific immune cell subpopulations in bronchoalveolar lavage fluid (balf) and lung tissue showed a significant attenuation in the total cell number in the balf of rgs -/-animals, predominantly made up of neutrophils and lowered myeloperoxidase (mpo) enzymatic activity in lung tissue. a similar picture was seen in the lps lung injury model. our in-vitro abstracts background: cystic fibrosis (cf) leads to airway colonisation with pathogens. the significance of colonisation with fungi is not entirely clear, and epidemiological data regarding colonisation with fungi are somewhat contradictory. candida albicans and aspergillus fumigatus have been most frequently reported, with colonisation rates between - % and - %, respectively.methods: we analysed results of sputum cultures from paediatric and adult patients of our centre taken between and . modified culture methods had been used for fungal cultures. to determine chronic colonisation we applied modified leeds criteria.results: , sputum specimens from patients were analysed. of , isolated pathogens, , ( . %) were fungi cultivated from , / , specimens ( . %). / ( . %) patients were at least colonised once. colonisation rates with fungi did not change significantly between ( / ; . %) and ( / ; . %). some species seem to be associated with chronic colonisation while others do not (fig. ) .conclusions: almost all patients showed colonisation with one or more fungi. the proportions of patients already colonised in childhood and over many years were very high. some species were detected at much higher rates than previously reported. these differences are more likely due to culture methods and the long observation period than to differences in cohorts. adequate culturing methods are crucial to study the impact of fungal-colonisation in cf patients.contact tracing (apps)) are of great importance. we analysed a rapidly increasing number of publications investigating virus transmission by aerosols and the role of masks/shields for prevention. in brief, infectious aerosols are produced by coughing, sneezing, speaking and even normal breathing of infected individuals demonstrating the role of the lung as an "aerosol generator". in aerosol the virus is stable for hours and coughing/sneezing in contrast to normal breathing can transport aerosol for a distance of about meters. half lifetimes of viable virus are h (aerosol, copper-surface), h (cardboard) and h (plastic-surface) underlining the need of masks/shields and adequate disinfection. a major number of professional masks/ face-shields were developed, e. g. n mask, surgical mask, face-fitting mask, mit face shield differing strongly in respect to their properties for filtering and infection prevention; however, comparative head-to-head studies are missing. in summary, masks/face shields play an important role for prevention of covid- infection. however, there are differences in respect to type of the masks/face shields and their indication for use, e. g. general population, health care workers and the use should be combined with other methods of disease prevention. airway colonisation with fungi in cystic fibrosis patients results: patients with a median age of years were identified. the most common histology was ewing-sarcoma (n = , %). ( %) patients underwent neoadjuvant therapy ( % cht, . % rt, . % immunotherapy). median tumor size at diagnosis was . cm (range, to cm). extended resection was necessary in % (n = ), intraoperative use of ecmo in patient. postoperative complications were observed in patients ( %). adjuvant therapy was administered in ( %) patients ( . % cht, . % rt, % chrt). -day mortality was . %. there was no significant difference in overall survival (os) or disease free survival (dfs) between ps and cws (p = . and p = . ) or in type of histology (ewing sarcoma vs others, p = . and p = . ). -year os and dfs were % and %, median os was not reached. median dfs was . months. patients requiring extended resection (> involved anatomical structures) had a trend for impaired os (hr . , p = . ) and significantly worse dfs (hr . , p = . ).conclusions: radical resection of primary malignant ps and cws offers good long-term outcome with low complication rate despite extended resections. however, extent of disease and subsequent necessity for extended resection is an unfavorable factor for long-term survival. background: the ests eurolung scores were established to predict postoperative morbidity and mortality in patients undergoing anatomic lung resections. since its introduction, the eurolung scores have been updated once and an easy-touse and free-of-charge smart phone app has been created. so far, the scores have not been validated in other patient cohorts. herein we aimed to elaborate the accuracy of the various eurolung scores in our vats cohort. methods: the eurolung scores were calculated for a consecutive cohort of patients scheduled for vats lobectomy. postoperative complications, as defined and used by the eurolung scores, were then analyzed in this prospectively maintained database.results: overall, the observed complication rate was . % in the vats lobectomy database. the eurolung predicted a mean risk of morbidity of . % with a weak eta correlation (η) (eurolung : η = . ; parsimonious eurolung : η = . ; parsimonious eurolung : η = . ). a better coherence was observed with the parsimonious eurolung ( ; . %) and the current parsimonious eurolung ( ; . %). binary logistic regression analysis of the included parameters showed that extended resections and ppofev % were associated with increased complications in the eurolung scores. -day mortality was . % (predicted mortality according to eurolung : . %, parsimonious eurolung : . %) and was associated with ppofev % for both scores and coronary artery disease for the eurolung score only. the eurolung showed a larger area under the roc curve than the parsimonious eurolung ( . vs. . ). again, only a very weak eta correlation between predicted and observed mortality was found for the eurolung (η = . ) and the parsimonious eurolung ( ) (η < . ).conclusions: even though predicted and observed morbidity/mortality rates were comparable in our cohort the scores were not useful to predict the individual risk in this vats cohort. therefore, the scores should not be used to permit or refuse surgical therapy. initial experience with intercostal catheter for postoperative pain management in vats background: postoperative pain and its management influences patients' rehabilitation, postoperative complications and quality of life. despite its impact there are no uniform guidelines. different centers seem to use various strategies for pain management. in this study we aim to analyze pain management regimens after vats lobectomy used in austrian thoracic surgery units with a special interest in opioid usage and strategies to avoid opioids.methods: a questionnaire was designed to assess the current use of regional anesthesia, post-operative pain medication and characteristics of individual pain management regimens. the questionnaire was sent to all thoracic surgery units in austria, with nine out of twelve departments returning them.results: pain management varied between all centers. all departments use regional anesthesia perioperatively. four out of centers use epidural analgesia or an intercostal catheter for postoperative regional anesthesia in at least % of patients. two departments follow an opioid restrictive regimen, depending on visual analogue scale (vas) and two administer opioids on a fixed schedule. three out of departments use nsaids on a fixed schedule. the most used medication is metamizole ( out of centers; on a fixed schedule, two depending on vas) followed by piritramid ( out of centers; none as a fixed prescription). all centers reported that their regimen is standardized (with centers basing it on an in-house standard) and all assessed their patients pain scores on a regular basis.conclusions: there is no standardized postoperative pain management regimen after anatomic vats resections. there seems to be a trend towards prolonged postoperative regional anesthesia to reduce opioid consumption in some centers. a further prospective study is in preparation to evaluate the feasibility of opioid-free postoperative pain management and its impact on quality of life. perioperative mortality and morbidity following pneumonectomy for severe inflammatory disease of the lung background: some cases of severe pulmonary inflammation are not amenable to conservative treatment. if pneumonectomy is required in highly septic and instable patients the inherent risk of the procedure increases further. in a retrospective study we analysed these patients comparing them to elective pneumonectomy in patients with malignant disease.methods: during the last years patients (age: . +/- . years; males: , females ) underwent pneumonectomy. of these cases had underlying severe inflammatory disease (central necrotizing abscess or pulmonary gangrene with accompanying empyema) whereas had resection for malignant tumours. abstracts results: the inflammatory group was significantly younger ( . +/- . vs. . +/- . years; p = . ) and had a significantly lower bmi ( . +/- vs. . +/- . ; p = . ) than the malignant group. there were no differences concerning cigarette or alcohol consumption or copd, coronary artery disease or peripheral arterial occlusive disease. both the rate of severe perioperative complications ( . % vs. . %) and of perioperative death ( . % vs. . %) were significantly higher in patients with inflammatory disease (p = . ). in spite of the high perioperative mortality rate of pneumonectomy in inflammatory disease, -years survival rate ( . % vs. . %) showed no statistically significant difference between the two groups.conclusions: though sometimes required as a life-saving procedure in severe inflammation of the lung, pneumonectomy in such conditions carries a high perioperative morbidity and mortality. if the first months after pneumonectomy are survived however, the prognosis of this subgroup is fair. problem at the pneumonectomy stump. salvage by myoplastic closure background: for primary closure when material is lacking and for the treatment of bronchial stump dehiscence following pneumonectomy a variety of methods such as pericardial or omental flap as well as myoplastic techniques have been advocated. we present our experience with myoplasty for closure of the main bronchus stump.methods: retrospective analysis of pneumonectomies within the last years (age: . +/- . years; males: , females ). in patients ( . %) problems at the bronchial stump were present ( on the right and on the left side), thereof primary impossibilities of direct closure and secondary dehiscences.results: in one case dehiscence occurred one day after pneumonectomy, in the remaining patients dehiscence became evident after a mean of . days ( - days). the impossibilities of direct closure of the stump derived from necrosis and fistula following bifurcational stenting in lung cancer, from lack of viable bronchial tissue during completion pneumonectomy following left-sided sleeve resection and from bronchial necrosis in aspergillosis. closure of the stump was done by pedicled pectoralis major flap in , by pedicled diaphragmatic flap in and by pedicled sternoleidomastoideus flap in one patient. if deemed necessary, second-look procedures and/or thoracostomy and vac were additionally used. one patient did not survive his septic condition and died within days ( . %). the overall years survival rate was %.conclusions: pedicled myoplastic flaps provide reliable closure even in detrimental cases of dehiscence of the main bronchus stump.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -n iscmr authors: solaimanzadeh, isaac title: nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for covid- date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: n iscmr dihydropyridine calcium channel blockers (ccb) are typically used agents in the clinical management of hypertension. yet, they have also been utilized in the treatment of various pulmonary disorders with vasoconstriction. severe acute respiratory syndrome coronavirus (sars-cov- ) has been implicated in the development of vasoconstrictive, proinflammatory, and pro-oxidative effects. a retrospective review was conducted on ccb use in hospitalized patients in search of any difference in outcomes related to specific endpoints: survival to discharge and progression of disease leading to intubation and mechanical ventilation. the electronic medical records for all patients that tested positive for sars-cov- that were at or above the age of and that expired or survived to discharge from a community hospital in brooklyn, ny, between the start of the public health crisis due to the viral disease up until april , , were included. of the patients that were identified, survived until discharge and expired. seven patients from the expired group were excluded since they died within one day of presentation to the hospital. five patients were excluded from the expired group since their age was above that of the eldest patient in the survival group ( years old). with patients left, were found to have been administered either amlodipine or nifedipine (ccb group) and were not (no-ccb group). patients treated with a ccb were significantly more likely to survive than those not treated with a ccb: ( %) survived and expired in the ccb group vs. six ( . %) that survived and ( . %) that expired in the no-ccb treatment group (p<. ; p= . ). ccb patients were also significantly less likely to undergo intubation and mechanical ventilation. only one patient ( . %) was intubated in the ccb group whereas ( . %) were intubated in the no-ccb treatment group (p<. ; p= . ). nifedipine and amlodipine were found to be associated with significantly improved mortality and a decreased risk for intubation and mechanical ventilation in elderly patients hospitalized with covid- . further clinical studies are warranted. including either nifedipine or amlodipine in medication regimens for elderly patients with hypertension hospitalized for covid- may be considered. of the patients that were identified, survived until discharge and expired. seven patients from the expired group were excluded since they died within one day of presentation to the hospital. five patients were excluded from the expired group since their age was above that of the eldest patient in the survival group ( years old). with patients left, were found to have been administered either amlodipine or nifedipine (ccb group) and were not (no-ccb group). patients treated with a ccb were significantly more likely to survive than those not treated with a ccb: ( %) survived and expired in the ccb group vs. six ( . %) that survived and ( . %) that expired in the no-ccb treatment group (p<. ; p= . ). ccb patients were also significantly less likely to undergo intubation and mechanical ventilation. only one patient ( . %) was intubated in the ccb group whereas ( . %) were intubated in the no-ccb treatment group (p<. ; p= . ). nifedipine and amlodipine were found to be associated with significantly improved mortality and a decreased risk for intubation and mechanical ventilation in elderly patients hospitalized with covid- . further clinical studies are warranted. including either nifedipine or amlodipine in medication regimens for elderly patients with hypertension hospitalized for covid- may be considered. nifedipine and amlodipine are dihydropyridine calcium channel blockers (ccbs) regularly used to treat hypertension. yet, both medications have been utilized in the treatment of various pulmonary disorders with vasoconstriction as well. severe acute respiratory syndrome coronavirus (sars-cov- ) has been described to use the angiotensin-converting enzyme (ace ) receptor for entry into target cells expressed by the epithelial cells of the lung, leading to vasoconstrictive, proinflammatory, and pro-oxidative effects [ ] . this vasoconstriction may play a role in the pathogenesis of the disease. dysregulation or loss of hypoxic pulmonary vasoconstriction is suspected in coronavirus disease (covid- ) as well [ ] [ ] . a retrospective review of patients on either nifedipine or amlodipine was conducted in search of any difference in outcomes, including survival to discharge and progression of disease leading to intubation and mechanical ventilation. patients in this population were prescribed either of these medications for the treatment of hypertension. yet, reviewing outcomes in this context may reveal a benefit for the treatment of covid- as well. it is important to note the difference between dihydropyridine calcium channel blockers and non-dihydropyridines, as physiologic effects are likely not the same [ ] . whenever this article refers to a ccb, it is referring specifically and only to either nifedipine or amlodipine. nifedipine was found to increase pulmonary vasodilation without decreasing arterial oxygenation or causing systemic hypotension in patients that suffer pulmonary hypertension from a chronic airflow limitation [ ] . in tandem, amlodipine taken orally also produces acute pulmonary vasodilatation in patients with pulmonary hypertension [ ] . furthermore, amlodipine was also found to be an effective pulmonary vasodilator in patients with chronic obstructive pulmonary disease (copd) with pulmonary hypertension [ ] . in addition to being a safe and effective pulmonary vasodilator in these patients, it was also shown that amlodipine leads to an improvement in the right heart function [ ] . during hypoxia, nifedipine significantly reduces pulmonary vascular resistance at both rest and exercise and inhibits hypoxic pulmonary vasoconstriction in patients with copd [ ] . in the same study, it was also found to substantially increase oxygen delivery during both rest and exercise. moreover, in patients with normal pulmonary artery pressures, nifedipine was shown to attenuate hypoxia-induced increases in pulmonary artery pressure and acutely dilates the constricted vascular bed associated with hypoxia in patients with copd [ ] . although modulated via the endothelium, the core mechanism of hypoxic pulmonary vasoconstriction is in the smooth muscle cell [ ] . the reversal of vasoconstriction with the use of dihydropyridine calcium channel blockers may be a method to improve outcomes in covid- . nifedipine was previously observed to shift the pulmonary pressure-flow relationship to the right and increase the dispersion of blood flow distribution at rest and during exercisestrongly suggesting the release of hypoxic pulmonary vasoconstriction [ ] . in light of this, the concomitant use of either nifedipine or amlodipine in patients hospitalized with covid- was reviewed. again, patients herein were treated with the calcium channel blockers for hypertension. yet, this review sought to discover if a mortality benefit could be revealed in an acute illness requiring hospitalization for covid- . a retrospective review of electronic medical records for all patients admitted to a community hospital who tested positive for sars-cov- , who were at or above the age of , and who either expired or survived to discharge from hospital between the start of the public health crisis due to the viral disease (earliest admission date of a patient that tested positive at this hospital: february , ) and april , . it is important to note that only patients with a final disposition on the day of study conclusion were included and that many more patients still hospitalized were not included in this review. the two groups were: ( ) treated with either nifedipine or amlodipine as part of the ccb group or ( ) not treated with either amlodipine or nifedipine as part of the no-ccb group. being "on" either of these medications required that they received more than one dose. all patients in both groups were managed by a clinical team wherein antibiotics were administered in addition to hydroxychloroquine depending on patient consent and/or qtc prolongation status. patient outcomes were assessed for survival to discharge or signed out independently against medical advice (ama) and expiration. also looked at as a secondary outcome was the need for intubation and mechanical ventilation. clinical co-morbidities were reviewed in addition to demographic and clinical data. results were analyzed for statistical significance with the use of software available on these web pages: https://www.socscistatistics.com/tests/chisquare/default .aspx and https://www.socscistatistics.com/tests/fisher/default .aspx. the chi-square test and fisher exact test calculator for a x contingency table were utilized for a statistical significance limit of p<. except where indicated. to check for any significance between groups for factors that were continuous variables, the standard deviation was derived from the following website enlisted for statistical dispersion: http://www.alcula.com/calculators/statistics/dispersion/. thereafter, the following website was utilized to calculate the comparison of means: https://www.medcalc.org/calc/comparison_of_means.php. a total of patients were identified. of these, survived until discharge and expired. one patient signed out against medical advice (ama) and this was included in the survival group. seven patients from the expired group were excluded since they died within one day of presentation to hospital and the time frame of clinical deterioration limited potential therapeutic interventions. in order to attempt to age match the case and control groups, five patients were excluded from the expired group since their age was above the eldest patient in the survival group ( years old). for the record, of these, only one was on a ccb and four were not on a ccb. with patients left, were found to not have been treated with either nifedipine or amlodipine and were found to have been prescribed and taking either nifedipine or amlodipine during the course of hospitalization. demographic data are outlined in table in patients treated with a ccb, ( %) survived and expired, whereas only six ( . %) survived and ( . %) expired in the no-ccb treatment group (p<. ; p= . , see table ). considering this from a different perspective, % ( / ) of patients that survived and that were successfully discharged from the hospital were on a ccb, whereas % ( / ) of patients that expired were not on a ccb ( figure ). blocker. patients treated with a ccb were significantly less likely to have undergone intubation and mechanical ventilation. since only one patient ( . %) in the ccb group was intubated and mechanically ventilated and ( . %) were not, whereas ( . %) were intubated and mechanically ventilated and ( . %) were not in the no-ccb treatment group (p<. ; p= . , see table and figure ). other sample medications administered were not significantly different between groups (see table ). broad-spectrum antibiotics could be qualified with various medication regimens such as ceftriaxone in combination with azithromycin or doxycycline, vancomycin and meropenem, etc. intravenous fluid comprised all patients that were administered at a minimum of ml/hr at some point during the course of hospitalization. steroid use included any type such as methylprednisolone, dexamethasone, or hydrocortisone. several other factors, including vital signs and laboratory findings at initial presentation, were compared between groups as well ( table ) . some patients did not have specific laboratory tests drawn; the number of patients included is indicated. also, the first recorded pulse oximetry measure in many patients from both groups include levels obtained after immediate placement of oxygen supplementation was already initiated. these results reveal that dihydropyridine calcium channel blocker (nifedipine or amlodipine) usage is associated with significantly improved mortality in elderly patients hospitalized for covid- . they also reveal that ccb usage is associated with a significantly decreased risk for intubation and mechanical ventilation. this study reveals the possible benefits of nifedipine and amlodipine in patients hospitalized with covid- . larger clinical studies are warranted. for those that already have hypertension and present to hospital with elevated blood pressure, assuming no contraindications exist, it may be fair to give preference to a ccb as first-line therapy for concomitant benefit. further studies of other potential therapies that function as vasodilators in the pulmonary arterial flow should be pursued as well. clinical data comparisons between groups at the time of presentation were significant for differences in systolic as well as mean arterial blood pressure. this may indicate higher levels of hypotension or at least a lack of elevated blood pressure measures in the no-ccb group at presentation and/or foreshadow treatment with a ccb anti-hypertensive medication. differences in erythrocyte sedimentation rate, d-dimer, and lactate dehydrogenase may reflect a disparate severity of disease upon presentation. however, on the other hand, this reasoning may be countered since results between levels of lactic acid, c-reactive protein, b-type natriuretic peptide, and interleukin- were not significantly different, in addition to no significant difference between hemoglobin and glomerular filtration rate (gfr). it is not known if patients were taking a ccb at home or not. this may be another avenue to explore with consideration to decipher if the severity of disease expression is diminished or halted by ccb medication -prior to virus exposure. future studies may investigate different patient populations. moreover, ccb treatment, while monitoring blood pressure closely in patients that are suffering from covid- , and that do not have underlying hypertension, may be envisaged. blood pressure is generally not hypotensive in many hospitalized patients suffering from covid - and can even be higher in patients in the intensive care unit (icu) [ ] . the limitations of this study may be inherent in the small sample size, possible confounding factors not otherwise accounted for, and even selection bias as part of prior clinical decisionmaking to treat hypertension with a ccb or not. therefore, larger and more rigorous studies should be pursued. prospective studies may be considered as well. large health systems may be in a unique position to help advance knowledge on this subject matter by conducting a more robust retrospective review. if clinical researchers therein would peruse electronic medical records (emr) for similar outcomes, as described in this paper, that can aid in gaining a better understanding of the role that ccbs may have in mitigating disease. particular attention may be paid, where possible, on patient adherence to outpatient medication regimens prior to acute hospitalization. for example, if the rates of hospitalization for patients that were adherent to ccbs were decreased, that might indicate preventative benefits. this could potentially explain significant differences of clinical data at the initial presentation described above, but this remains to be investigated. with the current emr technology available at some institutions, this may be investigated rapidly. results obtained may yield benefits for thousands of patients across the country and throughout the world that have not yet fallen ill but remain at risk for contracting this disease. the need for mechanical ventilation likely represents the continuum of progression of the disease. it can be regarded as an intervention aimed at curtailing a trajectory towards mortality. however, mechanical ventilation should not be considered an all-encompassing treatment option for patients with covid- . in a recent study, amongst patients intubated, only ( . %) were discharged alive, with . % that died and over % still in hospital [ ] . avoiding intubation with the utilization of potential countermeasures, such as with ccbs and other vasodilators described below, can be considered and evaluated since they may aid in the achievement of improved outcomes. when precisely during the course of the illness (early vs. late) these medications may be most effective may also be examined. furthermore, perhaps beneficial effects of ccbs and other vasodilators described below can be extended to patients that are already mechanically ventilated. clinical studies may investigate if successful weaning from mechanical ventilation is promoted by the use of vasodilators. therefore, it is incumbent upon the medical community to exert their best efforts, on behalf of the many patients at risk, and pursue further evaluation as part of efforts to enhance clinical interventions that compel augmentation. this data provides an impetus to explore different approaches to the treatment of patients with covid- . focusing on vasodilatory agents may allow for an alternative treatment strategy. herein, improved flow via the alveolar-capillary unit may be achieved. with improved flow, impediments to oxygenation, including inflammation and vasoconstriction, may be better negotiated. furthermore, blood transit improvement as a result of vasodilation may potentially offset clot formation. lastly, fluid accumulation or edema that can inhibit oxygenation may be collectively reduced as well. altogether, the improved flow may attenuate the precipitous progression of the disease. virchow's triad highlights three aspects compromising blood flow: stasis, hypercoagulability, and endothelial injury. all three may be occurring in advanced covid- . yet, the progression to severe disease consisting of an inability to oxygenate may be the endpoint of a gradual process. in other words, flow (or micro-perfusion) via the alveolar-capillary unit may be slowly but surely decreasing as a result of a vicious cycle wherein inflammation secondary to viral injury begets hypercoagulability as well as the impedance of blood flow. clot formation certainly lulls or wholly undermines segments of previously oxygenating pathways passing through the alveolar-capillary unit. moreover, inflammation by itself, enhanced by the recruitment of cytokines, leukocytes, and the whole gamut of caustic endogenous mechanisms, may further render viable tissue non-functional. additionally, with inflammation comes fluid or edema formation -this also compromises oxygen diffusion. on top of all this exists the innate disposition or tendency for hypoxic pulmonary vasoconstriction [ ] . perhaps, vascular inflammation also contributes to elicit reactive vasoconstriction independently. altogether, a microvascular process may be occurring over numerous alveolar-capillary units, which yields a macro result. in sum, with increasing hypoxia and respiratory failure, the following challenges are faced and each promotes the other perhaps in sequence but not necessarily: ( ) viral injury provoking inflammation, ( ) recruitment of an immune response, ( ) fluid accumulation, ( ) vasoconstriction or compromised vascular flow, and ( ) hypercoagulability and clot formation. multi-faceted challenges are faced in various clinical cases. however, the ultimate development of clot formation may not be applicable to many, if not most, patients upon presentation. these patients must be distinguished as not being in a category wherein the precipitous decline just described has already been realized. this is especially early on in the illness, since some may be managed, improve, and recover with supplemental oxygen and conservative fluid management or gentle fluid restriction alone. herein, a vasodilator can be utilized from the outset since inflammation has not been prolonged, whereby flow via the alveolar-arterial complex is still consistent and clot formation likely has not already developed. however, in patients that have had prolonged symptoms, a consistent deterioration of oxygen saturation and/or hypoxemia should be evaluated with the consciousness that all five challenges may have already been established and taken form. other patients maybe somewhere in between. this being said, consideration of other vasodilatory agents should be pursued. these may include phosphodiesterase inhibitors sildenafil and tadalafil, as well as acetazolamide among others. for example, sildenafil was shown to increase exercise capacity during severe hypoxia, as well as reduce hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure [ ] . the same study also revealed that it yields an increased maximum workload and maximum cardiac output compared with the placebo. beyond this, phosphodiesterase inhibitors have the added benefit of improved renal perfusion and gfr -a valuable commodity as kidney disease is associated with the in-hospital death of patients with covid- [ , ] . also, when not administered with nitrates, sildenafil use resulting in hypotension, orthostatic hypotension, and syncope were found to be less than % [ ] [ ] . tadalafil once daily was found to improved exercise capacity and reduced time to clinical worsening in patients suffering from pulmonary arterial hypertension (pah); offering an alternative to sildenafil as well [ ] . finally, combining tadalafil with acetazolamide, rather than taking acetazolamide alone, can be an even more effective method for the prevention of some conditions [ ] . dosing of sildenafil is less restrictive in cases of compromised renal function. acetazolamide also attenuates hypoxic pulmonary vasoconstriction but has the added benefit of increasing minute ventilation and oxygenation [ ] [ ] [ ] . acetazolamide, however, requires close monitoring of arterial blood gases, prior to and following use, as treatment is contraindicated in metabolic acidosis; a condition that it can spur. however, some of the adverse effects of acetazolamide can be avoided by reducing the dose to compensate for age-related reductions in renal drug clearance [ ] . in any case, the addition of sodium bicarbonate can be utilized to counteract an acid tide and may be administered repeatedly in an alternating fashion with acetazolamide [ ] . acetazolamide also acts to inhibit carbonic anhydrase in vascular smooth muscle and this mechanism may be achieved by means of ph changes therein [ ] . clinical status and work of breathing must also be monitored closely. patients that are already on a ventilator may also stand to benefit most from acetazolamide, as the control of various parameters may be adjusted for the optimization of therapy. an additional asset of acetazolamide includes diuresis of fluids -many, if not most, patients have significant crackles present on auscultation, and this likely hinders oxygenation as well (the latter is a clinical observation) [ ] . thus, acetazolamide can provide a triple benefit: diuresis of fluid/pulmonary edema, improved ventilation, and reversal of pulmonary vasoconstriction. there is a caveat to all of this. that is, improvement of oxygenation and ventilation can only be pursued if clot formation does not exist or is previously adequately treated. a recent study found that an incidence of thrombotic complications is up to % of icu patients with covid- [ ] . this must be addressed as well. for example, in patients that are early stage and without markedly elevated d-dimers, preferably younger and not elderly, wherein crackles are grossly apparent on auscultation, the use of a vasodilator such as acetazolamide or a ccb may potentially stave off intubation independently. however, in an elderly patient, with markedly elevated d-dimers and little to no crackles with clear air movement on auscultation, it may be ineffective as alveolar-capillary units that are already clotted may harbor a formidable barrier towards improvement. therefore, treatment with anti-coagulation prior to vasodilator therapy should be considered in these patients. treating any clots or microclots first may allow for the effective flow once vasodilator therapy is implemented. the vasodilatory agents mentioned in this article may enhance clinical outcomes in patients suffering from covid- . yet, they should be accompanied with considerations for anticoagulation and anti-inflammatory agents as well, not to mention antibiotics for the prevention of co-infection and anti-virals that may also contribute towards resolution. since adding a vasodilatory agent in a patient that has had prolonged disease and may have already developed a clot or microclots may not suffice. anti-coagulation, whether in prophylactic or treatment doses, may aid in reducing clot formation or extension. therefore, combining regimens particularly in elderly patients and/or those that have had a prolonged course may be prudent. if anti-coagulation is administered, certainly close monitoring for any signs of bleeding must be implemented. nonetheless, some patients may recover without anticoagulation as well, and clinical acumen is necessary in all circumstances. fluids are an important subject matter that must be appreciated within the context of overall management, although it certainly deserves further assessment beyond this article. generally, in patients that have stable blood pressure, no significant clinical signs of dehydration, and crackles on auscultation, conservative fluid management seems to be best. ground-glass opacities present on imaging may be reflective of fluid collection as well. in these cases, avoiding intravenous fluid hydration and relegating to oral fluid intake as needed may decrease the risk of excess fluid accrual in the lungs. this approach is not feasible in many clinical situations such as where co-morbid diabetic ketoacidosis, severe dehydration, hypernatremia, or rhabdomyolysis occurs. nonetheless, oxygenation impedance as a result of edema formation is still worth taking into account in clinical management over an extended course of hospitalization. on the other hand, patients that are dehydrated from the outset or were previously on anti-coagulation prior to presentation and perhaps taking a ccb may have relatively clear sounding lungs on auscultation -this is a clinical observation. those previously taking anti-coagulation and/or a ccb might possibly be less prone to fluid accumulation given preemptive counters to the impedance of flow and clot formation. this may be analogous to a pipe wherein, if flow is preserved, fluid may pass without interference. however, if it is clogged then certainly running more water will rebound and not successfully traverse the pipe without backing up or collecting proximally. in the former, where significant interference is not present, fluid may be a boon to expedite the clearance of inflammation. in the latter, where viral triggers of inflammation, down the five-step theoretical pathogenesis described above, have already exerted influence, it may worsen clinical status. the "pipe" analogy should be further qualified since, in our case, vascular channels may not be intact, as endothelial injury and capillary permeability are both likely. moreover, inflammation in itself is prone to fluid accumulation as seen in patients with bowel wall edema following surgery, ascites in cancer, or serositis. yet, while abdominal fluid accumulation may be a cause for significant discomfort, even mild pulmonary edema development may swiftly compromise oxygenation. finally, the use of steroids in severe cases and potentially in all hospitalized patients may aid in alleviating inflammation but, certainly, this is under investigation. with the concomitant use of vasodilators and anti-coagulation, the benefits of steroid use in covid- may become more apparent. all in all, in severe cases, early utilization of one or more vasodilator agent(s), anti-coagulation, steroids, and a diuretic (if no contraindications exist, preferably acetazolamide, given the additional benefits mentioned above), in addition to antibiotics and potential antivirals may be one protocol pathway to consider ( table ). therapeutic interventions herein reflect the five-step progressive course outlined above. patients that are otherwise stable but requiring oxygen supplementation to maintain a stable saturation level may improve with a vasodilator such as nifedipine or amlodipine (maximizing the dose to achieve ideal blood pressure may be of interest), prophylactic anti-coagulation, steroids, antibiotics and antiviral therapy alone without the use of a diuretic agent. yet, if the clinical disease progresses and suspicion of need for invasive ventilation emerges, a diuretic such as acetazolamide may be considered. in ventilated patients, acetazolamide may be a key to promote weaning as described above. frequent and repeated doses of acetazolamide may be necessary since the inflammatory effects of the viral provocation, as well as capillary permeability, will not vanish instantaneously and following a brief course of treatment reaccumulation of fluid may materialize. therefore, consistent perseverance may be a successful strategy to quell the buildup of fluid, maintain vasodilation, and allow for conquest over time. indeed, all vasodilation agents may exert their benefit over a gradual time course. just like the decline of patients succumbing to covid- occurs over an extended time course of worsening pathogenesis, so too the vasodilation agents may mitigate the same pathogenic process over an extended course of the viral illness. in other words, treating for just two days may not suffice even though some clinical improvement is observed. stopping at that point may incur a rebound in status. rather, a course of treatment at least five to seven days and up to two to three weeks in severe cases may be best. it is worth noting that a relatively minor subset of patients, tending to be elderly and frail, has been observed to have disproportionately cold hands and feet relative to their extremities and the rest of their body. additionally, they may be markedly sleepy and difficult to arouse. a pulse oximeter may fail to retrieve a saturation level when placed on their fingers and may yield a result only after being placed on their forehead. this may reflect an underlying lack of perfusion to extremities and conserving mechanisms for blood distribution. these patients are extremely ill and, although they may have stable vital signs, may be at risk for rapid deterioration. similar treatment may ensue, but with compromised oral intake, intravenous fluid hydration may be needed; this may be best conducted at a gentle, gradual, and consistent rate. this subgroup should be recognized as possibly being part of a separate group of patients with an advanced illness that may require special attention. any clinician that has encountered patient presentations on a covid unit, icu, or emergency department is aware that presentations of covid- are disparate and each individual case is different. nonetheless, while correcting any concomitant disturbance (e.g. renal failure, hyperosmolar syndrome, hypernatremia, etc.), bearing in mind the central role of pulmonary deterioration in overall clinical demise is crucial. ultimately, morbidity and mortality in covid- may be a result of a failure to accommodate the pathogenic sequelae of toxic viral provocation rather than an immunologic deficiency. therefore, aiding in the adaptation and negotiation of a physiologic response to the transient viral insult may effectively mitigate disease burden and promote improved outcomes. altogether, implementing a strategy that optimizes flow via the alveolar-capillary unit may be a progressive path forward. in this small retrospective review, dihydropyridine ccbs were found to be significantly associated with improved mortality, as well as a decreased risk for intubation and mechanical ventilation in elderly patients hospitalized with covid- . larger clinical studies are warranted. future studies may also elucidate results in different patient populations and possibly reveal benefits even in mechanically ventilated patients. consideration of treatment with a ccb in patients who are suffering from covid- and that do not have underlying hypertension may be studied as well. other potential therapies that function as vasodilators in pulmonary arterial flow should be pursued. potential benefits may outweigh the risks of including nifedipine or amlodipine in the treatment regimens of elderly patients with hypertension hospitalized with covid- . human subjects: consent was obtained by all participants in this study. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. covid- ) infection and renin angiotensin system blockers to a "typical" acute respiratory distress syndrome covid- pneumonia: ards or not comparative effects of nifedipine, verapamil, and diltiazem on experimental pulmonary hypertension nifedipine dilates the pulmonary vasculature without producing symptomatic systemic hypotension in upright resting and exercising patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension a comparison of two long-acting vasoselective calcium antagonists in pulmonary hypertension secondary to copd the effect of amlodipine on exerciseinduced pulmonary hypertension and right heart function in patients with chronic obstructive pulmonary disease nifedipine inhibits hypoxic pulmonary vasoconstriction during rest and exercise in patients with chronic obstructive pulmonary disease. a controlled double-blind study nifedipine attenuates acute hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease hypoxic pulmonary vasoconstriction hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease clinical features of patients infected with novel coronavirus in wuhan, china. lancet. presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area hypoxic pulmonary vasoconstriction sildenafil increased exercise capacity during hypoxia at low altitudes and at mount everest base camp: a randomized, double-blind, placebo-controlled crossover trial sildenafil improves renal function in patients with pulmonary arterial hypertension caution on kidney dysfunctions of covid- patients use of sildenafil (viagra) in patients with cardiovascular disease overall cardiovascular profile of sildenafil citrate tadalafil for the treatment of pulmonary arterial hypertension tadalafil and acetazolamide versus acetazolamide for the prevention of severe high-altitude illness acetazolamide reduces hypoxic pulmonary vasoconstriction in humans acute mountain sickness and acetazolamide: clinical efficacy and effect on ventilation acetazolamide improves oxygenation in patients with respiratory failure and metabolic alkalosis acetazolamide blood concentrations are excessive in the elderly: propensity for acidosis and relationship to renal function the alternating use of an alkalizing salt and acetazolamide in the management of cystine and uric acid stones vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle carbonic anhydrase by a direct mechanism of action acetazolamide: a forgotten diuretic agent incidence of thrombotic complications in critically ill icu patients with covid- the authors would like to thank dr. baoying lin-chen, director of infection control at interfaith, and the industrious members of her team who have helped prepare parts of the database utilized to conduct this review. key: cord- -qa bcsbu authors: starkel, julie l.; stapke, christina; stanley-o’malley, abigail; noland, diana title: respiratory date: - - journal: integrative and functional medical nutrition therapy doi: . / - - - - _ sha: doc_id: cord_uid: qa bcsbu lung disease rivals the position for the top cause of death worldwide. causes and pathology of the myriad lung diseases are varied, yet nutrition can either affect the outcome or support treatment in the majority of cases. this chapter explores the modifiable risk factors, from lifestyle changes to dietary intake to specific nutrients, anti-nutrients, and toxins helpful for the nutritionist or dietitian working with lung disease patients. general lung health is discussed, and three major disease states are explored in detail, including alpha- antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. although all lung diseases have diverse causes, many integrative and functional medical nutrition therapies are available and are not being utilized in practice today. this chapter begins the path toward better nutrition education for the integrative and functional medicine professional. anti nutrients and inhibitors of lung physiology - lung disease is far more prevalent worldwide than commonly thought. in fact, death from chronic lung disease is increasing, and as of , chronic obstructive pulmonary disease (copd) has become the third leading cause of death in the united states in the past decade, disproportionately affecting the elderly [ ] . another lung disease, asthma, affects in , or about million americans, according to the centers for disease control and prevention and the national center for health statistics [ ] . this is . % of adults, more women than men, and . % of children. asthma is the leading chronic disease in children [ ] . this disease has been increasing since the early s in all age, sex, and racial groups. in europe, lung disease represents % of all deaths -the fourth leading cause. according to the world health organization (who), in , . million people died from acute or chronic lung disease, representing one sixth of the global total deaths [ ] . worldwide, four respiratory disease categories appear in the top ten leading causes of death in [ ] . specifically, copd was the third leading cause of death, followed by lower respiratory infections as the fourth, lung cancer as the fifth, and tuberculosis as the tenth [ ] . the major risk factor is smoking, leading to % of all lung disease-related deaths in europe, where smoking is more prevalent ( % prevalence) than in the united states ( % prevalence) by nearly twofold [ , ] . lung cancer, particularly non-small-cell lung cancer (nsclc) subtype, is the leading cause of cancer-related death worldwide [ ] . added together, lung disease rivals the position for the top cause of death. throughout the life cycle, diet and lifestyle are important modifiable risk factors in the development, progression, and management of obstructive lung diseases, such as asthma and copd [ ] , as well as restrictive lung diseases such as pulmonary fibrosis and sarcoidosis. inflammation, in particular, seems to be the leading contributor toward the progression of lung diseases. as with many diseases, maintaining a healthy lifestyle, including sufficient sleep, low stress, regular exercise, a whole foods diet rich in phytonutrients from plants (fruits and vegetables), and potential anti-inflammatory supplements, is beneficial in supporting the body during these difficult diseases. inflammation, in particular, seems to be the leading contributor toward the progression of lung diseases. high inflammatory foods should be avoided, such as fried foods and foods disproportionately high in carbohydrates, sugar, alcohol, and excessive protein. a healthier suggestion would be a diet with more than half of all food consumed as vegetables, about one third as protein, and the remainder (one sixth) as other foods, such as fruits, dairy, grains, or starches. some dietary supplements may also be recommended for their anti-inflammatory benefits, which will be discussed later in the chapter. as human life expectancy increases, we can expect to see more chronic disease. the world health organization estimates that by , chronic lung disease will account for % (one fifth) of all deaths [ ] , up from one sixth in . despite these growing numbers, relatively little human nutrition research exists for respiratory health, compared to other, less prevalent, diseases. investigators in the areas of aging and lung biology suggest some hope, using genetics and animal models, as well as epidemiological research, to further the general medical approach to lung disease. the pulmonary system is composed of the upper and lower respiratory tracts. air flows in through the nose or mouth, past the frontal and maxillary sinuses, down the pharynx (throat), past the larynx (voice box), and then down the trachea. this makes up the upper respiratory tract. once past the trachea, the air divides into the left and right bronchi, which supply the left and right lungs, each divided into five sections called lobes. the bronchi then divide into smaller bronchioles, at the end of which are air sacs called the alveoli. this makes up the lower respiratory tract [ ] (. fig. . ). the diaphragm is the central muscle that is used for breathing. the intercostal muscles, located between the ribs, and the abdominal muscles are helpful for breathing out when the breath becomes labored, such as during exercise. the neck muscles and the muscles in the collarbone area help with breathing when the other muscles are compromised or impaired. in some neurological diseases, such as amyotrophic lateral sclerosis (als) [see chap. , newton], nerve damage from the brain to breathing muscles can result in impaired movement of these muscles and thus impaired breathing. in certain cases, such as in lung cancer when a lobectomy, removal of part of the lung, is required, there is an expected decrease in short-and long-term pulmonary function and oxygenation. however, respiratory muscle strength may be preserved [ ] . in a pneumonectomy, removal of the entire lung, dramatic changes in thoracic anatomy take place, such as elevation of the hemidiaphragm, hyperinflation of the remaining lung, and influx of fluid into the postpneumonectomy space [ , ] . there are phagocytic macrophages on the cellular surface of the alveoli, type i epithelial cells and type ii epithelial cells. phagocytic macrophages destroy inhaled bacteria and serve an important role in suppressing or activating the immune response to antigens and pathogens, similar to dendritic cells discussed below. macrophage function has been shown to be inhibited by cigarette smoke [ ] . alveolar macrophages also secrete enzymes, arachidonic acid metabolites, growth factors, immune response components, cytokines, and lymphocytes [ ] . type i cells are responsible for maintaining the structure of the alveolar wall, whereas type ii cells and clara cells are responsible for the production of pulmonary surfactant (composed of - % lipid and - % protein as lecithin and myelin), which is essential for lung function. the surfactant reduces surface tension, facilitating easier stretching and collapsing of alveoli during respiration [ ] . diseases associated with inadequate surfactant production are acute/adult respiratory distress syndrome (ards) and infant respiratory distress syndrome (irds) [ ] . irds is seen in premature babies born prior to weeks of gestation due to immature development of pulmonary surfactant, which only begins to develop around the th week of gestation [ ] . dipalmitoylphosphatidylcholine, phosphatidylglycerol, and cholesterol compose the lipid portion of the surfactant, where apoproteins and proteins found in blood plasma compose the protein portion [ , ] . the importance of cholesterol is minimized in today's medical community. those with higher levels of cholesterol tend to have more in their fatty cell membranes which resist pathogenesis at a cellular level. low cholesterol predicts a greater risk of dying from gastrointestinal, neoplastic, or respiratory diseases. it occupies - % of our cell membranes, enhances the mechanical strength of the membrane, and reduces permeability [ ] . it suppresses main-phase transition of the lipid bilayer [ ] . collagen, a fibrous protein, along with elastin and proteoglycans, is a fundamental component of the connective tissue that composes the lungs, and collagen is present in the blood vessels, bronchi, and alveolar interstitium [ ] . connective tissue in the lung is key for the passive diffusion of oxygen and carbon dioxide that characterizes alveolar-capillary gas [ ] . collagen homeostasis is vital to maintaining respiratory function, where collagen production and degradation are balanced. dysregulated collagen homeostasis that favors collagen production over degradation can lead to pulmonary fibrosis and compromised lung function [ ] . some key nutrients to consider for collagen synthesis and crosslinking to maintain connective tissue integrity are vitamin c, vitamin b , iron, copper, zinc [ ] , riboflavin, thiamin, and pantothenic acid [ ] . the airways of the respiratory system (with the exception of parts of the nose and mouth) have cilia, special hairs coated with mucus that trap pathogens and other particles that enter with the air that is inhaled. cilia are responsible for triggering this mucus upward toward the pharynx where these particles or bacteria can be coughed out or swallowed. mucus present in the lungs can also trap inhaled particles such as viruses, bacteria, and smoke particulates [ , ] . along the lining of the respiratory tract, there are several types of cells that are involved in immune response, such as secretory cells (i.e., goblet cells and clara cells) and mast cells. ciliated epithelium and mucus secreted by glands present on airways, goblet cells, and the secretory products of clara cells serve an important mechanism for lung protection. however, excessive goblet cells or hypertrophy of mucous glands may result in increased viscosity of mucus seen in pathologies like bronchitis [ ] . ciliary function is also impaired by cigarette smoke [ ] . dendritic cells are also found in the airway lining from the trachea to the alveoli. immature dendritic cells phagocytize bacteria or other antigens, where they then mature and travel to lymphoid tissues to communicate with the immune system. this delivery of antigens can promote tolerance of the antigen by releasing anti-inflammatory cytokines. conversely, this delivery can also trigger the opposite response if the antigen is recognized as a pathogen, where t lymphocytes are activated and inflammatory cytokines are released [ ] . one potential cause of infections in the upper respiratory tract or bronchial tubes, such as bronchitis, or deep in the lungs, such as pneumonia, is when cilia become damaged and do not trap inhaled germs and particles as effectively. in diseases such as cystic fibrosis, thick mucus secretions can accumulate in the airways and lungs, making it hard to clear and thus increasing risk for infection. in asthma, specific inhaled particles can trigger a reaction causing the airways to narrow, restricting breathing [ ] . surface enzymes and factors can also be found in the lining of the airways that compose the majority of the innate immune system of the respiratory tract. these include: lysozymes: found in leukocytes with bactericidal properties lactoferrin: a bacteriostatic agent (inhibits bacterial reproduction) synthesized by lymphocytes and glandular mucosal cells alpha- antitrypsin: an antiprotease to protect lung tissue from excessive enzymatic activity interferon: an antiviral substance that may be produced by lymphocytes and macrophages complement: participates as a cofactor in antigenantibody reactions [ ] gas exchange takes place in the alveoli so oxygen can enter the body to support metabolic function and the carbon dioxide product from these functions can be removed. this is accomplished through millions of capillaries in the alveoli. these capillaries in the alveoli then connect to arteries and veins that move blood throughout the body. the pulmonary artery supplies carbon dioxide-rich blood to these capillaries within the alveoli to remove carbon dioxide, and the oxygen-rich blood then gets delivered to the heart through the pulmonary vein. the lungs also serve the vital function of maintaining acid-base balance through changes in minute ventilation. these changes affect the ph of the blood by either retaining or excreting carbon dioxide [ ] . poor physiologic management of co and bicarbonate can lead to the conditions of respiratory acidosis and respiratory alkalosis. respiratory acidosis is characterized by higher blood concentrations of co and h + , caused by hypoventilation or decreased rate of breathing. hypoventilation can have acute or chronic etiologies, resulting from copd, interstitial lung diseases, respiratory muscle fatigue (i.e., extended asthma attack), or mechanical abnormalities (i.e., deformities). respiratory alkalosis is characterized by lower blood concentrations of co and h + due to hyperventilation, or increased rate of breathing. possible causes of hyperventilation can also be chronic or acute, such as pneumonia and fever, increased stress and anxiety, liver disease, stroke or meningitis, pregnancy, overuse of aspirin and/or caffeine, excessive mechanical ventilation, or increases in altitude [ ] . a pulse oximeter tool can be used to measure the percentage of oxygenated hemoglobin in an individual's blood to determine their overall respiratory status. typically, oxygen saturations of % or less are indicative of central hypoxia [ ] . pulse oximetry is especially useful for assessing individuals with asthma and copd [ ] . oral health must also be considered as a contributing factor to respiratory health [ ] . for example, in patients affected with periodontal disease, mm of dental plaque could contain around of bacteria. one potential mechanism of this connection is aspiration of bacteria from the oropharynx into the upper or lower respiratory tracts, leading to their adherence to the alveolar and bronchial lining, potentially colonizing respiratory ducts and causing respiratory infections. in addition, cytokines and enzymes associated with inflammation of periodontal tissues can be transferred into the lungs, potentially triggering or exacerbating lung infections [ ] (. fig. . a systematic review done in examined oral health in the elderly and its association with risk of aspiration pneumonia. this review suggested that maintaining oral health, such as brushing after each meal, cleaning dentures once per day, and professional oral healthcare, potentially reduced the amount of potential respiratory pathogens that resulted in lower incidence of aspiration pneumonia [ ] . several other systematic reviews have found that adequate oral hygiene plays an important role in preventing pneumonia, particularly in clinical settings where there is increased risk for hospital-acquired pneumonia (hap) and ventilatorassociated pneumonia (vap), as well as in older populations [ ] . in addition, associations have been made between copd and the risk of periodontitis, although systematic reviews have established that these associations are preliminary and further studies are needed [ ] . another important consideration in respiratory health is orofacial development and structure. anatomical obstructions at the level of the nose and pharynx, such as those caused by allergic rhinitis and hypertrophy of the tonsils, pose an increased risk for obstructive sleep apnea syndrome and respiratory infections due to lack of airflow through the upper respiratory system [ ] . it has been established that the lung has a microbiome of its own that may have a large impact on health and disease [ ] . the fungal microbiome, or mycobiome, may also have a significant impact on respiratory health, although more research is needed to determine definitive associations [ ] . dysbiosis may occur in the lungs with a bacterial infection. a few specific bacterial strains have been studied, and one, in particular, pseudomonas aeruginosa, seems to grow in inflammatory conditions. it then seems to encode inflammatory components causing further inflammation. anti-inflammatory nutrients could help stop the cycle, and vitamin d use has some research supporting this. recurrent bacterial respiratory infections may damage lungs and lead to worse outcomes in future lung disease [ ] . an increased interest in research of the relationship of the airway and gut microbiome is indicating potentially positive results regarding the use of probiotics in pediatric populations that may aid in asthma prevention and intervention [ , ] . the gut-lung axis has also been established, where the microbiomes of the lung and gut have been immunologically linked and are thought to have an impact on respiratory disease [ , ] . the autophagy mechanism within our microenvironment provides a constant "cleanup" system to recycle cell debris from microscopic biowaste generated by dynamic cellular biochemistry [ ] . enzymes such as neutrophil elastase function like garbage disposals recycling waste molecules. alpha- antitrypsin is a thermostat-like control factor that signals the proteolytic enzymes to stop and protect healthy tissue from being affected. antiproteases in the lung, such as alpha- antitrypsin, are required to prevent the overactivity of neutrophil elastase to prevent the degradation of healthy lung tissue. those with the genetic mutations of a at deficiency are at disadvantage, and subsequent lung tissue damage can occur promoting lung diseases like copd, asthma, bronchitis, and emphysema. key components of lung structure are elastin and collagen, which provide support for the bronchioles and clusters of alveoli (acini). the key enzyme present in these cells is neutrophil elastase, which is responsible for the destruction of respiratory bacteria. protease and antiprotease imbalance in the lung resulting in emphysema can be caused by alpha- antitrypsin deficiency and nicotine in cigarette smoke or polluted inhalant exposure [ ] . ifmnt approaches to the a at-deficient patient assess for nutrient insufficiencies for some of the important connective tissue, collagen, and elastin system key nutrients: vitamin c, vitamin d, biotin, balanced fatty acids, and gut microbiome. when insufficiencies or deficiencies are identified, appropriate food and dietary supplementation interventions can be recommended. it should be noted that if an individual is identified with a at deficiency genotype, the status of liver health should also be assessed, as a at pathophysiology can express in liver cirrhosis. more recent studies of respiratory disease [ ] have revealed the relationship with bacterial or viral infections exacerbating the individual's genotype eliciting expression of the associated diseases. one of the most recognized inherited conditions of altered autophagy mechanisms is alpha- antitrypsin deficiency, with - genetic variants affecting severity of lung expression. low levels of circulating a at allow potentially harmful enzymes like neutrophil elastase to remain in the lungs unchecked. low levels of a at, and the consequent proliferation of neutrophil elastase, leave lung tissue vulnerable to destruction, resulting in a decline in lung function. there are several categories of lung disease and many diseases within those categories (. table . ). some micronutrients and phytonutrients have important antioxidant and methyl-donating properties important for the lungs and therefore have great role in a nutritional approach to lung health. iron's interaction with the lungs is essential. it carries oxygen from the lungs to the peripheral parts of the body, as well as carbon dioxide back to the lungs to be exhaled. however, too little or too much iron can pose a problem for the lungs. before iron administration, it is important to rule out hemochromatosis, or iron overload, for an individual. iron-deficiency anemia often presents in many chronic diseases including those of the lung, such as copd, lung cancer, and ipf [ ] . increased mortality, decreased quality of life, increased hospital admissions, and cost of treatment have been reported for those with chronic disease and low iron [ ] . anemia of chronic disease (acd) is usually at the root of this. acd is often the result of inflammation. inflammatory proteins, including il- , stimulate the production of hepcidin in the liver, which inhibits absorption and increases storage of iron resulting in a functional iron deficiency. typical iron markers, such as transferrin saturation, total iron binding capacity (tibc), and ferritin, are also affected by inflammation and are less useful markers in chronic disease. soluble transferrin receptor (stfr) seems to be a lesser known marker that is less affected by inflammation [ ] . because of the difficulty with iron absorption, intravenous iron is often used to replete deficiencies. as iron is a pro-oxidant, researchers studied any negative repercussions. there does not seem to be any increased oxidative stress with intravenous iron, but glutathione, the body's endogenous super antioxidant, does seem to decrease, likely in response to the pro-oxidative activity of iron. in a recent study, administration with vitamin e was seen to eliminate these negative effects [ ] . excessive iron can also be problematic for lung health for those with the genetic mutation for hemochromatosis (hfe). disorders of iron overload are increasingly being recognized as risk factors for most of the chronic diseases like cardiovascular, alzheimer's, and cancer [ ] . high iron can catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. in the instance of lung cancer and other cancers affecting the lungs, tumors sequester iron for their own growth, usually leaving the patient with iron-deficiency anemia. in fact, % of cancer patients undergoing chemotherapy are iron deficient. inflammation also plays a role in iron homeostasis. the pro-inflammatory cytokines cascade down to affect the proteins that regulate . chronic obstructive pulmonary disease (copd) disease that restricts airflow through either inflammation of the lining of the bronchial tubes or destruction of alveoli increased risk of emphysema if genetic variant of alpha- antitrypsin deficiency and smoking or exposed to high levels of air pollution [ ] bronchiectasis a disorder of the airways that leads to airway dilation and destruction, chronic sputum production, and a tendency toward recurrent infection [ ] bronchiolitis airway injury that can be caused by infections, irritants, toxic fumes, drug exposures, pneumonitis (typically viral), organ transplants, connective tissue disorders, vasculitis, or other insults [ ] dyspnea shortness of breath or difficulty breathing [ ] emphysema thinning and destruction of the alveoli, resulting in decreased oxygen transfer into the bloodstream and shortness of breath. increased risk of emphysema if genetic variant of alpha- antitrypsin deficiency and smoking or exposed to high levels of air pollution [ ] alpha- antitrypsin deficiency a deficiency of a at, a protein produced in the liver that protects the lungs from excessive neutrophil elastase, an autophagic enzyme. a at may also accumulate in liver and cause liver disease [ ] obstructive asbestosis fibrotic lung disease resulting from extensive inhalation of asbestos fibers [ ] desquamative interstitial pneumonitis (dip) form of idiopathic interstitial pneumonia that is more common in cigarette smokers but may be seen in nonsmokers, in patients with underlying connective tissue diseases or those exposed to inorganic dust/particles [ ] sarcoidosis immune-mediated systemic disorder that is characterized by granuloma formation of the lung parenchyma and the skin [ ] restrictive pathophysiologyneuromuscular weakness amyotrophic lateral sclerosis (als) progressive neurological disease that affects the motor neurons of the nervous system [ ] guillain-barre syndrome progressive immune system attack on the peripheral nerves, usually following an infectious illness such as a respiratory infection. may eventually cause respiratory distress syndrome [ ] restrictive pathophysiologychest wall/pleural disease kyphoscoliosis kyphoscoliosis: a deformity of the thoracic cage that results in restriction of the lungs and impairs pulmonary function [ ] ankylosing spondylitis autoimmune inflammatory disorder characterized by inflammation of the axial skeleton and peripheral joints [ ] chronic pleural effusions chronic accumulation of fluid between the two outer membranes surrounding the lungs [ ] pulmonary vascular disease pulmonary embolism blood clot that typically originates from thrombi in the deep venous system of the legs and travels to the lungs pulmonary arterial hypertension (pah) progressive disorder of primary pulmonary arterial vasculopathy characterized by a mean pulmonary arterial pressure > mm hg at rest (> mmhg during exercise) [ ] iron homeostasis [ ] . iron can also impair cytokine secretion, which can leave those with an iron overload much more susceptible to infection, increasing the morbidity and mortality of infectious diseases, including those of the lung [ ] . oxidative stress may contribute to injury of lung tissue, causing further fibrosing in those lung diseases with that characteristic. allele variants in the genes associated with iron homeostasis (c y, s c, and h d hfe) are significantly more common in those with idiopathic pulmonary fibrosis (ipf) than those without ipf ( . % ipf patients vs . % non-ipf) and are associated with higher irondependent oxygen radical generation [ ] . iron is implicated in lung pathology. monitoring iron status and using supplements or diet to aid the body in increasing or decreasing the iron load are imperative for the nutritionist working with lung disease patients. choosing a good non-constipating form of iron is important, such as iron glycinate. the b vitamins are also important to monitor for lung health. vitamin b and its bioactive form, p- -p, are typically known to protect dna from mutation or damage [ ] . however, there is mixed evidence on its role for lung cancer. some research has shown that it is helpful for lung cancer patients as it is important for apoptosis when using chemotherapy, because it sensitizes cancer cells to apoptosis [ ] . however, research in showed that adult male smokers taking greater than mg vitamin b /day for long periods tended to have a greater risk for lung cancer. many variables, including genetic variants, form of b , and the status of other co-nutrients may be at play [ ] . other studies showed that men in the top quintile of vitamin b serum concentration had about one half the risk of lung cancer, and specifically, vitamin b and folate were inversely associated with risk of lung cancer [ ] . . squamous cell (epidermoid) carcinoma about - % of all lung cancers. these start in early versions of squamous cells, which are flat cells that line the inside of the airways in the lungs. often linked to a history of smoking and tend to be found in the central part of the lungs, near the bronchus [ ] large cell (undifferentiated) carcinoma about - % of lung cancers. it can appear in any part of the lung and tends to grow and spread quickly. a subtype of large cell carcinoma, known as large cell neuroendocrine carcinoma, is a fast-growing cancer that is very similar to small-cell lung cancer [ ] small-cell lung cancer (sclc) about - % of lung cancers are sclc. typically start in the cells lining the bronchi and parts of the lung such as the bronchioles or alveoli [ ] infectious diseases pneumonia inflammation of the lungs, usually caused by bacteria, viruses, or fungi [ ] bronchitis inflammation and eventual scarring of the lining of the bronchial tubes accompanied by restricted airflow, excessive mucus production, and persistent cough [ ] tracheitis bacterial infection that can develop in the trachea [ ] infant respiratory distress syndrome also known as hyaline membrane disease (hmd) or respiratory distress syndrome, this condition affects the alveolar ducts and terminal bronchioles in which the hyaline membrane is a fibrinous material composed of blood and cellular debris, caused by the absence of proper surfactant production due to an immature or poorly developed lung [ ] upper respiratory infection (uri) acute infections involving the nose, sinuses, pharynx, larynx, trachea, and bronchi, referred to as the common cold [ ] bronchopulmonary dysplasia (bpd) chronic lung disorder which may affect infants who have been exposed to high levels of oxygen therapy and ventilator support [ ] other cystic fibrosis disease characterized by abnormally thick mucus secretions from the epithelial surfaces of many organ systems, including the respiratory tract, the gastrointestinal tract, the liver, the genitourinary system, and the sweat glands [ ] acute lung injury clinical and radiographic changes in lung function associated with critical illness (acute respiratory distress syndrome is most severe form) [ ] respiratory because of disagreement in research, particularly with smokers or former smokers, using food first for b vitamins may be a prudent way forward. good sources of vitamin b are fish, chickpeas, chicken, potatoes, turkey, bananas, ground beef, and winter squash. pyridoxal kinase (pdxk) is the enzyme that converts pyridoxine and other vitamin b precursors to its bioactive form of p- -p. dysfunction of this enzyme is a good prognostic for lung cancer and other lung diseases. mthfr aa genotype is associated with a higher risk of lung cancer in women but not in men. the mthfr tt genotype was associated with a significantly decreased risk of lung cancer in women but not in men. in contrast, the mthfr c t and a c polymorphisms interacted with smoking status in men but not in women [ ] . methylation gene testing is imperative to understand the patient's status. some studies suggest that a higher intake of riboflavin (vitamin b ) may protect against lung cancer in smokers [ ] . folate deficiency was also associated with asthma and attacks of shortness of breath [ ] . correcting acidosis may preserve muscle mass in diseases where wasting is an issue, such as copd or ipf. for those receiving chemotherapy, a higher ph (more alkaline status) is helpful for muscle mass protection. high alkaline diets contain more fruits and vegetables, and those supply more magnesium, which is needed to activate vitamin d. as discussed below, vitamin d is extremely helpful for lung health. sleep quality involves maintaining adequate - hours with good sleep hygiene (see chap. ). good rem cycling, feeling refreshed upon awakening, and other characteristics of good sleep play significant roles in maintaining healthy acid-base balance. dietary intake of the minerals magnesium, potassium, sodium, chloride, and calcium promotes the balance of acidbase microenvironment. after exposure and tissue retention of toxic minerals and metals, these substances can contribute to perturbations in the acid-base metabolic milieu. some conditions reduce oxygen intake and should be addressed. one of the most common oxygen-impairing conditions is sleep apnea, altered sleep with random halting of breathing during sleep that is often accompanied by snoring. other limiting conditions are respiratory diseases like copd, a at deficiency, asthma, cystic fibrosis, etc. vitamin a is an important antioxidant and a general umbrella term for several fat-soluble retinoids, including retinol, retinal, and retinyl esters. there are also other substances that are provitamin a carotenoids or precursors to vitamin a. two forms are found in foods, the preformed forms of retinol or retinyl esters, which are found in dairy, fish, caviar, and meats (especially liver), and the provitamin a carotenoids, including the most important and common provitamin a carotenoid, beta-carotene, as well as others including alpha-carotenes and cryptoxanthin, which are found in plant-based foods. our bodies must convert these two forms within our cells to retinal and retinoic acid, the active forms of vitamin a in the body. new studies of the gene, β-carotene , ′-monooxygenase (bcmo ), which is responsible for the enzymatic conversion of β-carotene to vitamin a, are revealing that individuals with heterozygous or homozygous bcmo snps have - % less efficient conversion than those with normal gene function (see chap. ) [ ] . other carotenoids found in food, such as lycopene, lutein, and zeaxanthin, are not converted to vitamin a but have other antioxidant benefits in the body. most vitamin a is stored in the liver as retinyl esters, and deficiency is not visible until these stores are nearly depleted. vitamin a's role as an antioxidant helps the lungs in several ways, including maintaining alveolar epithelium cells and preventing development of respiratory tract infections. most of the developed world's population does not have a risk of deficiency due to sufficient vitamin a intake. however, most people with cystic fibrosis have pancreatic insufficiency, which reduces the ability to absorb fat and therefore the fat-soluble vitamins a, d, e, and k. according to a study in , between % and % of people with cystic fibrosis had a vitamin d deficiency, also a fat-soluble vitamin. with the addition of pancreatic replacement treatments, better nutrition, and vitamin a supplementation, deficiency has become rare. however, improved vitamin a status has not been thoroughly studied as of , and therefore it is largely unknown if an improved vitamin a status has any effect on cystic fibrosis [ ] . vitamin a deficiency has been shown to be associated with emphysema in rats. smoke exposure significantly decreases vitamin a concentration in lung tissue, significantly more in those with copd [ ] . retinoic acid seems to play a beneficial role in the treatment of ipf. a review showed that in all studies, retinoic acid decreased fibrosing, the formation of collagen, and reduced the expression of alpha-smooth muscle actin (alpha-sma), all hallmarks of ipf [ ] . it is important to not take large doses of vitamin a if one is in a malnourished state as it can cause toxicity and should be monitored with blood testing of vitamin a retinol. nourish the body with all foods and all nutrients slowly. the non-provitamin a carotenoids have also shown some benefit. lycopene, found in high amounts in guavas, watermelon, tomatoes, papaya, grapefruit, sweet red peppers, asparagus, purple cabbage, mangos, and carrots, slowed forced expiratory volume (fev) decline in former smokers [ ] . vitamin d's importance with lung health cannot be understated. vitamin d deficiency, or even insufficiency, is linked to accelerated decline in lung function, increased inflammation, and reduced immunity in chronic lung diseases. vitamin d has a role in the regulation of inflammation, immunity, cellular proliferation, senescence, differentiation, and apoptosis. sufficient vitamin d levels are correlated with better asthma control, better immune response related to respiratory infections, and reduced severity of exacerbations with copd and asthma when exposed to inflammation-causing pathogenic activity [ ] . vitamin d is obtained through sunlight on the skin (without sunscreen) and very few dietary sources. therefore, supplementation is generally recommended. higher vitamin d levels are shown to be protective in many lung disease states. sufficient levels improve treatment response with medications and reduce asthma severity [ ] . with infectious diseases of the lung, higher vitamin d concentrations are shown to have a protective action [ ] . vitamin d has a protective effect on lungs of smokers, and higher levels of vitamin d inhibit the pro-fibrotic phenotype of lung fibroblasts and epithelial cells. current data suggest an inverse association between serum vitamin d and lung cancer risk, and vitamin d deficiency at - weeks' gestation is associated with impaired lung function and asthma at years of age [ ] . lower levels of vitamin d are associated with an increased risk for respiratory infections, cystic fibrosis, chronic obstructive pulmonary disease, and interstitial lung disease [ ] . vitamin c is an important antioxidant that helps decrease oxidative damage in the body, including in lung tissue. it is also essential for lipid metabolism. it is present in the airway surface liquid and creates an interface between the epithelial cells and the external environment. vitamin c is a cofactor in collagen synthesis, which can aid in repair of bronchial and alveolar tissue when damaged. it also provides beneficial control of lipid peroxidation of cellular membranes, including those surrounding as well as those within intracellular organelles. vitamin c has some of the best lung protective capabilities, according to current research. vitamin c may also diminish oxidative attack on nonlipid nuclear material and is an antioxidant component of plasma and extracellular fluids surrounding the lungs. it is an antioxidant that not only fights oxidative stress but also reduces oxidized vitamin e and glutathione, allowing them to become active as antioxidants again. vitamin c is antiinflammatory and is helpful in all inflammatory states of the lung, even allergies. there are many ways in which vitamin c, along with its antioxidant partners, glutathione, vitamin e, vitamin a, and plant-based phytonutrients, affects lung health. it is well established that increased levels of vitamin c in the diet improve health outcomes for smokers and their offspring, as smoking depletes vitamin c [ , ] . vitamin c is also helpful in fighting infectious diseases such as respiratory infections and pneumonia, copd regardless of smoking status, asthma, and lung cancer [ ] . specifically, in certain lung cancers, vitamin c, along with other nutrients such as lysine, proline, epigallocatechin gallate, and zinc, can inhibit the proliferation of certain carcinoma lines and induce apoptosis, as well as inhibit lung cancer metastasis [ ] . even in lung transplants, vitamin c is helpful against oxidative stress by reducing glutathione and lowering lipid peroxidation, along with vitamins a and e [ , ] . the literature suggests these benefits can be achieved at - mg/day. check iron status before administering vitamin c supplementation as vitamin c doubles iron absorption from foods. vitamin e's primary role is as an antioxidant, breaking free radical chain damage and preventing peroxidation of lipid molecules. this vitamin also is promising with regard to beneficial effects on lung function preservation. oxidative stress and inflammation are key features in many lung diseases; therefore nutrients with antioxidant capacity can be useful. a few studies suggest that alpha-tocopherol found in sunflower and olive oils has a beneficial effect on fev (forced expiratory volume), whereas gamma-tocopherol found in canola, soybean, and corn oils has a negative effect on fev [ ] . however, from these authors' perspective, this is likely due to the source and type of the oils, which can be inflammatory, rather than the form of vitamin e. for example, a recent study showed that gamma-tocopherol was protective in allergic asthma [ ] . in addition, sufficient levels of vitamin e, in the alpha-tocopherol form, were found to reduce susceptibility of the elderly to acquiring pneumonia. some of the positive effects of vitamin e are synergistic with vitamin c [ ] . phytonutrients have been found to have two effects with respect to lung disease: one is a symptom-improving pattern, and the other is a rate-reducing pattern [ ] . idiopathic pulmonary fibrosis (ipf) is largely characterized by reduced antioxidant and increased inflammatory action. recent literature is showing the ability of certain flavonoids, in particular quercetin, to reduce inflammation and act as a strong antioxidant countering the pro-oxidant environment of ipf. quercetin is recognized as the most potent ros scavenger. taken together with glutathione, the impact is even greater, and it seems to help improve the antioxidant and inflammatory status more for those with ipf than non-diseased controls [ ] . curcumin has been shown to slow or limit fibrosing in murine studies related to lung, liver, or kidney fibrosing [ ] [ ] [ ] [ ] . it has also been shown to attenuate metastatic melanoma in the lungs when delivered in a nanoparticle [ ] . the potential for curcumin is interesting and hopeful. fisetin and fenugreek have also been studied as useful phytonutrients that help combat inflammation in lungs [ , ] . fisetin is found in apples, strawberries, persimmons, cucumbers, and onions, among many other fruits and vegetables. fenugreek is a plant used frequently in south and central asian cooking, where both the seeds and leaves are used. there are now supplements available for both of these phytonutrients. this is a reminder to eat a primarily plantbased diet when combating inflammation and to broaden our palates to include healthy foods and ingredients from other cultures than our own. lastly, the powerful antioxidant cannabidiol (cbd), from the cannabis and closely related hemp plants, is a powerful shield against oxidative stress, prevalent in lung disease [ ] . the research is not robust regarding lung function and minerals, and most has been done with regard to cystic fibrosis where bone density is associated with general nutritional status, including minerals. there have also been many studies trying to determine a correlation between mineral status and copd, where, again, the research shows that mineral status is not predictive but overall nutrient status may fall if not monitored. in contrast, one study in japan showed an inverse association between dietary calcium and the risk for copd [ ] . in an nih-aarp diet and health study, magnesium, iron, selenium, zinc, and copper intakes, both dietary and supplemental, were studied with respect to lung cancer. mineral supplementation did not affect lung cancer risk, yet dietary intake of calcium, along with vitamin d, and iron reduced the risk, and dietary intake of magnesium increased risk [ ] . boron has been shown to be protective against lung cancer, along with other nutrients, at levels of mg/day [ ] . there is some research showing that selenium is helpful, particularly for smokers, for improved fev. higher magnesium status is correlated to better fev but is not yet seen as an association. this may be due to magnesium's role as the vitamin d activator. there have been a few studies showing increased copper levels are related to decreased fev. some recent research has also shown that dietary zinc and iron are associated with reduced lung cancer, but the same was not seen with calcium, copper, magnesium, or selenium [ ] . low mineral bone density is prevalent at a higher rate among cystic fibrosis patients, and therefore supplementation with vitamin d, vitamin k , magnesium, calcium, and the trace minerals can be helpful [ ] . alpha-lipoic acid (ala) is a powerful antioxidant endogenously produced in the human body from foods such as yeast, organ meats, spinach, broccoli, and potatoes and is both water-and fat-soluble. ala, along with n-acetyl cysteine (nac), glycine, and vitamin c, is an important precursor to glutathione, which is a powerful endogenous antioxidant and the primary antioxidant in the lungs. ala has been shown to be anti-inflammatory in lung tissue in those with acute lung injury, and the proposed action is via inhibition of the nf-kappab signaling pathway [ ] . ala has also been shown to downregulate some cancerpromoting actions prevalent in lung cancer, likely by this same pathway [ ] . it also may alleviate nicotine-induced lung oxidative stress [ ] . n-acetyl cysteine (nac), another precursor to glutathione, is a powerful antioxidant on its own as well. in relation to the lungs, nac helps the clearance of mucus in the lungs by pulmonary cilia. this has been shown to be effective at - mg/day in divided doses [ ] . there is significant research on nac and lung health, showing improvement with nearly all lung issues, including nearly studies showing improvement for bronchitis [ ] , infectious diseases by reducing the bacterial count [ ] , smokers, and people with asthma and copd, through both its antioxidant effects and by reducing the viscosity of sputum and mucus. at an oral dose of mg/day, the mean glutathione concentration in lung tissue increased by % on one study [ ] . there are additional studies showing improvement for those with copd, asthma, cystic fibrosis, pulmonary fibrosis, and symptoms related to allergies or other infections. the dose that has been studied and has been shown to be most useful is mg twice daily and more effective if nebulized [ , ] . both ala and nac supplementation should be accompanied by vitamin b and the complex of b vitamins to prevent an elevation in liver enzymes (. fig. . ). there are several specialty labs that conduct micronutrient analysis and functional testing, such as genova diagnostics and spectracell. these tests can be useful for evaluating levels of individual nutrients as they function in the body, rather than just in serum, which is not an accurate indicator of tissue or functional status. patients suffering from copd, interstitial lung disease, and other diseases tend to have muscle and weight loss related to respiratory acidosis, and increasing weight and muscle mass helps with quality of life. respiratory acidosis occurs with co buildup where the lungs are no longer able to effectively exchange o and co . nutritional supplementation should attempt to reduce metabolic co production. fat metabolism produces less co than carbohydrate metabolism, so emphasizing a higher fat, lower carbohydrate diet can be helpful [ ] . in general, a high intake of omega- fatty acids is associated with poorer forced expiratory volume (fev) in patients with lung disease because of their pro-inflammatory nature. however, a complete fatty acid panel or a red blood cell membrane fatty acid test would reveal more details about the status of an individual's omega- pathway. certain omega- s and the work of their corresponding metabolizing enzymes such as elongase and delta- or delta- -desaturase may allow healthful omega- s (linoleic (la), gamma-linolenic (gla), lipoxins [ ] , prostaglandin series metabolites) to flow down an anti-inflammatory pathway instead. important cofactors for this pathway are vitamin b , vitamin b , vitamin b , vitamin b , biotin, vitamin c, zinc, and magnesium. lipid metabolism dysregulation is understood to be part of the pathogenesis of idiopathic pulmonary fibrosis. in ipf, free fatty acids play a role in the proliferation of fibroblasts. certain fats, in particular palmitic acid, oleic acid, and linoleic acid, are elevated in the lungs of those with ipf, whereas stearic acid is low. stearic acid is found in meat, poultry, fish, grain products, and milk and milk products. the palmitic, oleic, and linoleic acids enhance the tgf-ß -induced expression of α-smooth muscle actin (sma) and collagen type in mrc- cells, which can lead to fibrosis. stearic acid inhibits the levels of these fibrosing cells. stearic acid also improves the thrombogenic and atherogenic risk factor profiles [ ] . in one study on patients with copd, omega- fatty acids were found to reduce inflammation in bacterial infections of the lungs without suppressing the ability to clear the bacteria. those taking epa, dha, ala, and gla had improved exercise capacity and had lower risk of developing copd [ ] . although results have been mixed over the years possibly due to doses used in studies, a recent prospective study showed that pufas (omega- s) from fish help prevent lung cancer and can be part of treatment during lung cancer. in general, the strongest evidence for improved lung function and slowing decline is with the epa and dha forms of omega- fatty acids [ ] . because of toxicity issues in fish, increasing quality supplements vs fish intake may be more prudent. protein is essential for all lung conditions, and lack of it can result in poorer pulmonary function, decreased exercise capacity, and increased risk exacerbations. since many lung diseases have oxidative stress as a characteristic, it can cause protein carbonylation which may negatively affect dna expression and lipid membranes. nutritional supplementation with added protein and healthy carbohydrates can increase body weight and muscle strength and improve quality of life. those with copd, interstitial lung diseases, and others that affect oxygen absorption and co exhalation have greater levels of hypoxia and sometimes respiratory acidosis, which exacerbates the loss of muscle through oxidative stress and inflammation. supplementation of free essential amino acids versus complete proteins has been shown to help prevent muscle wasting among copd patients. muscle-building exercise is often prescribed for those with copd and interstitial lung diseases [ ] . supplemental l-carnitine at - g/day for - weeks increased the capacity of copd patients to rehabilitate and build muscle and helped inspiratory muscle strength. carbohydrates should be monitored for sufficient but not excessive levels. more co is produced with the utilization of carbs versus fats for energy. therefore, with gas exchange being an issue with most lung disorders, a slightly higher fat and lower carbohydrate diet may be indicated. it is worth mentioning fiber for a moment, as it is mostly delivered in carbohydrate-rich foods. there is evidence that consuming whole fruits and vegetables higher in dietary fiber is associated with reduced severity of asthma and copd [ ] . a diet that derives its carbohydrates from vegetables and fruits rather than from processed carbohydrates such as grains, breads, pasta, or added sugars will deliver fewer carbohydrate grams. glutathione (gsh), a tripeptide composed of cysteine, glutamine, and glycine and produced from methionine, is in every cell in the body. it is the most powerful and abundant endogenous antioxidant in the airway epithelial lining and is responsible for detoxification of electrophilic compounds, the scavenging of free radicals, and modulation of cellular processes such as dna synthesis and repair, differentiation, apoptosis, and immune function [ ] . it is also a heavy metal chelator. it is more effective than some other antioxidants because it is intracellular and extracellular. in isolated type ii alveolar epithelial cells, extracellular glutathione inhibits hyperoxia-induced injury, inhibits pro-inflammatory cytokine release, and promotes cell growth. it is obviously very important to maintaining lung function as this is the inflammatory process that begins lung cell or tissue damage, as mentioned above. the highest levels of glutathione concentrations in the body are in the lungs, liver, and brain. gsh depletion leads to activation of nf-kb (pro-inflammatory signaling) and increased pro-inflammatory gene transcription and cytokine release from histone deacetylase suppression in epithelial cells. total and reduced gsh concentrations are much lower in people with ards, pulmonary fibrosis, and hypersensitivity pneumonitis than observed in healthy adults. alterations in alveolar and lung gsh metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, and asthma [ ] . we make glutathione in the body with cysteine and methionine, and it is difficult to take exogenously because digestion can destroy it. the precursors of cysteine (essential), glutamine, and glycine and cofactors (vitamin c, vitamin e, vitamins b , b , b , and b , folate (b ), minerals selenium, magnesium, and zinc, and alpha-lipoic acid, see below) are therefore recommended so that the body can produce it on its own. the two enzymes necessary to produce it, gamma-glutamylcysteine synthetase and glutathione synthetase, must also be functioning well. we also recycle glutathione if the precursors and cofactors are available. cysteine is usually the most rate-limiting precursor, and many people supplement with n-acetylcysteine to provide the body with this nutrient. although glutathione is produced in every cell of the body, the greatest production is in the liver, so focusing on liver health is important to maintain good glutathione production. production declines with age and with lung disease, as well as other conditions. there are very few foods containing glutathione; they are raw or very rare meat, especially liver, unpasteurized milk and other unpasteurized dairy products, and freshly picked fruits and vegetables, such as avocado and asparagus. however, as mentioned earlier, it may be destroyed during digestion. glutathione contains sulfur molecules, which may be why foods high in sulfur help to boost its natural production in the body. these foods include: cruciferous vegetables, such as broccoli, cauliflower, brussels sprouts, and bok choy allium vegetables, such as garlic and onions eggs nuts legumes lean protein, such as fish and chicken other foods and herbs that help to naturally boost glutathione levels include: milk thistle (a liver-regenerating herb) flaxseed guso seaweed whey glutathione is also negatively affected by insomnia. getting enough rest on a regular basis can help increase levels. addressing a drop in glutathione for lung health involves maintaining good levels of the precursors and cofactors mentioned above. a good way to bring in the less abundant amino acid cysteine is to take n-acetylcysteine (nac). doses of - mg were more effective than placebo in reducing symptoms [ ] . supplemental selenium can also help with glutathione production. glutathione supplementation has also become more effective. there are several forms, from capsules to topical liposomal, which have shown good absorption. inhaled gsh has good research for use in cystic fibrosis (cf), chronic otitis media with effusion (ome), hiv seropositive individuals, idiopathic pulmonary fibrosis (ipf), and chronic rhinitis. it is not recommended for asthma due to significant side effects, and additional evidence is needed to determine if use with emphysema is recommended although theoretically it should be useful. it is also not recommended to use inhaled gsh during cancer chemotherapy treatment as it may interfere with the medication's actions. the mechanism of action of inhaled glutathione is limited to the upper airways and lungs and does not seem to affect serum levels. before considering inhaled gsh treatment, the patient should undergo urine sulfite sensitivity testing using a readily available special test strip called "em-quant sulfite test. " if positive, inhaled gsh should not be used as bronchoconstriction may occur. the recommended dose is - mg per day, depending on response, and whether inhaled gsh is considered safe. efficacy should be tested using a baseline pulmonary function test and a follow-up test after a prescribed time later [ ] (. fig. . , box . ). there are also serum tests for glutathione levels. these cofactors are vitamin c; vitamin e; vitamins b , b , b , and b ; folate (b ); minerals selenium, magnesium, and zinc; and alpha-lipoic acid. what do the glutathione cofactors do that makes them so important? direct cysteine toward glutathione production and increase cellular uptake of cysteine help form the glutathione molecule out of the three precursor amino acids help recycle glutathione from its oxidized gssg form back to its reduced (active) gsh form help maintain glutathione levels and keep the gssg-gsh ratio balanced recycle each other, improving overall antioxidant activity stimulate the activity of the whole glutathione enzymatic system co is a fat-soluble compound produced endogenously and also available through food and supplementation. it is required in the production of atp, is a powerful antioxidant, and therefore is helpful against oxidative stress, an important issue in lung disease. coq achieves its strong effects through a set of different mechanisms. it influences genes through its epigenetic effect to reduce inflammation, helps with the immune system, and even reduces aging by reducing systemic oxidative stress and mitochondrial aging [ ] . lungs are the most susceptible organ to oxidant damage because they interact directly with oxygen. therefore, it makes sense that antioxidants, and those that especially affect the lungs, are helpful in tissue and lung cell preservation [ ] . coq levels are significantly lower in those with copd and asthma with insignificant amounts of research on the levels of coq with other lung issues. it has been shown that supplementing patients with coq resulted in measurable benefits. in one study, patients with copd using steroids to reduce inflammation were able to reduce their steroid dosage when using coq [ ] . in another study, benefits were shown for copd patients during exercise, measuring performance, tissue oxygenation, and heart rate at a low dosage of mg/day [ ] . the levels of coq in the blood have been shown to indicate the degree of systemic oxidative stress, which implies it could be used as a marker to assess copd [ ] . several studies confirm the beneficial role of coq in decreasing oxidative stress, cardiovascular risk, and modulating inflammation during aging. dosage levels of mg/ day of coq have been shown to be therapeutic. however, in the reduced, more absorbable form, ubiquinol, mg/ day, was shown to be as effective. there is a wide range of toxins and anti-nutrients that can significantly impact the respiratory system. this can occur through acute or chronic exposure to these agents. the earth's air is the source of oxygen, and the lungs provide access to that oxygen to support life. the human need for oxygen is precarious because humans can only survive for about minutes without the precious gas. from about to sometime between and in europe and the united states, the ramp-up of new industrial revolution manufacturing processes opened a new era of increasing chemical and heavy metal atmospheric contamination. these pollutants can enter the body through breathing the polluted air. the more concentrated atmospheric pollutant densities cluster around areas of dense population. the dirty air provides a serious direct threat to those with respiratory diseases. an integrative and functional approach to assessing an individual with respiratory disease needs to include consideration of potential environmental contributors to the etiology of a condition. . table . lists environmental pollutants that are known to promote lung pathology. a study published in the canadian respiratory journal examined exhaled fractional nitric oxide (feno)an indicator of inflammation in the lungs -in school children at three different schools located three different distances from a large steel mill [ ] . steel processing is known to be a source of ambient iron, nickel, lead, copper, vanadium, and zinc. the study found statistically significant differences in feno between the two closer schools compared to the farthest school from the mill, indicating potential increased lung inflammation caused by heavy metals and/or air pollutants [ ] . although acute metal toxicity is possible, chronic, low-grade exposure is more common and may contribute to respiratory complications and disease. an individual's ability to vitamin c -as an antioxidant, it assists glutathione in this function and has been shown scientifically to raise glutathione levels short term; it is recycled by glutathione from its oxidized state back to its active state, thus strengthening antioxidant defenses; vitamin c also recycles vitamin e and alpha-lipoic acid vitamin e -as an antioxidant it also assists glutathione in eliminating free radicals much like vitamin c; it is also required for the proper functioning of glutathione enzymes; it recycles vitamin c and alpha-lipoic acid b vitamins -vitamins b and b maintain glutathione and its enzymes in their active forms; vitamin b participates in the formation of a glutathione molecule; vitamin b influences glutathione synthesis indirectly as it is important for the proper functioning of amino acids including gsh precursors; vitamin b increases the amount of magnesium (a vital cofactor) that can enter cells; folate (b ) pushes cysteine toward glutathione production rather than homocysteine production; folate and vitamin b work together in amino acid metabolism and protein synthesis. you can read more vitamin b deficiency and its effect on immune health at http://www. immunehealthscience. com/vitamin-b -deficiency. html selenium -part of the enzyme glutathione peroxidase (gpx). glutathione peroxidases, also known as selenoproteins, are a family of antioxidant enzymes that speed up the reaction between glutathione and free radicals magnesium -required for the proper functioning of the enzyme gamma-glutamyl transpeptidase (ggt) involved in the synthesis of glutathione zinc -zinc deficiency reduces glutathione levels, especially in red blood cells. however, zinc levels above normal have pro-oxidant properties and reduce glutathione too alpha-lipoic acid -an antioxidant produced by the body; it has been scientifically proven to enhance and maintain glutathione levels by stimulating enzymes involved in the synthesis of glutathione; it also helps increase the cellular uptake of cysteine, the crucial building block of glutathione; in addition, alpha-lipoic acid recycles vitamins c and e based on data from ref. [ ] eliminate these metals via detoxification in conjunction with gastrointestinal health and other factors can serve as important factors in whether or not these metals accumulate in the body. chronic arsenic exposure may be linked to respiratory complications [ ] . chronic arsenic ingestion via contaminated drinking water may be connected to respiratory symptoms such as chronic cough, shortness of breath, blood in sputum, and abnormal breath sounds [ ] . arsenic can also be ingested through foods such as rice and rice products, shellfish, and seaweeds, which have been shown to have high levels of inorganic arsenic (more toxic than organic arsenic found in fish) [ ] . however, ingested inorganic arsenic is typically biotransformed and excreted in the urine [ ] . that said, altered biotransformation has been observed depending on an individual's age, gender, nutritional status, and genetic polymorphisms responsible for the biotransformation of inorganic arsenic [ ] . chronic inhalation versus ingestion may result in irritation of the throat and respiratory tract [ ] . individuals most affected by arsenic exposure are children, nursing children, and infants of exposed pregnant mothers [ ] . acute inhalation of cadmium may lead to dyspnea and coughing [ ] . long-term exposure to cadmium has been reported to contribute to emphysema, dyspnea, and inflammation of the nose, pharynx, and larynx [ ] . individuals most affected by cadmium toxicity are those with occupations with cadmium exposure, such as those who work in certain types of factories, women, due to higher intestinal absorption because of low iron stores, and residents of asia due to high intake of rice grown in contaminated soil [ ] . the us national health and nutrition examination survey (nhanes) demonstrated an association between obstructive lung disease and serum lead and cadmium concentrations in the blood, where cadmium was shown to partially mediate the association between smoking and obstructive lung disease [ ] . in the korean nhanes, obstructive lung function was found to be associated with higher serum blood levels of cadmium and lead as well [ ] . the specific mechanism of heavy metal burden and its effects on respiratory health must be further investigated. although testing and treatment of heavy metal burden have its limitations, it is worth considering as heavy metal accumulation can wreak havoc on the body. an example of heavy metal testing that can be used in practice is urine provocation testing with a chelating agent, such as fda-approved dmsa. eliminating heavy metals from the body can be potentially harmful and requires careful monitoring and guidance by an experienced healthcare professional. air pollutants that are used as indicators of air quality are carbon monoxide, lead, nitrogen dioxide, ozone, particles, and sulfur dioxide [ ] . air pollution has been shown to have adverse effects on human health [ ] . a systematic review and meta-analysis done in china showed an association between respiratory disease and ambient nitrogen dioxide, which is increased through fuel combustion, industrial production, and fuel exhaust [ ] . diesel exhaust particles in particular have been associated with an increase in cytokines such as il- , il- , and ige in nasal mucosa [ ] . nitrogen dioxide in particular can potentially contribute to respiratory disease as it is a free radical that is highly reactive and poorly water-soluble and can be deposited in the lungs when inhaled [ ] . in another study performed in england, air concentration of nitrogen dioxide was significantly associated with respiratory hospital admissions [ ] . other pollutants, such as fine particulate matter and ozone, have been shown to significantly affect respiratory function in copd patients [ ] . increased ozone exposure has also been associated with increased airway inflammation and respiratory symptoms along with decreased respiratory function in children [ ] . optimization of nutrition and antioxidant status is essential to combating the potential health effects of air pollutants. . [ ] . it would be reasonable to assume having adequate stores and ability to utilize these nutrients may protect against other insults to the respiratory system as discussed in this section through their anti-inflammatory properties. acute and chronic exposure to certain chemicals can also pose a risk to respiratory health. obtaining a full occupational and social history when assessing individuals is important in order to identify any potential exposure to chemicals. one of the most well-known and common toxic chemical exposures that affects respiratory health is cigarette smoke. smoking cigarettes has been identified as a main cause of copd [ ] . increased oxidative stress from inhaling cigarette smoke appears to activate the nf-kb inflammatory pathway, increasing the production of pro-inflammatory cytokines such as interleukin (il)- , il- , and il- and tumor necrosis factor-ɑ (tnf-ɑ) [ ] . it also appears to reduce anti-inflammatory cytokines such as il- [ ] . electronic cigarettes, or e-cigs, have been increasing in popularity in recent years and are marketed as a better alternative to tobacco cigarettes. however, recent evidence suggests that the vapor and associated chemicals produced by e-cigs may be harmful to the respiratory system, although further research is needed to determine the mechanism [ , ] . exposure to metalworking fluid aerosols has been associated with asthma, hypersensitivity pneumonitis, impaired lung function, allergic alveolitis, and sinusitis [ ] . a review also identified an association between occupational exposure to pesticides and increased risk of asthma and chronic bronchitis [ ] . there are many chemicals that are toxic when inhaled. for example, inhalation of chlorine is toxic to the lungs, where low doses can cause airway injury and high doses can cause both airway and alveolar injury [ ] . these injuries can manifest as dyspnea, hypoxemia, pulmonary edema, and pneumonitis [ ] . high doses of carbon dioxide, such as that released from dry ice, can also induce respiratory failure. stress may also play a role in respiratory health and the body's ability to combat insults imposed on the respiratory system. from a physiological standpoint, it is worth noting that acute stress via activation of the sympathetic nervous system increases ventilation through the production of glucocorticoids [ ] . repeated acute stress may also affect growth and repair mechanisms [ ] . chronic biological stress in the form of infections can also be inflammatory and negatively affect the immune system and may affect an individual's susceptibility to respiratory complications. see the chronic infections and respiratory health section on page # below for further information on this association. however, appropriate amounts of physical stress, such as in the form of exercise, can be beneficial to respiratory health. some research has indicated a benefit of aerobic exercise to respiratory muscle strength in cystic fibrosis patients [ ] . chronic stress can be defined as recurrent acute stress or inability to moderate acute stress responses [ ] . this can be in the form of physical or emotional stress. chronic stress and negative emotions such as depression, anxiety, and anger may be linked to endocrine and immune processes [ ] . immunoglobulin e (ige) and cytokine production, as well as respiratory inflammation, are markers that characterize the asthma response and have been shown to respond to stress in some capacity [ ] . it has been hypothesized that increased stress may increase susceptibility to air pollution given its effects on the inflammatory response [ ] . another connection between emotions and respiratory health is acknowledged in east asian medicine, noting the association between the lungs and feelings of sadness, grief, and anxiety [ ] (. table . ). asthma is a chronic inflammatory lung disease, triggered by either an ige allergic reaction or nonallergic factors, and results in reversible airway obstruction and inflammation of the airway [ ] . it is characterized by recurrent episodes of wheezing, breathlessness, coughing, and chest tightness [ ] . severe asthma or asthma that is chronic or poorly controlled may lead to airway and lung remodeling that involves deposition of fibrotic tissue which leads to constriction of the bronchi [ ] . although the exact mechanisms have not yet been identified, compromised nutritional status, such as deficiencies in selenium, zinc, and vitamins a, c, d, and e, has been connected to asthma [ ] . the pathophysiology of asthma, nutrition considerations, genotypic characteristics, and lifestyle influences will be discussed in this section. there are numerous potential triggers to the development and/or exacerbation of asthma which can be summarized in box . . the various causes of asthma have led to the classification of several different subtypes and endotypes of asthma in hopes of choosing more targeted treatments. the pathophysiology of asthma is complex and not fully understood, due in part to its heterogeneous nature, which necessitates its organization into individual phenotypes and endotypes. this organization is important to be able to utilize targeted treatments by identifying the root causes of the symptoms. however, more research is needed to more clearly identify the specific pathological mechanisms of each phenotype and particular treatment responses [ ] . two of the most common asthma phenotypes are allergic and nonallergic asthma [ ] ; allergic is characterized by increased th immunity (th high) and nonallergic defined by varying mechanisms depending on the trigger (th low) [ ] (see also chap. ) . allergic asthma involves the ingestion of typically harmless environmental triggers (listed in . table . ) by antigenpresenting cells in the bronchi, which interact with immature helper t cells that, in turn, trigger an unwarranted allergic response [ ] . this reaction occurs from repeated exposure to a trigger and is referred to as the type hypersensitivity response [ ] . this increased th immunity upregulates eosinophilic inflammation, tissue damage, airway hyperresponsiveness, and bronchoconstriction [ ] . mast cell activation disorders, which is characterized by diseases and conditions related to mast cell mediators and the activation of mast cells, must also be considered when addressing allergic asthma [ ] . in contrast, nonallergic asthma can be caused by other factors such as anxiety, exercise, stress, dry air, cold air, viruses, hyperventilation, smoke, or other irritants [ ] . . inhaled cadmium (cd) is deposited in the alveoli where it is then absorbed into the bloodstream cd is transported to erythrocytes or bound to albumin, where it is then taken up by the liver to form a complex with metallothionein (mt) cd interferes with the absorption of zinc and competes for the same enzyme binding sites enzymatic activity of zinc-dependent enzymes reduces preferential binding of cd to mt can cause zinc deficiency altered biotransformation and excretion of ingested arsenic via contaminated water are linked to respiratory complications chronic inhalation of arsenic may result in irritation of respiratory tract diesel exhaust particles in particular have been associated with increase in cytokines such as il- , il- , and ige in nasal mucosa [ ] nitrogen dioxide is a free radical that is highly reactive and poorly water-soluble and can be deposited in the lungs when inhaled [ ] rising pollen and mold counts [ ] increasing ozone [ ] chemicals increased oxidative stress from inhaling cigarette smoke may activate the nf-kb inflammatory pathway, increasing the production of pro-inflammatory cytokines such as interleukin (il)- , il- , il- , tumor necrosis factor-ɑ(tnf-ɑ) cigarette smoke may reduce anti-inflammatory cytokines such as il- [ ] stress repeated acute stress may also affect growth and repair mechanisms [ ] ige and cytokine production, as well as respiratory inflammation, are markers that characterize the asthma response and have been shown to respond to stress in some capacity [ ] increased stress may increase susceptibility to air pollution given its effects on the inflammatory response [ ] ( individuals suffering from nonallergic asthma will tend to be less responsive to th -targeted treatments due to a differing immune response at play [ ] . some of the additional proposed phenotypes are eosinophilic, exacerbation-prone, exercise-induced, fixed obstruction/airflow limitation, poorly steroid-responsive, and adult-onset obesity-related [ ] . several of the proposed endotypes are summarized in . the american partnership for eosinophilic disorders defines eosinophilic asthma as a type of asthma characterized by especially high levels of eosinophils, more commonly developed later in adulthood, although may occur in some children [ ] . many with eosinophilic asthma do not have underlying allergies or history of allergic conditions such as eczema, food allergy, and hay fever, which are thought to be seen more in people with allergic asthma [ ] . in contrast to allergic asthma, the cause of eosinophilic asthma is still unknown. histamine intolerance must also be considered in assessing the root cause of asthma. ingesting histamine-rich foods and beverages such as bananas, grapes, strawberries, citrus fruits, tomatoes, nuts, chocolate, pineapples, fish, spinach, fermented foods, and beverages [ ] has been shown to provoke a histamine response that may result in asthma exacerbations, among many other potential signs and symptoms [ ] . disruptions in redox, or oxidation/reduction, reactions in addition to hindered antioxidant defense have been . usually not responsive to glucocorticoids [ ] based on data from ref. [ ] found to be a risk factor for asthma severity and development [ ] . the levels of glutathione, one of the lung's most predominant antioxidants in both reduced and unreduced forms, are thought to be important for lung homeostasis and tied to asthma [ ] . more research is needed to determine the exact differences in the pathophysiologies of the various subtypes of asthma in order to develop more targeted treatments. minerals such as zinc, selenium, copper, and manganese may serve as cofactors to major enzymes with antioxidant activity in the lung, such as superoxide dismutase, catalase, and glutathione peroxidase [ ] . asthma has been associated with decreased activity of these enzymes [ ] . low selenium intake has been associated with multiple chronic diseases including asthma [ ] . selenium serves as a cofactor to glutathione peroxidase, an enzyme with antioxidant activity in the lung that is responsible for maintaining gsh/gssg redox balance [ ] . imbalance between oxidants and antioxidants seems to serve an important role in asthma. levels of nonenzymatic antioxidants glutathione, ascorbic acid, alpha-tocopherol, lycopene, and beta-carotene, in addition to antioxidant enzymes superoxide dismutase (sod) and glutathione peroxidase, were significantly lower in asthmatic children compared to healthy controls [ ] . the amino acids glycine and glutamine, which are important in glutathione synthesis, were also found to be significantly lower in children with asthma [ ] . dha has also been found to be abundant in airway mucosa, where it is decreased in individuals with asthma and cystic fibrosis [ ] . magnesium is known to elicit the relaxation of bronchial smooth muscle, decrease responsiveness to histamine, have an anti-inflammatory effect, and decrease the susceptibility of animals to developing anaphylactic reactions [ ] . it is estimated that two-thirds of the population in the western world is not consuming the recommended daily allowance of magnesium [ ] . magnesium can be used intravenously as an effective treatment of acute asthma attacks. one double-blind controlled trial that used . g of magnesium sulfate when patients did not respond to treatment with beta-agonists found decreased likelihood of hospitalization and improved lung function [ ] . magnesium sulfate as an adjunct therapy with bronchodilators and steroids has also been shown to have a benefit in children with moderate to severe asthma [ ] . although the exact mechanism is not yet known, magnesium is thought to increase glutathione concentrations in the lung [ ] . more research is needed to determine additional associations between specific nutrients and asthma. however, optimization of the nutrients discussed in this section has the potential to reduce the severity and/or progression of asthma (. fig. . ) . asthma has a strong genetic component, with more than genes associated with it in varying degrees across many populations [ ] . more recent potential genetic associations include filaggrin, which encodes for the epithelial barrier; ormdl , which encodes transmembrane protein; beta- adrenergic receptor gene, expressed throughout smooth muscle and epithelial cells of the lung; and interleukin- receptor gene, which has a variant associated with elevated ige [ ] . a systematic review and meta-analysis showed that deficiencies in selenium, zinc, vitamins a, c, d, and e, and low fruit and vegetable intake could be associated with the development of asthma [ ] . although this data is tenuous due to lack of randomized controlled trials, it does give some indication of the relationship between nutrition status and dietary patterns with respect to asthma development. more research needs to be done to isolate the impact of these nutrients and dietary patterns on asthma prevention and development. a review conducted by berthon and wood noted the protective effects of the mediterranean diet for allergic respiratory diseases as evidenced by epidemiological studies. this diet emphasizes minimally processed plant foods in the form of fruit, vegetables, cereals, beans, breads, nuts, seeds, and olive oil and low to moderate intake of dairy, poultry, fish, and wine, as well as low intake of red meat [ ] . this association was the strongest in children, where the mediterranean diet had a protective effect on atopy, wheezing, and asthma symptoms [ ] . however, there is less data available to support this pattern in adults. the same review noted an association between the "western" diet, which emphasizes refined grains, red and cured meats, french fries, sweets and desserts, and highfat dairy products and increased risk of asthma in children [ ] . a meta-analysis and systematic review done in showed a reduction of risk in childhood wheezing with high fruit and vegetable intake and also showed negative association between fruit and vegetable intake and asthma risk in adults and children [ ] . in contrast, food allergy has been especially linked with allergic asthma in children [ ] . a study examining food allergy in asthmatic children identified higher serum levels of ige in asthmatic children compared to healthy controls, where all asthmatic children in the study were also identified as having a positive skin prick test (spt) to various food allergens [ ] . a study done on children under the age of diagnosed with asthma, with or without allergic rhinitis, was placed on a meat-based formula of carrots, beef, broccoli, and apricots for weeks. it was found that % had nearly complete resolution of symptoms [ ] . this same study also found that the most common food triggers were milk, egg, chocolate, soy, legumes, and grains [ ] . while food allergy as a cause of asthma is more common in children, hidden food allergy has been reported to be the root cause of asthma in around % of adults [ ] . improvement in respiratory symptoms was also seen in a small study of adults given an antigen-free elemental diet in a hospital setting [ ] . removal of food triggers has also been linked to improvement in exercise-induced asthma [ ] . identifying food allergies can be a complicated process because many of the testing methodologies such as skin prick tests (spts) and blood tests can yield false-positive results for up to - % of cases, according to the food allergy research & education organization [ ] . a food elimination diet and/or oral food challenge can be a powerful tool in determining food allergy specific to asthma symptoms, where a dietitian or nutritionist in conjunction with physician and/or allergist can serve an important role through this process to support the individual. oxidative stress may play a key role in the development of asthma, which can also be true for the development of chronic diseases such as cardiovascular disease, diabetes, and cancer [ ] . it has been shown that obesity may be a risk factor for people with and without allergy and may worsen pre-existing asthma [ ] . individuals with asthma are twice as likely to have gastroesophageal reflux disease (gerd) than people who do not have asthma, especially those resistant to treatment [ ] . celiac disease and asthma have also been linked. an italian cohort study was done that showed a significant association between treated asthma and celiac disease, where antibiotic exposure in the first year of life was controlled for and not found to contribute to this association [ ] . it has also been found that individuals with celiac disease following a glutenfree diet experienced improvement in asthma symptoms [ ] . it is well-known that toxic exposure to particulate matter, airborne pollutants, or cigarette smoke can trigger asthma symptoms [ ] . more specifically, a dose-dependent relationship between cigarette smoke exposure and rates of asthma has been shown [ ] . traffic density and asthma exacerbations have also been clearly demonstrated [ ] . certain medications may also serve as triggers to asthma. aspirin-exacerbated respiratory disease (aerd) is considered another asthma subtype caused by nonsteroidal anti-inflammatory drugs (nsaids) and is characterized by asthma, chronic rhinosinusitis, and acute respiratory reactions [ ] . in addition, overuse of antibiotics in childhood has been linked to asthma [ ] , indicating a connection between the microbiome and asthma development. allergic bronchopulmonary mycosis (abpm) noted in . table . is caused by a hypersensitivity reaction to fungal colonization of the airways [ ] . this is typically caused by the fungus aspergillus fumigatus. without treatment, this may lead to fixed airflow obstruction and bronchiectasis [ ] . the progression of asthma is complex and multifaceted, from preconception through childhood and adulthood. research suggests that early life events are largely predictive for regulatory mechanisms within the pulmonary immune system [ ] . for example, prenatal exposure to a farming environment, one rich in microbial compounds, is thought to influence innate immune patterning in the mother which may affect the development of the neonatal immune system [ ] . this influence in immune patterning can be seen through higher expression of toll-like receptors and and cd on peripheral blood cells, which implies possible desensitization to allergens in children [ ] . t regulatory cells, which serve an important role in immune regulation and are thought to play an important role in asthma by suppressing the th inflammatory response to harmless air particles, have been shown to be impaired in the cord blood of neonates at hereditary risk for allergy [ ] . in the study performed by singh et al. looking at serum ige and cutaneous sensitivity to food allergens in asthmatic children here was a negative correlation of total ige and duration of breastfeeding, indicating a connection between breastfeeding and the immune response [ ] . additionally, reduced maternal intake of vitamins d and e and zinc during pregnancy has been associated with increased asthma symptoms in children [ , ] . vitamin d has been associated with the maintenance and/or development of the t regulatory cells stated earlier in mice; however more research is needed to determine a definitive association in humans [ ] . a clinical trial performed on non-smoking asthmatic patients showed higher vitamin d levels were associated with greater lung function; furthermore, supplementation with vitamin d showed improved treatment response to glucocorticoids [ ] . vitamin d may also directly increase the antiinflammatory cytokine, interleukin (il)- and also enhance steroid-induced il- production (see . fig. . ) [ ] . more research is needed to determine the exact mechanism of vitamin d in asthma and respiratory disease. beta-agonists, combined with corticosteroids, serve as the primary conventional therapy [ ] . typically, a short-acting beta-agonist will first be prescribed to manage symptoms as needed, where low-dose inhaled corticosteroids may also be prescribed [ ] . if symptoms persist, it is recommended to evaluate problems such as adherence to use, inhaler technique, or persistent allergen exposure and comorbidities [ ] . once these are ruled out, the step-up treatment is a combination of an inhaled corticosteroid with a long-acting beta-agonist [ ] . a summary of other conventional treatments and their mechanisms can be found in . table . below. unfortunately, conventional methods for the treatment of asthma may have harmful side effects. for example, the use of . fig. . effect of asthma treatments on regulatory pathways. (reprinted from lloyd and hawrylowicz [ ] . with permission from elsevier) systemic glucocorticoids may lead to immunosuppression, cataracts, and osteoporosis, where long-acting beta-agonists have the potential of increasing asthma exacerbation risk and death [ ] . beta-agonist desensitization is thought to be one of the reasons for increasing asthma exacerbation risk and death [ ] . related to several subtypes of asthma and their differing pathophysiologies, it is important to first determine the subtype before deciding on treatment. for example, in an individual with allergic asthma, this could be a potentially simple fix once the allergen that exacerbates symptoms is identified. a more conventional approach may involve starting the individual on an inhaled corticosteroid or an ige antagonist (i.e., omalizumab) [ ] , rather than identifying the root cause of the patient's symptoms. while medications may be warranted until the trigger is identified, finding the underlying causes may not be common practice in many conventional settings. in contrast, the ifmnt assessment takes a much deeper dive into identifying triggers and any nutrient insufficiencies, inflammation or immune dysregulation, biochemical individuality, lifestyle, energy dysfunction, toxic load, sleep, and stress issues are taken into account. with this information, the practitioner can make more targeted dietary, lifestyle, and supplement recommendations to obtain sustained resolution of symptoms by treating the root cause (. table a -year-old female presented with a complaint of reactive airway disease, which was diagnosed as asthma and had been prescribed inhalers. she reported that she felt like she had difficulty breathing most of her life, especially when exercising. however, her condition was not severe enough to seek help until she was years of age. she reported a lot of stress during this time related to applying for a postgraduate training position. she also reported year prior to diagnosis developing new allergic symptoms. her past medical history was significant for conditions related to airways, including chronic sinus infections, strep throat, bronchitis, and recurrent pneumonia. she could not remember the last time she felt well but assumed it was sometime as a young child. her nutrition and health goals were to breathe better and to not have to rely on inhalers. the following data was collected on her initial visit. . methyl xanthine found in tea used less commonly due to side effects relaxes airways due to inhibition of phosphodiesterases; acts as a functional antagonist in airway smooth muscle [ ] based on data from ref. [ ] . table . summary of an integrative and functional medical nutrition therapy assessment adequacy of nutrient-dense foods to begin to assess nutritional status organic or nonorganic to assess toxic load and nutrient intake food preparation and processing to assess nutrient content and identify potential contaminants (e.g., plastic endocrine disruptors) assess food sensitivities or intolerances to identify potential triggers microbiome status: assess comprehensive digestive stool analysis for microbiology and fermented food intake; history of antibiotics or microbiota agonists (medications, toxins, stress, etc.) toxin intake via plastics or inhalation and skin absorption which may affect immune response assess flavonoids intake as they are antioxidant and anti-inflammatory compounds with mast cell inhibitory action; adequacy may reduce airway reactivity consider celiac disease and gluten intake as potential inflammatory antigens mineral assess and restore zinc, selenium, magnesium, manganese, iron, and iodine status to normal reference. caution to not supplement or intake of food sources higher than reference antioxidants assess and restore antioxidant balance; vitamins a, c, d, and e and glutathione assess quercetin intake (leafy vegetables, broccoli, red onions, peppers, apples, grapes, black and green tea, red wine) as it may act as mast-cell stabilizing agent inhibiting release of histamine, tnf-alpha release, formation of prostaglandin d , reducing interleukin production consider supplementation of quercetin if quercetin intake is low [ ] protein status assess and restore to support connective tissue and immune status ensure adequate glutamine and glycine intake oils/lipid/fatty acids assess fatty acid balance as dha important in lung tissue integrity assess adequate serum cholesterol and fat intake to support lipid bilayer important for cellular function in lung (epithelial cells, surfactant production, etc.) methylation assess methylation status and detoxification capacity of toxins related to asthma exacerbation; important assessment biomarkers suggested: mcv/mch, homocysteine, methylmalonic acid, rbc folate, genomic methylation snps inflammation/immune dysregulation assess asthma biomarkers to help identify root cause (see . fig. extreme exhaustion, depression, add, anxiety (accompanied by panic attacks), constipation, pain in legs, neuropathy in feet (numbness and tingling), rapid heartbeat, and a very severe rash on feet known as chilblains. utis -recurrent as a child. poor immune function (frequent infections). antibiotic use (very frequent from childhood into adulthood). sinus infections, strep throat, and bronchitis -she had recurrent sinus infections and strep throat about once a year every year and often this would lead to bronchitis, she could not remember if she had these issues before middle school. depression, anxiety, add. acne. peptic ulcers. yeast infections -multiple throughout college. eczema. two recent episodes of pneumonia the last episode resulted in her asthma diagnosis. asthma. evaluate exposure to fungus to identify allergic bronchopulmonary mycosis assess individual's medication history, considering short-and long-term use of conventional treatments evaluate exposure to particulate matter, airborne pollutants, cigarette smoke, or toxic metals such as cadmium and arsenic sleep and stress assess sleep adequacy ( - hours with -hour rem sleep) and quality (good sleep hygiene with little light/ sound/emf disturbance) to support detoxification of toxins that may worsen respiratory status and aid in repair of damaged lung tissue . periostin plays a role in the pathogenesis of allergic diseases, including asthma, as it is associated as a downstream molecule of the cytokine, il- . periostin is used as a biomarker for type immunity and can be used to determine the potential effectiveness of medications used to treat asthma, such as anti-ige antibodies and anti-il- antibodies. asthmatic patients with high serum periostin tend to be aspirin intolerant, eosinophilic, late asthma onset, and have a high nitric oxide fraction. high periostin can also indicate a reduced response to inhaled corticosteroids [ , ] . periostin in the right panel is stained brown and is localized in the thickened basement membrane in asthmatic patients. (reprinted from izuhara et al. [ ] . with permission from the korean academy of asthma, allergy and clinical immunology) for several weeks, led to being immobile for almost weeks th- th grade: was often sick (strep, sinus infections, bronchitis); described it as being constantly sick from fall through winter every year; also developed eating disorder during this time; had severe menstrual cramps (induced vomiting) accompanied by acne, which led to being put on birth control at age as a precursor to accutane (never prescribed); chronic constipation starting during this time university freshman -sophomore year: eating disorder was most severe during this time. first semester of freshman year: developed digestion issues, after eating certain foods (especially mexican or salsas), stomach would become distended, experienced pain, and often would result in vomiting. pain so severe during finals week she was admitted to er with no diagnosis. ct scan revealed possible peptic ulcers. junior-senior year: depression, anxiety, and inability to focus were most severe during this time which resulted in missing a lot of class and struggling as a student; suffered multiple panic attacks; gained a lot of weight (from to lb); end of senior year became engaged to be married -moved to dallas, tx. lived in dallas for months, continued to experience depression and anxiety and weight gain, and moved back to home state initially started running (~ miles a day) and experiencing inability to breathe, diagnosed with pneumonia, prescribed inhaler to help with running; other symptoms: eczema around the eyes and neck (after running outside), pain in calves, numbness and poor circulation in feet (pulse not detected by several health professionals), and development of chilblain rash (very painful, itching, lasts about - weeks from development to resolution); increased running -ran a half-marathon. visited pcp and several specialists for help with chilblain rash with no resolution or diagnosis; lost a lot of weight (from to lb). ongoing increased depression, anxiety, and inability to focus; pcp rx cymbalta (depression and anxiety); cymbalta discontinued after ~ months (did not tolerate side effects), continued psychological therapy for several months; chilblain rash continued. stopped running long distances. gained weight back (from to lb); subsequently saw blog for integrative rd and followed suggestion to eliminate gluten and focusing on whole foods diet. chilblains and eczema began to resolve while following integrative rd recommendations of gluten-free diet with some improvements. however, difficulty breathing got worse, and diagnosis of asthma was made with fast-acting inhaler used for exercise; as time progressed, breathing continued to worsen, led to daily inhaler use. weight at this time is still at around lb. high dairy diet (consumed dairy products at most meals and snacks), consumed three smaller meals with three snacks in between meals and snacks balanced with protein, fat, and carbs, with carbs coming from fruits and vegetables and fat mainly from full fat cheese, greek yogurt, and butter mostly nonorganic produce and commercially raised meats digestion, assimilation, and elimination hx of peptic ulcers and chronic constipation (bm ~ - times a month) bms currently at about × per week on encounter utilization, cellular, and molecular (mapdom) hx of likely gluten sensitivity. presented symptoms of possible dairy sensitivity (bloating, acne, asthma). evidence for compromised intestinal barrier. minerals: infrequent bms could indicate low fiber or low mineral status (mg); when bms do occur, they are hard and dry (low mg); severe menstrual cramps (low mg); labs showed low k and na, on yaz birth control (low zinc and low b vitamins). antioxidants: consumed adequate fruits and vegetables each day. protein: has some evidence of poor/slowed wound healing as evidenced by sore on leg that has not completely healed after a year; cuts that take months to heal. d and fat-soluble a, e, and k vitamins -hx of poor immune function (low d), vdr +/+ (low d and possibly a). oils/fatty acids: high omega- /omega- ratio, higher intake of damaged fats, very low intake of omega- . methylation: symptoms of depression, anxiety, add combined with mthfr c t snp and on yaz (low b and folate). eicosanoid fatty acids status -suspect issues with pge series pathway to control inflammation due to following signs and symptoms: allergies, autoimmune condition (asthma), peptic ulcers, eczema, and severe menstrual cramps immune function -suspect gut dysbiosis due to following s&s: poor immune function, yeast infections, hx frequent antibiotic use, cyst, and constipation body composition genetic makeup that indicated prone to gluten and dairy sensitivity, low vitamin d status, and impairment in methylation broad spectrum probiotic + fermented foods bioactive b complex (includes mg p p b and mcg thf) mg gla evening primrose oil and zinc . aim to eat three larger meals a day, allowing space in between of ~ hours; increase omega- intake by adding in small fatty fish, such as sardines or anchovies, once per week and taking fish oil; decrease omega- intake, switch from conventionally raised meats to organic, pasture-raised; and replace fat in diet from dairy with coconut sources, more nuts, and avocados. patient presented ~ months after the initial visit (september ). her breathing had improved immensely. she was able to stop taking her albuterol inhaler before exercise, recently stopped daily inhaler. after dairy-free diet for months, reintroduced dairy (cheese, butter, yogurt). asthmatic symptoms returned about - days after the addition of each. noticed the more dairy consumed, the worse her symptoms became. at time of appointment, diet whole foods, gluten-free, and dairy-free. weight loss lb within the first month of going dairy-free, continued to lose some weight. when reintroduced dairy symptoms of bloating and increase in weight, which resolved returning to dairyfree diet. bms are regular now at ~ × daily. this patient case followed some common patterns in the development of chronic disease and the comorbidities that are common, especially autoimmune conditions like asthma. the first is the genetic susceptibility of the individual; several snps are prone to dairy sensitivity. second, significant evidence for gut dysbiosis, promoted compromised gut barrier, can contribute to the development of dairy sensitivity. third is the exposure to dairy protein antigen. diet history evidenced trigger for asthmatic condition. additionally, inflammation, immune dysfunction, and methylation issues present. signs and symptoms significant for decrease in pge series anti-inflammatory pathways. low dietary omega- s potential contributor to asthma. immune dysfunction evidenced by extensive history of infection-antibiotic use. genomic snp mthfr c t gene, which indicated a greater need for folate. the use of yaz birth control and symptoms of depression, anxiety, and add known further to deplete b and folate. the diet and supplements recommended targeted control of inflammation, restore gut ecology, promote proper methylation, and replete nutrient insufficiencies. results from -month follow-up showed successful outcome in helping improve breathing and wean her off of inhalers. this case is an example of the ifmnt approach able to address the complexity of the whole patient story and bring the metabolic priorities into a manageable intervention program for the individual. one study found that the composition of the nasopharyngeal microbiota in children was linked to the frequency of upper respiratory tract infections and acute sinusitis [ ] . a study that intranasally inoculated mice with lactobacillus fermentum reduced the amount of s. pneumoniae in the respiratory tract and increased the number of macrophages in the lung and lymphocytes in the trachea [ ] . these findings may indicate a benefit of manipulating the upper respiratory tract microbiota with orally or nasally administered probiotics in the prevention and/or treatment of upper respiratory tract infections. allergic bronchopulmonary mycosis (abpm) is caused by a hypersensitivity reaction to fungal colonization of the airways. this is typically caused by the fungus aspergillus fumigatus. without treatment this may lead to fixed airflow obstruction and bronchiectasis [ ] . guillain-barre syndrome (gbs) is a rare neurological disorder in which the body's immune system attacks the peripheral nervous system, known as the network of nerves located outside of the brain and spinal cord [ ] . it is often preceded by a bacterial or viral infection. there are several potential mechanisms in which these infections trigger gbs. if an individual contracts a campylobacter jejuni bacterial infection, antibodies made to fight this infection can attack axons in motor nerves, which can potentially cause paralysis and respiratory failure [ ] . campylobacter can be ingested via contaminated food or other exposures [ ] . pérez-guzmán states that hypocholesterolemia is common among tuberculosis patients and suggests that cholesterol should be used as a complementary measure in antitubercular treatment [ ] . alpha- antitrypsin (a at) deficiency is an underrecognized disease in the united states, with around documented , people suffering from it, according to the alpha- foundation. this deficiency is inherited through autosomal codominant transmission, meaning affected individuals have inherited an abnormal aat gene from each parent [ ] . individuals with this deficient allele present with aat levels at less than % to low-end normal levels [ ] . however, it is also possible for individuals with a variant of this allele to be asymptomatic given different environmental conditions or lifestyle factors, such as refraining from smoking to reduce lung disease development risk [ ] ( box . ). a at deficiency most often manifests in the lungs as chronic obstructive pulmonary disease (copd) (i.e., emphysema or bronchiectasis or "genetic copd"). a at deficiency is often undiagnosed because people with genetic copd experience the same symptoms as people with copd, such as [ ] : shortness of breath wheezing the only way you will know for sure if you have genetic copd due to alpha- is to get tested. ________ a at deficiency can manifest in the liver as cirrhosis. symptoms related to the liver unexplained liver disease or elevated liver enzymes eyes and skin turning yellow (jaundice) swelling of the abdomen (ascites) or legs vomiting blood (from enlarged veins in the esophagus or stomach) a at expresses sometimes in the skin as panniculitis [ ] . panniculitis typically appears as raised red spots on the skin, which may break down and give off an oily discharge. while panniculitis spots (called nodules) may appear anywhere on the body, the most common places are the thighs, buttocks, and areas subject to injury or pressure. normal genotype m m most common abnormal genes are called s and z abnormal variant combinations: zz (highest risk) sz (lower risk increasing if smoker, inhalant pollutants) mz (lower risk of carrying an a at gene variant; considered "carriers") alpha- is the most commonly known genetic risk factor for emphysema up to % of all people diagnosed with copd may have undetected alpha- alpha- can also lead to liver disease. the most serious liver diseases are cirrhosis and liver cancer the world health organization (who), american thoracic society (ats), and the european respiratory society (ers) recommend that everyone with copd be tested for alpha- alpha- is a progressive disease that benefits from early detection. it can cause serious lung diseases, such as copd and emphysema when undiagnosed. in some cases, alpha- can also cause liver disease [ ] symptoms related to the lung [ ] : shortness of breath wheezing chronic bronchitis, which is cough and sputum (phlegm) production that lasts for a long time recurring chest colds less exercise tolerance year-round allergies bronchiectasis the alpha- antitrypsin (a at) protein protects the body, especially fragile lung tissues, from the damaging effects of a powerful enzyme called neutrophil elastase that is released from white blood cells. in a at deficiency, a genetic mutation reduces levels of the protective protein in the bloodstream. a at deficiency can lead to chronic obstructive pulmonary disease (copd), specifically emphysema, and liver disease. smoking, which can inhibit what little a at protein an affected person does have, increases the risk of lung disease. alpha- antitrypsin deficiency is completely determined by mutations in a single gene. the severity of symptoms is mostly a function of which mutations a person has and how many copies. however, smoking can greatly increase the risk of lung disease due to aat mutations. andme reports data only for the pi * m, pi * s, and pi * z versions of the gene that encodes aat. keep in mind that it is possible to have another mutation that causes this condition that is not included in this report [ ] . a at deficiency is a genetic disorder that reduces circulating levels of a protein that protects the lungs by trapping a at in the liver, where the protein is produced, and prevents a at from entering circulation. a at deficiency can lead to chronic obstructive pulmonary disease (copd), specifically emphysema, and liver disease. when a disease-causing mutation is fairly common, as the pi * s and pi * z mutations are in europeans, it suggests that the mutation actually conferred an evolutionary advantage at one time. some researchers have suggested that several thousand years ago when the pi * z and pi * s mutations first arose, these versions of the gene for a at gave people a survival advantage by creating an environment in their lungs that helped fight off infections. the scientists theorize that the antimicrobial benefits of the aat mutations outweighed the cost of an increased risk of copd and liver disease in the era before antibiotics were available [ ] . in contrast to lung disease, manifestation of liver disease related to a at can be referred to as a "toxic gain of function, " due to accumulation of mutant a at protein rather than protease deficiency within the liver [ ] . when taken together, fibrotic lung diseases are the leading cause of mortality worldwide. under the umbrella of interstitial lung disease (ild), pulmonary fibrosis (pf) is the most common. any ild that involves scarring of the lungs falls in the pulmonary fibrosis category. pulmonary fibrosis is the scarring of lungs, which destroys tissue over time, making it impossible to transfer oxygen from inhaled air into the bloodstream. there are more than different diseases under the pulmonary fibrosis umbrella. because pf is often misdiagnosed or goes undiagnosed, there is not an accurate count of those with these diseases. however, it is estimated that as many as in adults over , or , people in the united states, are affected [ ] . there are more than , deaths from ipf every year in the united states. more people die each year from idiopathic pulmonary fibrosis than from breast cancer [ ] . there are other forms of interstitial lung disease including the newly identified pleuroparenchymal fibroelastosis, cryptogenic organizing pneumonia (cop), desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, hypersensitivity pneumonitis, acute interstitial pneumonitis, interstitial pneumonia, sarcoidosis, and asbestosis [ ] . symptoms include cough and dyspnea, restrictive pulmonary function tests with impaired gas exchange, and progressive lung scarring. the disease progresses with an initiation of inflammation. fibrosing starts with the action of transforming growth factor-β (tgf-β)-dependent differentiation of fibroblasts to myofibroblasts, which then express α-sma (smooth muscle actin) [ ] . after the tgf-β-dependent differentiation of fibroblasts to myofibroblasts, which express α-sma, there is sustained, excessive deposition of collagen by the myofibroblasts in the lung interstitium leading to the progressive lung damage in patients with pf [ ] . research published in supported the idea that dysfunctional type ii aecs (alveolar epithelial cells) facilitate lung fibrosis through increased susceptibility to injury, leading to excessive and dysregulated remodeling [ ] . the disease seems to progress in steps, and inflammation is not typically present continuously, except during certain periodic episodes of deterioration (. fig. . ). there are five main categories of pf causes: drug-induced, radiation-induced, environmental, autoimmune, and occupational. of these five, four have identifiable causes. some of the autoimmune diseases that can lead to pf are rheumatoid arthritis, scleroderma, sjogren's syndrome, polymyositis, dermatomyositis, and antisynthetase syndrome. idiopathic pulmonary fibrosis (ilp) is defined as pf with an unknown cause, including a genetic cause for some families [see . fig. . ]. the symptoms of ilp are a dry, hacking cough, shortness of breath, fatigue, chest discomfort, loss of appetite, and unexplained weight loss, all caused by the fibrosing of the lungs. diagnosis can be difficult, and pf is often misdiagnosed as copd or other more common lung diseases. in addition, in the recent past, path to a true diagnosis was invasive. since damage to the lungs, even through a diagnostic biopsy, can trigger further lung damage or a period of fibrosis, many physicians or patients are cautious with a biopsy approach to diagnosis. since the current treatments are limited, one must evaluate whether defining the exact form of pf is necessary for treatment and follow-up. difficulty breathing, crackling sounds while breathing, and low oxygen levels are the first indicators. clubbed fingernails may also be a symptom. high-resolution ct scans are performed, which can show scarring. the pulmonologist will ask many questions and order more blood tests to try to distinguish between the forms of pf. the future is pointing to molecular endotyping as a more accurate way to diagnose. molecular endotyping includes genetic, metabolic, transcriptional, and environmental factors to help determine the pathophysiology [ ] . genetic research has been progressing for a couple decades with illuminating results. there are more than a dozen genetic variants that have been associated with this family of diseases. researchers now believe at least % of idiopathic pulmonary fibrosis (ipf) patients with multiple family members suffering from ipf have some common familial genetic variants, which may allow researchers to eventually drop the term idiopathic and further define various forms or categories, with differing progression or outcome. the name given to this version of interstitial pneumonias is familial interstitial pneumonia (fip) [ ] [see . currently two categories of genetic focus have been defined: those genes related to telomere biology (shorter telomeres) and those related to surfactant protein processing. the genes related to shorter telomeres are tert, terc, htr, dkc , and rtel . more mutations have been found in the tert gene, which encodes the protein component of telomerase, than any other gene. further research may allow targeted therapies to affect the genetic expression associated with the development of ipf [ , ] . a common variant within the promoter of the muc b gene is the most replicated single-nucleotide polymorphism related to familial and sporadic forms of ipf as well as early radiographic findings of ipf [ ] (. figs. . and . ). wound contraction and re-epithelialization . fig. . the cellular and molecular mechanisms of fibrosis in multiple organs. the cellular and molecular mechanisms of fibrosis in multiple organs. once an injury occurs in an organ, epithelial and/or endothelial cells are impaired, which results in the release of chemokines and growth factors, including il- and tgf-b . macrophages and monocytes are recruited and activated, both of which further release cytokines and chemokines and further induce fibroblast activation. activated fibroblasts transform into a-sma-expressing myofibroblasts and migrate into the wound along the fibrin lattice. ecm is excessively accumulated, and some parenchymal cells (hepatic stellate cells in the liver, tubular epithelial cells in the kidney, alveolar epithelial cells in the lung, or cardiomyocytes in the heart) are further differentiated into myofibroblasts or fibroblasts by the stimulation of cytokines and chemokines, especially for tgf-b . after the inflammatory phase, two events occur. one is the regeneration of injured tissues followed by wound contraction and reepithelialization. in contrast, once chronic injury, inflammation, and necrosis occur, myofibroblasts are perpetually activated, and excessive ecm is deposited, finally resulting in fibrosis formation. ctgf, connective tissue growth factor; ecm, extracellular matrix; egf, epidermal growth factor; emt, epithelial-mesenchymal transition; hsc, hepatic stellate cell; il, interleukin; mmp, matrix metalloproteinase; tgf, transforming growth factor; timp, tissue inhibitors of metalloproteinase. (reprinted from chen et al. [ ] . with permission from elsevier) conventional treatment is typically palliative. the american thoracic society recognizes that supplemental oxygen and transplantation are the only suggested treatments for ipf. supplemental oxygen is prescribed, and the need for oxygen increases over the progression of the disease. keeping the oxygen saturation level over % (normal is in the upper s) is ideal and is how healthcare providers determine the level of supplemental oxygen to be used. cardiovascular exercise, in this case called pulmonary rehabilitation, is recommended to maintain as much use of the lungs as possible. infrequently, nutrition and counseling are recommended and are placed into the category of symptom management. nutrition can have a significant role in the management of this disease, but little implementation exists in some of the proposed protocols. there are currently two medications available in the united states with minor impact on the disease progression: nintedanib (commonly called ofev) and pirfenidone (esbriet). histopathological quantification showed similar amounts of dense collagen fibrosis, fibroblast foci, and alveolar macrophages in untreated or pirfenidone-or nintedanibtreated ipf patients [ ] . both have significant side effects, including fatigue and gi issues, and patients may have to evaluate their quality of life versus length of life. other antiinflammatories or immune-suppressing medications used are corticosteroids, mycophenolate mofetil/mycophenolic acid (cellcept®), or azathioprine (imuran®). immunesuppressing drugs may be harmful for those with short telomeres, and researchers are exploring this potentially contradictory recommendation [ ] . lung transplantation is a final effort. about is half of all transplants. with the prevalence of this disease closer to , , this is a small fraction of those with the disease. some of those with the transplant go on to live productive lives, while others develop pf again, in the transplanted lungs. overall, there is a shorter life expectancy in those with pf, because of telomere shortening. bone marrow or immune response abnormalities have been found in some ipf cases before and after lung transplantation, which increases the associated morbidity. as stated above, inflammation occurs at the beginning and throughout the progression of all fibrosing diseases, including those of the lungs. therefore, reducing inflammation is one wise strategy to slow fibrosing. there are several nutrients that can help slow or reverse the inflammation involved in the fibrosing process. the following two-part diagram shows where in the fibrosing pathogenesis each phytonutrient acts [ ] (. fig. . ). a few of those compounds are discussed in more detail here. curcumin, the active constituent in the common spice turmeric, has been shown to reduce fibrotic activity in several studies. in mice, curcumin inhibited collagen secretion of ipf fibroblasts. it affects the signaling of tgf-β, in a dosespecific manner, resulting in reduced expression of α-sma, which is responsible for inappropriate fibrosing. this was shown in vitro and in vivo in mice, with intraperitoneal, but not oral, administration. at the time of the study, oral ingestion of curcumin was not adequately absorbed into plasma, and there was greater than ten times plasma concentration of curcumin following an intraperitoneal injection [ ] . however, some new oral products on the market are showing greater absorption. the results of this study suggest more research into curcumin, including improved delivery into patients. for example, some delivery options may include nebulized curcumin directly into the lungs, binding it to highly absorbable agents for oral use or liposome-encapsulated curcumin suitable for intravenous use (already shown to be effective in an animal model). according to manufacturers of curcumin products, some are more readily absorbed than others. one study on fibrosing suggested that a dose of around mg curcumin split into three doses taken with meals including pepper (bioperine) achieved doses that were sufficient to exert the desired therapeutic effect. research into using quercetin also has some promising results in slowing the progression of ipf. quercetin reversed lung fibrosing in mice and reversed the disease progression normally caused by typical pulmonary senescence markers [ ] . it is worth mentioning that n-acetylcysteine (nac), a long-used therapeutic agent for breaking down mucus in the lungs, has not been found to be effective in those with ipf. in fact, due to its acidic nature, it has even been shown to be harmful when used in the inhaled form [ ] . several of the drugs being developed have a natural product as a model or foundation. until a drug or gene therapy is developed that stops or reverses this disease, it may make sense for the patient to focus on anti-inflammation and reducing myofibroblast activation, the extracellular matrix (ecm) accumulation, and the epithelial-mesenchymal transition (emt) process. the phytochemicals listed in . fig. . would be good ones to investigate. with the recent identification of genes associated with ild, a call for gene-related therapies both related to telomere lengthening and connective tissue disease has been initiated, and this type of therapy, as with any disease, could be personalized [ ] . one recent study looked at various biomarker values as a more precise way of diagnosing. the biomarker molecules were classified according to their involvement into alveolar epithelial cell injury, fibroproliferation, and matrix remodeling as well as immune regulation. furthermore, genetic variants of tollip, muc- b, and other genes associated with a differential response to treatment and with the development and/or the prognosis of ipf were identified. research into personalized medicine for treatment is starting [ ] . although controversial, because of the lack of research on interpretation of the results, telomere length testing is available directly to consumers and through healthcare . fig. . antifibrosis therapy. the molecular mechanisms and therapeutic targets of natural products against fibrosis. a tgf-b exerts a profibrotic effect through smad-dependent [target ( )] and smadindependent pathways [target ( ) ]. in the smad-dependent pathway, tgf-b directly phosphorylates and activates the downstream mediator smad and smad through tgf-b receptor i, and then smad and smad bind smad , which forms a complex that moves into the nucleus and initiates gene transcription. smad , transcribed by smad , is a negative regulator of tgf-b/smad signaling, and the imbalance between smad and smad contributes to fibrosis. pi k, erk, and p mapk are downstream mediators of the smad-independent tgf-b pathway. pparg [target ( )] could inhibit tgf-b to reduce fibrosis, while ctgf [target ( )], a matricellular protein, contributes to wound healing and virtually all fibrotic pathology. additionally, gas contributes to fibrosis through the tam receptor, which further activates the pi k/akt pathway. similarly, lpa triggers fibrosis through the lpa receptor [target ( ) ] that stimulates b-catenin to induce fibrogenesis. the activation of the hedgehog pathway [target ( ) ] induces the transcriptional activity of gli to express target genes, which have an important role in interstitial fibrosis, undergoing myofibroblast transformation and proliferation. il pathway [target ( ) ] stimulates nf-kb [target ( ) ] to activate tgf-b to induce fibrogenesis, while nrf [target ( ) ] antagonizes nf-kb activity to protect against fibrosis. b the chemical structures of isolated compounds and their therapeutic targets are presented. ctgf, connective tissue growth factor; il, interleukin; lrp, low-density lipoprotein receptor-related protein; ri, transforming growth factor-b receptor i; rii, transforming growth factor-b receptor ii; sara, smad anchor for receptor activation; stat, signal transducer and activator of transcription; tcf, t-cell factor; tgf, transforming growth factor. (reprinted from chen et al. [ ] practitioners. there are a few different methods: quantitative polymerase chain reaction, or qpcr, which has a % variability rate, and flow cytometry and fluorescent in situ hybridization, or flow-fish, which has a % variability rate. most research labs use flow-fish for research. telomere length is a hot topic in research, the antiaging industry, and with popular health blogs. shorter-thanaverage telomeres have also been linked to heart disease and heart failure [ , , ] , cancer [ ] , diabetes [ ] , and osteoporosis [ ] . research has shown ways to slow telomere shortening. some include reducing stress, meditation, practicing loving kindness (a technique encouraging compassion) [ ] , reducing exposure to air pollution and toxins [ ] , cardiovascular exercise [ ] , and a healthy fat and high vegetable diet [ , ] . one study showed that minutes of cardiovascular exercise three times per week resulted in longer telomeres representing years of biological age, similar to those of marathon runners, compared to those who didn't exercise much or at all [ ] . intermittent fasting, which reduces oxidative stress and keeps weight in check, has exploded in the scientific literature as a way to increase longevity and slow telomere shortening [ , ] . nicotinamide adenine dinucleotide (nad+) supplements may also help maintain telomere length by activating sirtuins, the antiaging enzymes; parps, which are involved in dna repair; and cd , which plays a role in insulin production. another supplement, cycloastragenol, derived from the herb astragalus, has also been shown to activate telomerase in mice. an ingredient called ta- has been derived and is used in supplements [ ] . overall, a healthy lifestyle and diet seem to delay the shortening of telomeres. with relation to pf, the gene mutations involved in telomere shortening may or may not be influenced by the above interventions. more research is needed for this. pulmonary fibrosis is a devastating disease with no management or a known cure. the integrative and functional medicine nutritionist can help her/his patient by managing weight, encouraging a healthy diet full of anti-inflammatory foods and encouraging a healthy lifestyle with exercise and stress reduction. there is some promising research into natural supplement use to target the different areas of progression within the disease process and some ongoing drug and gene therapy development to follow. the prevalence of lung disease in the united states and worldwide is growing and will continue to grow rapidly with the deterioration of earth's atmosphere, which is caused by pollutants such as industrial and construction toxins and volcanic and wildfire particulates. poor maternal, childhood, and adult nutrition from micronutrient-poor diets resulting in nutrient insufficiencies, not necessarily nutrient deficiencies, is also contributing to increased lung disease diagnoses or poorer results during treatment [ , ] . lifestyle choices and habits also play a role in the development of many of the lung diseases in today's world, such as smoking or vaping, which uses chemicals that are poorly studied to date. other lung diseases have their roots in genetics. some key processes drive many lung diseases, with the inflammatory process being the most important, according to current literature. nutrition can be of great help with inflammation, using a diet rich in whole foods providing micronutrients and phytonutrients. understanding genetics is also key to unraveling the causes and potential future treatments for many lung diseases. those patients with both genetic and environmental determinants, such as in those who smoke and have genes associated with copd, are at the greatest risk [ ] . despite the prevalence of lung disease, there is a general lack of nutrition knowledge among practitioners, including familiarity with the research about the use of nutrition for prevention, slowing disease progression, or as a treatment of lung disease. historically, nutrition has been used in a supportive role, primarily monitoring macronutrients to prevent weight loss, muscle atrophy, and acid/alkaline balance. although this is extremely important, more attention needs to be directed toward emphasizing micronutrients and phytonutrients. research is strong regarding the benefits of vitamins, minerals, and pre-and probiotics, and indeed, some integrative and functional practitioners are using vitamin and mineral nutritional therapy in oral, intramuscular, and intravenous applications, when allowed, in practice. a newer area of research is around nutraceuticals, including targeted vitamins, minerals, and plantderived constituents concentrated to therapeutic doses. some exciting research around the use of curcumin and quercetin, for example, has been shown to dampen inflammation to the point of disrupting the disease process (see above). the expanding knowledge of the microbiome is identifying the importance of the lung 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is shorter in women with osteoporosis loving-kindness meditation practice associated with longer telomeres in women association between leukocyte telomere shortening and exposure to traffic pollution: a cross-sectional study on traffic officers and indoor office workers physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall association of marine omega- fatty acid levels with telomeric aging in patients with coronary heart disease telomere length, oxidative damage, antioxidants and breast cancer risk physical activity and telomere length: impact of aging and potential mechanisms of action protein restriction, epigenetic diet, intermittent fasting as new approaches for preventing age-associated diseases fasting mimicking diet is very relevant for health and longevity cycloastragenol is a potent telomerase activator in neuronal cells: implications for depression management periostin: an emerging biomarker for allergic diseases zemaira® | alpha- antitrypsin deficiency diagnosis assessment of quality of life in children suffered from asthma identifying maternal conditions affecting altered embryologic development. neonatal advanced practice nursing: a case-based learning approach susceptibility for cigarette smoke-induced damp release and damp-induced inflammation in copd key: cord- - ty rsy authors: busana, mattia; schiavone, marco; lanfranchi, antonio; battista forleo, giovanni; ceriani, elisa; beatrice cogliati, chiara; gasperetti, alessio title: non‐invasive hemodynamic profile of early covid‐ infection date: - - journal: physiol rep doi: . /phy . sha: doc_id: cord_uid: ty rsy introduction: little is known about the systemic and pulmonary macrohemodynamics in early covid‐ infection. echocardiography may provide useful insights into covid‐ physiopathology. methods: twenty‐three covid‐ patients were enrolled in a medical ward. gas exchange, transthoracic echocardiographic, and hemodynamic variables were collected. results: mean age was ± years. the patients were hypoxemic (pao( )/fio( ) = . ± . mmhg) and mildly hypocapnic (paco( ) = . ± . mmhg, ph = . ± . ). mean arterial pressure was decreased ( . [ . – . ] mmhg). cardiac index was elevated ( . ± . l∙min(‐ )∙m(‐ )) and the resulting systemic vascular resistance index low ( , [ – ] dyn∙s∙cm(‐ )∙m(‐ )). the right heart was morphologically and functionally normal, with pulmonary artery pressure (papm, . ± . mmhg) and total pulmonary resistances (tpr, . [ . – . ] mmhg∙l(‐ )∙min(‐ )) within normal limits. when stratifying for svri, patients with an svri value below the cohort median had also more severe oxygenation impairment and lower tpr, despite a similar degree of cxr infiltrates. oxygen delivery index in this group resulted supranormal. conclusions: in the early stages of covid‐ infection the hemodynamic profile is characterized by a hyperdynamic circulatory state with high ci and low svri, while the right heart is functionally unaffected. our findings suggest that hypoxemia, viral sepsis or peripheral shunting are possible mechanisms for the vasodilation that dominates at this stage of the disease and may itself worsen the gas exchange. mismatch, rather than on true right-to-left shunt only. it is by now clear that covid- infection is whole-body disease: together with severe pneumonia, hypercoagulability (panigada et al., ) , myocardial (shi et al., ) and encephalic involvement (mao et al., ) , the presence of the virus has been detected in the endothelium of different organs (varga et al., ) . moreover, autoptic findings showed a remarkable degree of intrapulmonary microthrombosis (patel et al., ; wichmann et al., ) and reports highlight the high incidence of overt pulmonary embolism (patel et al., ; poissy et al., ) , which may also justify the high v a /q mismatch observed (tsang et al., ) . failure of the hypoxic vasoconstriction has been put forward as an alternative or concurrent mechanism for the development of low v a /q regions (gattinoni et al., ) . nevertheless, while this should lead to normal or even decreased pulmonary vascular resistances, widespread microthrombosis should have opposite effects on the pulmonary circulation with possible impairment of the right heart function. little is known about the hemodynamic asset of covid- in the early stages of the disease and, unfortunately, the direct right heart catheterization out of an intensive care unit does not appear feasible, especially during pandemics. transthoracic echocardiography (tte) is a non-invasive alternative for a thorough hemodynamic evaluation, also feasible in the non-critical patient. this study provides data that could help to understand the interplay between the macrohemodynamics and the mechanisms of the severe hypoxemia in the early stages of covid- infection. the study was approved by the ethical committee of the institution. consecutive, non-critical, non-intubated covid- positive patients undergoing tte from nd march to th of april were screened for enrollment in a medical ward. patients with a history of ischemic, myocardial, valvular heart diseases, or suspicion of present acute cardiac illness were excluded. the arterial blood gas analysis was acquired either in room air or during the oxygen administration through low-flow nasal cannulas or venturi mask. the inspired oxygen fraction (fio ) was estimated accordingly. continuous positive airway pressure (cpap) or non-invasive ventilation (niv) were, at this stage, not applied. the alveolar-arterial o gradient (a-ao ) was calculated as: the systemic blood pressures (systolic, diastolic, and mean) were measured non-invasively. tte measurements and cardiac function analysis were performed in accordance with the american society of echocardiography recommendations. stroke volume (sv) was calculated from the velocity-time integral profile of pw doppler on the left ventricular outflow tract (lvot) and multiplied by the heart rate to calculate the cardiac output (co). systolic pulmonary artery pressure (paps) was assessed measuring the tricuspid regurgitation velocity and the right atrial pressure (rap) was estimated through the collapsibility of the inferior vena cava (rudski et al., ) . mean pap (papm) was calculated as proposed by chemla et al. ( ) . the systemic vascular resistances (svr) were calculated as: sv and co were divided by the body surface area (bsa) to calculate the stroke index (svi) and cardiac index (ci). the systemic vascular resistance index was calculated as: the total pulmonary resistances (tpr) were calculated as papm/co. the oxygen delivery (do ) and the oxygen delivery index (do i) were calculated as the arterial oxygen content (cao ) multiplied by co and ci, respectively. the chest x-ray scans (cxr) were were graded into five levels of severity according to taylor et al (taylor et al., ) : normal = grade ; patchy infiltrates/hyperinflation/bronchial wall thickening = grade ; focal consolidation in no more than one lobe = grade ; multifocal consolidation = grade ; and diffuse alveolar consolidation = grade . the normal distribution of the variables was assessed with the shapiro-wilk test. data are presented as mean ± standard deviation or median [interquartile range] as appropriate. the statistical significance of the difference between the variables was assessed with student's t test or kruskal-wallis test as appropriate. two-tailed p values <. were considered statistically significant. the data analysis was performed with python . . twenty-three patients were enrolled (figure ) , aged ± years, % of which were females, . ± . days after the onset of symptoms. only % suffered from chronic obstructive pulmonary disease, global initiative for obstructive lung disease stage (n = ) and stage (n = ). seventeen percent of patients suffered from diabetes. the anthropometric characteristics and comorbidities of the population are presented in table . the patients were hypoxemic (pao / fio = . ± . mmhg) and mildly hypocapnic (paco = . ± . mmhg, ph = . ± . ) with of a moderately increased respiratory rate ( [ - ] breaths per minute). moreover, the a-ao was markedly increased ( . [ . - . ] mmhg). in contrast, the cxr resulted only mildly altered (taylor score = [ - . ] out of ). the patients had no sign of altered mental status. body temperature was . ± . °c. only two patients had a temperature > . °c. they were all hemodynamically stable, with blood lactate levels were . [ . - . ] mmol/l. heart rate was ± bpm and stroke index . ± . ml•m - . cardiac index (ci) was on average elevated ( . ± . l•min - •m - ) and % of the patients exhibited a ci greater than l•min - •m - . the distribution of the svri is reported in figure , panel a. as shown, svri was low in the majority of patients ( , [ - ] dyn•s•cm - •m - ). in panel b we show the distribution of the oxygen delivery index (do i) which was elevated above the physiological value ( ml•min - •m - ) in % of the population. in table , we report the measured variables stratified above and below the median value of svri. of note, in the lower svri group, the hypoxemia was more severe, with higher need of fio despite an equal pao and a remarkably higher a-ao . despite that, do i, was particularly elevated especially in this group. interestingly, the cxr score was similar between patients with lower or higher svri. no intracardiac shunts, moderate-to-severe tr or additional echocardiographic signs suggesting pulmonary hypertension (ph) were detected. right heart function, dimensions, and pressures were within physiological limits: tricuspidal annular plane systolic excursion was [ - ] mm, paps . ± . mmhg, papm . ± . mmhg, estimated rap . [ . - . ] mmhg. interestingly, the tpr was normal ( . [ . - . ] mmhg•l - •min - ). in figure , panel a, we report the relationship between tpr and svri. as shown, the two variables were remarkably proportional (p < . , r = . ). in contrast, tpr and ci were inversely related (p < . , r = . ). in this study, we found that in the early stages of the disease, covid- infection leads to a hyperdynamic circulatory state characterized by an elevated ci and low svri. moreover, patients with particularly low svri, despite a supranormal do i, had more severe oxygenation impairment. the right heart function was unaffected, and pulmonary pressures were normal, despite the high ci, particularly in the low svri range. the negative quick sofa score (no altered mentation, respiratory rate < bpm, systolic arterial blood pressure > mmhg), the absence of fever, normal white blood cell count, and lactates within normal ranges make the hypothesis of a septic status unlikely. the effects of hypoxemia on cardiac output (kontos et al., ) and on the svri is known for decades (guyton et al., ) . indeed, to increase the oxygen delivery, heart rate and stroke volume increase and the arterial smooth muscles relax, thereby lowering the peripheral resistances. however, most of the observations show that this homeostatic response actually occurs when pao and, consequently, sao decrease to such extent that the arterial oxygen content (cao ) is extensively reduced (fernandes et al., ) . our population, instead, thanks to the oxygen administration, showed a near normal pao and sao . this, together with the increased cardiac output, led to a supranormal do i, particularly in the low svri group. therefore, it is tempting to speculate that hypoxemia alone may not fully justify the peripheral vasodilation and a direct action of the virus, given also its tropism for the ace- receptor, may be at play., viral sepsis has been suggested in covid- , but such an entity is stilly poorly characterized (li et al., ) . our findings may represent the early hyperdynamic phase of viral sepsis. furthermore, sonzogni et al. ( ) described severe alterations in hepatic blood flow with massive portal vessel dilations in autopsies from covid- patients. peripheral shunting and the associated reduction in transit time may per se justify the high ci and low svri observed in our population. in this context, it is possible that the overall reduction of vasomotor tone further worsens the hypoxemia. notably, patients with lower svri were more hypoxic, despite similar severity of the chest x-ray infiltrates. the hyperdynamic state may itself lead to further v a /q mismatch, through a reduction of the transit time and diffusion limitation as during exercise (dempsey & wagner, ) . a high ci itself leads to a global lowering of the v a /q ratio. for this reason, the beneficial effects of continuous positive airway pressure (cpap) on oxygenation may act, at least in part, by reducing the disproportionate co. lung recruitability in covid- is moderately low (pan et al., ) and blood diversion with cardiac output reduction may justify the reported oxygenation improvement at high positive end expiratory pressure (peep). and our non-elderly cohort showed elevated d-dimers (max , ng/ml). thus, we would have expected to find signs of increased pulmonary pressure, but this was not the case. indeed, we found normal estimated pulmonary pressures and tpr were lower in patients with higher ci, suggesting that pulmonary capillary recruitment worked efficiently. we are by no mean implying that pulmonary microembolism is not present in the early stages of the disease. rather, our findings suggest that the balance between vasodilation and vessel occlusion, at this stage, is shifted toward the former. a recent interesting report showed increased intrapulmonary neoangiogenesis (ackermann et al., ) that, by increasing the pulmonary vascular bed may, at least partly, explain this finding. pathological vasodilation of the pulmonary vasculature is also supported by the short duration and quick reversibility of the beneficial oxygenation effect during prone position (elharrar et al., ) and the positive response to almitrine infusion (losser et al., ) . these preliminary data have several limitations, primarily the low number of patients enrolled and the indirect estimation of the echo-acquired pulmonary pressures. even if we excluded subjects with probable pathological elevation of wedge pressure, these values must be confirmed by pulmonary artery catheterization. it is worth noting, however, that positive pressure ventilation and/or development of overt pulmonary embolism may change dramatically the overall picture. in the early stages of covid- infection, we detected a hyperdynamic state characterized by high ci and low svri. this was in turn associated with the severity of the hypoxemia, in absence of macrohemodynamic signs of pulmonary embolism. rather, pulmonary pressures were normal despite the high ci, favoring the hypothesis of a reduction of the pulmonary vasomotor tone or an increased vascular bed. none. open access funding enabled and organized by projekt deal the authors report no conflicts of interest to disclose. ms, al, gbf, ec, cbc, and ag collected the data. mb analyzed the data. mb, ms, and ag wrote the first draft of the manuscript. all authors critically revised and approved the manuscript. the study was approved by the ethical committee of the institution. the dataset of the study is available upon a justified request. https://orcid.org/ - - - pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- new formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure exercise-induced arterial hypoxemia use of prone positioning in nonintubated patients with covid- and hypoxemic acute respiratory failure reduced arterial vasodilatation in response to hypoxia impairs cerebral and peripheral oxygen delivery in hypertensive men covid- does not lead to a "typical" acute respiratory distress syndrome evidence for 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hospitalized patients with covid- in wuhan liver histopathology in severe covid respiratory failure is suggestive of vascular alterations a chest radiograph scoring system in patients with severe acute respiratory infection: a validation study spatial pattern of ventilation-perfusion mismatch following acute pulmonary thromboembolism in pigs endothelial cell infection and endotheliitis in covid- autopsy findings and venous thromboembolism in patients with covid- key: cord- -mnpu kl authors: lipscomb, mary f.; bice, david e.; lyons, c. richard; schuyler, mark r.; wilkes, david title: the regulation of pulmonary immunity date: - - journal: adv immunol doi: . /s - ( ) - sha: doc_id: cord_uid: mnpu kl thechapter describes the cells and structures of the lung that participate in pulmonary immunity and how the lung responds to challenges fromforeign antigens, with particular emphasis on animal models that have been developed to explore these issues. some ligands-receptor interactions are specific while others are not, and it is the particular pattern of surface molecules and secreted factors expressed by interacting immune cells that determines the type of immune response that develops during central processing. the cells that are the major initiators and regulators of immunity in the lung include macrophages, dendritic cells (dcs), and lymphocytes, each expressing surface molecules and secretory products that depend on perturbations in the environments. immune cells and structures of the lung and lung immunity to noninfectious particulate and soluble antigens are discussed. several models for regulation of pulmonary immunity such as models for immunity in lung infections, models for hypersensitivity lung disease, models for lung transplantation, and graft versus host are also presented. demonstration that lung cells regulate both nonspecific inflammation and immunity through the expression of adhesion molecules and the secretion of cytokines offers hope for ways to design more effective vaccines, enhance microbial clearance in immune-suppressed hosts, and to suppress manifestations of immunologically mediated lung disease. the human lung is exposed daily to over , liters of inspired, ambient air and the continuous aspiration of small amounts of nasopharyngeal secretions during sleep (kikuchi et al., ) . depending on the quality of air in the environment or the resident flora in the nasopharynx, the respiratory tree faces the enormous task of oxygenating blood across a moist, thin alveolar-capillary wall (approximately pm) and yet resisting infection. mechanical mechanisms and other innate host defenses are important in preventing infection, but acquired immunity is essential to prevent recurrent and chronic infection as made strikingly evident by the increased numbers and severity of pulmonary infections in immunocompromised hosts (newhouse et al., ; mason and nelson, ) . the lung, as is true of other epithelial surfaces that interface with the environment, has developed several strategies to avoid infection. as an important component ofthese strategies, the host must be able to downregulate both nonspecific and immune-mediated inflammation. failure to regulate local immunity results in diseases such as asthma, hypersensitivity pneumonitis, and perhaps sarcoidosis and idiopathic interstitial pneumonitis (holt, ; djukanovic et al., ; o'connor and fitzgerald, ) . thus, the desire to enhance protective pulmonary immune responses by vaccination and to prevent or control unwanted responses underlie the need to study basic immune mechanisms in the lung. furthermore, understanding critical immunoregulatory mechanisms may lead to strategies for preventing and controlling lung transplant rejection and immune-mediated lung damage in bone marrow transplant patients. a number of recent reviews have discussed important issues in the development of pulmonary immune responses (agostini et al., ; hance, ; lipscomb et al., a; gyetko and toews, ; holt, ; bice, ) . the goal of this chapter is to describe the cells and structures of the lung that participate in pulmonary immunity and to summarize studies that help explain how the lung responds to challenges with foreign antigens, with particular emphasis on animal models that have been developed to explore these issues. features of the immune apparatus that are unique to the lung will be highlighted, and important questions currently under investigation will be indicated. an important challenge is to understand how the host protects itself from infection yet regulates immunity to prevent tissue damage. tissue culture has been a powerful tool for understanding how immunologically relevant cells interact. the study of how various extracellular signals influence gene expression in cultured cells has given important insight into how the milieu could influence cell behavior at various anatomic sites. however, because it is not yet possible to know what all of the influences within a tissue are, hypotheses generated from cells in culture must be tested in uiuo. for example, alveolar macrophages (am) exist attached to epithelial cells and migrate within a layer of surfactant rather than attached to plastic in a layer of medium. a recent review in this series discussed the importance of placing lymphocytes in their spatial context within the host to properly understand their function (kroemer et al., ) . this consideration is especially important in the lung. in considering the development of pulmonary immunity in a spatial context, it is useful to divide the evolution of an immune response in the lung into three distinct but overlapping phases (see fig. ; lipscomb, a) : ( ) in the afferent phase, antigen reaches the lung, is fig. . a model for afferent, central processing, and efferent phases of a pulmonary immune response. in the afferent phase (aff), antigen that reaches bronchoalveolar spaces can directly enter lymphatics (l) or be processed by intraepithelial or interstitial dendritic cells (dc) that enter lymphatics and migrate to lung-associated lymph nodes (laln). in the central processing phase (cp) antigen on lung dcs (or, perhaps, antigen processed by resident lymph node dcs) present antigen to t lymphocytes (t) to initiate the expansion of t cell clones that, in turn, may help b cells expand when b cell immunoglobulin receptors recognize "native" antigenic determinants. in the efferent phase (eff), recently activated t cells and b cells (not shown) leave lalns and circulate; they are subsequently recruited to the lung at sites of inflammation. exposure of t cells to relevant antigen results in the release of cytokines that amplify an inflammatory response by recruiting nonspecific effector cells, such as monocytes (m), to the site and activating them to kill and/or growth-inhibit microorganisms. take up by antigen-presenting cells (apcs), and presented to naive t cells expressing the relevant t cell receptors (tcrs); ( ) in the central processing phase, specific lymphocyte clones are expanded and differentiate; and ( ) in the effector phase, effector t cells and b lymphoblasts find their way to pulmonary sites requiring expression of a specific immune response. at each phase, events must be tightly regulated to allow an effective immune response yet avoid excess, potentially destructive inflammation. the location in the respiratory tract where each of these phases occurs is somewhat controversial, but the bulk of evidence indicates that in the normal host after reaching the lungs, antigen is carried on apcs, in phagocytes, or free in lym-phatic fluid to draining lung-associated lymph nodes (lalns) (lauweryns and baert, - ; lehnert, ) where central processing occurs. effector cells are released into the efferent lymph and reach the blood stream where they are recruited from the vasculature into the lung (berman et al., ) . many investigations have considered the lung in the broader context of mucosal immunity. this conceptual framework is useful, but the respiratory tract has several distinctive features that require that initiation and expression of lung immunity be considered separately from immune responses at other mucosal sites. the respiratory tract shares features of other organs, i.e., skin, gut, and urogenital tract in which an epithelial layer interacts with the environment. for internal organs, the concept of a common mucosal system was developed based on evidence that immune lymphocytes generated at one surface migrated to both homologous and distant mucosal sites (mcdermott and bienenstock, ; mcghee et al., ) . we will return to this concept shortly, but in addition to this concept, the lung must be understood immunologically from the point of view that both an upper and lower respiratory tract system exist (kaltreider, ; kazmierowski et al., ) , and each system exhibits distinctive as well as common immune mechanisms. the upper respiratory tract starts at the nares and extends to the level of the terminal bronchioles. a pseudo stratified to single layered columnar epithelium covers vascularized connective tissue, the lamina propria, which, depending on the level of the airway, also contains variable numbers of mucous glands, smooth muscle, and, in the larger airways, is bounded by cartilage. by contrast, in the lower respiratory tract (which by definition includes the alveolar ducts and alveoli), the epithelium is markedly attenuated and frequently separated from the pulmonary capillary endothelium by only a fused basement membrane. the mechanisms of antigen handling and the types, location, and numbers of immunologically relevant cells differ even within areas of the upper respiratory tract, but are most strikingly different between the upper versus lower respiratory tracts. for example, mucociliary clearance is the major mechanism for clearance of particulates in the upper tract. in contrast, phagocytosis by resident am which subsequently attain the level of the upper tract to be removed by the mucociliary elevator characterizes particulate clearance in the lower tract (lauweryns and baert, - ; lehnert, ) . another distinctive feature of the upper versus lower tracts relates to the organization of lymphoid tissue. in the upper tract, lymphocytes reside in both aggregates and diffusely distributed along the mucosa of the upper tract, and in some animal species may infiltrate the epithelium (bienenstock et al., a,b; sminia et al., ) . in the lower tract, lymphocytes are present in variable numbers both within alveoli and in the interstitium, but, in the normal host, organized aggregates do not occur (sminia et al., ; pabst, ) . other important features of the upper versus lower tract involve the relative importance of iga as the protective antibody. thus, igasecreting b cells occur in the mucosa of the upper tract, and iga is the major immunoglobulin in secretions of the upper respiratory tract; although iga is present in the lower tract, igg and igm predominate in bronchoalveolar lavage (bal) fluids (kaltreider, ) . the development of immunity in the lung, as elsewhere, requires that relevant cells display appropriate surface molecules for contact and secrete appropriate factors. some ligand-receptor interactions are specific while others are not, and it is the particular pattern of surface molecules and secreted factors expressed by interacting immune cells that determines the type of immune response that develops during central processing. furthermore, at sites of pulmonary inflammation, other patterns of adhesion molecules and cytokine/chemokine expression by immune and parenchymal cells direct the tempo and magnitude of accumulation of recruited cells. many recent studies emphasize the critical importance of cytokines and chemokines and the expression of adhesion molecules in regulating pulmonary inflammation and immunity (kunkel et al., ; stein-streilein and phipps, ; redington et al., ; standiford et al., ; jordana et al., ; lukacs et al., a) . the cells that are the major initiators and regulators of immunity in the lung include macrophages, dendritic cells (dcs), and lymphocytes, each expressing surface molecules and secretory products that depend on perturbations in the environments. however, other cells in the milieu, e.g., epithelial cells, fibroblasts, mast cells, and various recruited blood leukocytes, also play important regulatory roles which will only be briefly examined in subsequent sections. first, however, the special feature of lung macrophages, dcs, and lymphocytes are discussed. originally proposed as important apcs in the lung (lipscomb, ) , this diverse group of cells is now best understood in the context of lung immunity as phagocytes and as regulators of both immunity and nonspecific inflammation (holt, ; lipscomb et al., a) . indeed, the bulk of evidence indicates lung macrophages are unlikely apcs in the initiation ofprimary immune responses. these cells reside within the airways at all levels of the respiratory tract, in the lamina propria, the interstitium, the alveolar regions and pleura, and within pleural spaces; in ruminant species, lung macrophages are found within the pulmonary capillaries (lehnert, ; brain, ) . all lung macrophages originate from the bone marrow (van oud alblas et al., ; springmeyer et al., ; godleski and brain, ) , but maintenance of at least some of these resident populations partly derives from self-replicating pools (pinkett et al., ; bowden and adamson, ; sorokin et al., ; tarling et al., ; shellito et al., ) . pulmonary macrophages are both phenotypically and functionally diverse, even within a single compartment. because of ready access to bronchoalveolar macrophages using bal, the diversity of these cells has been most frequently studied. macrophages obtained by lavage include resident am as well as macrophages that reside within the lumen of the bronchi and bronchioles (intraluminal macrophages); a distinction between these two cell populations cannot be readily made. however, the vast majority of cells obtained during a human lavage are from the alveoli, since the technique is performed with a wedged flexible fiberoptic bronchoscope and the large alveolar surface area relative to the bronchial surface area is sampled (reynolds, ; american thoracic society, ). in small rodents, e.g., mice and rats, a catheter is typically placed in the trachea and a larger proportion of the recovered cells are from the bronchi and bronchioles, but the majority of cells are still from alveoli if the procedure is performed correctly. functional attributes of subpopulations of resident am have been studied. most studies exploit the differences in density (murphy and herscowitz, ; shellito and kaltreider, ; oghiso, ) , predominantly a function of cell size. another fractionation technique depends on differences in the cells' capacity to be readily lavaged, a function of their adherence to epithelium and/or their residence in the bronchial lumen versus in alveoli . within subpopulations, am differ in expression of class i major histocompatibility antigens (mhc), fc and complement receptors, phagocytic capacity, responses to chemotactic stimuli, cytotoxicity, cytokine production, and capacity to suppress in vitro immune responses murphy and herscowitz, ; shellito et al., ; shellito and kaltreider, ; oghiso, ) . furthermore, the size, function, and phenotype of am shifts during an inflammatory response (van oud alblas et al., ) . although alternate explanations for these changes have been offered, the most likely one is that am recently arrived from the peripheral blood are similar in the size and phenotype to circulating monocytes, the precursors of am. thus, in the study of am and their subpopulations and, indeed, in any study of lung immunity, it has become a dictum that investigators must be careful to avoid low levels of chronic inflammation by housing experimental animals in specific pathogen-free environments. because respiratory infections are so common in nearly all animal species and can markedly affect experimental results, this consideration cannot be overstated. interstitial macrophages (im) when compared with am also exhibit size, functional, and phenotypic differences. these differences may reflect the stage of differentiation from blood precursors, but more likely reflect the environment and physiological roles of phagocytes in these two distinct locations. important membrane molecules that determine the function of macrophages include complement, fc, mannose, and scavenger receptors, as well as class i and i mhc, adhesion, and other signaling molecules. important differences in many of these exist depending on the location of lung macrophages. for example, in mice, im express c receptors, whereas most resident am do not (van oud alblas and van furth, ) . few studies exist on the role of interstitial, pleural, or intravascular lung macrophages in immune responses. however, numerous studies have examined the role of am in stimulating mitogen, alloantigen, and antigen stimulated responses in vitro. not surprisingly, these studies have often reached conflicting conclusions, a result of the differing animal species used, the level of superimposed am suppressive activity, and the assay procedure that was used (holt, ; lipscomb, ) . most studies support the concept that am are poor apc for priming t cells even when they express high levels of class i mhc, as human am do (holt, ; ansfield et al., ; toews et al., a; lipscomb et al., ) . bronchoalveolar cells, which contain up to % am, fail to act as effective apc in vitro because they are either actively suppressive or because they fail to express some other poorly understood accessory function which may manifest as poor lymphocyte-accessory cell binding (shellito et al., ; lyons et al., ; kradin et al., ) . most current evidence indicates that dcs are the most efficient apc in stimulating naive t cells, especially cd t cells, although class i mhc-positive cells of many cell types are capable of stimulating recently primed t cells (steinman, ; croft, ) . variable contamination of cells with lung dcs (pollard and lipscomb, ) and the presence of recently activated t cells in responder populations may well explain reports that am can function as effective apc (rich et al., ) . mechanisms utilized by populations of bal cells to suppress immune responses are likely to depend on variables of the assay systems and are particularly dependent on animal species. in dogs, pgez production (demenkoff et d., ) and the synergistic activity of pgez and oxygen radicals (kaltreider et al., ) were shown to be important. in humans, am/lymphocyte contact leading to inhibition of receptor-induced intracellular calcium increases in responder t cells has been described (yarbrough et al., ) . resident murine macrophages, particularly at high numbers relative to numbers of stimulator lung dc, suppress a mixed lymphocyte reaction (mlr) by secreting tgfp (lipscomb et al., b) . furthermore, nitric oxide (no) made by murine am may inhibit the development of potent apc cell function of lung dc . evidence that am suppression plays a role in vivo has been indirectly shown by depleting am with an intratracheal dose of liposomes containing a macrophage cytotoxic drug (dichloromethylenediphosphonate) followed by immunizing via the respiratory tract. the animals demonstrated increased numbers of antibody-forming cells (afcs) in lalns compared to immunized controls pretreated with only liposomes (thepen et al., ) . igg, iga, and ige afcs were all increased. am-suppressive activity is important to prevent the development ofhypersensitivity reactions, but in circumstances in which lungimmunity is important for protection, am-suppressive activity could be counterproductive. however, suppressive activity of murine macrophages can be inhibited by exposure to gm-csf and to a lesser extent by other selected cytokines (bilyk and holt, ) . the major role of ams seems to be to phagocytose and remove potentially dangerous particulates and soluble antigens from the alveoli and to inhibit local lung immune responses. however, immunity may develop in the presence of otherwise suppressive ams by the recruitment of leukocytes to the alveolus with opposing activity or by strong environmental influences that result in cytokine secretion that diminishes am suppressor function. immunologists have long recognized that adherent cells are required for optimal in vitro immune responses whether one measures t cell lymphoproliferative responses, t cell cytokine production, or tdependent b cell responses. they have also developed an increasing appreciation of the role of dcs in priming naive t cells since they were first identified in the spleen (steinman and cohn, ) . since then, the role of dcs in immune responses initiated at the epithelial surface is being clarified. little doubt exists that dcs play a pivotal role in initiating immune responses in the skin (reviewed by steinman, ) . furthermore, substantial support has developed for the concept that intraepithelial dcs are functionally different from those that have migrated into regional lymph nodes. thus, freshly isolated langerhans cells are capable of processing antigen and stimulating t cell clones, but they require "maturation" in vitro before they are fully effective in stimulating naive t cells in an mlr; at this time they have a markedly reduced capacity to process antigen (romani et al., ) . data indicate that lung dcs share a number of characteristics of skin dcs and likely also play a critical role in initiating lung immunity (holt, ) . apcs must not only process antigen and express it in the context of class i mhc, but also express appropriate accessory molecules to enhance the interaction of the apcs with t cells. recent studies emphasize the importance of the interaction of € on the apc cell surface with cd and/or ctla expressed on responder t cells to deliver a second signal (reviewed by june et al., ) . failure to trigger this second signal may cause t cells interacting with apcs via only the tcr-peptide/mhc i interface to become anergic (harding et al., ; boussiotis et al., ; chen and nabavi, ) and produce a state of tolerance in oivo (van goo et al., ) . b is a receptor family of at least two molecules in the immunoglobulin supergene family. b - , (cd ), and b - (cd ) are both expressed constituitively on dcs in contrast to macrophages and b cells that must be activated to express these molecules (vandenberghe et al., ) . other important accessory molecules, usually identified phenotypically by standard immunocytochemistry and functionally by the ability of specific antibodies to block an immune function, include cd , cd (icam-l), and cd (lfa- ) (steinman, ) . present on many lung dcs, but data are incomplete on the expression of cd , cd , and cd family. the high levels of constitutive class i mhc and the dendritic shape of dcs has been exploited to examine their location in tissue sections of lung by a number of investigators. dcs form an interdigitating network in the airway epithelium of all species in whom they have been investigated (sertl et al., ; holt, ) similar to the network described for skin langerhans cells. intraepithelial dcs are particularly dense in the trachea and gradually diminish in concentration as the airways branch, but are increased at sites of chronic inflammation . dcs also exist in the connective tissue surrounding bronchi and bronchioles, in perivascular connective tissue, in alveolar septa, in the pleura, and in very small numbers in alveolar spaces (sertl et al., ; holt and schon-hegrad, ; kradin et al., ; havenith et al., ; van haarst et al., ) . in rats, intraperitoneal injections of ifny increased the numbers of intraepithelial and septa dcs without increasing their accessory cell function , and inoculation of bacillus calmette-guerin (bcg) increased the numbers of dc that could be lavaged from the alveolus (havenith et d., ) . thus, the numbers of lung dcs in various anatomic sites depend on signals delivered that are coincident with inflammation. lung dcs have been isolated with a variable degree of success utilizing adherence, density, and class i mhc expression properties; their function and other phenotypic features have been studied. lung macrophages are the most difficult cells to separate from dcs in single cell suspensions of lung cells. effective procedures for isolating fairly pure dc populations require exploiting the phagocytic and autofluorescent properties of lung macrophages (nicod et al., , a pollard and lipscomb, ; havenith et al., a) . using these techniques, the function of dc-enriched lung cells has been assessed. functional assays have included stimulation of periodate-treated lymphocytes, mlrs, and antigen-induced stimulation of either memory t cells or lymphoblasts. all have shown that lung dcs function as well or better than dcs from other sources rochester et al., ; pollard and lipscomb, ) . dcs isolated from whole lung preparations are phenotypically heterogeneous, and cell markers differ somewhat among animal species and even within individuals of a species. an example of this latter variation relates to cdla (okt ), expressed by human langerhans cells in the skin, which has been variously described as being present on from less than % (sertl et al., ; nicod et al., ) to % (van haarst et al., ) of lung dcs in man. this antigen may be important in stimulating y t cells, a potentially important interaction for host defenses in the lung in view of observations that y t cells may recognize heat-shock proteins of mycobacterium tuberculosis (mtb) (born et al., , kaufmann and kabelitz, ) . variation in expression of cytoplasmic and surface markers also occurs within populations of lung dcs. for example, in the mouse, the interdigitating cell antigen (nldc- ) and cr are present on about half of lung dcs, while the majority of lung dcs express cd and the heat-stable antigen (as defined by j d; pollard and lipscomb, ) . the latter two markers are also uniformly expressed on murine thymus and skin dcs, but are absent from the majority of splenic dcs , indicating the likelihood of a closer relationship of lung dcs to tissue dcs rather than to dcs that primarily home from bone marrow to lymphoid tissue. additional evidence that lung dcs are distinct from the majority of splenic dcs is that lung dcs fail to express the splenic dc marker recognized by the monoclonal antibody d (pollard and lipscomb, ) . in both rat and mouse, another heterogeneous marker is fcrii, positive on about half of lung dcs (pollard and lipscomb, ; xia et al., ) . interestingly, langerhans cells freshly isolated from the skin express fcrii which is downregulated as the cells mature in culture. thus, it is possible that the fcr expression in the lung denotes a population similar to freshly isolated skin dcs. in the rat, dcs in the epithelium lining the airways are more likely to be fcr+ , whereas parenchymal dcs are nearly uniformly fcr- . murine dc in the epithelium of the trachea also express fcrii (sertl et al., ) . this suggests the possibility that intraepithelial dcs are poised to take up and process antigens at the epithelial/environment interface and enter the interstitium to traffic to laln. thus, at least some interstitial dcs which fail to express fcr may be in transit. on the other hand, the presence of fcr-dcs in lung parenchyma, including alveolar septa, may indicate distinct immune functions for this subset of lung dcs. no difference was found in mice in the capacity of the fcr+ or fcr-subsets to stimulate an mlr (pollard and lipscomb, ) . however, in the rat, the fcr-population was a more potent stimulator of naive t cells in an mlr and in responses to lectins, but fcrand fcr+ were equally capable of presenting soluble and particulate antigens to antigen-sensitized t cells (kradin et al., ) . of interest in these later studies was that % of fcr-and only % of fcr+ cells expressed the adhesion molecule cd (kradin et al., ) , an observation that might partly explain the increased ability of the fcrcells to stimulate an mlr. in elegant studies in which lung intraepithelial dcs were isolated from the rat, these cells were shown to present antigen to primed t cells more efficiently than did parenchymal dcs. in man, further enrichment for fcr+ decreased the ability of lung cells enriched in dc to stimulate an mlr , although these studies are complicated by the large numbers of contaminating fcr+ macrophages in the dc populations. nevertheless, fcr positivity has been a useful marker for identifying subsets of lung dcs and the majority of data are consistent with the concept derived from langerhans cells that a population of fcr+ intraepithelial dcs may take up antigen from the bronchial lumen and differentiate into cells that can stimulate naive t cells upon migration into draining lymph nodes. dcs in all tissue sites originate from the bone marrow (steinman, ) . they can be cultured from precursors in bone marrow and peripheral blood using gm-csf and, for adult human dcs, from peripheral blood with il (inaba et al., (inaba et al., , thomas et al., ; sallusto and lanzavecchia, ) . in one study, ia+ lung dcs were first recognized in rat lung parenchyma in fetal life at day of gestation . intraepithelial dcs were present by day and continued to increase during postnatal development . comparison of fetal lung dcs demonstrated that they were not as efficient as adult dcs in stimulating an immune response, but were fully functional at birth. in contrast, another study failed to detect ia+ dcs in rat lung epithelium or parenchyma until birth, and the numbers increased rapidly until weeks of age when they approximated those found in adults . ia+ dcs were first observed in the nasal turbinates and intensity of ia staining increased in time, first in the trachea and later in lung parenchyma, compatible with environmental exposure effecting the change. using another marker for dc, ox (which also detects y t cells), these same authors found cd -negative, x -positive dcs at all levels of the lung in fetal rat lung and speculated that environmental influences upregulated ia expression and subsequent function of these cells. consistent with this speculation was that ifny increased the numbers of la+ cells in airway epithelium while steroid inhalation decreased the numbers relative to control rats. the conflicting findings of the two groups may be based on the differences in the housing environments for the two groups of rats. thus, nelson and collaborators ( ) used dust-free bedding in contrast to mccarthy et al. ( ) . it was quite likely that in utero influences affected the numbers and function of lung dcs. numerous studies have demonstrated that dcs from spleen, lymph node, and skin have extraordinarily potent ability to immunize recipient animals following inoculation either iv or subcutaneously (knight et al., ; mckinney and streilein, ; sornasse et al., ) . lung dcs have not been used to immunize experimental animals to date, but several lines of evidence suggest that they have an important role in uiuo. as discussed, their location within the epithelium places them in an optimal position to take up and process antigens that breach the epithelial barrier; perivascular and septa dcs should be poised to process antigens that reach the lung via the vasculature. studies have shown that splenic dcs instilled into the lung may reach laln (havenith et ul., b) and if pulsed with antigen may induce an immune response (havenith et al., ~) . in this latter study, ams pulsed with antigen were also capable of initiating an immune response, but in contrast to dcs heat-killed ams were also able to immunize suggesting that ams stimulated responses by having the antigen reprocessed by the host's own apcs. additionally, explanted lung dcs had gained the ability to stimulate primed t cells following the intratracheal delivery of the relevant antigens . last, consistent with the dynamic activity of epithelial dcs in carrying environmental antigens into laln, irradiation of rats resulted in a loss of % of resident dcs by hr and reconstitution of tracheal dcs from bone marrow precursors by days . lung dcs most surely play a major role in regulating lung immunity and, as discussed previously, are likely themselves regulated by multiple environmental factors. it remains to be determine whether antigen presented by lung dcs is more likely to result in th versus th responses in the lungs and whether bypass of dcs in immunization of the host is more likely to deliver a tolerogenic signal, or whether other factors are more important in determining these outcomes. compartments (holt and schon-hegrad, ; stein-streilein, ; been described either by evaluating markers in situ or by obtaining cells from bal or collagenase digestion of lung tissue. as with lung macrophages and dcs, lung lymphocytes are a dynamic population with the capacity to enter and leave the lung depending on influences in the milieu. in several species including rat, rabbit, and chicken, large numbers of lymphocytes are located in organized bronchus-associated lymphoid tissue (balt), which is discussed below. however, balt is not constitutive in all species and not regularly seen in hamsters, mice, and humans. in these latter species, the majority of lung lymphocytes are present in the interstitiurn, diffusely scattered in the mucosa, alveolar septa, or pleura. also, depending on the species, there may be an intraepithelial and/or an intravascular pool of lymphocytes (pabst, ) . a population of lung lymphocytes exists in the bronchoalveolar spaces and is recovered by bal. in animals kept in specific pathogenfree environments, lymphocytes range from to % of cells recovered by bal (agostini et al., ; pabst, ) . in normal, nonsmoking humans the figures vary from less than to % (daniele et al., ; davidson et al., ; becker et al., ) . the proportion of t cells to b cells and nk cells varies to some degree with the compartment in which the lymphocytes are present. the composition of lymphocytes in bal fluids is generally representative of the proportion of t cells, including cd and cd t cells, and b cells found in peripheral blood. interestingly, in humans, differences in the phenotype and function of nk cells occur between the peripheral blood and the alveolus. thus, nk cells in human alveoli fail to express cytolytic activity and are largely negative for cd , although cd -expressng nk cells with cytolytic activity exist in the interstitium . relatively high numbers of cytolytically active nk cells also exist in the interstitium of mice. fifteen to % of cells fractionated on nylon wool columns following isolation from enzyme-digested lungs express the allotypic nk . marker, detectable in c bu mice . when leukocytes are isolated from the lung parenchyma of guinea pigs, mice, rats, and humans, the relative percentage of lymphocytes varies from to over %. the variance likely depends on the strain of animal, whether they are kept specifically pathogen-free, and the rigor by which small monocytes are excluded (much of the data are derived from examining wright-giemsa-stained cytospin preparations) (lipscomb et al., ; stein-streilein et al., ; holt and schon-hegrad, ; nicod et al., a,b) . flow cytometric analysis of t cell and b cell populations of lung lymphocytes indicates that the relative proportion of b cells is either increased or the same, and the cd /cd ratios are either decreased or similar compared to peripheral blood abraham et al., ; marathias et az., ; huffnagle et al., ) . intraepithelial lymphocytes are common in the gut mucosa and exist in lung epithelium of some animal species, but are relatively less common than those in the gut (holt and schon-hegrad, ; fournier et al., ) . in humans, no b cells were found in airway epithelium, and cd outnumbered cd t cells (fournier et al., ) . in an examination of epithelium of the upper respiratory tract (in the nose and covering the tonsil and adenoids), both b cells and t cells were found. notably, y t cells occurred in aggregates where they comprised up to % of the total t cells, although in general - % of t cells expressed the cup tcr (graeme-cook et al., ) . in studies examining cells isolated from human lung parenchyma, y t cells made up less than % of t cells and were cd +, cd -, and cd - (abraham et al., ; marathias et al., ) . in a study of mice, on the other hand, - % of resident lung lymphocytes were cd + and ap tcr-, and were presumably y t cells. y t cells increased following aerosol delivery of m . tuberculosis (augustin et al., ) . the regulation of movement of lymphocytes into and out of the lung is still incompletely understood. nevertheless, with increased information about the role of adhesion molecules in regulating the traffic of lymphocytes (springer, ) , investigators are beginning to unravel what regulates steady-state movement of cells into the lung as well as possible preemptive signals that occur with inflammation. research on emigration of cells into the lung has centered on the accumulation of neutrophils within pulmomary vasculature and their immigration into the air spaces of the lung because these cells are likely to play a critical role in the development of the acute respiratory distress syndrome. recent information indicates that the adhesion molecules, p-and e-selectin, the integrins, and icam- and icam- play important roles in the accumulation of neutrophils in the lung (pilewski and albelda, ) , the relevance of each adhesion molecule likely depends on the inflammatory stimulus that provokes the recruitment (hellewell et al., ; doerschuk et az., ; doerschuk, ; mulligan et al., a-e) . the regulation of lymphocytes into the lungs is less well understood even though, as mentioned above, evidence exists that lymphocytes isolated from laln or collected from the efferent lymphatics of laln have a predisposition to return to the lungs (mcdermott and bienenstock, ; spencer and hall, ; joel and chanana, ) . several studies have demonstrated that t lymphocytes isolated from lung lavages of normal humans predominantly express a memory phenotype, e.g., they are cd ro+, cd ra-cells (saltini et al., ; becker et al., ) . other important markers for naive versus memory t cells are the hyaluronic acid receptor (cd ) and l-selectin. naive t cells express low levels of cd and high levels of l-selectin, memory t cells express high levels of cd and low levels of l-selectin (reviewed in sprent, ) . thus, with the recognition that memory t cells accumulate preferentially in the lung, the issue becomes what is the stimulus for their entry and why do naive cells fail to accumulate. the role of naive t cells with their multitude of diverse receptors is to continuously recirculate through secondary lymphoid organs, i.e., spleen and lymph nodes, so that antigen-bearing apcs can interact with appropriate t cells at that site. this apc-t cell interaction results in clonal expansion and subsequently provides challenged tissues with a population of cells able to specifically react and protect the host. thus, naive t cells have receptors that allow them to migrate to secondary lymphoid organs (butcher et al., ; jutila ) . in contrast, lymphocytes that must enter challenged or inflamed tissues might be expected to express a different set of homing receptors. indeed, this is the case. although accumulation in markedly inflamed sites seems to be nonspecific, when only low levels of inflammation exist, where immune cells accumulate may be determined in the draining lymph nodes from which they derive (picker, ) . teleologically, this would be a more efficient way for the immune system to selectively redirect cells to sites where they are needed. indeed, evidence suggests memory lymphocytes bearing the cutaneous lymphocyteassociated antigen seem to specifically home to the skin (reviewed in picker, ) . studies also suggest that memory cells in the lung may have a unique set of homing receptors compared to memory cells in the skin or at mucosal sites . thus, cd +, cd ro high/cd ra low t cells in the skin were e-selectin+ and cla+, but were a p -and aefi -, while lung memory t cells were e-selectin-, cla-, and a p -, but % of the cells were aep -. the lung phenotype was different from the overall memory t cell phenotype in blood, suggesting that there might be an unidentified receptor on lung t cells that specifically selected them for emigration into the lung. an important issue is whether any naive lymphocytes traffic through the lungs. naive t cells migrate into peripheral lymph nodes via high endothelial venules (hev) using an l-selectin/peripheral lymph node addressin interaction. some animal species have balt in which hev are present. thus, in these animals, naive cells could enter the lungs and be available for primary immune responses to develop at these sites. however, evidence to support this possibility does not exist. despite scanty information about the migration of naive and long-term memory t and b cells into the lungs, several studies have noted that lymphoblasts (or recently divided lymphocytes) have a tendency to migrate into both inflamed and uninflamed lung (daniele et az., ; berman et al., ) . the location and mechanisms of lymphocyte transmigration are under investigation. e. organized balt macrophages, dcs, and lymphocytes are diffusely distributed throughout all of the compartments of the lung. in addition, in most animal species examined, at least some organized lymphoid tissue may be found in variable amounts lining bronchi and bronchioles. these structures have been recognized for many years, but were first carefully described in (bienenstock et al., a,b) . more recently, some controversy about these structures has been raised because of the inability to readily detect them in all species. thus, they are relatively rare in normal humans, cats, and young pigs (pabst, (pabst, , . when first described they were compared to intestinal peyers patches; they had the appearance of a follicle without a capsule. furthermore, lymphocytes infiltrates the overlying bronchial epithelium which demonstrated alterations in morphology compared to adjacent epithelial cells. they were originally described in the bronchial mucosa of all species examined, e.g., rabbits, guinea pigs, rats, mice, dogs, pigs, chickens, and man (bienenstock et al., a) . these early studies revealed that neonatal thymectomy failed to affect the normal development of balt in rats and chicks, and that tritiated thymidine labeling and autoradiography indicated that there was rapid cell proliferation of cells constituting balt (bienenstock et al., b) . transplantation of fetal lungs into extrapulmonary sites did not interrupt the development of the balt, although it was not as cellular, suggesting that antigenic stimulation was required for full development. since these early studies, two comprehensive reviews have summarized the morphology and function of balt (mcdermott et al., sminia et al., ). an individual aggregate of balt or bronchusassociated lymphoid unit (balu), a term defined by sminia and col-leagues, consists of a focal area of t and b cells admixed with fibroblasts, reticulum cells, macrophages, interdigitating cells which are comparable to ia-positive dcs, and follicular dendritic cells. balus have no capsule, subcapsular sinuses, nor afferent lymphatics. nevertheless, they have peripheral sinus-like lymphatics which subsequently drain into lymph nodes (lauweryns and baert, - ) . furthermore, there are arterioles, capillaries, and venules which include high endothelical venules (hev) (otsuki et al., ) . the structure of a balu with the demonstration of hev indicates the likelihood that naive t cells might migrate to these structures and initiate a primary immune response against an antigen translocated from the bronchial lumen, comparable to the role for peyers patches in the gut. although early studies failed to demonstrate antigen could cross the overlying epithelium, more recent studies have suggested that soluble antigens might be translocated from the bronchial lumen across the epithelium overlying a balu (fournier et al., ; myrvik and ockers, ; . in balus lymphocytes are partitioned into b and t cell areas with central b cells surrounded by t cells. the dome over these areas and underneath the epithelium is a mixture of b and t cells (sminia et al., ) . in balus, igm-and igg-bearing cells are present in significant numbers together with iga-positive cells which contrasts with peyers patches in which iga cells predominate (sminia et al., ) . in rats, balt has been examined with monoclonal antibodies to determine the type of t cells present; cdcpositive cells outnumber cd positive cells, but in the b cells aggregates nearly all of the t cells are cdcpositive cells (sminia et al., ) . important studies relating to the traffic of t and b cells to balus have been published (van der brugge-gamelkoorn and kraal, ) demonstrating in vitro binding of equal numbers of t and b lymphocytes to both rat and guinea pig balus. this finding is clearly different from peyers patch binding of t and b cells in which the numbers of b cells that bind are much greater than t cells that bind at a ratio of five b cells for every t cell . this finding corresponds to the increase in b cells in peyers patches relative to the numbers of b cells in balus (crawford and miller, ) . taken together, these studies indicate that the specificity of hev in balus is different from that in peyers patches and more closely resembles the specificity of the hev in mesenteric lymph nodes (van der brugge-gamelkoorn and kraal, ) . it is important to address the issue of a similarity of balt with gutassociated lymphoid tissue. balt is prominent in certain species including chicken, rabbit, and rat, but is clearly much less prominent in other species, including man. in some members of these species, balt may be completely absent (pabst, ) . nevertheless, even in man, other studies have shown that after birth, there is a gradual increase in loose aggregates of lymphoid cells that collect beneath the epithelium, particularly at points of bifurcation of bronchi. in man, mouse, and hamsters, these collections of lymphoid cells do not involve the epithelium nor modify the epithelium over the aggregate. in view of the relative lack of prominence of these structures in certain species, it suggests that their role in protective immune responses in the lung is not essential. since an important function in the gut is for these structures to initiate iga responses, it is possible that the lack of well-organized balt in some species predicts that local initiation of iga responses is not required for health. it also suggests that the common mucosal system in which iga b cell precursors are developed in the gut and migrate to the lung may function to successfully protect the host from lung infections. since the late s, investigators have been systematically exploring mechanisms in the development of immune responses to particulate and soluble protein antigens in the lung (pepys, ) . a major impetus was to understand what caused hypersensitivity lung diseases, such as asthma and hypersensitivity pneumonitis, to develop in some individuals, but not in others, although antigenic exposures were the same. models to examine immune responses to various respiratory antigens were developed in many animal strains, including mice, rats, hamsters, guinea pigs, ferrets, dogs, monkeys, horses, and cattle; antigens were delivered via aerosol, intranasal, intratracheal, or intrabronchial instillation. the end point for immunity in experimental animals was generally measured by assessing the development of hypersensitivity disease clinically and morphologically, measuring serum and/ or bronchoalveolar antibody, or characterizing some aspect of cellmediated immunity (cmi) such as migration inhibition, delayed-type hypersensitivity (dth) via skin test, or lymphoproliferation (richerson, ; newhouse et al., ; kaltreider, ; kazmierowski et al., ; ganguly and waldman, ) . among the important findings of these early studies were that soluble antigens instilled into the lungs, in contrast to particulate antigens, often failed to produce immunologic lung damage (schatz et al., ; fink, ) , and that soluble antigen repeatedly instilled into the lung could lead to local tolerance (ratzjczak et al., ; holt and leivers, ) . interpretation of early studies did not benefit from the current perspective that the type of immune response that develops, i.e., cmi versus antibody (including the predominant isotype of the antibody), is regulated by cytokines secreted by t cells and other cells present at sites of antigen deposition (mosmann and coffman, ) . more recent studies have expanded the important concepts derived from earlier studies by focusing on the regulatory mechanisms in the development of lung immunity. in order to understand how various forms of antigen might reach the immune apparatus and, therefore, antigen clearance is discussed. then, while t and b cell immunity are clearly interdependent, studies that have focused on measuring specific t cell responses versus immunoglobulin synthesis in response to noninfectious lung antigens are summarized. models that specifically examine the lung's response to infectious agents and alloantigens or lead to hypersensitivity disease are covered later. many studies have shown that the lalns are responsible for primary immune responses after lung immunization (bice et al., b; kaltreider et al., ; stein-streilein and hart, ; lipscomb et al., ) . lalns function as effective filters to remove particulate materials cleared from the lower respiratory tract via the lymphatics (brain et az., ; green et al., ; morrow, ) . although lalns are largely responsible for the induction of immunity after primary immunization, the mechanisms responsible for the clearance of antigen from the lung to lalns are not completely understood. most antigen deposited in the lung is cleared by phagocytosis by ams and neutrophils that transport foreign material up the mucociliary escalator and out of the lung, although some antigen is transported to lalns where an immune response is produced. at least some of this latter antigen is carried free in lymphatic fluid and apparently occurs in circumstances of limited inflammation (lauweryns and baert, - ) . the induction of pulmonary inflammation by antigen exposure appears particularly important in the translocation of immunogens from the lung to lalns. exposure of the lung to noninflammatory doses of antigen often fails to induce immune responses (yoshizawa et al., ; bice et al., ) . it is possible that an immune response to airway antigens requires a dose that overwhelms normal phagocytic and clearance mechanisms (bice and muggenburg, ; bice et al., ) . the observation that elevated immune responses are produced in lalns if antigen is deposited in the lungs of animals that have inhaled inflammagens further supports the importance of pulmonary inflammation in the translocation of antigen from the lung to the lalns (bice et al., , ) . it is possible that inflammation may also alter the relative proportion of antigen reaching lalns in cells as opposed to antigen free in lymphatic fluid. in dogs inoculated via the airways with sheep red cells, a large number of neutrophils enter the lung from the vasculature with a peak response about day after instillation of antigen . furthermore, neutrophils can phagocytize particles in the alveoli and migrate to the lalns carrying the particles (harmsen et al., ) . ams can also phagocytize particles in the lung and transport them to lalns (corry et al., ; harmsen et al., ) . the relative contribution of neutrophils and am in the translocation of antigen from the lung to lalns is not known. however, neutrophils with phagocytized particles reach lalns earlier than ams and, may be more important for antigen transport to lalns than ams. antigen transported to the lalns may be released from both neutrophils and ams and reprocessed by resident apcs to initiate pulmonary immunity. in addition to ams and neutrophils, as previously discussed, lung dcs also likely carry antigen to the lalns, and recent studies in which pulsed splenic dcs inoculated into the trachea were capable of immunizing the hosts supports this concept (havenith et al., ~) . whether antigen or lung dc initiates a different type of t helper subset response than antigen arriving in phagocytes or free in lymph has not been determined. nevertheless, if lung inflammation enhances the transport of antigens from the lung to the lalns, it is possible that inhalation of materials that induce pulmonary inflammation might lead to increased recognition of airborne antigens. thus, pulmonary inflammation caused by inhaled pollutants (osebold et al., ) and passive cigarette smoke (murray and morrison, ; ehrlich et al., ) might increase the immune recognition of allergens and be responsible for increasing rates of asthma (evans et al., ; platts-mills et al., ) . in addition, inflammation induced by pulmonary viral infections may also be important in the induction of immunity to low levels of environmental antigens, e.g., allergens responsible for asthma (castleman et al., ; duff et al., ) . b. t cell-mediated lung immunity several important questions relate to the development of cmi in the lung and include ( ) do antigens instilled into the lung cause local and/or systemic cmi? ( ) does the form of antigen, i.e., soluble, particulate, expressed by viable microorganisms influence the out-come? ( ) does iv or subcutaneous inoculation of similar antigens generate similar degrees of cmi in the lung? ( ) what redirects the immune t cells back into the lungs? inoculation of antigens into the lung can result in both local and systemic cmi (kaltreider, ) . as discussed previously, both soluble and particulate antigens can induce immunity, but soluble antigens induce a less easily detectable cmi response than a similar antigen delivered in particulate form as shown by experiments in which either soluble or aggregated human serum albumin were used as the immunogen (burrell and hill, ; hill and burrell, ) . infectious organisms which replicate in situ are even more capable of producing cmi both locally and systemically (waldman et al., ; spencer et al., ; ganguly and waldman, ; lipscomb et al., ) . haptens, such as trinitrobenzene (stein-streilein, ) , or metals (parker and turk, ) , such as beryllium oxide , may also induce cmi in the lung following direct instillation into appropriate animal models. haptens and metals are agents that lead to sensitization of humans exposed to these agents in the workplace and are associated with hypersensitivity reactions. a number of early studies addressed the issue of whether subcutaneous, iv, or direct lung instillation of antigens resulted in differences in the expression of cmi. in three separate studies, guinea pigs injected via the lung with human y-globulin (hgg), dnp-hgg, or heatkilled influenza virus accumulated specific t cells among lymphocytes recovered from the lungs as measured by migration inhibition factor release or by antigen-induced lymphoproliferation assays. however, subcutaneous or iv injection of these antigens failed to result in measurable specific t cell accumulation in the lungs, although systemic cmi could be measured in lymphocytes from nodes draining the subcutaneous inoculation site or from spleen (waldman and henney, ; nash and holle, ; lipscomb et al., ) . however, the initiation of a mild inflammatory response in the lungs resulted in the accumulation of immune t cells in the lungs of the animals immunized via the extrapulmonary route (waldman et al., ; nash and holle, ; lipscomb et al., ) . using a live, attenuated rubella vaccine or another live strain of rubella virus, the kinetics of a local cmi response was studied following the inoculation of guinea pigs either subcutaneously or by an intranasal inoculation (morag et al., ) . in these studies, migration inhibition factor activity was the parameter for measuring cmi responses and was initially detected in the lungs weeks after immunization, peaked at weeks, but was no longer detectable by weeks. when primary immune responses are generated in the laln, what stimulus recruits cells back to the lungs? lymphoblasts rapidly exit lymph nodes during developing immune responses (joel and chanana, ) . these cells enter the circulation and, under the control of adhesion molecules and locally generated chemotactic and other adhesion molecule-stimulating cytokines, are recruited into inflamed lungs (berman et al., ) . as previously discussed, although markedly inflamed lungs nonspecifically recruit both t cells and b cells, memory t cells generated in lalns may also have homing molecules that specifically direct their return to the lung ). an important factor in retaining recruited immune-specific cells is the continued presence of specific antigens within tissue and at least two groups have shown that this can occur (lipscomb et al., lyons and lipscomb, ; emeson et al., ) . thus, t cell blasts enriched for two different antigens and labeled with two distinguishable radioisotopes were shown to be retained in lung lobes nonspecifically, but with an additional selectivity in lung lobes containing the relevant antigen (lipscomb et al., ) . selective retention was induced by antigen carried by apc deposited in the lungs and was class i mhc restricted, suggesting that the t cells were retained in the lung lobes by binding to the apc in vivo . these studies added validity to a concept that four general mechanisms relate to recruitment and retention of immune cells in the lungs: ( ) recently activated t and b cells, i.e., lymphoblasts, from any lymphoid tissue are nonspecifically recruited into inflamed lungs; ( ) cells recently activated in lalns express adhesion molecules that are uniquely designed to target their binding to lung endothelium; ( ) matrix and lung parenchymal cell adhesion molecules expressed under the control of local environmental perturbations facilitate the emigration of immune cells; and ( ) antigen expressed on the appropriate mhc in the lung leads to preferential retention and further expansion in the lung. specificity of recruitment for b cells has not been shown (see below), but in the presence of retained antigen and specific t helper cell recruitment, specific b cells could divide and differentiate. c. b cell-dependent lung immunity antigen-specific antibody produced in lalns after a primary lung immunization is released into blood (bice et az., a; shopp and bice, ) . in addition, large numbers of antigen-specific igg, iga, and igm afcs produced in lalns also enter the blood after lung immunization of sevral species, e.g., dogs, cynomolgus monkeys, chim-panzees, humans (bice et al., aj b; kaltreider et al., ; mason et al., ; weissman et al., ) . in studies of larger animals, afcs in blood are recruited into a lung lobe exposed to antigen, but significantly fewer afcs are found in the other lung lobes of the same animal that are exposed to saline or nothing. there appear to be two factors that control the entry of afcs into the lung. first, afcs must have been recently produced in an immune response . the lymphoid tissue in which they are produced exerts no control on their entry into the lung because afcs produced in the popliteal lymph nodes enter the lung at the same rate as afcs produced in lalns (hillam et al., ) . second, afcs enter sites of inflammation produced by instillation of antigen into the lung (bice et al., a; hillam et al., ) . however, the recruitment of afcs into inflammatory sites in the lung is not antigen specific because they also enter lung lobes inflamed by instillation of particles or other inflammatory agents. plasma cells are found in the alveoli and interstitial lung tissues of immunized lung lobes suggestig that afcs that enter the lung mature to plasma cells (bice et al., a) . most antigen-specific igm, igg, and iga antibody in the lung after a primary exposure to antigen is produced locally by these cells (hill et al., ) . the few afcs in control lung lobes exposed to saline also actively produce antigenspecific antibody (bice et al., a ) . the results of several studies show that afcs in the lung after a primary immunization are recruited into the lung and are not produced locally (mason et al., ; bice et al., ) . in addition, cell numbers are not amplified by interaction with antigen that might have been retained in the lung after primary immunization (bice et al., a) . in addition to afcs, large numbers of other lymphocytes enter the lung with a peak response occurring between to days after immunization with a mean of % of the total lavage cells being lymphocytes . species differences exist in the release of afcs into the blood from lalns and in the recruitment of afcs into the lung. dogs (bice et al., b) , nonhuman primates (bice et al., a , mason et al., , and humans (stevens et al., ; lue et al., ; weissman et al., ) all have large numbers of afcs in their blood after immunization, and blood afcs enter the lung. in contrast, data from a single immunization of the lungs of rats, guinea pigs, rabbits, and mice suggest that few or no afcs are released into blood, and that relatively few afcs appear subsequently in the lung (bice and shopp, ) . however, the use of adjuvants and large doses of antigen appears to increase the number of afcs in the lung of guinea pigs and mice (shopp and bice, ; curtis and kaltreider, ) . it is possible that the strain of species being evaluated may also be important, although no data are available that compare pulmonary b cell responses in different strains of laboratory animals. although primary immune responses are not produced in the lung independently of secondary lymphoid tissues, data suggest that memory responses may be detected in the lung to antigen challenges that are independent of lalns (mason et al., ; ada, , ; bice et al., ) . the most logical explanation for the production of afcs and antibody in the lung after an antigen challenge is that immune memory cells are recruited into and/or develop in the lung after a primary immunization. unlike a primary immune response, most specific igg and iga antibody produced in an immunized lung after a rechallenge with antigen appears to come from local immune memory b cells and localized production of afcs, rather than by afcs recruited into the lung from blood. only minimal specific igm is produced in the lung after antigen rechallenge (bice et al., ) . specific antibody continues to be produced in the lung for several years after the last exposure to antigen (bice et al., ) . lavage fluid from immunized and challenged lung lobes contained significantly more specified igg several years after the last exposure to antigen than was present in lavage fluid from control lung lobes. thus, once an intense, localized antibody response was established in the lung, immune mechanisms supported continued localized antibody production for several years after the last exposure to antigen, but only at the site of antigen exposure. although afcs were identified in lavage fluid from exposed lung lobes several years after antigen challenge, it was possible that cells in interstitial lung tissue, as well as in lalns or distant lymphoid tissues, were all important in long-term antibody production. however, the evaluation of antibody production in lung and various extrapulmonary tissues showed that most long-term antibody production occurred in interstitial tissue in the immunized lung lobe . cells from control lung lobe tissue, from lalns that received lymphatic drainage from the immunized lung lobes, from spleen, gutassociated lymph nodes, or popliteal lymph nodes did not produce significant levels of antibody years after the last antigen challenge. therefore, immune cells retained in lung tissue previously exposed to antigens may be an important source of antibody to protect the lung. in addition, the absence of antibody production in lalns or in other distant lymphoid tissue suggests that antibody produced in lung tissue exposed to antigen could possibly enter the bloodstream and provide immune protection for unexposed lung lobes and extrapulmonary tissues. two possible mechanisms could be responsible for long-term antibody production in lung lobes previously exposed to antigen. first, antigen retained in the lung, possibly on follicular dendritic cells, could stimulate antibody production by antigen-specific memory b lymphocytes that migrate through the lung. alternatively, b lymphocytes recruited into or produced in the lung in response to the initial antigen challenge might live for several years and continuously secrete antibody. because continuous antibody production occurs only in lung lobes exposed to antigen, an antigen depot may be essential. data have been published that support both possibilities (tew et al., ; peeters and carter, ) . in summary, studies suggest that pulmonary humoral immunity can be maintained both by continued long-term spontaneous antibody production and by antigen challenge restimulating local pulmonary memory b cells to secrete antibody. despite the ability of the lung to express both natural and acquired immunity, respiratory tract infections are the most common type of infections experienced by humans. certainly the common cold alone wins this competition hands down! vaccination has been a powerful intervention to protect against many respiratory tract infections including the bacteria bordetella pertussis, corynebacteria diphtheriae, hemophilus influenzae, streptococcus pneumoniae, and m . tuberculosis and viruses, including one virus that primarily infects the respiratory tract, i.e., influenza, and several which initially infect via the respiratory tract, rubeola, rubella, and mumps. a major impetus for current research in infectious diseases is to learn more about natural host defenses in infections and how the immune system amplifies these defenses (mason and nelson, ) . by better understanding these strategies, the hope is to optimize vaccination of immunocompetent hosts and perhaps even hosts who are immunosuppressed, yet retain some capacity to respond immunologically. alternatively, in immunosuppressed individuals, once we are better able to understand how immunologically derived cytokines function in the normal host during infections, recombinant forms might be administered as replacement. the use of animal models has considerably enhanced our understanding of lung infections and the role of immunity in controlling them. in most pneumonias caused by extracellular bacteria, recruited phagocytes and opsonins, especially antibody and complement, are required to effectively control infections, even when antibiotics are used. thus, the goal for vaccination in these pneumonias is to raise the level of local antibody. for chronic pneumonias and pneumonias caused by intracellular microorganisms, the goal of vaccination is less clear, although protection against the viruses listed previously correlates with serum antibody levels. the best evidence supports the probability that enhancing cmi would be protective for immunization against many obligate and facultative intracellular bacteria, fungi, and parasites (lipscomb, ; campbell, ) . in this section, examples of animal models of infectious disease that address how pulmonary immunity develops to various etiologic agents are discussed, and the type(s) of immunity that afford protection are indicated. while investigators have used experimental models to study nearly all of the infectious agents that produce respiratory infections, space dictates that only a few representative studies be included here. the administration of s. pneumoniae into the lung leads to a rapid accumulation of neutrophils in the alveolar space. the development of this local inflammatory response during s. pneumoniae pulmonary infections was noted in early histopathological studies (loosli, ; wood, ; loosli, ) . subsequent studies confirmed the requirement for intact granulocyte function in the host to eradicate the pulmonary infection (wood et al., ; heidbrink et al., ) . studies have examined the mechanisms responsible for neutrophil recruitment during the early stages of s. pneumoniae pulmonary infection bruyn et al., ) . several groups demonstrated that animals systemically decomplemented with cobra venom factor had an impaired ability to recruit neutrophils and to clear the organisms from the bronchoalveolar space. a role for c in the recruitment of neutrophils in response to intratracheally delivered s. pneumoniae was assessed by using congenic c -sufficient (c +) and c -deficient (c -) mice . the results indicated that c was important in producing optimal, early neutrophil recruitment and bacte-rial clearance in response to s . pneumoniae, but other chemotaxins must be involved, because chemotactic activity and neutrophil recruitment was found in both c + and c -mice. once phagocytic effector cells were recruited into the lung, neutrophils and macrophages required the opsonins, immunoglobulin and complement, for efficient phagocytosis of the s . pneumoniae (guckian et al., ; coonrood and yoneda, ) . the presence of c b on the surface of the pneumococci is vital for phagocytosis. c b can be deposited on s . pneumoniae by either the classical complement pathway through interaction with antibodies or through the alternative complement pathway (winkelstein, ; joiner et al., ) . streptococcus pneumoniae that are not killed by the initial pulmonary inflammatory reaction drain to lalns and eventually enter the systemic circulation resulting in a bacteremic phase (austrian, ) . during this phase, type-specific antibody to capsular polysaccharide is produced. it has been demonstrated through passive immunization studies that the presence of type-specific antibody (igg and igm) in the serum is protective against severe pneumococcal infection (musher et al., ) . nontype-specific antibodies to s . pneumoniae are made during infection, including antibodies to cell wall components (brown et al., ) , surface protein a (szu et al., ) , and the f polysaccharide (au and eisenstein, ) . in general, most animal studies indicate that these latter antibodies play a minimal role in providing effective protection against infection by s . pneumoniae (szu et al., ; brown et al., ) . the role of secretory iga in the prevention of pneumococcal disease is unclear, although one mouse model demonstrated that s . pneumoniae-specific iga could "arm" lung lymphocytes which subsequently demonstrated antibacterial action against s . pneumoniae (sestini et al., ) . iga has been reported to fix complement and act as an opsonin (hiemstra et al., ; gorter et al., ) and thus could play a role preventing s. pneumoniae infection. finally, humoral factors other than antibody have been implicated in protection against s . pneumoniae, particularly c-reactive protein which can activate complement and act as an opsonin when bound to the capsule. although a role for c-reative protein has been demonstrated in clearing s. pneumoniae from the bloodstream (volanakis and kaplan, ; horowitz, et al., ) , a role for c-reactive protein in the pulmonary stages of infections has not been demonstrated. models for acute pulmonary infection with h . influenza have been developed in the rat (wallace et al., ) and mouse (esposito and pennington, ; toews et al., b) . the latter method delivers a reproducible bolus of organisms to the lower respiratory tract via an endobronchial catheter. using this technique it was determined that the clearance of both typable and nontypable h . influenza from lungs occurred at a very similar rate. the clearance of the organisms appeared to occur in two phases. during the initial hr postinoculation, the organisms increased in numbers three-to fivefold, while during the next hr the organisms were rapidly cleared (toews et al., ) . studies indicated that the rapid clearance phase corresponded to the influx of neutrophils into the lung and that the presence of these leukocytes was vital for effective clearance (toews et al., ) . the effect of specific antibody to the h . in.uenza on the rate of pulmonary clearance was examined using both active immunization and passive administration of immune sera. the results indicated that the presence of specific antibody in the serum and the bal fluid of immunized mice correlated with an increased rate of clearance from the lung. that systemic igc could provide protection in the lower respiratory tract of animals was also demonstrated by experiments showing enhanced clearance of h. influenza from the lungs of mice that had received immune sera. taken together, these results indicated that in the presence of elevated titers of serum igg, protective antibodies could enter the airways of infected lungs to provide protection against pulmonary pathogens. in contrast to the organisms discussed previously, previous immunization with s. aureus does not appear to enhance clearance or provide protective antibody in pulmonary infections ( jakab, ) . recent studies suggest that the pulmonary clearance of this organism may be dependent on locally produced opsonins that enhance phagocytosis by am. surfactant protein a, produced by type i pneumocytes, can bind to s. aureus and increase phagocytosis, while this protein does not enhance uptake of s. pneumoniae by am (mcneely and coonrood, ) . lung infections with two microorganisms, mtb and cryptococcus neoformans (cne) , are discussed in this section as examples of infections requiring intact cmi for resolution. animal models of chronic lung infections with several other important pathogenic organisms have been studied, including pneumocystis carinii (walzer, ; shel-lit et al., ; harmsen and stankiewicz, ; boylan and current, ) , histoplasma capsdatum (baughman et al., ; defaveri and graybill, ; fojtasek et al., ; allendoerfer et al., ) , blastomyces dermitiditis (morozumi et al., ; moser et al., ; frey et al., ; williams et al., ) , paracoccidiodes braziliensis (brummer et al., ; defaveri et al., ) , coccidiodes immitis (cox et al., ) , chlamydia trachomatis and psittaci , rhodococcus equi (kanaly et al., ) , and mycobacterium auiumintracellulare (takashima and collins, ) . although infection with legionella pneumophila can cause an acute pneumonia in susceptible hosts, it is a facultative intracellular bacterium; cmi is thought to be necessary for resolution of the infection. an animal model to study this infection has also been developed (skerrett and martin, ) . a central role for cmi (in which t cells recruit and activate macrophages) in controlling intracellular bacterial infections was first proposed by george mackaness using a listeria monocytogenes murine infection model (mackaness, ) . after finding an important role for cmi in controlling an aerogenous listeria infection in mice, mackanew extended his studies to propose that cell-mediated hypersensitivity might be an important cause of lung disease (mackaness, ). however, he and his collaborators observed that, in contrast to protection afforded by active immunization, adoptive transfer of listeria immune splenocytes seemed to afford only minor protection against an aerosolized infection (truitt and mackaness, ). in retrospect, adoptive immunity might have been transferred more successfully if lalns or lung lymphocytes from aerosol-infected mice had been used instead of spleen cells from systemically immunized mice; these latter cells likely homed inefficiently to the infected lung (huffnagle et al., b) . nevertheless, in experiments with virulent mtb, when organisms were given iv, the lung developed effective resistance, although less effectively than spleens and livers (mackaness, ) . these early studies suggested that cmi in the lung might be more rigidly downregulated, perhaps to prevent excessive damage to delicate structures. however, mackaness offered an additional explanation, e.g., lung infections with mtb may be more difficult to control locally because organisms are sequestered in am, macrophages that, in contrast to recruited monocytes, might resist activation signals delivered by t cells. the role of pulmonary immunity during mtb infection has been analyzed in a variety of animal models (smith and wiegehaus, ) including rabbits (lurie, ) , mice (orme and collins, ; north and izzo, ) , and guinea pigs . initial experiments involved intranasal or intratracheal inoculation and the development of the middlebrook chamber (middlebrook, ) provided a means of aerosolizing mtb into animals. early studies examined the number of mtb required for a reproducible infection in animals. mice exposed to a mist of virulent mtb developed discreet lesions that were progressively fatal over a - week period (schwabacher and wilson, ) . these initial studies were extended by comparing aerosol versus intranasal delivery of mtb and it was found that both routes produced similar pathology. it was observed that a deposited inoculum of about organisms was required for reproducible infection, while a dose of approximately , organisms resulted in death (glover, ) . resident am undoubtedly play a role during an mtb infection. mtb deposited into the lung are rapidly taken up by am. evidence for a role for am in defense against mtb partly comes from epidemiologic studies examining mtb infections in individuals with silicosis (snyder, ) . silica exposure results in the uptake of silica particles by am. these silica particles remain in the phagolysosomes of am throughout the life of the individual (allison and d'accy hart, ) and likely affect their function. essentially all epidemiological studies examining the incidence of mtb infections in a silica-exposed population have concluded that the incidence of mtb infections in this group is significantly higher than the incidence of mtb infection in a non-silicaexposed population (snyder, ) . several studies have shown that both human and/or mouse am are stimulated to produce chemotactic factors and cytokines in response to mtb or components of the mtb cell wall (barnes et al., ; chatterjee et al., ) . these released products may represent an early native defense system against mtb. thus, chemotactic factors can act to recruit neutrophils and monocytes from the circulation, while amreleased cytokines, such as tnfa, can activate both local am and newly recruited cells. indeed, some studies indicate that cytokineactivated am and/or monocytes can inhibit the growth of or kill mtb (crowle, ; rastogi, ; denis, a) . more recent data suggest that macrophage cytokines, including il , may enhance the development of the t h l subset leading to protective immunity (hsieh et al., ) . data indicating that avirulent mtb can elicit a greater cytokine response from macrophages than virulent mtb have lead to the hypothesis that the observed differences in mtb virulence may be due to an intrinsic ability of virulent mtb to prevent or decrease the release of factors by am (barnes et al., ; chatterjee et al., ; roach et al., ) . ethnic differences observed in susceptibility to mtb (coultas et al., ) might be due to a genetic disposition for a poor initial response by am to mtb. a role for cmi was demonstrated for protection against mtb infection (suter, ; leveton et al., ) . in a guinea pig model, it was demonstrated that in animals given a low dose of mtb, the organisms replicated in a log phase until days or , after which exponential growth ceased . the decrease in growth coincided with the onset of tuberculin skin test sensitivity and the development of detectable bacillemia. bacteriostasis ensued over the next - days after which the numbers of mtb in lung were gradually reduced. although these data were consistent with a role for the development of an acquired cmi response for resolution of the mtb infection, it was not until orme and collins ( ) , by examining the immune response in a mouse model, that direct evidence was provided for a role of t cells in pulmonary immunity against mtb. in a series of adoptive transfer experiments, they removed splenic t cells from a mouse that had received an iv inoculation of mycobactel-ium bovis or bcg. after injecting these bcg-immune t cells into thymectomized, sublethally irradiated nonimmune mice, the mice were challenged with an aerosol dose of mtb that deposited lo organisms into the lungs. two important findings in these studies were ( ) adoptively transferred immune t cells enhanced clearance of mtb from the lung; and ( ) by differentially removing subsets of t cells with specific antisera, the skin test tuberculin sensitivity was dissociated from protective antituberculous immunity which indicated that separate populations of t cells may be responsible for the two events. in a followup study (orme, ) , only mtb-immune cd t cells adoptively transferred protection to mice challenged with a lethal aerosol inoculum ( . x lo organisms) of mtb, while either cd or cd cells could transfer protection to mice exposed to a low dose ( organisms) of mtb. in comparison to the pulmonary inoculation studies, models using intraperitoneal or iv routes of inoculation have produced different results. in an intraperitoneal model, an mtb-reactive cd t cell clone provided both a dth response and protection as measured by the growth of mtb in the peritoneum (pedrazzini and louis, ). similarly, an mtb-immune cd t cell clone provided protection, as measured by reduced splenic cfu, following an iv mtb infection. another study using in vivo depletion of t cell subsets demonstrated that depletion of cd t cells decreased resistance to iv infection, while depletion of cd t cells did not have a significant effect (pedrazzini et al., ) . in contrast, in a similar model, transgenic mice incapable of producing cd t cells were shown to have a decreased resistance to mtb compared to normal mice (flynn et al., ) . a role for y t cells in pulmonary defenses against mtb is unresolved (o'brien et al., ; kaufmann and kabelitz, ) . because y t cells release ifny, it is tempting to speculate that these t cells represent an initial defense mechanism in the lung to provide activating cytokines to enhance local effector mechanisms to help control the infection until the development of protective immunity by ap t cells. initial studies demonstrated an increase in the number of lung y t cells after an intratracheal dose of ppd (janis et al., ) . other studies suggested that many y t cells responded to the heat-shock protein of mtb (born et al., ; kaufmann and kabelitz, ) . other studies suggested they may play a role in granuloma formation (modlin et al., ) . however, in humans with active mtb infections, there was no increase in y t cells in the granuloma as determined by immunohistochemical staining (tazi et al., ) . more work in animal models and human natural infections is required to define the role of y t cells in mucosal immunity, particularly regarding their role in mtb infections. complex interactions exist in the development of protective immunity by t cells and the type of cytokines produced during an infection. similar to the studies that show an important protective role for t h l cells that preferentially secrete ifny in leishmania infections (locksley et al., ) , it is likely that mechanisms for production of appropriate cytokines are critical in the development of protective immunity against mtb (flesch, ; denis, b; kawamura et al., ; barnes et al., ; orme et al., ) as well as in the maintenance of a resistant state during the chronic infection stage. an important role for ifny in mtb resistance was recently demonstrated in both an aerosol and an iv mtb infection model. comparing infected normal and ifny knockout mice (cooper et al., ; flynn et al., ) , it was demonstrated that a lack of ifny resulted in a significant increase in mtb susceptibility. however, since ifny was absent throughout the course of infection, it was unclear at what stage in the immune response ifny was required (flynn et al., ) . indeed, ifny may be important for all aspects of the response to mtb including t cell development, cell recruitment, and activation of effector mechanisms. other studies in mice examined the granulomatous response to ivinjected bcg in animals that had received neutralizing antibody to tnfa (kindler et al., ) . these and other studies (amiri et al., ) indicate that tnfa also plays a critical role in protection against m tb, particularly in the development and maintenance of granulomas. attempts to vaccinate animals with avirulent or killed mtb have provided important data regarding potential vaccines. in general, studies suggest that to enhance the immune response against virulent mtb, viable organisms must be used (larson and wicht, ) . the route of immunization with viable organisms can be either iv or by aerosol. further, vaccination does not prevent infection, but rather limits tissue destruction and the degree of hematogenous dissemination . immunization with nonviable cellular elements does not afford protection. in summary, the development of protective immunity to a pulmonary infection with mtb requires the coordinated activity of multiple cell types, particularly macrophages and t cells. the continued study ofthe mtb pulmonary infection should aid in understanding the mechanisms for developing effective cmi in the lung and suggest strategies to enhance pulmonary defenses. cne is an encapsulated yeast found in desiccated form in soil, particularly in areas contaminated by pigeon feces. cne usually causes only an asymptomatic infection in humans following inhalation. normal individuals typically clear the organisms, but in those who are susceptible, particularly those with defects in cmi, the organism may disseminate via the bloodstream and produce an extrapulmonary infection, usually meningitis. mice have been used as experimental models for studying the host defenses against this microorganism, which because of the capsule resists endocytosis and thus typically replicates in tissues in an extracellular location. in murine models the organism was frequently inoculated iv or ip, although it had been established many years ago that mice housed on contaminated bedding (smith et al., ) , exposed to aerosols (karaoui et al., ) , or that received intranasal inoculations of the organism (ritter and larsh, ) developed infection. these early studies validated the concept that the organism was acquired by the respiratory tract. murphy and her colleagues have contributed substantially to the understanding of immune and natural defense mechanisms in protection against this yeast and demonstrated that animals inoculated intranasally developed pulmonary infection that disseminated, but following the development of dth gradually cleared the infection (lim et al., a) . furthermore, these investigators demonstrated that transfer of t cell-enriched splenocytes from mice immunized by an intranasal infection was capable of protecting mice against an iv challenge (lim et al., b) . of importance was that in these studies, passive transfer of serum failed to protect mice. we and others developed an intratracheal inoculation infection model with cne to study pulmonary immune mechanisms in mice (hill and harmsen, ; huffnagle et al., a; huffnagle and lipscomb, ). in our model, the organism is inoculated in small amounts directly into the trachea and yeasts in the lungs are quantitated by homogenizing the organ and measuring colony-forming units (cfu). over an initial days, the organisms grow rapidly followed by a gradual decrease in cfu in appropriate mouse strains, a process referred to as "lung clearance" (huffnagle and lipscomb, ). an important aspect of this model, as is true of many other lung infection models, is that both the strain ofmicroorganism and the strain of mouse determine whether the infection will be cleared from the lung and at what rate (huffnagle et al., a) . in studies using a relatively low virulence encapsulated yeast, athymic nude mice, mice with severe combined immunodeficiency (scid), or mice depleted of cd and cd t cells were incapable of pulmonary clearance (huffnagle et al., a,b; huffnagle and lipscomb, ; hill and harmsen, ) . furthermore, protection of the lung was adoptively transferred to scid mice by splenic lymphocytes, but adoptive immunity was more effective if lymphocytes isolated from the lungs and lalns of animals that had been immunized during a lung infection were used (huffnagle et al., b) . interestingly, using a more virulent organism, cd t cells were responsible for increased resistance to the highly virulent organism following extrapulmonary spread, but did not demonstrate an effect in controlling the infection within the lung (mody et al., ) . these latter studies demonstrated, as did the earlier studies of mackaness, a dichotomy between the ability of immunized animals to demonstrate effective immunity in the lung compared to extrapulmonary organs. what is the role of cd and cd t cells in immune protection? the absence of either reduced the numbers of inflammatory cells, including macrophages, but they were even more profoundly decreased when both were absent (huffnagle et al., ) . a role for cd t cells was repeatedly shown in strains of mice that demonstrated acquired resistance to low-virulence cne, i.e., balb/c, c.b- (congenic to balb/c, but with the igh locus of c bl/ mice), and cba mice (hill and harmsen, ; huffnagle et al., a; mody et al., ) . a role for cd t cells in this infection was particularly curious, although cd cells clearly participate in the development of immunity to intracellular organisms. mechanisms proposed include secretion of ifny or lysis of infected targets following recognition by cd t cells of peptides in the context of class i mhc (kaufmann, ) . however, it is not known how cd cells function in murine cne disease in which the organism is primarily extracellular. one important mechanism may be related to their capacity to enhance either the clonal expansion or the recruitment of cd cells to the lung (huffnagle et al., ) . thus, cd t cell depletion of cne-infected mice reduced the numbers of cd t cells in infected lungs. a second role may relate to the finding that lung cells isolated from cd t cell-depleted animals were capable of secreting ifny in mitogen-stimulated cultures, suggesting cd cells in this setting could also contribute to ifny production and play a role in macrophage activation. it was also demonstrated that cd cells played a critical role in the development of dth to cne in cneinfected mice and could adoptively transfer dth . this is an important observation because it proves cd t cells can recognize antigens of extracellular organisms in the context of class i mhc. thus, it is possible that cd t cells might lyse am that phagocytose the organism, but cannot kill it, so that activated macrophages or other effector cells may play a role. c.b- mice were particularly adept in the development of a t h l response characterized by clearing cne from their lungs, and this ability was related to enhanced secretion of il- and ifny by laln cells early in infection . the heightened resistance in c.b- mice correlated with expression of the inducible nitric oxide synthase (inos) gene in the lungs, was accompanied by secretion of no by lung cells during the early clearance phase, and was completely abrogated by both anti-ifny treatment and feeding animals an inhibitor of no production (lovchik et al., ) . thus, in c.b- mice, clearance in the lung was related to the capacity of the animals to make ifny and no. if t cells are necessary to protect lungs from cne infections, is the effector mechanism mediated mainly by activation of macrophages? the answer to this question is still uncertain, but rat am activated by ifny were able to inhibit the growth of cne (mody et al., ) . furthermore, prolonged incubation with gm-csf also activated am for cne growth inhibition . murine macrophages from the peritoneum of bcg-immunized mice inhibited the growth of cne in vitro by an arginine-dependent mechanism and were related to no production (granger et al., ; alspaugh and granger, ) consistent with the in vivo data of lovchik ( ) . an important aspect of growth inhibition by this no-dependent mechanism was that it did not require endocytosis, although endocytosis enhanced the growth inhibition (granger et al., ) . others have demonstrated that ifnyactivated mouse macrophages kill cne, but determined that a secreted protein was important (flesch et al., ) . activated human macro-phages make little if any no unlike rat and mouse macrophages leaving open the question of what effector mechanism human macrophage may use to growth inhibit cne. human neutrophils and macrophages not only inhibited growth, but killed, cne in cultures that include fresh complement (miller and mitchell, ) . the organism fixes complement by the alternate pathway resulting in c bi binding to the yeast capsule and allowing phagocytosis by cr -positive neutrophils and macrophages (kozel and pfrommer ; kozel et al., ) . this mechanism was shown to play an important role in clearing cne from the pulmonary vasculature during fungemic states in mice (lovchik and lipscomb, ) . however, cne in tissues tend not to provoke brisk inflammation, and bronchoalveolar spaces (and cerebrospinal fluid) do not contain significant complement. furthermore, am may not express cr . thus, t cells must amplify effector systems by recruiting and/or activating nonspecific effectors or by themselves becoming direct effectors. recent studies indicated that human nk cells and t cells had direct activity in vitro against cne (levitz et al., ; murphy et al., ) , although there was conflicting evidence that human nk cells had no growth-inhibiting activity unless antibody against the organism was present (miller et al., ) . we demonstrated that murine nk cells had a minor effect against the organism following iv inoculation, but failed to play a role in early lung clearance if the organism was inoculated via the trachea . recently a t cellindependent, partially protective host defense mechanism was found in lung clearance in scid mice and balb/c mice depleted of cd andcd tcells. athyl+,cd -,cd -,asialogml-cell was responsible (hill and dunn, ) . further studies are clearly indicated to examine the role of this cell in animal models and to identify its origin, particularly in view of the possible importance of these cells in human cne infections. histologic examination of murine lungs during the clearance phase demonstrated that yeasts were surrounded by macrophages with an activated appearance (hill, ; huffnagle and lipscomb, ) . this appearance was similar to that seen in the lungs of humans with cryptococcomas who are known to be able to resolve their infections without antibiotic therapy. when the lung becomes inflamed and complement is available, neutrophils may play some role in killing cne in the lung, although the relative importance of neutrophils over t cells and activated macrophages remains to be clarified. continued studies using a murine cne lung infection model should help elucidate the mechanisms that lead to the development of a thl-like response in lalns early during infection and subsequent recruitment of lymphocytes and macrophages into the lung. a closer examination of what effector mechanisms are at work in the lungs of animals that clear a cne infection, particularly in resistant mouse strains that may not utilize no from activated macrophages, may help elucidate host defense mechanisms in man. c. viral pneumonias viruses are intracellular organisms that usurp host cellular machinery to replicate. viral entry into cells can be blocked by antibodies. however, once inside the cell, the virus is resistant to both antibody and t cell recognition until viral peptides are presented in the context of class i mhc antigens on the cell surface and allow specific cytotoxic t cells to lyse the infected cell (zinkernagel, ) . as viral replication ensues and particles are released from the cell surface, antibody again has an opportunity to block the further spread of the virus. in general, cytotoxic t cells play an important role in controlling local viral replication, while antibody can prevent initial infection and extracellular spread within the host. in some viral infections, there seems to be a relatively minor role for cd t cells (zinkernagel, ) . however, in a number of viral infections in mice, depletion of cd t cells increased mortality and reduced the rate of clearance. the role for cd cells may relate to providing help for cytolytic t lymphocyte (ctl) development (reiss and burakoff, ) and for b cell production of high-affinity igg and iga antibodies. the role of y t cells, nk cells, and macrophages in acute viral infections is still not clear. furthermore, whether memory ctls play an important role in preventing recurrent infection is also uncertain (zinkernagel, ) . it is also uncertain whether persistence of long-term memory t or b cells against viruses requires the continued presence of virus or viral particles (zinkernagel, ; sprent, ) . a large number of viruses infect the respiratory tract, including rhinoviruses, coronaviruses, adenoviruses, influenza, and parainfluenza viruses, respiratory syncytial virus (rsv), measles, mumps, and rubella viruses. good models in mice exist for both rsv and influenza a infections and are discussed to highlight experimental models that have provided insight into immune defenses against viral respiratory tract infections. immunization against influenza a with killed or fractionated viral antigens protects against influenza, but immunization against rsv has been problematic (salk and salk, ; wright et al., ; graham et al., ; alwan et al., ) . protection against rsv, which produces a bronchiolitis in infants and is the most common cause for hospitalizing infants in western countries, was not afforded by immunization with formalin-inactivated virus. subsequent infection after such immunization sometimes resulted in unusually severe infections and even death (kapikian et al., ; kim et al., ) . the mechanism is unknown, but various theories include immune complex disease, a cd t cellmediated dth reaction, or a ctl-mediated pneumonitis (graham et al., ) . recent efforts using rsv infections in mice have sought to understand what the mechanisms for protection might be, and why immunization might lead to enhanced pathogenicity with a subsequent challenge. depleting mice of either cd or cd cells reduced the disease in the lung following an initial rsv infection, but also enhanced virus replication (graham et al., ) . thus, control of viral replication during even a primary infection resulted in lung pathology. at least two groups attempted to determine whether various viral subunits might initiate protective immunity, yet cause minimal pathology. mice vaccinated either parenterally or by intranasal inoculation, followed by nasal rsv challenge, lead to the expression of cytokine mrna in the lungs (graham et al., ) . the specific cytokine mrna detected was dependent on whether live, heat-killed, or subunit vaccines were given. inactivated virus or subunit fusion (f) protein induced cytokine expression that suggested a th -like lymphocyte response with increased il- mrna relative to ifny expression. in contrast, when mice were primed with parenteral or nasal live virus, t h l responses were prominent. formalin-fixed virus and the f protein component were somewhat protective. however, the most effective protection was induced by immunizing intranasally with the live virus. furthermore, this immunization protocol resulted in the least lung pathology after rechallenge. experiments were designed to determine which t cell types caused pathology and whether specific rsv subunits evoked specific pathology-producing immune t cells. cell lines were developed from immune lymphocytes of mice immunized against the f protein, the major surface glycoprotein (g), and a -kda matrix protein expressed by recombinant vaccinia virus (alwan et al., ) . f protein lead to the development of both ctl and cd t cells with a t h l phenotype. g protein facilitated the development of cd cells with a th phenotype. immune cells from the -kda protein-immunized mice resulted in predominantly cd ctl. representative cell lines from each of these groups transferred both protection and pathogenic effects to rsv-infected mice, but the th cells seemed to be the most damaging. furthermore, combinations of lines afforded the greatest protection. thus, protection is often synonymous with pathology and it may be difficult to dissoeiate the two. l, it has been clear for some time that serum antibody correlates with protection against influenza viruses. influenza viruses exhibit antigenic drift and shift that requires individuals be immunized yearly for protection against the prevalent virus strain (zinkernagel, ; salk and salk, ) . while immunization against influenza has been successful, it is possible that new immunization protocols might be developed that would be broadly protective. in contrast to b cell epitopes, t cell epitopes may be cross-reactive; cytotoxic t cells seem to play an important role in controlling influenza infections (zinkernagel and althage, ) . early studies established that recovery of mice from infections with influenza a required the development of a ctl response to the virus, and protection was afforded by the adoptive transfer of immune cells into naive-infected hosts (yap et al., ; lukacher et al., ) . further studies indicated that both class i and i mhc-restricted t cell clones could promote recovery from a lethal pulmonary infection (mcdermott et al., ) . these t cell clones were preferentially retained in lungs of influenza-infected mice, independent of any viral antigenic specificity, and migrated from the pulmonary vessels into the bronchiolar lumens. thus, the immune cells accumulated at a site appropriate to provide protection against a viral challenge. mice die within days of lethal influenza infections. an array of cytokines could be detected in bal fluids in these mice, but none that were unequivocally indicative of a t cell response (hennet et al., ) . thus, while il-la, il-lp, il- , tnfp, gm-csf, ifny, and leukotriene b were identified in lavages, il- , il- , and il- were not. on the other hand, in sublethal infections in which the influenza infection was resolved, examination of cells from lavages as well as from lalns demonstrated t cell cytokine production (carding et al., ; sarawar et al., ) . in a primary infection, the kinetics of cytokine mrna was compatible with an initial response occurring in the regional lymph nodes with the effector t cells appearing later in the lungs. among the ap t cells, transcripts for ifny and tnfp were predominantly found in cd cells, but there was a tendency for il- and il- to appear in cd cells. interestingly, y t cells were identified and expressed il- , il- , and ifny. during a secondary response, t cell cytokine mrna was found almost simultaneously in lalns and in the lung (carding et al., ) . in related studies, mrna was detected by in situ hybridization and by cytokine production identified in individual cells by elispot. the majority of cells in lavages produced il- , il- , and ifny with relatively little tnf and il- . depletion of cd and cd cells caused a significant reduction in il- -and il- -producing cells, but ifny-producing cells remained and were likely cd -, cd ap, or y t cells; both populations were present during the infection. these studies are typical of recent studies examining cytokine patterns in various lung infections in the lung attempting to learn what determines the type of immune response that develops to airway antigens. b -microglobulin-deficient mice were used to determine the effect of ifny on influenza clearance. mice did not develop cd ctl because of the absense of class i mhc, but residual cd cells were capable of mediating clearance, possibly related to the development of antibody of the igg a subclass (sarawar et al., ) . treatment of the mice with anti-ifny antibody delayed clearance for at least days, whereas antibody to il- had no effect. however, all mice survived and eventually cleared the virus. notably, neither antibody to ifny nor il- altered the cytokine profiles detected in freshly isolated lung lymphocytes. the conclusion was that although ifny played an important role in viral clearance, its role was not to drive cd cells to become t h l t cells. y t cells developed as a prominent component of the late inflammatory process during murine influenza infections . these cells expressed all known y genes, although some predominated at times. a suggested role for these cells was that they recognized heat shock proteins on inflammatory macrophages and decreased their numbers. however, close examination of the data failed to show an inverse relationship of the numbers ofy t cells and lung macrophages . in another study, y t cells were found to be noncytolytic, but expressed mrna for ifny, gm-csf, and tnfp (eichelberger et al., ) . the hypothesis was presented that these cells, through their capacity to make cytokines, provided nonspecific protection against secondary infections. thus, although t cells are a component of the host response to viral lung infections, their role remains unknown. blue ribbon panel on vaccine research was convened in by anthony fauci, director of the niaid, to assess the long-term goals for vaccine research and to recommend immediate priorities for the institute. among the panel's recommended priorities was the development of vaccines for respiratory infections of children, and to improve the current vaccines for pertussis and measles. an additional priority was to develop vaccines for reemerging infectious diseases, including influenza because of its inherent problems of antigenic drift and shift. the jordan report, a publication of the division of microbiology and infectious diseases of the niaid, has reviewed on a yearly basis the progress in vaccine research. in the report, respiratory tract infectious diseases for which vaccines were either being developed or improved were listed and discussed. they included the bacteria groups a and b streptococci, h. influenzae type b, nontypable h. influenzae, neisseria meningitidis, s . pneumoniae, b . pertussis, pseudomonas aeruginosa, and m . tuberculosis; the viruses rubeola, rubella, adenoviruses, influenza, and parainfluenza viruses, and respiratory syncytial virus; mycoplasma pneumoniae; and the fungi, h. capsulatum, c. immitis, and c . neoformans. thus, an enormous scientific effort is being directed at designing vaccines to protect the host from respiratory pathogens. and yet the report also highlighted the gaps in our knowledge about normal host defenses at mucosal surfaces, what immune defenses we should attempt to enhance with vaccinations, and the best methods for immunization. important issues for vaccine research have been discussed in recent publications (lambert, ) including reviews on the possibilities of immunization against tuberculosis (kaufmann and young, ) and on novel approaches to vaccination such as inoculating polynucleotides encoding antigens directly into muscle (donnelly et al., ) . important general goals for any vaccine are that it be efficacious, easy to store, easy to give, and be free of side effects. specific goals for vaccines for respiratory infections are ( ) the immune response generated must be protective (a corollary is that the immune response to a microbial challenge should not cause lung pathology.); ( ) the immune response must be quickly available in the respiratory tract and at the site within the respiratory tract where the microorganism is likely to seek entrance and/or produce disease; and ( ) immune memory should be long term. the study of the type of protective immune responses that develop during natural infections in man or induced infections in experimental animals has provided important clues to what responses should be enhanced by immunization. this has been a productive approach for viral infections and those caused by intracellular pathogens. however, host responses that can prevent a second infection may differ from the immune responses that bring an acute infection under control. for example, in many viral infections, although cytotoxic t cells may bring a primary infection under control, antibody may prevent reinfection. another example of this principle is that although cmi controls cne infections in mice, in special circumstances, antibodies to cne can be protective (mukheqjee et al., ) . the isotype of the predominating antibody in preventing infection may also be extremely important, e.g., upper tract infections may be more dependent on iga responses, while in the alveolar spaces, igg may be more effective. as already discussed, an important consideration for viral vaccines is whether subunit vaccines are as effective as live attenuated organisms in initiating the desired type of immune response. an innovative strategy for generating cmi responses against nonviable antigens is to inoculate a regulatory cytokine at the time of antigen delivery (afonso et al., ) . the vaccine could even consist of a fusion protein of the antigen and the cytokine (tao and levy, ) . the immune response at the time of challenge must develop in the correct site. if the organism infects the upper respiratory tract, local iga is important. if infection is initiated in the lower respiratory tract, it may be sufficient that protective cells and antibody are available in circulation if recruitment can occur immediately following challenge. however, if significant inflammation is required before recruitment of immune cells occurs, some clinical manifestations of infection must necessarily develop, before the protective response neutralizes the infection. feasible strategies for generating iga in the upper respiratory tract are to aerosolize the antigen, to deliver the relevant antigens on the surface of a nonpathogenic microorganism, such as streptococcus gordonii, that have the potential to colonize the nasopharynx (pozzi et al., ) , or to immunize with oral vaccines with antigens either chemically bound to cholera toxin b-subunit (mcghee et al., ) , enclosed in a liposome or biodegradable microsphere (mestecky and eldrigde, ) , or encoded in a plasmid carried by live attenuated salmonella spp. (ckdenas and clements, ) . ample evidence has documented that iga precursors generated in the gut home to bronchial mucosa (weisz-carrington et al., ; chen et al., ; rued et al., ) , although the converse does not appear to occur to an appreciable extent (mcdermott and bienenstock, ; joel and chanana, ; vancott et d . , ) . however, a cautionary note in relationship to immunizations that enhance iga responses is that they could also stimulate ige responses and lead to allergic responses in the lungs. oral immunization with protein antigen and cholera toxin resulted in anaphylaxis in mice following an intraperitoneal antigen challenge (snider et al., ). an important issue for any vaccine is whether long-term memory is possible. based on the data derived from immunization with subunit vaccines or killed microorganisms, it seems unlikely that sufficient t cell memory could be induced for long-term cmi protection against respiratory tract infections. however, in the presence of continuous antigen, such as would occur with low levels of replicating attenuated viruses or retained intracellular microorganisms in ia-positive apc, memory t cells should persist. furthermore, follicular dendritic cells are present in balt, and long-term b cell memory could also persist due to the retention of nonviable antigens in the form of antigen-antibody complexes on these cells. evidence that long-term b cell memory occurs in the lungs of dogs has been obtained as discussed previously. however, it is important to remember that this observation was made in animals in which the antigen was directly instilled into the lung. therefore, it is not obvious that extrapulmonary immunization would induce retention of long-term local b cell memory, and suggests that lung immunity might be more effective if primary immune responses to pulmonary pathogens were boosted by intranasal or aerosol antigen delivery. animal models of human lung disease have been used to test hypotheses under well controlled conditions and to dissect mechanisms of injury, inflammation, and repair. these models have been particularly useful in distinguishing direct lung toxicity from injuries that result from immune mechanisms. to prove that a lung injury is immune mediated requires previous exposure to an appropriate agent, evidence of a specific immune response, and evidence that the injury involves recognized immunologic mechanisms. early work concentrated on dissecting isolated aspects of the immune response, i.e., the role of antibody, antibody plus complement, or t cells, emphasizing in vivo analogs of in vitro events. current models of immune-mediated injury emphasize the interrelationships among these aspects of the immune response. in particular, the importance of t cells (especially cd t cells) in regulating the type of the immune response is better appreciated. early studies of immune-mediated lung disease in animals were performed by administering different antigens via different routes and with different adjuvants to guinea pigs (richerson, ) . immune responses varied depending on the type of antigen, method of immunization, and the presumed predominant response. animals immunized with ovalbumin (ova) in complete freund's adjuvant (cfa) developed specific complement-activating antibody and hemorrhagic pneumonitis with a predominant neutrophil response after aerosol antigen challenge. in contrast, animals immunized with aba-n-acetyltyrosine in cfa exhibited dth without demonstrable serum antibody. later, ova aerosol challenge in sensitized animals produced scattered focal areas of alveolitis with thickening and increased cellularity of alveolar septa and alveolar filling with mononuclear cells. other work (brentjens et al., ) confirmed the hemorrhagic nature of immune complex-mediated lung disease. hemorrhagic neutrophilic pneumonitis could be transferred with serum and suppressed by administration of cobra venom factor, which depletes c' in vivo (roska et al., ) . richerson and colleagues described the results of aerosol ova exposure of rabbits systemically sensitized to ova in cfa. acute exposure lead to transient foci of acute pulmonary inflammation (richerson et al., ) , whereas chronic exposure caused decreasing inflammation (richerson et al., ) . t cells were prominent in both the acute and the chronic lesions (upadrashta et al., ) . inhalation of muramyl dipeptide could substitute for systemic immunization with ova in freund's adjuvant . the pulmonary inflammatory response could be decreased by administration of cyclosporin a at the time of aerosol challenge (kopp et al., ) , implicating dth in the etiology of pulmonary inflammation in the rabbit ova model. diminution in the pathologic response in the lungs despite continuing challenge could be produced by either repeated iv or aerosol exposure of rabbits to ova and was not associated with decreased antigen-specific lymphocyte proliferation nor decreased blood or bal antibody response (richerson et al., ; butler et al., ) . a similar decrease in pulmonary inflammation has been observed in rabbits, guinea pigs, and mice subjected to repeated exposures to micropolyspora faeni, the agent that causes farmer's lung disease in humans (schuyler et al., (schuyler et al., , (schuyler et al., , , and thermoactinomycetes vulgaris, which causes humidifier lung (takizawa et al., ) . the decrease in pulmonary inflammation during continued challenge has been attributed to desensitization, defined as suppression of preexisting dth by administration of homologous antigen. however, desensitization is clearly not present in the above models of lung disease, because lymphocyte proliferation and antibody responses were not depressed. since desensitization in other systems can be achieved by administration of an antigen by an unusual route, such as orally (weigle, ) , it is rather surprising that immunologic desensitization was not evident in models of repetitive pulmonary instillation of antigen. two other possible mechanisms, increased degradation of inhaled antigen or increased suppression of lymphocyte proliferation by am, were not present in these models (schuyler and schmitt, ; kopp et al., ) . additional possibilities, including decreased exposure of the lung to antigen due to changes of clearance mechanisms or change of t lymphocyte subtypes, were not investigated. b. immune complex-mediated lung injury ward and colleagues extended these studies on immune complexmediated lung injury using intratracheal instillation of antibody to bovine serum albumin (bsa), followed by iv administration of bsa. lung injury was measured using morphology, leakage of labeled intravascular protein and red blood cells into the lung, and quantitation of the neutrophil enzyme, myeloperoxidase, in the lung (johnson and ward, ) . marked differences were shown in responses to instilled igg versus iga immune complexes. igg immune complex-mediated damage was characterized by neutrophil infiltration into the lung and evidence of increased pulmonary vascular permeability. it was neutrophil dependent (warren et al., ) and required il-lp and platelet-activating factor (warren, ) , which were likely produced by tnfa-stimulated macrophages (warren et d., ) . expression of vla- and cd (mulligan et d., b,c) , functioning cr receptors (mulligan et al., a) , and cdlla (but not cdllb), and icam- expression, were also involved (mulligan et al., ~) . there was upregulation by elam- on pulmonary venules and capillary endothelium, perhaps mediated through a rat analog to il- (mulligan et al., (mulligan et al., , a , and upregulation of icam- expression modulated through tnfa (mulligan et al., a) . in contrast, iga immune complex lung injury was characterized by accumulation of mononuclear cells (warren et al., ) , perhaps mediated through monocyte chemoattractant protein (mcp- ) ( jones et al., ) . the injury was neutrophil and tnfa independent and was not modulated by increases of elam- expression (mulligan et al., c) or tnfa secretion, despite a tnfa-induced increase of elam- expression. iga-mediated injury was similar to igg immune complex injury in that it was vla- , cd , and icam- dependent, but was dissimilar in that it is more dependent on c d l l b than c d l l a expression (mulligan et az., d) . iga immune complex lung injury was apparently mediated through nitric oxide or its derivatives . il- and il- protected against the pulmonary response to igg immune complexes, whereas only il- protected against iga immune complex-mediated injury (mulligan et al., e) . c. asthma models there are multiple animal (e.g., primate, sheep, guinea pig, dog, rabbit, rat) models of asthma which have been used to explore pathophysiologic aspects of asthma (wegner et al., ; abraham, w; murray et al., ; lukacs et al., b; yamaya et al., ; du et al., ; waserman et al., ; coyle et al., ) and as a method to test the effectiveness of various therapeutic agents. although all have some resemblance to human asthma, there are substantial differences, especially in regard to the physiologic response to airway challenge and in methods to induce immune hyperreactivity. typical protocols use intraperitoneal administration of antigen with aluminum hydroxide and/or bordetella adjuvants. guinea pigs immunized intraperitoneally with ova in aluminum hydroxide adjuvant, often with the addition of pertussis (handley et al., ; mauser et al., ) , can be induced to form ige and igg, antibodies, exhibit airway and blood eosinophilia, and display early and late-phase bronchoconstriction (cerasoli et al., ) when reexposed to ova. these animals also demonstrate increased bronchial reactivity to histamine or acetylcholine administered iv. using this method of sensitization, guinea pigs exhibit strain differences in blood eosoniphilia and bronchial hyperreactivity (winthereik et al., ) . increased responsiveness to acetylcholine after antigen challenge and late-phase bronchoconstriction correlates with bal neutrophilia (asano et al., ) . this method of immunization is very different from that which occurs in humans, and the pulmonary physiologic response of guinea pigs is dissimilar to human asthma. guinea pigs exposed to various parasite antigens also exhibit airway hyperreactivity (yamaya et al., ) . nonhuman primates exposed to ascaris suum antigen via the airway exhibit immediate skin test reactivity and either early or both early and late increases in airway resistance (patterson and harris, ) . dual responses are associated with more bal eosinophils and a greater increase of bal neutrophils (gundel et al., ) . hirshman and colleagues found that ascaris-sensitized basenji greyhound dogs exhibited a number of changes similar to those in humans with asthma including increased specific and nonspecific airway reactivity and increased numbers of bal mast cells (hirshman et al., (hirshman et al., , . spontaneous and induced histamine release from bal mast cells was increased compared to control animals (hirshman et al., ) . tracheal muscle from these animals exhibited impairment of the usual increase in cyclic amp in response to isoproterenol (emala et al., ) , and coincident with the measurement of collateral airway resistance, high resolution ct scanning detected airway narrowing (herold et al., ; corddry et al., ) . chronic treatment with methylprednisolone decreased nonspecific airway reactivity and bal eosinophil number (darowski et al., ) . others have induced an asthma-like syndrome with increased bronchial reactivity and reaginic antibody in dogs immunized intraperitoneally as puppies with hapten-carrier complexes in aluminum hydroxide adjuvant (kepon et al., ) . later work extended this model by using ragweed antigen (baldwin and becker, ; becker et al., ) . immunized dogs exhibited immediate-and late-phase skin test reactivity (becker et al., ) , increased antigen-specific and nonspecific bronchial reactivity, and increased bal mast cells, eosinophils, and histamine (becker et al., ) . t cells appear to be important in animal models of asthma. frew and colleagues demonstrated a substantial influx of non-cd (presumably cd +) t cells into bronchial wall mucosa and adventitia of aerosol antigen challenged guinea pigs undergoing late-phase bronchoconstriction (frew et al., ) . using picryl chloride epicutaneous sensitization, mice challenged with intranasal hapten exhibited peribronchiolar cellular infiltration and increased pulmonary resistance in vivo (garssen et al., ) . hypersensitivity to carbacol was present in tracheas from such animals and could be transferred with t cells from sensitized animals. this phenomenon could not be produced in athymic mice (garssen et al., ) . cyclosporin a and fk administration prevented the development of both the late asthmatic response and bronchial hyperresponsiveness after antigen challenge (fukuda et al., ) . il- -deficient and class i mhc-deficient mice which lack mature cd + t cells could not express peribronchiolar inflammation or bal lymphocytosis and eosinophilia when exposed to ova (brusselle et al., ) . exposure of mice to certain parasites, e.g., schistosomes, also caused the appearance of intrapulmonary and bal eosinophilia via an il-cdependent mechanism (lukacs et al., b) , perhaps by altering the balance of th versus t h l t cell numbers in the lungs. antibody to il- can ablate the eosinophilic airway response to ova exposure in sensitized guinea pigs and can even block the ovainduced increased sensitivity to substance p (chand et al., ; mauser et al., ) . eosinophil infiltration into the tracheas of sensitized mice after aerosol antigen challenge is dependent on cd cells and il- (nakajima et al., ) and can be blocked by inoculations of ifny (iwamoto et al., ) . gelfand and colleagues developed a model of asthma in balb/c mice (typically high ige responders) induced by repetitive inhalation of ova. these animals exhibited increased specific ige production, increased sensitivity to iv methacholine, and evidence of sensitized cells in lalns and spleen capable of producing specific ige and iggl. isolated trachea from sensitized animals were hyperresponsive to electrical field stimulation. specific ige antibody and increased airway reactivity could be induced in naive recipients by transfer of sensitized cells from lalns, but not spleen cells, followed by a single aerosol ova exposure. low-ige responding sjl/ l mice failed to develop either ige antibodies or increased bronchial responsiveness, although they developed specific igg antibodies (larsen and wicht, ) . local airway challenge, as well as systemic sensitization, was required for the development of airway hyperreactivity . this suggested that local factors in addition to systemic sensitization were required for bronchial hyperreactivity. in this model, ifny administration during ova sensitization both decreased specific ige production and ablated increased airway reactivity. the effect of ifny was dependent on the route of administration. systemic administration decreased serum-specific ige, but not lalnspecific ige production. perhaps most importantly, the ova-induced increase of airway reactivity was ablated by airway, but not systemic, ifny administration (lack et al., ) . these results were compatible with an ifny-induced shift from a predominant th to a t h l t cell response and also gave evidence for compartmentalization of both systemic and airway immune responses. thus, airway hyperresponsiveness correlated with laln, but not systemic sensitization. d. t cell-mediated hypersensitivity t cell-mediated inflammation in the lung can result in pulmonary fibrosis or hypersensitivity pneumonitis (hp). exposure of mice to a hapten instilled into the lungs caused systemic sensitization as measured by ear swelling after reexposure to the sensitizing hapten (stein-streilein, ) . furthermore, following epicutaneous sensitization with lipophilic trinitrophenylchlorobenzene and an intratracheal challenge with the water-soluble hapten, trinitrophenyl, pulmonary fibrosis developed. intratracheal rechallenge with an unrelated hapten (dinitrophenol) did not produce pulmonary fibrosis (stein-streilein et al., ) . this model was similar to previous models of contact sensitivity using the skin for both sensitization and challenge and was consistent with a t cell-mediated dth process (polack, ) . different inbred mouse strains of animals exhibited coincidence of skin reactivity and the ability to develop pulmonary fibrosis (kimura et al., ) . induction of tolerance by injection of hapten-coupled splenocytes before sensitization depressed both the skin and the pulmonary responses following tracheal challenge (kimura et al., ) . the inflammatory and fibrotic responses to intratracheal hapten challenge were transferred with immune lymphocytes, but not with immune serum. in uivo administration of anti-cd and anti-cd antibodies to sensitized mice prevented or ameliorated the inflammatory and fibrotic responses to tracheal challenge. the development of pulmonary fibrosis is associated with bal il- activity and lymphotoxin mrna in bal nonadherent cells (garcia et al., ). an increased ratio of procollagen type :iii mrna in the fibroblasts from immunized, challenged animals developed, indicating that qualitative as well as quantitative collagen differences occurred (stein-streilein et al., ). bleomycin is a mixture of glycoproteins from streptomyces uerticullus used clinically for its antineoplastic properties, but which predictably causes pulmonary fibrosis, in a hamster model, intratracheal administration of a single dose of bleomycin to experimental animals caused pulmonary fibrosis which resembled clinical pulmonary interstitial fibrosis, albeit with some differences in the pattern of fibrosis from usual interstitial fibrosis (snider et al., ) . evidence has accumulated that cytokines are important mediators in animal fibrosis models. increased tgfp (khalil et al., ) , tnfa (piguet et al., a) , il- and il- (jordana et al., ) , mcp- (brieland et al., ) , and macrophage-derived growth factor for fibroblasts (denholm and phan, ) have been detected in lungs or pulmonary cells derived from animals exposed to bleomycin. administration of anti-tnfa can prevent fibrosis (piguet et al., a) . although many of the cytokine studies concentrated on the role of am, recent reports indicate that pulmonary endothelial cells constitutively produced il- which is increased by exposure to bleomycin (karmiol et al., ) . mcp- is produced by fibroblasts (rolfe et al., ) and tgfp is produced by pulmonary artery endothelial cells (phan et al., or lung fibroblasts (breen et al., ) . therefore, the source of cytokines in bleomycin-induced pulmonary fibrosis could include nonmacrophage pulmonary cells as well as macrophages. despite the evidence of toxicity of bleomycin-induced macrophagederived cytokines, several studies have suggested that t cells may also be important. different strains of mice responded differently to intratracheal bleomycin (schrier et al., a) . pulmonary fibrosis did not occur in athymic nude mice (schrier et al., ) and depletion of both cd and cd t cells prevented fibrosis (jordana et al., ) . cormier and colleagues described a model of hp associated with alveolitis and fibrosis, and which was caused by repeated pulmonary instillation of m. fueni. it was associated with increased bal il-la, il- , and tnfa (denis et al., ) . cyclosporin a administration blocked pulmonary fibrosis, but not alveolitis, and bal il-la and tnfa, but not il- (denis et ul., a), which suggested a role for t cells in producing fibrosis. pulmonary fibrosis was also prevented by anti-tnfa antibody (denis et al., ) . evidence was also found for a role for am-secreted tgfp in promoting fibrosis (denis and ghadirian, a) . secretion of tnfa, which probably originated from pulmonary macrophages, was fostered by csf- and gm-csf secreted by lymphocytes exposed to m. faeni . in contrast to an adoptive transfer model of hp to be described, in uivo depletion of t cells did not substantially affect the pulmonary histologic response to m. faeni . this might be related to repetitive challenges with an agent which has adjuvant effects (bice et al., ) , so that inflammation in this model was macrophage, rather than lymphocyte, driven. pulmonary fibrosis induced by repeated challenges with m. fueni, but not an increase of bal inflammatory cells, was reduced by administration of anti-cd la, implicating integrins in the processes that lead to fibrosis in this model (denis and bisson, ) . lymphocytes can be implicated in other models of hp. cyclosporin a administration ameliorated pulmonary lesions in animals subjected to airway challenges with t. uulgaris (takizawa et al., ) . nude mice did not exhibit pulmonary lesions of hp after exposure which was able to produce lesions in t cell-sufficient littermates. the ability to express pulmonary lesions could be transferred with t cells from sensitized mice (takizawa et al., ) . schuyler and colleagues have developed an adoptive transfer murine model of experimental hp using m. faeni. cells for adoptive transfer were obtained from spleen, peripheral lymph nodes, lalns, and peritoneal exudate from immunized animals. the cells were restimulated in culture with relevant antigen and could then transfer to naive recipients a susceptibility for increased lung inflammation following an intratracheal rechallenge with antigen (schuyler et al., ) . ifnr and il- were present in substantial quantities in cultures (fei et al., ) , and cd cells were required at the beginning of culture to generate effective cells for the adoptive transfer (schuyler et al., ) . the transferred cells were a mixture of naive and memory cd t cells, as defined by cd , cd rb, and l-selectin expression (schuyler et al., a (schuyler et al., , . successful transfer was also dependent on the presence of cd t cells in the recipient (schuyler et al., b) , suggesting the necessity of an important interaction between host and recipient cd t cells. despite different methods to develop models for lung allografting or gvhd, the immunologic responses in the lung show similar histologic patterns. several studies have documented these similarities (atkinson et al., ; emeson et al., ; piguet et al., b; randhawa and yousen, ; stein-streilein et al., ; yousem et al., ) . the histoincompatible allografted lung is recognized as "foreign" by the recipient and, therefore, is subject to rejection (randhawa and yousem, ) . in gvhd, donor immunocompetent allogenic cells recognize the recipient as foreign (farrara and deeg, ) . in both of these disorders, pulmonary manifestations of lung allograft rejection and gvhd may be separated into acute and chronic changes. in acute lung allograft rejection, the initial pathologic lesions of perivascular mononuclear cell infiltrates is termed "minimal rejection" or grade (yousem eta,?., ) . a more severe perivascular mononuclear cell infiltrate consisting of activated lymphocytes, plasma cells, and macrophages is called "mild acute rejection" or grade (yousem et al., ) . in some instances rare eosinophils are present (yousem et al., ) . vascular changes may include degeneration of the endothelium (endothelialitis) (yousem et al., ; randhawa and yousem, ) , and lymphocytic infiltration of the bronchioles may be present (yousem et al., ) . in grade acute lung cancer allograft rejection, also known as moderate acute rejection, infiltrates progress and become more apparent around pulmonary veins, arterioles, and peribron-(gvhd) in the lung: a pathologic comparison chiolar areas (yousem et al., ). in grade or "severe acute rejection" mononuclear cell infiltrates extend into air spaces and involve vessels and bronchioles. necrotizing vasculitis and parenchymal necrosis may also be visible (randhawa and yousem, ) . in contrast to acute lung allograft rejection, the pulmonary pathology of acute gvhd has not been assigned histologic grades. beschorner et al. ( ) first described the acute changes of gvhd in the lung in recipients of bone marrow transplants. in these patients, the pathology was limited to that of lymphocytic bronchitis (beschorner et al., ) . more recently, atkinson et al. ( ) reported an acute pulmonary syndrome after bone marrow transplantation that resembled acute gvhd of the lung. the lesions included lymphocytic peribronchial infiltrates, bronchial epithelial degeneration, and lymphocytic perivascular infiltrates (atkinson et al., ) . relative to the histology of acute lung allograft rejection, the pulmonary changes observed in acute gvhd of the lung are analogous to a grade rejection response. in animal models, investigators have reported acute "gvhd-like" changes in the lung (piguet et al., b; stein-streilein et al., ; wilkes et al., a) . in these studies the histologic lesions included alveolitis, lymphocytic bronchitis, and vasculitis. the histologic changes of acute gvhd were analogous to grade or severe acute rejection in a lung allograft. in both allograft rejection and gvhd of the lung, the pathologic lesions of the airway began at the level of the bronchioles and extended into alveolar spaces. the chronic stage of lung allograft rejection and gvhd is associated with the development of bronchiolitis obliterans (bo) (farrara and deeg, ; rhandhawa and yousem, ; yousem et al., ). bronchiolitis obliterans is not a lesion specific to allograft rejection or gvhd and, in fact, has been associated with a variety of conditions (epler, ) including toxic fume inhalation, rheumatoid arthritis, penicillamine use, postinfectious etiologies, as well as idiopathic causes. the histology of bo shows granulation tissue plugs within the lumens of the small airways, epithelial cell damage, mononuclear cell infiltrates, and, at times, complete obstruction of the airways (epler, ; randhawa and yousem, ) . bronchiolitis obliterans observed in chronic lung allograft rejection and gvhd involve the membranous and respiratory bronchioles, and possibly involve more proximal airways (randhawa and yousem, ) . in contrast to the pathology observed in the acute disease, lymphocytic perivascular infiltrates are present in only % of bo cases associated with chronic lung allograft rejection (randhawa and yousem, ) . the degree of vascular involvement in bo associated with chronic gvhd is unknown but is likely less than that of acute gvhd. both canine and rat models have been utilized to study lung transplantation and the immunopathogenesis of rejection (benfield, ; prop et al., a,b) . however, the availability of more immunological reagents has allowed the rat model developed by marck, prop, and wildevuur to be more extensively studied (marck et al., ) . orthotopic transplantation of the brown norway rat lung allografts (rt") into lewis (rt') rats resulted in histological and immunological changes analogous to that of human lung transplantation (marck et al., ; prop et al., a,b) . the rejection process occurred in four phases (prop et al., a,b) : ( ) the latent phase which occurred immediately after transplantation in which no immunological activity was described in the graft (day after transplantation); ( ) the vascular phase, characterized by infiltration of balt and perivascular tissue by lymphocytes (days or after transplantation); ( ) the alveolar phase, with mononuclear cell infiltration of the alveolar walls (days or after transplantation); and ( ) the destruction phase, characterized by intraalveolar edema and destruction of airways and vessels by infiltrating mononuclear cells (day after post-transplantation). significantly, these four phases resemble somewhat the four grades associated with acute rejection in humans (yousem et al., ) . while these studies described the histological changes associated with acute rejection, only two reports currently exist in the literature describing animal models of chronic rejection, known as bo (hertz et al., ; uyama et al., ) . utilizing the previously described rat lung allograft model, rats made tolerant to their allografts by cyclosporin developed the typical changes of bo around months after transplantation. the airway lesions were associated with upregulated class i mhc expression on the epithelium in the large airways, aggregates of dcs in the submucosa, and ulcerated epithelium (uyama et al., ) . in a murine model utilizing hetertopically transplanted airways, the characteristic lesions of bo developed in the allograft after days (hertz et al., ) . a significant difference between the rat models and that of clinical transplantation is that only one or two doses of the immunosuppressant drug, cyclosporin, results in indefinite acceptance of the donor rat lung (uyama et al., ) . human lung allograft recipients usually require life-long therapy to prevent rejection (trulock, ) . however, without cyclosporin, the rat lung allograft undergoes a rapid rejection process which usually results in the destruction of the allograft in or days posttransplantation (prop et al., a,b) . although lung transplantation has become an increasingly utilized modality for the treatment of many endstage lung diseases (trulock, ) , the lung allograft, in both animal models and humans, is more prone to rejection than other solid organs (prop et al., a,b; trulock, ) . the presence f many immunocompetent cells present in the donor lung that can stimulate a rejection response may be the explanation (prop et al., a,b; trulock, ) . notably, despite the large numbers of t lymphocytes present in the lung and thus carried into the recipient, the clinical syndrome of systemic gvhd has not been reported in human lung allografted individuals. however, gvhd in lung transplantation was reported in an animal model in which the recipient was rendered severely immunoincompetent by total body irradiation (prop et al., ) . acute lung allograft rejection is believed to be initiated by donor lung apc, i.e., dcs and perhaps macrophages, interacting with recipient lymphocytes (winter et al., ) . although there is no direct evidence that these accessory cells mediate allograft rejection, several studies suggest their role in the rejection responses. acute rejection episodes commonly occur at a time when there is an abundance of donor dcs and lung macrophages, i.e., the first to weeks after transplantation, and diminish when these cells are replaced by those of the recipient (paradis et al., ; uyama et al., ) . utilizing a murine model of renal transplantation in which dcs had been depleted, lechler demonstrated that repletion of dcs resulted in the rejection of the allograft (lechler and batchelor, ) . similarly, blocking antibodies to dcs resulted in the prolongation of survival of murine pancreatic islet allografts (faustman et al., ) . as discussed previously, dcs exist within the epithelium and subepithelial areas of the bronchi/bronchioles, areas that are involved in both acute and chronic rejection. additionally, ifny, a cytokine crucial to the rejection process (o'connell et al., ) , was shown to upregulate the number of dcs in the interstitium surrounding pulmonary capillaries, within the alveolar interstitium, and in the bronchial epithelium . finally, dcs accumulate in areas of bo during the course of chronic allograft rejection (uyama et al., ) . collectively, these studies suggest a central role for dcs in the pathogenesis of lung allograft rejection. lung macrophages, although suppressive of many immune cell functions, may also be involved in the initiation of the rejection response. lung accessory cell-lymphocyte interactions occur through cytokines and intercellular signals and result in upregulated cellular and humoral immunity (wilkes and weissler, ) . cellular immunity is crucial in lung allograft rejection (prop et al., a,b) and may result from the differential stimulation of t h l versus th cells. t h l lymphocytes play a significant role in the pathogenesis of solid organ allograft rejection (jordan et al., ; o'connell et al., ) . for example, in a murine example of pancreatic islet rejection, allograft infiltrating lymphocytes preferentially expressed mrna for il- and ifny, and not il- (o'connell et al., ) . similarly, in rat lung allografts, ifny mrna was expressed during the rejection episodes (jordan et al., ) . the clinical importance of t h l lymphocytes in allograft rejection is exemplified by the fact that the primary immunosuppressive agent used in recipients of human lung allografts is cyclosporin, which preferentially inhibits il- and ifny production from lymphocytes (cockfield et al., ) . in contrast, th lymphocyte activity, i.e., production of il- and il- , which downregulates t h l activity, has been strongly associated with prevention of allograft rejection (gorczynski and wojcik, ) . both allogeneic am and parenchymal lung dcs were potent inducers of ifny, but not il- , from lymphocytes (wilkes and weissler, ) . collectively, these data suggest that allograft rejection is in part mediated by lung macrophages and dcs stimulating t h l lymphocytes. cytokines from t h l and th lymphocytes can both result in specific immunoglobulin production (kitani and strober, ) . therefore, the upregulated t h l lymphocyte activity observed in allograft rejection might be responsible for the enhanced local immunoglobulin production observed during the rejection process (wilkes et al., b) . ifny, a t h l cytokine, can stimulate igg a from murine b lymphocytes (kitani and strober, ) . furthermore, ifny production, induced by human lung macrophages, selectively stimulated igg production from allogeneic peripheral blood mononuclear cells (wilkes and weissler, ) . in recipients of lung allografts undergoing rejection, wilkes ( ) demonstrated that local production of igg was selectively upregulated and, thus, served as a marker for the rejection response (wilkes et al., b) . few studies have demonstrated a role for alloantibodies in mediating the process of lung allograft rejection. coronary atherosclerosis secondary to murine cardiac allograft rejection was in part mediated by antibodies directed against the donor coronary epithelium (russell et az., ) . similarly, igg , but not iggl, igg , or igg , produced locally during human lung allograft rejection, preferentially bound to perivascular and peribronchial extracellular connective tissue matrices which are the anatomic locations involved in the rejection process (wilkes, manuscript in preparation) . taken together, these studies suggest a role for a thl-dependent humoral responses in the pathogenesis of lung allograft rejection. while lung accessory cell-t lymphocyte interactions initiate organ rejection (winter et al., ) , the production of proinflammatory cytokines, il- and tnfa, has been identified as a mediator ofthe rejection process saito et al., ) . evidence that tnfa was involved in rejection was demonstrated by demeester who reported that tnfa mrna and protein were upregulated in lung tissue during acute rejection of rat lung allografts . significantly, anti-tnfa antibodies reduced the vasculitis and hemorrhagic lesions in rejecting lung allografts (saito et al., ) . similarly, il- was upregulated in the lung during rejection and was postulated to be clinically important in following the activity of the rejection process . c. models of graft versus host disease in the lung gvhd is a systemic process, and relatively few have described pulmonary involvement in animal models of gvhd (piguet et al., ; stein-streilein et al., ) . stein-streilein et al. ( ) , utilizing a murine model, reported gvhd "reactions" in the lung. in these studies, suspensions of parental (mha) lymph node cells were instilled into the trachea of f hybrid (mha x cb) recipient hamsters. the histology observed in the recipient lungs showed mononuclear cell infiltration in the interstitium, alveolar, peribronchiolar, and perivascular areas. some of the animals developed thymic atrophy and splenomegaly which suggested a systemic component to the disease process (stein-streilein et al., ) . interestingly, when the cells were given iv or intracutaneously, the animals developed systemic gvhd without any distinctive pulmonary pathology (stein-streilein et al., ) . piguet also studied the pulmonary disease associated with gvhd. in these studies, irradiated f hybrid (cba x b ) mice were injected with either parental t lymphocyte-depleted bone marrow cells or with parental bone marrow cells together with suspensions of lymph node cells as a source of t lymphocytes. in addition to the induction of systemic gvhd, the histology of the lung was similar to that reported by stein-streilein. additionally, these investigators demonstrated the central role of t lymphocytes in the lung pathology of gvhd in that injection of t lymphocyte-depleted bone marrow cells did not induce pulmonary pathology (piguet et al., b) . wilkes et al. ( a) recently reported that allogeneic (c bl/ ) bal accessory cells (>go% macrophages), when instilled intratracheally into the lungs of normal balb/c mice weekly for weeks, induced a lymphocytic alveolitis, bronchitis, and vasculitis analogous to gvhd of the lung or acute lung allograft rejection. unlike other animal models of gvhd (piguet et al., b; stein-streilein et al., ) , these recipient mice had no evidence of systemic disease. additionally, if no further allogeneic challenges were performed, the pulmonary lesions eventually healed. as previously stated, the clinical manifestations of chronic gvhd in the lung are associated with the development of bo (farrara and deeg, ; randhawa and yousem, ; yousem et al., ) . in contrast, no animal models of chronic gvhd have reported an association with this type of pulmonary disease. the immunopathogenesis in animal models of gvhd has been well described (antin and farrara, ; piguet et al., ) . similar to acute lung allograft rejection, acute gvhd has been associated with the production of several proinflammatory cytokines including tl- , tnfa, and il- ( antin and farrara, ; piguet et al., b) . in fact, il- receptor antagonist was shown to significantly inhibit gvhd . relative to the lung, anti-tnfa antibodies partially prevented the pulmonary pathology of gvhd (piguet et al., b) . while proinflammatory cytokines are involved in the pathogenesis of gvhd, t lymphocytes initiate the process (antin and farrara, ) . t h l lymphocytes are crucial in acute gvhd. in amurine model of gvhd, ifny and il- were preferentially produced in the course of acute gvhd (allen et al., ) with similar findings to those reported by other investigators (antin and farrara, ) . therefore, the immune response to alloantigens in both lung allograft rejection and gvhd seems to be associated with upregulated t h l lymphocyte activity. a role of humoral immunity in gvhd has not been well defined. however, wilkes et al. reported ( a) that allogeneic bal cells instilled into murine lungs resulted in the predominant local production of igg a. additionally, only igg a was shown to be deposited in the perivascular and peribronchiolar extracellular connective tissues, the same anatomic locations involved in lung allograft rejection and gvhd of the lung. these data suggest that locally produced immunoglobulins recognize component(s) of the extracellular connective tissue matrix and may be involved in the pathogenesis of gvhd of the lung. no evidence has emerged which suggests that the principles of immunity derived from studies on cells from other body sites are contradicted in the lung and its associated lymphoid tissue. what is clear, however, is that the environment dictates the types of cells, their relationship to one another, and what perturbing events will set in motion either the development of an "active" immune response or tolerance. investigating mechanisms for the development of lung immunity has increased our understanding of how human diseases develop and is continuing to suggest new ways to manipulate pulmonary immune responses. demonstration that lung cells regulate both nonspecific inflammation and immunity through the expression of adhesion molecules and the secretion of cytokines offers hope for ways to design more effective vaccines, enhance microbial clearance in immunosuppressed hosts, and to suppress manifestations of immunologically mediated lung disease. important lung diseases targeted for intensive research efforts in the immediate future are tuberculosis, asthma, and fibrotic lung disease. perhaps even the common cold might be conquered. considering the pace of current research on lung immunity, it may not be too ambitious to predict that these diseases may be conquered in the next decade. purification and characterization of intraparenchymal lung lymphocytes. . lmmunol the potential role of bradykinin antagonists in the treatment of asthma the adjuvant effect of interleukin- in a vaccine against leishmania major pulmonary immune cells in health and disease: lymphocytes. 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mechanism ofrecovery in pneumococcal pneumonia. i. the action of type specific antibody upon the pulmonary lesion of experimental pneumonia studies on the mechanism of recovery in pneumococcal pneumonia. iv. the mechanism of phagocytosis in the absence of antibody administration of a highly attenuated, live respiratory syncytial virus vaccine to adults and children accessory cells of the lung. . ia+ pulmonary dendritic cells display cell surface antigen heterogeneity mechanisms of decrease in cytoplasmic motility of alveolar macrophages during immediate asthmatic response in dogs human alveolar macrophages inhibit receptor-mediated increases in intracellular calcium concentration in lymphocytes enhancement of systemic immune response by immunization into chronically inflamed lungs a working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: lung rejection study group antiviral protection by virus-immune cytotoxic t cells: infected target cells are lysed before infectious virus progeny is assembled immunity to viruses. i n "fundamental immunology the authors thank their secretarial staff for their excellent help in preparing the manuscript, specifically patricia sanchez, becky snyder, rebecca flores, gerri chavez, and christine cave. key: cord- -mk y authors: michelakis, evangelos d.; archer, stephen l. title: pulmonary arterial hypertension date: journal: cardiovascular medicine doi: . / - - - - _ sha: doc_id: cord_uid: mk y the first description of the circulation of blood through the lungs has been attributed to ibn nafis ( – ). the concept was rediscovered by michael servetus, a spanish physician during the renaissance ( – ) and recorded, oddly enough, in two pages of his religious treatise, christianismi restitutio ( ). the definitive exposition of the pulmonary circulation was made by william harvey in demotu cordis ( ). the first observation of the pulmonary capillaries was first reported by marcellus malpighi ( ). heart catheterization in humans, driven by a desire to obtain the perfect mixed venous specimen and measure cardiac output, was first performed in by the german urologist forssmann, using a ureteral catheter to access his own right atrium. over a decade later, cournand and richards at columbia university in new york subsequently used right heart catheterization to record pulmonary artery pressure (pap) in patients with shock and secondary forms of pulmonary hypertension (pht). for these accomplishments, which were inspired by an interest in the pulmonary circulation and pht related to mitral stenosis, forssmann, cournand, and richards received the nobel prize in . the first description of the circulation of blood through the lungs has been attributed to ibn nafis ( - ). the concept was rediscovered by michael servetus, a spanish physician during the renaissance ( - ) and recorded, oddly enough, in two pages of his religious treatise, christianismi restitutio ( ). the definitive exposition of the pulmonary circulation was made by william harvey in demotu cordis ( ). the first observation of the pulmonary capillaries was first reported by marcellus malpighi ( ). heart catheterization in humans, driven by a desire to obtain the perfect mixed venous specimen and measure cardiac output, was first performed in by the german urologist forssmann, using a ureteral catheter to access his own right atrium. over a decade later, cournand and richards at columbia university in new york subsequently used right heart catheterization to record pulmonary artery pressure (pap) in patients with shock and secondary forms of pulmonary hypertension (pht). for these accomplishments, which were inspired by an interest in the pulmonary circulation and pht related to mitral stenosis, forssmann, cournand, and richards received the nobel prize in . pathologic findings consistent with primary pht were first noted in autopsy specimens as a form of arterial sclerosis by romberg and monckeberg over a century ago. however, the first diagnosis of primary pht in a living human was not made until , by dresdale et al. over the past years it has become clear that primary pht is largely a disease of the pulmonary circulation, and the pathology is focused in the small pulmonary arteries, which are characterized by intimal fibrosis, medial hypertrophy, adventitial proliferation, obliteration of small arteries, and, on occasion, vasculitis or changes in the walls of the pulmonary veins. in addition, there are angioproliferative lesions, called plexiform lesions, which are uniquely found in pulmonary arterial hypertension (pah) and not in other forms of pht. in utero, the pulmonary circulation is largely bypassed, as oxygenation is the responsibility of the placenta. the fetal right ventricle, relative to the adult ventricle, is hypertrophied, and the arteries in this high pressure-low flow circuit have thickened media and adventitia. at birth there is a transition to a high-flow, low-resistance circuit designed for gas exchange, and the right ventricle becomes a thin-walled, afterload-intolerant pump. the adult pulmonary circulation accommodates the entire right heart cardiac output at % the pressure and resistance of the systemic vasculature. the pulmonary circulation is composed of large, extrapulmonary, "conduit" arteries, which anatomically and embryologically resemble systemic arteries, and small, muscular intrapulmonary arteries, which control regional distribution of pulmonary blood flow and largely determine pulmonary vascular resistance (pvr). these arteries perfuse an extensive thin-walled, metabolically active, capillary bed where gas exchange occurs. blood then courses to the left atrium via the venous circulation, which has active tone and which, as it approaches the left atrium, acquires a sleeve of cardiac myocytes. the normal physiologic function of the pulmonary veins is uncertain, although they may be involved in coordinating venous flow with atrial function. in disease, the pulmonary veins can be a source of ectopy, which leads to atrial fibrillation. pulmonary hypertension is a condition defined as an increase of the mean pap to more than mm hg at rest or mm hg with exercise. this definition was used in the national institutes of health (nih) registry of patients with primary pht, a form of pah in which the etiology is unknown and the pathology is focused in the arterial portion of the pulmonary circulation. although this chapter focuses on pah, the most common forms of pht are "passive," relating to left ventricular dysfunction with increased left ventricular end-diastolic pressure due to myocardial or valve disease. in this pathology there is usually relatively minor pulmonary vascular pathology, although some patients with left heart failure or mitral stenosis have more severe pht than would be predicted based on their left atrial pressure, suggesting a reactive form of pah. the use of pap as a means to diagnose pah is flawed because it is not precise in anatomically localizing the cause of the hypertension. for example, the elevated pap in left heart diseases is due to the elevated pulmonary capillary wedge pressure and the gradient between the pa diastolic pressure and the wedge pressure is minimal. in contrast, in pah this gradient is more than to mm hg, localizing the problem (obstruction) within the pulmonary circulation, proximal to the left atrium. pulmonary artery pressure increases slightly with age and normally increases with conditions that elevate cardiac output (e.g., exercise), even in healthy, young individuals. in healthy older men (ages to years), the mean pap can increase to more than mm hg during exercise. with exercise, pap, wedge pressure and cardiac output are all elevated but pvr is relatively unchanged. consequently, pvr (table . ) is a better parameter with which to define pulmonary arterial pathology. conversely, pap may be minimally elevated in a patient with pah and very low cardiac output; in such a case pvr is usually ele-vated at rest. in borderline cases, exercise can be used to elicit dramatic increases in pvr. the upper limit for pvr index [(pap-wedge pressure)/cardiac index] in normal subjects increases from approximately . mm hg/l/min/m ( to years) to . ( to years) to . ( to years). pulmonary vascular resistance must be measured in order to diagnose pah. the occurrence of pht, whether as a primary disease or a complication of heart or airway disease (cor pulmonale) is an independent predictor of increased morbidity and mortality. this is because the impact on the function of the afterload-intolerant right ventricle is the same, regardless of the specific etiology of pht. the function of the thin-walled adult right ventricle decreases abruptly even with small increases in its afterload, resulting in decreases in stroke volume and thus cardiac output. this is in sharp contrast to the left ventricle, which can compensate for much greater increases in afterload ( fig. . ). (table . ) twenty-five years following the original meeting, the world health organization (who) sponsored the second international primary pht meeting in evian, france, where a new classification of pht syndromes was adopted. importantly, primary pht (both sporadic and familial) was grouped with several other forms of pht that strongly resembled primary pht under the rubric of pulmonary arterial hypertension. these "primary pht-like" cases were associated with identifiable pathogenic stimuli or disease states, such as the use of anorectics, collagen vascular disease, infection with hiv, congenital systemic to pulmonary shunts, and persistent pht of the newborn. this reclassification reflected the fact that the clinical presentation and the histologic picture . the large resulting decrease in cardiac output that results with even small increases in the rv afterload [i.e., the pulmonary vascular resistance (pvr)] is responsible for many of the symptoms in pht. the rapid deterioration of the rv function in pah is also responsible for the much worse prognosis in patients with pah, compared to that of the patients with systemic hypertension. (table . ) the term primary pht was replaced by idiopathic pah (ipah), which occurs in sporadic (spah) and familial forms (fpah). the current who classification for defining functional class for pah patients is shown in table . (see also fig. . ). the prevalence, incidence, and mortality of pah in the general population remain unknown. early estimates identified pah as a rare or "orphan" disease with a prevalence of to per million, based on data from limited cohorts in the united states, france, and israel. [ ] [ ] [ ] these studies, which did not perform population surveillance, identified a very high mortality in pah patients, often worse than that of metastatic breast cancer. for reasons discussed below, it is very likely that the prevalence of pah is underestimated and the mortality overestimated, based on emerging data from centers that have earlier disease detection and offer improved therapies. the largest primary pulmonary hypertension (pph) natural history study was based on the nih primary pht registry, which followed patients from to . primary pht was defined as mean pulmonary artery (pa) pressure > mm hg at rest (or > mm hg with exercise) in the absence of secondary causes for pht, a definition different from the current definition of pah, which includes pht due to more common diseases like collagen vascular disease, hiv infection, portal hypertension, congenital heart disease as pah (table . ). the mean age was ∼ years with a female to male ratio of . : . the mean right atrial pressure at diagnosis was ± mm hg and mean pa pressure ± mm hg, suggesting that this cohort had very severe pht. a subsequent survival study of patients from the nih registry showed a median survival of . years, with survival rates at , , and years were %, %, and %, respectively. mortality increased with advanced new york heart association (nyha) class, elevated right atrial or mean pa pressure, and decreased cardiac index. similar data were reported from smaller cohorts from israel, india, and japan. an increase in the number of deaths in the u.s. attributed to ipah has been reported. analysis of cause of death data (based on death certificates) showed an ageadjusted increase in the number of deaths ascribed to ipah in the u.s. from to ( fig. . ). the rate patients with pht who are comfortable at rest but in whom ordinary levels of physical activity causes undue dyspnea or fatigue, chest pain, or near syncope iii patients with pht resulting in marked limitation of physical activity with minimal physical activity; they are often comfortable at rest; less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope iv patients with pht with inability to carry our any physical activity without symptoms; these patients manifest signs of right heart failure; dyspnea and/or fatigue may even be present at rest and increases with physical activity . an increase in the incidence of idiopathic pah (ipah) has been documented recently, based on death certificate diagnoses in the united states. the increase has been higher in black men and black women. of the increase was greatest amongst african-american women. this increase could be due to a true increase in the incidence of deaths from ipah (for example, due to the use of anorectic agents, which caused an outbreak of ipah during that period), better case recognition (due to the increased access to noninvasive means of measuring pa pressure and the increased access to the specialized pah clinics), or both. indeed, widespread access to noninvasive diagnostic techniques (e.g., doppler echocardiography) has led to an increase in the number of patients who are diagnosed at earlier stages of the disease, sometimes even before the onset of symptoms. however, the isolated measurement of pa pressure without measurement of cardiac output and wedge pressure has led to many misdiagnoses of pht. in addition, there has recently been a dramatic increase in the awareness of pah due to a number of factors, including an increase in the interest of the pharmaceutical industry, the medical community ( www.phcentral.org/talk/index.html). patient empowerment has increased the number of self-referrals and referrals from general practitioners to pah specialists. it is likely that the availability of oral therapies for pah (such as bosentan and sildenafil) has also enhanced the interest in making the diagnosis of pah. because of the lack of ongoing national databases and registries since the nih registry closed, data on the current prevalence and natural history of pah are lacking. however, anecdotal evidence suggests that the epidemiology has changed. for example, in the university of alberta pulmonary hypertension program (a tertiary care program serving a catchment population of . million) there have been referrals for documented pht over the past years. from these, had pah, which was a new diagnosis in % of cases ( fig. . , see also table . ). the female to male ratio is ∼ : and the mean age, in years, is for men and for women. almost half of the patients are nyha class i or ii ( fig. . ). although this is small and predominantly caucasian cohort, it is consistent with anecdotal evidence that pah is more common and more prevalent in older ages, and that current pah cohorts are less sick than the original nih cohort, which was predominantly young, female, and quite ill. organized and independent, publicly funded, databases and registries are urgently needed to determine the true prevalence, incidence, and natural history of pah, much like the nih registry in the s. to understand pah it is essential to review the unique features of the pulmonary circulation and its embryology. the pulmonary or "lesser" circulation has fascinated physiologists for over a century. its many differences from the systemic vascular beds have only recently begun to be understood. for example, the pulmonary circulation is a lowpressure circulation with thin-walled arteries and it accommodates the whole cardiac output at a pa pressure of < / mm hg, in contrast to the higher-pressure systemic circulation ( / mm hg) with its thick, muscular arteries. the purpose of the two circulations is also different: o uptake for the pulmonary circulation, and o delivery for the systemic circulation. in this regard, the pulmonary circulation constricts in response to acute hypoxia (hypoxic pulmonary vasoconstriction, hpv ), which is the major mechanism to optimize ventilation-perfusion matching and thus o uptake; in contrast, the systemic circulation dilates in response to hypoxia, which optimizes o delivery. in addition, the pulmonary circulation develops in utero in a relatively hypoxic environment, compared to the systemic circulation. in utero, the uninflated lungs are bypassed by oxygenated blood coming from the placenta, which is preferentially shunted to the systemic vasculature through the fossa ovalis and the ductus arteriosus. the diseases that afflict the pulmonary circulation are also relatively unique. in adult life, systemic hypertension and atherosclerosis spare the pulmonary circulation, and. conversely, pah usually occurs without substantial systemic vascular disease. however, systemic arterial vasospasm in the digits, which is a response to cold (raynaud's phenomenon), is not uncommon in pah (particularly in association with ingestion of anorexigens or collagen vascular diseases). the relative contribution of genetic versus environmental differences to these pulmonary-systemic arterial differences is unclear and perhaps both contribute. the systemic arteries and pulmonary arteries have different embryologic origins, but also experience markedly different local environments. for example, the small pulmonary arteries that control pvr are adjacent to the alveoli and experience much higher levels of ambient oxygen and much less shear stress than systemic arteries. understanding these differences will explain several important mechanisms in health and disease. for example, why is the pathology of pah restricted to the pulmonary vessels, leaving all the systemic vessels intact? the answer to this question has important clinical implications since currently a major challenge in the therapy of pah is the lack of selective treatments that lower pap without causing systemic vasodilatation. the pah patients tolerate systemic vasodilatation poorly because fixed and elevated levels of right ventricular afterload prevent compensatory increases in cardiac output in response to vasovagal stimuli or vasodilator therapies, promoting a vicious cycle of hypotension. therapeutic targets unique to the pulmonary circulations have not yet been identified. however, accessing the pulmonary vasculature via the airway permits selective therapy of the pulmonary circulation for compounds that are not systemically absorbed [e.g., iloprost®, inhaled nitric oxide (ino)]. the lung has two parallel circulations: the pulmonary arteries and the bronchial arteries. the bronchial arteries are thick-walled and muscular, and they supply blood to the bronchi and the wall of the large pulmonary arteries. in other words, they are vessels made to supply oxygen to support the lung's relatively minimal metabolic functions. in this regard bronchial arteries resemble systemic vessels. in contrast, the pulmonary arteries are involved in the central uptake of oxygen from the lungs. hypoxic pulmonary vasoconstriction is a homeostatic response, intrinsic to the pulmonary arteries, that optimizes oxygenation by matching ventilation to perfusion. in hpv, the small (< μm) arteries "sense" even small decreases in the local alveolar po and constrict to divert the blood to better ventilated areas, preventing the delivery of suboptimally oxygenated blood to the body; conversely, all systemic arteries vasodilate, thereby optimizing systemic o transport. the resistance pulmonary arteries, together with carotid body and airway neuroepithelial bodies, constitute the body's specialized o sensing system, the function of which is optimization of o uptake. interestingly, these tissues share common mechanisms to transduce changes in po into changes in arterial tone, ventilation, and airflow. hypoxic pulmonary vasoconstriction is strongest in the small, fourth-to seventh-division pulmonary arteries that are surrounded by alveoli; conversely proximal, extrapulmonary arteries do not contract, and may even dilate in response to hypoxia (fig. . c). these differences may be genetically programmed because the proximal pulmonary arteries have a different embryologic origin from the small intrapulmonary arteries. the proximal pulmonary arteries are derived from the truncus arteriosus, which divides into the aorta and pulmonary trunk by weeks of human gestation, by growth of the spiral aorticopulmonary septum. this occurs via angiogenesis, which is the branching of new vessels from preexisting ones. in contrast, the small intraparenchymal pulmonary arteries are derived from the sixth branchial arch arteries, the most caudal of the brachial arteries, by weeks' gestation in humans. this occurs via vasculogenesis, which is the development of blood lakes in the mesenchyme. recent evidence suggests that these arteries originate from a strand of endothelial precursors that connect the ventral wall of the dorsal aortae to the pulmonary trunk. distinct endothelial precursor cells have recently been identified in human embryos (fig. . a). a survival advantage to these endothelial cells is offered by a variety of survival and antiapoptotic factors, and it appears that insulin growth factor plays a central role very early in the process. both the angiogenesis (for the proximal pulmonary arteries) and the vasculogenesis (for the distal pulmonary arteries) are elegantly coordinated, and finally the two developing vascular segments are connected by a fusion process ( fig. . ). the different embryonic origins of vascular cells within the fetal lung may account for some of the endothelial and smooth muscle heterogeneity that characterizes the adult lung. for example, endothelial cells from the proximal arteries have a different phenotype compared to endothelial cells from distal pulmonary arteries. the differences between these two types of endothelial cells are maintained even in culture, emphasizing their genetic basis. similarly, smooth muscle cells (smcs) from the distal and proximal pulmonary arteries have different phenotypes and functional properties. portions of the pulmonary circulation thus might be due to tissue heterogeneity among expressed k + channels between pulmonary and systemic vascular beds (e.g., splice variants). this restricted localization of the hypoxic vascular response could also be due to the presence of unique sensors for hypoxia in the distal pulmonary arteries. it is the sensor, which, in response to hypoxia, alters the production of a mediator that regulates the function of o -sensitive k + channels. the sensor of hypoxia in the pulmonary arteries appears to be the smcs' mitochondrial electron transport chain, , , or possibly another vascular redox enzyme, reduced nicotinamide adenine dinucleotide phosphate (nadph) oxidase. this sensor changes the production of reactive oxygen species (ross) in response to mild hypoxia, and these ross serve as diffusible second messengers, changing the gating and opening of certain kv channels, such as kv . and kv . (fig. . ). in hypoxia, altered mitochondrial-derived ros production leads to kv channel inhibition and vasoconstriction. although the identity of the pulmonary vascular oxygen sensor remains controversial, and there is disagreement as to whether hypoxia increases or decreases ros, mitochondria are vascular o sensors in the pulmonary arteries, as first, distal pulmonary artery smcs (pasmcs) contract in response to hypoxia in vitro, whereas the cells from proximal pulmonary arteries dilate, like the smcs from systemic arteries. perhaps this reflects the fact that the smcs of small pulmonary arteries express relatively more oxygensensitive kv channels (particularly kv . and kv . ), whereas proximal pasmcs express more calcium-activated k + channels (kca). , this finding is important because these redoxand oxygen-sensitive kv channels, such as kv . , have been directly implicated in the initiation of hpv. inhibition of these channels leads to depolarization of the smcs, opening of the voltage-gated l-type calcium channels, influx of calcium, and contraction. the full manifestation of hpv is supported by calcium release from intracellular stores as well as by calcium sensitization of the contractile apparatus by rho kinase. hypoxic pulmonary vasoconstriction occurs even at mild levels of alveolar hypoxia, and at these levels of physiologic hypoxia, animals and patients do not develop seizures or arrhythmias (which would be expected if these channels were similarly inhibited in the brain and the heart, where they are also expressed). the restriction of hpv to certain well as in a variety of other oxygen-sensitive vascular tissues, including the ductus arteriosus and the carotid body. the mitochondria of the small pulmonary arteries are functionally distinctly different from the mitochondria of the systemic vessels (fig. . ). although some of these concepts have been introduced only during the past few years, their clinical implications have already become apparent. kv . , which is involved in the initiation of hpv, is selectively downregulated in both animal models of pah and humans with pph. [ ] [ ] [ ] this downregulation leads to depolarization and the activation of the voltage-gated calcium channels in the pasmcs. this likely explains the beneficial effects of l-type calcium channel blockers (such as nifedipine) in some patients with pah. these mechanisms can also explain why drugs that open k + channels (e.g., inhaled no and sildenafil) are beneficial in pah. in the future, perhaps therapeutic strategies can be devised to exploit mitochondrial diversity to create therapies that are selective for the pulmonary circulation. the mitochondria are promising targets for pah therapy because they not only regulate vascular tone but also are major determinants of rates of apoptosis in the vascular wall. induction of apoptosis in the media of remodeled pulmonary arteries in pah might be an effective and selective therapeutic strategy. in experimental pah, it appears that mitochondrial function is abnormal (as manifest by a hyperpolarized mitochondrial membrane potential and altered ros production), and this leads to inappropriately low rates of apoptosis and enhanced smc proliferation. strategies that induce mitochondria-dependent apoptosis may prove to be effective and selective treatments. dichloroacetate (an inhibitor of the the opposing effects of the pulmonary and the renal circulation to hypoxia are at least in part due to differences in the oxygen sensor, that is, the mitochondria. the traces shown here are from isolated rat lungs and kidney perfused in series. (b) the pulmonary artery smooth muscle cell (pasmc) mitochondria are more depolarized (as shown by the tmrm fluorescence and confocal microscopy) compared to the renal artery smooth muscle cell (rasmc) mitochondria, although they are imaged under identical condition. mitochondrial pyruvate dehydrogenase kinase, which has been used orally in human with congenital lactic acidosis) induces vascular apoptosis and reverses pah in rats, without affecting the systemic vessels. inhaled gene therapy with a dominant-negative construct that inhibits the inhibitor of apoptosis protein survivin also induces mitochondriadependent apoptosis and reverses pht in animals. histopathology pulmonary arteries in pah are characterized by intimal fibrosis, medial hypertrophy, adventitial proliferation, obliteration of small arteries, in situ thrombosis, and, on occasion, vasculitis or changes in the walls of the pulmonary veins (fig. . ) . a fascinating, focal vascular structure, the plexiform lesion, is found in many cases of pah and is typically absent in secondary forms of pht, due to hypoxia, cor pulmonale, left heart disease, and thromboembolism. plexiform lesions are somewhat reminiscent of renal glomeruli, their many vascular channels being lined with endothelial cells rich in type- nitric oxide synthase (enos), factor viii, vimentin, and the receptor for vascular endothelial growth factor (vegf). plexiform lesions may represent an angiogenic response to local ischemia or hypoxia, as occurs with the creation of collateral vessels associated with obstructed arteries in other vascular beds. certainly, computerized three-dimensional reconstruction of vessels in pah demonstrate that plexogenic lesions occur distal to obstructive vascular lesions. studying pah pulmonary arteries with either a plexiform lesion or intimal or medial hypertrophy, one is impressed by the increased cellularity in the vascular wall. the increased cellularity may represent infiltrating inflammatory cells (in some cases), but in most cases it reflects excessive cell proliferation or suppressed apoptosis. the therapeutic potential of reversing the imbalance between proliferation and apoptosis within the pulmonary artery wall is a very new area of research in pah and has already produced some attractive experimental treatments for pah, as will be discussed below. the challenge for any pathogenetic theory of pah is to account for the entire spectrum of the disease, that is, pulmonary artery vasoconstriction, obstructive vascular remodeling, and thrombosis in situ. however, pah is likely a syndrome, not a disease, consisting of several conditions that share similar features but result from diverse etiologic stimuli. it is also likely that classic pah is the end stage of multiple mechanisms and phenotypes, one or more of which might be an initiating mechanism, whereas others follow and exacerbate the condition. a "multiple hit hypothesis" is increasingly being accepted as the leading theory to explain the complexity, relative rarity, and pulmonary vascular selectivity of pah. much like cancer, a susceptible patient with a genetic predisposition [e.g., due to mutations of the bone morphogenetic protein receptor- (bmpr- ) or gene polymorphisms] appears to require additional environmental insults (like an anorectic drug or a viral infection) before pah is manifested. the many abnormalities that have been described in pah can be grouped into two large thematic categories: ( ) abnormalities that contribute to an imbalance between vasoconstrictors and vasodilators and thus promote vasoconstriction, and ( ) abnormalities that contribute to an imbalance between proliferation and apoptosis and thereby promote proliferative remodeling. specific cellular and biochemical abnormalities have been described in pah at all levels of the vasculature, from the blood (e.g., platelets) and endothelial cells through the smcs, fibroblasts, and inflammatory cells. in this discussion we emphasize the studies that have used patients or human tissues. while the mechanisms that we discuss below, alone or in combination, can explain most of the features of pah, no mechanisms so far can adequately explain perhaps the biggest mystery of this challenging disease: why are the vascular abnormalities in pah restricted to the pulmonary circulation? what is it that predisposes the pulmonary arteries or protects the systemic arteries from this disease? at the late stages of pah the pulmonary artery endothelium is highly abnormal. because pah is usually detected only in the late stages of the disease, studies of the endothelial function in patients with early pah are lacking. the final result of the endothelial dysfunction is an imbalance of endothelial-derived vasoactive factors, with an increase in the vasoconstrictors/vasodilator balance. both ipah and secondary pht patients excrete elevated levels of a thromboxane a metabolite and reduced amounts of a prostacyclin metabolite. thromboxane a is a potent vasoconstrictor and stimulus for platelet aggregation, whereas prostacyclin is an antiproliferative, antiaggregatory, vasodilator endothelial product. the fact that this platelet-endothelial abnormality occurs in both ipah and secondary pht suggests it is not the cause of ipah. nonetheless, this observation has had rich therapeutic value, as is discussed later. it is also postulated that there is an excess of the constrictor endothelin- (et- ) and a deficiency of the vasodilator no in ipah. the idea of a no deficiency in pah, the conventional wisdom, relates to the observed decrease in expression of endothelial nitric oxide synthase (enos) in the lungs of a few ipah subjects. however, nos function was not measured in this immunohistochemistry study. conversely, lung no production, which admittedly may not reflect only pulmonary vascular no production, is actually enhanced or preserved in pah. similarly, ipah patients have higher urinary cyclic guanosine monophosphate (cgmp) concentrations than asthmatic patients or healthy controls. since most blood vessels respond to elevation of tone with a homeostatic increase in no production, no deficiency in pah might represent a failure of this pathway in the late stages of the disease. alternatively, certain patients with endothelial dysfunction or an abnormal enos variant may be predisposed to certain forms of pah. depressed no production may contribute to the susceptibility to anorexigen-induced pah. endothelin- (et- ) is a potent peptide vasoconstrictor and mitogen. et- levels are increased in experimental and human pah. , the high levels of et- in arterial compared with venous plasma in pah and the increased expression in pulmonary arteries suggest that et- contributes to the increased pvr in ipah. increased et- levels also occur in other diseases, such as congestive heart failure. however, elevation of et- levels does not necessarily mean that antagonism of the pathway is beneficial. in congestive heart failure the endothelin receptor antagonists have been ineffective. , the mitogenic action of et- in the pasmcs occurs via the endothelin a (eta) receptor, whereas the endothelin b (etb) receptor is thought to mediate the clearance of et- from the pulmonary circulation and cause no-mediated vasodilatation. another vasodilator that has more recently been proposed to play a significant role in pah is the neurotransmitter vasoactive intestinal peptide (vip), which is a potent pulmonary vasodilator that also inhibits the proliferation of smcs and decreases platelet aggregation. the vip receptors are linked to adenylate cyclase and eventually lead to activation of both cyclic adenosine monophosphate (camp) and cgmp. both low serum concentration and low expression of vip have been reported in ipah pulmonary arteries, and inhalation of vip in eight ipah patients resulted in acute improvement in hemodynamics. disordered production of vasoactive mediators is not the only endothelial abnormality in pah. the endothelial cells also form plexiform lesions. these plexiform lesions, which are seen in several types of pah (but not in secondary forms of pht), have an abnormal proliferative phenotype. lee et al. assessed whether the proliferation of endothelial cells in plexiform lesions in ipah is the result of a monoclonal expansion, as occurs in neoplasia, or is polyclonal, typical of normal proliferation. they studied the methylation pattern of the human androgen receptor gene in endothelial cells microdissected from plexiform lesions, and showed that % of endothelial lesions were monoclonal, whereas in secondary pht % of the endothelial lesions (not plexiform lesions) were polyclonal. this intriguing hypothesis, that pah is somewhat of a "neoplastic" condition, remains controversial but merits further assessment. recent rodent studies confirm this hypothesis, by the finding that a potent inhibitor of apoptosis that was previously thought to be exclusively found in cancer cells, survivin, is selectively expressed in the pa wall in patients with pah but not normal controls (fig. . ). k + channel dysregulation k + channels are transmembrane spanning proteins that contain a pore with great selectivity for k + . they are tonically active in vascular smcs, allowing a slow efflux of k + along its intracellular/extracellular concentration gradient of / mm. there are several k + channel types: voltage-gated (kv), inward rectifier (k ir ), and calcium-sensitive (k ca ). kv channels have a voltage sensor and both respond to and help to establish membrane potential. inhibition of kv channels results in accumulation of positively charged k + ions within the cell, thereby raising the membrane potential to more positive levels (depolarization), which activates the voltagegated, l-type calcium channels. calcium then enters the cell, via the l-type, voltage-gated calcium channels, which are inhibited by nifedipine, activating the contractile apparatus, thus leading to vasoconstriction. indeed, acute hypoxia appears to initiate hpv by inhibition of kv channel in the pasmcs. , the intracellular calcium increase also activates a number of mechanisms that result in cell proliferation. intracellular k + causes a tonic inhibition of several caspases. the decreased intracellular k + that follows k + channel opening inhibits caspases, thereby activates apoptosis. thus a pah pasmc that is relatively deficient in k + channels, whether the basis is genetic or acquired (k + channel inhibition by hypoxia or anorexigens), would be depolarized, with increased levels of intracellular ca + and k + . this ionic environment places the cell in a contracted, proliferative, antiapoptotic state. in the presence of appropriate stimuli or growth factors, the vasoconstriction and the proliferation within the vascular wall likely contributes to the pa remodeling seen in pah. there is currently a search for the molecular identity of the k + channels involved in hpv and pah. there are nine families of kv families (kv - ), each with many members (i.e., kv . to kv . ). in humans with ipah, kv . messenger rna (mrna) levels are reduced in pasmcs, and this is circumstantially associated with membrane depolarization and elevation of cytosolic ca + . , less is known about kv . , although it is involved in setting membrane potential in rat pasmcs. it is fascinating that the anorexigens that caused several epidemics of pah during the past years inhibit k + current and depolarize pasmcs, leading to pulmonary vasoconstriction. they appear to do this by inhibiting both kv . and kv . . channels whose expression is also selectively downregulated in experimental pah. interestingly, reversal of this "ionic remodeling," whether indirectly by drugs or directly by k + channel gene therapy, improves the hemodynamic and remodeling abnormalities in experimental pht. taken together these data suggest that the selective downregulation of kv channels might play a role in the pathogenesis of pah; in other words, pah might be a form of a kv channelopathy. there is clearly a precedent for ion channelopathies causing human disease, including chloride channel mutations causing cystic fibrosis and mutation of k + and na + channels causing the long qt syndrome that results in sudden cardiac death. the kv channel hypothesis requires further investigation. survivin, a member of the mammalian "inhibitor of apoptosis" family, is known to be expressed in most cancers but not in most normal adult cell types. the cell cycle-dependent expression of the survivin gene in mitosis suggests a role for survivin in promoting cell proliferation. however, recent data point to a more selective role of survivin in antagonizing mitochondrial-dependent apoptosis, and a mitochondrial pool of survivin has recently been identified in cancer cells. survivin is expressed in remodeled resistance pas, but not normal pas, from pah patients and rats with monocrotaline (mct)-induced pah, a widely used model of pah. inhaled adenoviral gene therapy with a dominant-negative construct that inhibits endogenous survivin reverses established mct-pah. the therapeutic effect of inhibition of survivin is achieved by induction of mitochondria-dependent apoptosis in pasmcs. interest-ingly, this mechanism is also associated with activation of kv channels. survivin mutations, similar to those observed in oncogenic transformation, might occur in some patients with pah, resulting in spontaneous survivin expression, although this is entirely speculative. voelkel et al. have exposed fascinating similarities between cancer and pah, by showing that the proliferating cells in the neointimal plexogenic pah lesions are monoclonal. alternatively, survivin expression may be induced following endothelial damage, which is likely a critical early event in the pathogenesis of pah. , endothelial damage would allow direct exposure of pasmcs to circulating growth factors that are known to induce survivin expression. in addition to facilitating the pasmc transition to a proliferative state, survivin inhibits apoptosis by hyperpolarizing mitochondria. this will result in less cytochrome c and h o in the cytoplasm, thereby inhibiting kv channels. the resultant increase in the intracellular k + further suppresses apoptosis and, by depolarizing the cell membrane, increases the opening of the voltage-gated ca + channels, thereby enhancing ca + influx, causing vasoconstriction and amplification of proliferative signal pathways. several groups have hypothesized that serotonin ( -hydroxytryptamine, -ht) may be important in the development of pah. [ ] [ ] [ ] [ ] the majority of the circulating -ht is produced by the gastrointestinal tract chromaffin cells and pulmonary neuroepithelial bodies and is stored in the platelet dense granules. a key piece of evidence for the involvement of serotonin is the finding that plasma serotonin levels are increased in ipah patients versus controls, whereas platelets from ipah patients have decreased serotonin concentrations. serotonin released during in vitro platelet aggregation is also exaggerated in ipah patients relative to controls. moreover, these abnormalities persist after heart-lung transplantation, suggesting that this platelet abnormality is not secondary to the pht. the classical action of the anorexigens is to cause serotonin release and prevent the reuptake of serotonin. in addition, anorexigens are actively taken up into the cells by means of the -ht transporter ( -htt). it has been shown that there is overexpression of -htt in pasmcs from patients with pah, and as a result their pasmcs grow abnormally rapidly in response to serotonin or serum stimulation. -htt expression is also increased in the platelets and lungs from pah patients versus controls. -htt overexpression is predominantly evident in the media of the hypertrophied pulmonary arteries. -htt is encoded by a single gene in chromosome q . . the l-allelic variant of the -htt gene promoter, which induces a greater rate of -htt gene transcription than the s allele, has been reported, by one group, to be associated with -htt overexpression and increased pasmc growth. the l allele was present in homozygous form in % of french pah patients but in only % of controls. since this report is from a single country and since ethnicity is important in such polymorphisms, independent confirmation in a different population is needed. mice over-expressing the -htt gene exhibit spontaneous pht in normoxia and exaggerated pht in hypoxia. these data suggest that -htt activity might play a key role in the pathogenesis of pasmc proliferation in pah and that a -htt polymorphism confers susceptibility to pah. the serotonin hypothesis provides another genetic basis for a pah-susceptible genotype, in addition to mutations in bmpr . activation of -ht b receptors elicits vasoconstriction in human small pulmonary arteries by activating g i signaling, which inhibits adenylate-cyclase and decreases camp levels. in the chronic hypoxic model of pht, mice lacking -ht b receptors develop less vascular remodeling and have no right ventricular hypertrophy compared to the wild-type controls. similarly, mice lacking the -ht b receptor, which is the receptor activated by nor-dexfenfluramine, the active metabolite of dexfenfluramine, do not develop chronic hypoxic pht. both -ht b and -ht b receptor expression is also increased in pah. much of the evidence linking -ht and pah comes from the fact that the anorexigens cause -ht release. however, a link among k + channels, anorexigens, and -ht has been proposed. the anorexigens block kv channels in platelet progenitor cells, megakaryocytes. kv channel inhibition in platelets leads to serotonin release. furthermore, fenfluramine reduces kv . mrna levels by % in pasmcs from normotensive patients, suggesting that inhibited gene transcription and expression of kv channels may play an important role in anorexigen-pah. these data suggest that one of the reasons that -ht might be increased in pah is the lack of kv channels in platelets or pulmonary endothelial cells. vascular remodeling is a prominent feature of pah with muscularization of normally non-or partially muscularized peripheral arteries. the muscularization relates to differentiation of pericytes, medial hypertrophy, as well as proliferation and distal migration of pasmc. however, in pah there is also increased production of extracellular matrix (collagen, elastin, fibronectin, and tenascin-c). like the procoagulant state in pah, altered mitogenesis in pah appears to be a secondary response to an initial injury. rabinovitch , has suggested that endothelial abnormalities, early in the course of pah, permit extravasation of blood factors that stimulate smc production of a vascular serine elastase. this results in the liberation of matrix-bound mitogens, such as basic fibroblast growth factor (fgf- ), and also enhances matrix degradation by activating other matrix metalloproteinases (mmps). the mmps can lead to the production of a mitogenic cofactor, tenascin. tenascin binds to its α-β integrin receptors, leading to phosphorylation of growth factor receptors and smc proliferation. when mmps are inhibited, tenascin levels fall and apoptosis ensues. direct inhibition of mmp- and serine elastases leads to activation of apoptosis and suppression of proliferation in the media, and thus regression of medial hypertrophy. although mmps were conventionally thought to be solely important in remodeling, we have recently learned they can also affect vascular tone. mmp- and mmp- can activate platelets, while intravascular mmp- can enhance formation of vasoconstrictors, including a novel form of endothelin, and inhibit the action of endogenous vasodilators. the inhibition of mmps, if selectively targeted, could be an appealing therapeutic target for causing regression of pah. inflammatory mechanisms have been implicated in several animal models of pah (like the monocrotaline model) and human pah associated with collagen vascular diseases or hiv infection. immunosuppressive therapy, using cyclophosphamide and corticosteroids, has been reported to significantly improve pah in patients with systemic lupus erythematosus. , however, this is just anecdotal evidence from case reports. a potential role of inflammation in pah is also supported by the prevalence of antinuclear antibodies and increased circulating levels of proinflammatory cytokines [interleukin- (il- ), il- ] in pah patients. furthermore, the presence of a large number of inflammatory cells and expression of chemokines, like rantes and fractaline, has been described in and around the plexogenic lesions in pah. hypoxia inducible factor (hif- α) hypoxia inducible factor- α is a master gene that controls the transcription of many genes that are activated by hypoxia. rats with haploinsufficiency for hif- α, exposure to chronic hypoxia, manifest-delayed or reduced polycythemia, right ventricular hypertrophy, pht, and pulmonary vascular remodeling have greater weight loss compared with wildtype littermates. , interestingly, this partial deficiency of hif- α is also sufficient to impair hypoxia-induced depolarization and reduction of k + current, again tying the pasmc k + channels to pht. the pathophysiologic role of hif- α in nonhypoxic pah is unknown, but it is likely that this pathway is important, as discussed next. hypoxic activation of hif- α also results in increased production of vegf and increased expression of its receptors, flk and flt. disordered angiogenesis has been described in pah and has been implicated in the formation of plexogenic lesions. in this regard, it is noteworthy that most pah patients have systemic hypoxemia and reduced alveolar diffusion capacity, even though their alveolar po is normal. increased levels of vegf and increased expression of flt as well as hif- α and - β have been described in these lesions; on the other hand, plexogenic lesions have decreased levels of essential factors for angiogenesis including phosphoinositide- -kinase, akt, and src. these fi ndings have led to the hypothesis that the plexogenic lesions are not a primary abnormality in pah but rather a secondary phenomenon, caused by a disordered angiogenesis in response to local tissue hypoxia, distal to the obliterated pulmonary arteries. most cases of pah appear to be sporadic, but % to % of cases are inherited in an autosomal dominant manner with incomplete penetrance. the disease may skip generations and might affect only a few siblings in a generation. thus the actual proportion of familial cases may be underestimated. although clinical and pathologic features are the same in sporadic and familial forms, familial pah displays genetic anticipation and onset at decreasing ages in subsequent generations. loyd et al. reported a successive decrease in age of death from pah over three generations in one kindred, from ± to ± to ± years. this phenomenon has been observed in fragile x syndrome and several dominantly inherited diseases like myotonic dystrophy and huntington's disease. the occurrence of genetic anticipation suggests that the molecular basis of familial pah, similarly to myotonic dystrophy, may involve expansion of a trinucleotide repeat, although this has not been yet shown in ipah or fpah. the gene for familial pah, previously known as pph , was localized on q chromosome using genetic linkage analysis. , , a positional candidate approach led to the identification of bmpr as one of the genes causing familial pph. , heterogeneous germline mutations in bmpr have been identified in up to % of several kindreds with fpah. interestingly, mutations in this gene have been observed in a minority of sporadic pah patients ( %), suggesting bmpr may contribute to the pathogenesis of ipah occasionally. the bmps are a family of secreted growth factors that are part of the transforming growth factor-β (tgf-β) superfamily. originally described as the molecules that induce ectopic bone and cartilage formation when implanted subcutaneously, they are now known to be important regulators of mammalian development. for example, bmp- plays a critical role in embryonic lung development. transforming growth factor-β superfamily members interact with two classes of transmembrane receptor, serine-threonine kinases type i and ii receptors. type ii receptors have constitutively active cytoplasmic kinase domains, but they are unable to activate downstream signals in the absence of a type i receptor. furthermore, several tgf-β family members can use the same receptors as the bmps, adding significant plasticity to the regulation of the downstream responses. this plasticity is further enhanced by the fact that a variety of downstream signaling pathways, following the binding of bmps to bmp receptors i and ii, are activated in a cell-specific manner. an important signaling system is the smad system, which includes the bmpr-activated smads (smad- , - , and - ) and the common mediator smad (smad- ). the activated smad- , - , - -smad- complex enters the nucleus to regulate a number of dna binding transcription factors and cofactors that are required to initiate specific transcriptional responses. the smads were originally named after a gene called "mothers against decapentaplegic (dpp)," an upstream gene that controls the function of dpp, a gene of drosophila melanogaster that encodes a growth factor that belongs to the tgf-β superfamily that plays a central role in multiple cell-cell developmental signaling events. overall, activation of the bmpr- pathway leads to suppression of several transcription factors, favoring apoptosis. homozygous deletion of the bmpr in vivo is associated with embryonic lethality. over different germline mutations in the bmpr gene have been described in both familial and ipah cases and include missense and frameshift mutations. although it is known that at least some of the described mutations result in loss of function of the bmpr gene product, it is not known how this loss of function leads to the development of pah. recently, pasmcs from patients with ipah, but not secondary pht, were shown to exhibit enhanced growth responses to tgf-β and bmps. recent work with a conditional knockout of bmpr (using a smooth muscle specific, dominant negative strategy) shows that when the bmpr mutation is activated after birth, mice developed pht, right ventricular hypertrophy, and have increased medial hypertrophy of the pa, all without increase in systemic arterial pressure. nonetheless many questions remain regarding the "sufficiency" of bmpr mutations to cause pah. moreover, the mechanism by which mutations in a ubiquitously expressed receptor might result in the highly restricted pattern of disease pathology seen in patients with pah is unclear. it remains uncertain whether bmpr mutations result in disease by inhibiting a normal rate of apoptosis or whether something else stimulates a need for apoptosis, which cannot be supported when bmpr is dysfunctional. alternatively, one can speculate that since bmpr mutations alter the function of many transcription factors, they may work by several mechanisms, each relating to altered transcription of relevant genes, such as kv channels, et- or the -htt. is there a link between these diverse abnormalities? it is apparent that most of these abnormalities result in enhanced vasoconstriction, impaired apoptosis, or accelerated proliferation of the vascular cells. it is becoming clear that not all mechanisms might be operational at a given stage of the disease or in a given patient. for example, endothelial damage is likely an early event in pah, whereas increased proliferation/suppressed apoptosis of the smc is a late event. whereas one patient might be prone to increased proliferation in the vascular wall because of a bmpr mutation, susceptibility in another might relate to an abnormal -htt or dysfunctional k + channel. a multiple hit hypothesis has been proposed for pah (fig. . ). in this theory, one or more environmental insults have to occur on a predisposed genetic background because of one or more gene abnormalities. perhaps the pathogenesis of pah is too complex to be explained by a single unifying theory. while the discovery of bmpr mutations may explain some forms of familial pah and may predispose to pah in animals, it appears that the majority of ipah is not due to these mutations. a mechanism such as the loss or inhibition of k + channels (whether genetically or by anorexigens) could unify the -ht and the kv channel theories and, even if not the initiator of pah, explain much of the phenotype. similar "channelopathy" could afflict the platelets or the megakaryocytes. in this scenario the pasmcs would be predisposed to constriction and proliferation and would have impaired apoptosis, whereas the platelets would secrete excess -ht, thereby reinforcing smc contraction and proliferation. the increased expression of the inhibitor of apoptosis survivin significantly suppresses k + current. moreover, the idea that k + channels might be central to the pathogenesis of pah is supported by the observation that experimental therapies promoting the function and expression of k + channels have been effective in several animal pah models. in other words, apoptosis resistance and proliferation in the pulmonary vascular wall may occur due to dysregulation in the bmpr- pathway, -ht, survivin, and the kv channels, alone or in combination. symptoms (table . pulmonary arterial hypertension is an uncommon condition, and its symptoms are nonspecific. therefore, patients often have symptoms for months or years before a correct diagnosis is made, especially in ipah, where the lack of associated conditions does not provide additional clues. in the nih registry, the average time from onset of symptoms to diagnosis of pht was . years. although symptoms of pht do not directly reflect pap, patients usually remain asymptomatic until pap has doubled. the earliest and most common symptom of pah is dyspnea. in the nih registry, % of the patients had dyspnea as a presenting symptom, although % had dyspnea by the time they were enrolled in the registry. the causes of dyspnea in pah are diverse, varying somewhat according to the etiology of the syndrome. dyspnea is found in the majority of pulmonary hypertensive syndromes, with the notable exception of sleep apnea. in most cases, dyspnea appears to relate more to altered lung mechanics and reflex activation than to hypoxemia. in pah there is often a respiratory alkalosis with mild hypoxemia. in these patients, dyspnea may relate to increased j-receptor activity, possibly a result of decreased vascular and therefore lung compliance. hypoxemia may also lead to dyspnea in patients with pah due to intracardiac shunting (e.g., eisenmenger's syndrome). interstitial lung disease, with reduced lung compliance and hypoxemia, is another cause of dyspnea and is common in patients with pah due to connective tissue diseases (e.g., mixed connective tissue disease, scleroderma, crest syndrome). like dyspnea, fatigue is a common and nonspecific symptom in these patients. fatigue may reflect reduced cardiac output and impaired oxygen delivery to the tissues. in addition, pvr increases dramatically with exercise in patients with pah, unlike normal individuals. dyspnea and fatigue occur with similar frequency regardless of the cause of the pht. syncope and near syncope can occur in severe pah, particularly with exertion. during exercise, the obstructed or obliterated pulmonary vascular bed may be unable to correct for a fall in systemic vascular resistance by accommodating adequate increases in cardiac output, culminating in reduced cerebral blood flow and syncope. chest pain is not unusual in pah and may be described by the patient as sharp and pleuritic or as a dull ache. the dull chest ache noted by some patients with pht is suggestive of angina. potential mechanisms include right ventricular ischemia and distention of the pulmonary arteries. a somewhat unusual symptom of pht is hoarseness (ortner's syndrome). hoarseness results when the left recurrent laryngeal nerve, which passes between the aorta and the pulmonary artery, is compressed by the enlarged pulmonary artery. , hemoptysis also occurs in many types of pht. it has been reported that in the capillary bed of patients with pht there are microaneurysms that may be susceptible to rupture, resulting in hemoptysis. hemoptysis is a frequent cause of morbidity and mortality in eisenmenger's syndrome, accounting for % of deaths in one study. like the history, the findings on physical examination in pht are often nonspecific. a number of patients with pht have an entirely normal physical examination. furthermore, the physical examination rarely allows quantification of the severity of pht until the terminal stages of the disease, when right heart failure appears. the physical findings of pht reflect the presence of an enlarged, noncompliant right ventricle (rv) and insufficiency of the tricuspid or pulmonic valves. the most common clinical signs and their mechanism are shown in table . . although a loud pulmonic component of the second heart sound is common in patients with pht, as the hypertension becomes more severe the interval between closure of the aortic and pulmonic valves may decrease so that the valves close almost simultaneously, eliminating the value of this sign. however, if a second heart sound is heard at the apex (where the aortic component is not audible in normal hearts) it almost always is due to a loud p and suggests severe pah. the graham-steele murmur of pulmonic valve insufficiency occasionally accompanies severe pht. this diastolic murmur is usually best heard in the left second or third inner space near the sternum. pulmonary insufficiency may be distinguished from aortic insufficiency by observing the response to the valsalva maneuver. the pulmonary regurgitation murmur usually returns to pre-valsalva intensity within several beats, whereas the aortic regurgitation murmur usually takes longer to return to its intensity. the time delay occurs because the blood excluded from the thorax by the valsalva maneuver must first traverse the pulmonary circulation before reaching the aorta and augmenting the murmur. in some pht patients a diastolic murmur that enhances with inspiration occurs. this right-sided "austin flint murmur" is due to functional tricuspid stenosis due to valve closure caused by severe pulmonic insufficiency. although echocardiographic evidence of mild tricuspid and pulmonic regurgitation is prevalent even in normal individuals, audible or hemodynamically significant insufficiency is rare. however, pulmonic insufficiency can also occur fairly commonly in patients with fluid overload related to renal failure, which also reflects transient pht. the blowing systolic murmur of tricuspid regurgitation is best heard over the lower right sternal border and may briefly enhance with inspiration (carvallo's sign). the right-sided third heart sound occurs primarily once the rv has decompensated from chronic pressure overload, and is usually accompanied by a murmur of tricuspid regurgitation. clinical and laboratory assessment (table . ) diagnostic testing in pht may serve three purposes: ( ) documentation and quantification of pht; ( ) defining the etiology, particularly differentiating between pah and secondary pht; and ( ) assessment of prognosis. a major emphasis is detecting conditions that have a specific treatable cause of the pht (notably mitral regurgitation or stenosis and thromboembolic pht). our approach to the patient with presumed pht is to establish its presence, preferably by a noninvasive test, such as echocardiography. if the pressure is elevated or cannot be accurately measured, then a right heart catheterization is performed. a typical case is presented in figure . . once a diagnosis of pht is established, the next goal is to determine the etiology. the following tests should be obtained in all patients in whom the cause of pht is not evident: electrocardiogram (ecg), chest radiograph, arterial blood gases, complete blood count, electrolytes and liver function tests, pulmonary function tests (pfts), ventilation/ perfusion lung scan, serology for rheumatic diseases (e.g., fluorescent antinuclear antibody, fana), serology for hiv, ventilation perfusion (v/q) scan, and an echocardiogram with doppler assessment of pa acceleration time and tricuspid regurgitation velocity as well as an echo-contrast study, to exclude shunting. this relatively inexpensive and safe battery of tests can detect patients with chronic lung disease, valvular heart disease, left ventricular dysfunction, most intracardiac shunts, thromboembolic disease, lv dysfunction, and pah due to hiv, liver disease/portal hypertension, or connective tissue disease. in patients with abnormal pfts or inconclusive v/q scan, a chest computed tomography (ct) is also performed in order to exclude or confirm pulmonary fibrosis or thromboembolic disease. a right heart catheterization is performed in essentially all patients with evidence for pah, for the following reasons: ( ) to confirm the presence and magnitude of pht and establish an objective baseline for future therapies; and ( ) to determine or confirm the type of pah (e.g., to make the diagnosis of pah a gradient between the mean wedge pressure and the pulmonary artery diastolic pressure of more ( ) to determine the response to acute vasodilators (e.g., ino), since this is associated with prognosis and might guide choice of therapies (see below). after the diagnosis of pah is established and before the initiation of any treatment, a good assessment of the baseline functional class has to be established. the baseline functional class not only predicts prognosis but also guides immediate and future treatments. in addition to the nyha functional class, quantitative assessment of functional performance can be achieved with maxvo testing, or, if that is not possible, the -minute walk test. the -minute walk test has emerged as one of the most important end points in clinical trials over the past few years. it is simply the distance the patient covers during a -minute walk period on a standard corridor with standardized supervision. the -minute walk is a very strong predictor of survival in pah. the ability of this simple test to predict survival likely comes from the fact that it reflects cardiac output and more specifically the ability to increase cardiac output during mild exercise. this in turn reflects the performance of the right ventricle. in clinical practice one is impressed by the frequent dissociation between pvr and functional class and the better correlation with -minute walk and functional class. this is because, for reasons that we do not yet understand, the response of the right ventricle to the same increase in its afterload varies significantly among patients. a simple index of the compensation of the right ventricular condition is the problem is intrinsic to the pulmonary arteries, that is, that the patient has pah (e). there was a % decrease in the pulmonary vascular resistance (pvr) by a maximal dose of inhaled nitric oxide (no) ( ppm) and a % decrease in the pvr, minutes after a single dose of sildenafil ( mg po). because the pvr decreased by > %, this patient is considered a "responder" to pulmonary vasodilators. the patient was started on ca + blockers, but she could not tolerate even moderate doses of nifedipine because of peripheral edema, dizziness, and hypotension. although she responded very well to a single dose of sildenafil, she could not afford to pay for sildenafil ( mg po t.i.d. = cdn $ /month). she was started on bosentan mg po b.i.d. she continued to deteriorate, and months later her -minute walk had decreased from m to m. she was started on continuous intravenous epoprostenol and a workup for heart-lung transplantation was initiated. her condition has been stable for the following months (class ii), and her average minute walk performance is m. she has yearly right heart catheterizations and echocardiograms. she attends the multidisciplinary pah clinic every months where she also sees a dietitian and a psychologist. right atrial pressure. the jugular venous pressure and minute walk should be documented at each visit. more recently, a simple test that is currently available as a point-of-care test is emerging as another index of right ventricular size and function: the brain natriuretic peptide (bnp) levels. levels of bnp, a peptide released from the ventricles during stretch or ischemia, correlate well with hemodynamics and also predict survival in patients with pah. there are two assays available, and the advantage of the point of care assay that measures bnp itself (triage-bnp test®, biosite, san diego, ca; normal values are < pg/ml) over the automated probnp assay is its convenience (it can be done in the clinic) and its relative independence from confounding effects with age or mild to moderate impairment of renal function. measurement of bnp may prove a useful means to judge the success of therapy or provide early warning of right ventricular decompensation. central pulmonary artery enlargement and enlargement of the right ventricle are important clues to the presence of severe pah (see case report in fig. . ). "pruning" of the peripheral pulmonary arteries is a classic sign, which reflects vascular obliteration of the small arteries in the periphery of the lungs. understanding of this important finding becomes easier if one looks at the mr angiography with gadolinium from the same patient, where the obliteration of the peripheral pulmonary arteries is directly shown (fig. . ). other radiographic signs of pht include right heart enlargement (filling in of the retrosternal space on the lateral view) and pa enlargement, measured as the diameter of descending right pulmonary artery (normal values are . ± . mm). the absence of signs of secondary hypertension also can be documented with a chest x-ray; for example, the presence of septal thickening or pleural effusions suggests venous hypertension to left ventricular dysfunction, veno-occlusive disease, or pulmonary capillary hemangiomatosis. electrocardiography is a specific but insensitive means of diagnosing rv hypertrophy (rvh), and for this reason, even though it is simple, it is not a good screening test. nonetheless, by the time they are detected, most pah patients have clear-cut rvh and right axis deviation (fig. . ). lehtonen and sutinen compared four sets of ecg criteria for diagnosing rvh in patients whose rv thickness was measured at autopsy. hearts were considered normal if the total weight was less than g, the rv less than g, and the combined lv plus septum (s) weight less than g (ratio of lv + s/rv, . - . ). by combining aspects of the four sets of ecg criteria, they achieved a diagnostic sensitivity of % and a specificity of %. these combined criteria included right axis deviation greater than , r wave equal to or greater than s wave (in v or v ), r wave equal to or less than s wave in lead v , and the calculated value ar : pl of . , where a is the maximum r-wave amplitude in leads v or v , r is the maximal s-wave amplitude in leads i or v , and pl is the minimal s-wave amplitude in leads i or v . this set of criteria was quite specific, despite the presence of lv hypertrophy and myocardial infarction in the study population. a limitation of this study is that the autopsy was restricted to patients dying from respiratory failure, and perhaps these criteria might not be applicable in other causes of pht. for example, the chest size is enlarged in patients with chronic airway disease and influences the voltage and the axis in ecg. the ecg criteria for rvh become less specific in the presence of right bundle branch block, posterior myocardial infarction, left posterior hemiblock, and wolff-parkinson-white syndrome with a posteroseptal accessory pathway. these conditions, rare in pah except for the right bundle branch block, may cause right axis deviation or a predominant r in lead v , similar to the findings in rvh. fortunately, there are often clues that permit differentiation of rvh from these conditions. posterior infarction usually involves associated inferior infarction. one should be cautious in making a diagnosis of rvh in patients with inferior q waves and dominant r waves in v . furthermore, patients with rvh typically have right atrial (ra) enlargement (known as p-pulmonale), diagnosed based on the presence of asymmetrical peaked p waves greater than . mm in amplitude in any lead. therefore, if one is attempting to distinguish between a posterior hemiblock and rvh, the presence of atrial hypertrophy would militate in favor of the diagnosis of hypertrophy. pulmonary function tests are often abnormal in patients with pht. the abnormality of lung function may be the cause of the pht, as in chronic obstructive pulmonary disease, or vice versa (see table . ). for example, patients with thromboembolic and ipah often have mild restrictive or obstructive patterns noted on spirometry. diffusing capacity for carbon monoxide (dlco) is typically low in pah, more so in patients with scleroderma. there are a number of excellent articles and chapters reviewing the use of echocardiography in the detection and quantification of pht. , if the image quality is adequate and one integrates anatomic data (rv chamber size and thickness, mitral valve anatomy), physiologic measurements (doppler measurement of valve insufficiency and shunts), and a few simple calculations of pulmonary artery pressures, the echocardiogram is a reliable test for suggesting the presence of pht. the likelihood of finding and estimating the severity of pht is directly proportional to the diligence of the sonographer and the experience of the physician who interprets the study. although the m-mode echocardiogram is less widely used since the advent of two-dimensional echocardiography, it is occasionally a useful modality in the diagnosis of pht. the m-mode signs of pht are indirect measurements that predominantly reflect the rigid, noncompliant nature of the diseased pulmonary vasculature. a characteristic sign of pht is the absence of an "a" dip on the m mode of the pulmonic valve. the a dip, which occurs when atrial systole causes a bulging or partial opening of the pulmonic valve, is present only in patients in sinus rhythm. the sensitivity and specifi city of this sign are relatively low. a second sign of pht is the transient midsystolic closure of the pulmonic valve. the reasons for the premature closure of the pulmonic valve in pht include the reduced capacitance of the pulmonary vascular bed and a prominent flow reversal within the hypertensive pulmonary artery. on m mode is fairly specific but is insensitive as a test for pht and has been reported in patients with normal pap who have idiopathic dilatation of the pulmonary artery. the adult right ventricle is roughly one third the thickness of the lv. right ventricle hypertrophy can be measured using the m-mode echocardiogram or the electronic calipers on the two-dimensional image. care must be taken to ensure that the m-mode cursor avoids the papillary muscles and the rv muscular bands. the rv can be measured from many acoustic windows, but it is optimally measured from a medially angulated parasternal or subcostal window at the level of the tips of the tricuspid valve leaflets, using a -mhz transducer. with this technique, gottdiener et al. found that normal subjects have an rv wall thickness of ≤ mm. the rv has a complex geometric shape. unlike the somewhat ellipsoid configuration of the lv, the rv is crescentic and is not readily described by simple geometric equations. even measurement of wall thickness is difficult owing to the trabeculation, which can result in significant variation in wall thickness within a relatively small sample volume. goerke showed that rv volume could be calculated as area times length of the right ventricle, but the appropriate subcostal views could be obtained only in % of patients. the end-systolic configuration of the ventricular septum is a useful indirect measurement of the relative pressures in the lv and rv. as rv systolic pressure increases, there is a gradual change in septal configuration from convex (bulging toward the right ventricle) to flat, and finally to concave (indented toward the left ventricle) (fig. . ) . twodimensional estimates of rv mass are difficult, and a threedimensional technique, specifically magnetic resonance imaging (mri), is preferred to accurately measure rv mass. pericardial effusion is a common but nonspecific finding in chronic severe pht. in one study, largely comprising patients with thromboembolic pht, % had small or medium-sized effusions, none of which was symptomatic. the likelihood of effusion was increased in those patients with the highest ra pressure or pap. pulsed doppler (fig. . , table . ) pulsed doppler measurement of pulmonary artery flow velocity in the main pa is an extremely useful qualitative and quantitative technique for measuring pa pressure, and, unlike estimates based on tricuspid regurgitation velocity, is available in virtually all patients. in pht, the peak velocity of the doppler envelope decreases and the time to peak velocity (measured from the onset of flow) or acceleration time (paat) shortens. in severe pht there may be "notching" or early systolic deceleration, which, like the premature partial closure of the pulmonic valve on m mode, reflects the velocity waves and cancellation by reverse flow. this is due to the noncompliant nature of the distal vascular bed in pht. the normal pulmonary artery flow velocity is ± cm/s and occurs with a paat of ± seconds. a typical doppler signal in patients with pht is often of triangular shape rather than the normal broad shield shape seen in normotensive patients, and the paat is shortened. although there is a fair correlation between acceleration time and pulmonary artery systolic pressure, mahan et al. found a better correlation between paat and mean pap. they used a regression equation to develop the following formula predictive of mean pap: mean pa pressure = − . × paat. other groups have confirmed this relationship, albeit with modified regression equations (table . ). this technique is somewhat heart rate dependent, but it correlates well with mean pap in patients with heart rates between and . it is useful to express the paat as a ratio with the systolic ejection time (set), which also shortens in pht. a paat/set < . reliably indicates pht. these same doppler parameters are useful in assessment of rodent models of pht. , continuous wave doppler (fig. . ) continuous wave doppler measurement of tricuspid regurgitation velocities permits accurate, noninvasive measurement of systolic pap, even in many normal individuals. tricuspid regurgitation is extremely common, and increases in prevalence and severity as pap increases. berger et al. found tricuspid regurgitation in of patients with systolic pressures less than mm hg and in of patients with pressures greater than mm hg. they noted an excellent correlation between doppler and catheter estimates of pulmonary artery systolic pressure (r = . ). guided by color flow doppler, the continuous wave doppler must be positioned parallel to the regurgitant jet to accurately measure peak tricuspid regurgitation velocity. however, the jets are often eccentric and small, which results in incomplete envelopes that underestimate pap; pap is calculated using the modified bernoulli equation. systolic pap can be estimated as four times the square of the systolic tricuspid valve plus the ra pressure (the pressure into which the tricuspid regurgitation is ejected) ( in their study, tricuspid regurgitation velocity could be measured in of patients. there was a good correlation between the pressures obtained by catheter and by doppler. the utility of the tricuspid regurgitation jet in evaluating pulmonary systolic pressure has been well validated. it is apparent that accurate estimation of pap relies on knowledge of the ra pressure. ra pressure can be estimated at the bedside by measuring the jugular venous pulse (jvp). unfortunately, this is difficult in some patients, and sonographers, who perform most studies, are usually not trained to measure jvp. the ra pressure is approximated by the perpendicular height of the jvp above the sternal angle plus the estimated distance from the middle ra to the sternal angle (∼ cm in an average-sized adult). this estimated atrial pressure in cm h o can be converted to mm hg by dividing by . . the diameter of the proximal inferior vena cava is more readily measured by the sonographer and can be used to estimate ra pressure. at normal ra pressures, the vena cava decreases in size % with normal inspiration (inspiratory pressures of to mm hg). much higher inspiratory pressures are required to achieve the same degree of collapse in patients with elevated ra pressure. there is a good relationship between ra pressure and the inspiratory pressure required to alter caval size, but this requires the use of sonospirometry. measurement of caval diameter cm proximal to the ra junction at rest and with respiratory maneuvers, such as a sniff, permits approximation of right atrial pressure. as a rule, an inferior vena cava that is more than cm in diameter and that collapses by less than % when the patient sniffs is "plethoric" and usually reflects an ra pressure > mm hg. conversely, cavae that are under cm that collapse by > % with spontaneous respiration reflect normal atrial pressures ( to mm hg). in clinical practice, due to time constraints on sonographers, jet eccentricity, inaccurate estimation of ra pressure, and poor acoustic windows, the ability to accurately predict pap using tricuspid regurgitation (tr) velocity is substantially less than the % reported in select research cohorts, even if one enhances the tricuspid regurgitation jet with injection of contrast material. consequently measurement of rvh on a two-dimensional echocardiogram and paat, using pulsed doppler, should also be used in assessing possible pht. high-resolution ct is a significant aid in excluding occult parenchymal lung disease, pulmonary fibrosis, or chronic pulmonary embolism in possible pah patients. of patients with biopsy-proven interstitial fibrosis, % may have normal chest radiographs, and for these patients ct scans are a more sensitive technique. contrast-enhanced, multislice ct ( or, more recently, slice), can detect central chronic thromboembolic with a specificity of % to % and sensitivity of %. computed tomography scanning is also helpful in differentiating pah due to veno-occlusive disease from ipah. the presence of ground-glass opacities (particularly with a centrilobular distribution), septal lines, and adenopathy are indicative of pulmonary veno-occlusive disease in pah patients (fig. . ). multislice and electron beam ct was used to compare the pulmonary vascular and parenchymal characteristics of the lung in pah patients with eisenmenger's syndrome in eisenmenger's patients the proximal pas were consistently enlarged and % of patients were aneurysmal, which caused bronchial compression and atelectasis. thromboses were uniformly present on ct, although they were large in only % of patients. mural calcific deposits occurred in % of these patients. in addition, eisenmenger's patients often had pulmonary infarction, intrapulmonary hemorrhage, bronchial collateral vessels, and neovascularization. in contrast, ipah patients had consistent enlargement of proximal pas on ct, but no aneurysms, thromboses, infarcts, or neovascularity. however, like eisenmenger's patients, extensive mural calcific deposits were found in % of pah patients and they too had bronchial collaterals. ventilation perfusion scans (fig. . ) v/q scans are widely used in assessment of patients with pht to exclude thromboembolic pht. hull et al. compared the relative roles of v/q scans, objective testing for venous thrombosis, and pulmonary angiography in consecutive patients with suspected acute pulmonary embolism. this classic study proved that a segmental or larger unmatched perfusion defect was associated with an % frequency of pulmonary embolism (and thus could be considered "high probability"); however, the common clinical practice of excluding a diagnosis of pulmonary embolism based on the finding of a matched defect (perfusion and ventilation scans abnormal in the same area) was incorrect. segmental and subsegmental matched low-probability v/q abnormalities were associated with % and % incidence of angiographically confirmed embolism, respectively. fortunately, virtually all patients with chronic thromboembolic pht have one or more high-probability defects on their v/q scan. patients with ipah often have diffuse, inhomogeneous, or "moth-eaten" perfusion scans that are interpreted as being low probability. this reflects loss of small arteries in pah. there have been a handful of reports of death within minutes of injecting the albumin macroaggregates, which are the small particles ( mm) that are labeled with technetium. these complications have usually occurred in patients with severe pht and may represent the inability of a severely obstructed vascular bed to deal with a shower of microemboli. with the advent of -slice ct scanning, capable of sub- -mm resolution, the role of v/q scans will diminish. in a recent meta-analysis, based on studies of ct and v/q scanning in suspected pulmonary embolism, ct was found to have a sensitivity and specificity of % [ % confidence interval (ci), - %], and % ( % ci, - %), respectively. v/q scanning had a much lower sensitivity of . % ( % ci, - %), although specificity was also high at % ( % ci, - %). thus, ct is the technique of choice to exclude pulmonary embolism, although a positive v/q scan (high probability) is sufficient to predict pulmonary embolism. the challenge with "possible pah" patients is not to exclude acute pulmonary embolism, which can usually be done based on the presentation; rather, it is to actively exclude the diagnosis of chronic thromboembolic pht because the latter has a specific and often curative surgical therapy-pulmonary thromboendarterectomy. in a center with high volumes, such as university of california-san diego, results are excellent. in a series of patients with chronic pulmonary thromboembolism treated with thromboendarterectomy, survival was . % and pvr was decreased by dynes × sec × cm − . pulmonary angiography is primarily used to evaluate the possibility that the pulmonary hypertensive patient has chronic pulmonary emboli. in addition, angiography is a useful test to diagnose peripheral pulmonary artery stenoses, arteriovenous fistulas, and obliterative pulmonary vascular disease. in the university of alberta pah program, due to the use of v/q ct scanning and mri, conventional pulmonary angiography has not been required in characterizing any of the last consecutive being assessed for chronic pht, pulmonary angiography should be reserved for those with equivocal ct scans. pulmonary angiography typically involves placement of a catheter in the pulmonary artery using the seldinger technique. unless the femoral veins and inferior vena cava are shown to be free of thrombus, it is best to use an antecubital or internal jugular route for vascular access to avoid embolization. pulmonary angiography can be performed in pht patients with minimal morbidity and mortality. the incremental risk of injection of contrast beyond the risk of placing a catheter merely to measure pressures is relatively small. the patients most at risk for complications are those with rv end diastolic pressures greater than mm hg or those with overt evidence of right heart failure, and in these patients the technique should be used cautiously. whereas conventional angiography images the large vessels, an alternative angiographic technique, wedge angiography, can be used to study the microvasculature. this technique is primarily employed to assess the anatomy of the small vessels and capillary bed. small amounts of contrast are injected distal to the inflated balloon while the catheter is "wedged," and magnified angiograms are obtained. in normal subjects the subsegmental vessel is plump and smooth, and there is a distal blush produced by the microcirculation. narrowing of the vessel or reduction in the size of the microvascular bed occurs with progressive pah. findings on wedge angiography correlate fairly well with histologic assessment of the pulmonary vasculature obtained at lung biopsy. the literature contains many reports of deaths caused by pulmonary angiography, especially in patients with pht. advances in catheter design, use of nonionic contrast agents, and the advent of selective angiography have all contributed to improved safety. nicod et al. analyzed the safety of pulmonary angiography in patients with moderate to severe primary or thromboembolic pht. these authors observed no significant complications but noted occasional transient episodes of hypotension, cough, and flushing. supplemental oxygen to avoid hypoxemia and careful attention to analgesia are critical to safe pulmonary angiography. the prospective investigation of pulmonary embolism diagnosis (pioped) multicenter cooperative trial reported the safety and utility of pulmonary angiography in patients with acute pulmonary embolism. the pulmonary angiograms were performed with ionic contrast injected at to ml/s for a total volume of to ml. the mortality rate from pulmonary angiography was . %, with major, nonfatal complications in % and minor complications in % of patients. mean pap did not differ in those with major, minor, or no complications. a review of complications of pulmonary angiography revealed several incidents of cardiac perforation, which were attributed to the use of older, rigid catheters. catheterization of the pulmonary artery remains the gold standard for determination of pap, and, despite a plethora of available noninvasive techniques, is usually required to firmly establish a diagnosis of pah. the goals of right heart catheterization include measurement of pressure, flow, and resistance. in addition, the catheter is used to establish the type of pht. one can generally consider pht as being the result of vascular obstruction, as in thromboembolic and ipah, or a passive response to elevated lv end-diastolic pressure, as in congestive cardiomyopathy. in patients with pah, there is a large gradient between the pulmonary diastolic pressure and the wedge pressure (> mm hg). this may be due to fixed vascular obstruction in a narrowed and partially obliterated vascular bed or may be due, in part, to increased pulmonary vascular tone. based on studies of vasodilator therapy in patients with ipah, which consistently show only < % of them responding to vasodilators (defined as a % or greater fall in pap in response to inhaled no or iv prostacyclin), it appears that the majority of pah patients have fixed anatomic vascular disease as the sole cause of their transpulmonary gradient. even responders have a significant component of their pvr elevation as a consequence of vascular remodeling. in patients with left ventricular failure, pulmonary artery diastolic and wedge pressures are elevated to similar levels. in these patients, the total pulmonary resistance, which does not take into account the left atrial pressure, may be elevated but pvr is not increased (table . ). the right heart catheterization readily distinguishes these forms of hypertension, and thus aids in achieving a specific mechanistic diagnosis. additional studies may be necessary if there is a suspicion of intracardiac shunting or valvular disease. in any patient with a question of shunting, we perform oximetry in all right heart chambers to localize and quantify the shunt. right heart catheterization carries some risks in patients with pht. the risks of right heart catheterization can be divided into three categories: ( ) risks related to obtaining vascular access (e.g., vasovagal reactions); ( ) risks of having a catheter in the heart (pulmonary artery rupture, arrhythmia); and ( ) risks of administering medications (e.g., negative inotropic effects, systemic vasodilatation with hypotension). pulmonary hypertensive patients may be intolerant to vasovagal reactions that may occur during attempted vascular access. when systemic vasodilatation occurs, whether due to a drug or reflex, the dysfunctional rv and obstructed pulmonary vascular bed may not support the normal increase in left heart output that accompanies systemic vasodilatation. therefore, a simple vasovagal reaction may lead to a fatal cycle of bradycardia, hypotension, acidosis, and death. however, it is noteworthy that there were no deaths during diagnostic catheterization in the nih registry study, in which patients, mostly class iii and iv, underwent right heart catheterization. since the observation that patients who respond to acute pulmonary vasodilators with a > % decrease in their pvr have better prognosis and a high chance of responding to high doses of oral calcium channel blockers chronically, acute vasodilator testing has became a critical part of the pah patient management. although earlier studies used intravenous epoprostenol ( mg/kg/min, increase by this amount every minutes, until effect is observed or adverse effects occur) or adenosine ( mg/kg/min, increase by this amount every to minutes until effect is observed or adverse effects occur), ino has recently become the vasodilator of choice. the inhaled route of administration offers a high degree of selectivity, and the effect disappears almost instantaneously with cessation of inhalation. a special mask and a device for the controlled delivery of the gas are required (fig. . ), although ino is not hard to administer. unfortunately, the recent increases in its price make ino relatively expensive. in our center, we begin the delivery of ino at ppm and then we increase to , , , and ppm (maximal dose) every minutes. calculation of the pvr before and after the maximal dose is important. with the recent introduction of therapies that, in addition to vasodilator effects, have antiproliferative properties as well (epoprostenol, endothelin receptor antagonists, sildenafil), the usefulness of vasodilator testing in terms of selecting future therapy has become less clear. for example, in scleroderma, prognosis and response to epoprostenol are not associated with acute vasodilator response. nevertheless, the response to acute vasodilator testing remains an important means by which to determine the prognosis of pah patients, even before treatments are initiated. magnetic resonance imaging facilitates reproducible, noninvasive volumetric flow measurement in the major pulmo- nary arteries and rv. there are many advantages of mri, including the avoidance of intravenous contrast, its entirely noninvasive nature, and the high probability of obtaining an adequate image, even in patients with lung disease. although scan times remain significantly longer than those for ct scanning, the technique facilitates measurement of chamber dimension, rv mass, and increasingly of pressure and flow in the right heart. bogren et al. used mri to evaluate pulmonary arterial compliance (vascular distensibility) in normal individuals and patients with pht. compliance, measured as the change in pulmonary artery volume resulting from an observed change in pressure, was considerable less in patients with pht ( %) than in controls ( %). furthermore, patients with pht had a larger retrograde flow volume ( %) than normals ( %). this exaggerated reversal of pulmonary flow may explain the systolic closure ("notching") of the pulmonic valve in pht. recently, mri has been used to track regression of rv hypertrophy in two small trials of the phosphodiesterase- inhibitor sildenafil and the endothelin receptor inhibitor bosentan for pah. , magnetic resonance imaging can also be used to generate pressure volume relationships to define rv contractility. these techniques reveal that chronic rv pressure overload is associated with reduced rv pump function despite enhanced rv myocardial contractility in pht patients. the interesting approach of simultaneous catheterization, using special catheters and mri, holds clinical promise. three-dimensional ultrafast dynamic contrast-enhanced mri has been used to quantify regional lung perfusion in pht and normal individuals on a pixel-by-pixel basis. this may be helpful, when coupled with gadolinium-enhanced mri angiography, in assessing regression of pulmonary vascular disease (fig. . ). gadolinium-enhanced pulmonary mri can reliably detect chronic pht (based on the combination of dilated central pas (diameter > mm) and abnormal proximal-to-distal tapering of the pas). in addition, mri can be used noninvasively to measure pa systolic and diastolic pressures. it is likely that the comprehensive "one-stop" mri facilitating serial anatomic and functional assessment will become the gold standard for pah patients. lung biopsy biopsy of the lung parenchyma, either transbronchially via the fiberoptic bronchoscope or by open thoracotomy, is a critically important diagnostic tool in the approach to patients with a variety of diffuse lung diseases. however, lung biopsy plays a less important role in the diagnosis of pht in most clinical settings. a clinical diagnosis of ipah can be established with reasonable certainty clinically. indeed, pathology data from the nih registry demonstrated that no other diagnosis was made pathologically in patients entered into the registry when lung tissue became available for review. in cases where the etiology is less certain, such as patients with significant elevations in pap associated with moderately abnormal lung function tests or evidence of interstitial disease by chest radiograph or high-resolution computerized scans of the chest, or patients with serologic abnormalities or other clinical signs that are suggestive of a vasculitis, lung biopsy may be highly useful in establishing a diagnosis and guiding therapy. transbronchial lung biopsy is not advocated in patients with pht, since the small size of the specimen generally precludes establishing a definitive diagnosis, and the risk of hemorrhage from hypertensive pulmonary vessels is increased. open lung biopsy via a minithoracotomy had been considered the approach of choice; however, the risks of this procedure are increased in patients with pulmonary vascular disease, and such cases should be performed by experienced surgeons supported by a cardiovascular anesthetist. thoracoscopic lung biopsy, which is less invasive and provides adequate tissue for diagnosis, is the preferred approach when a histologic diagnosis is deemed necessary. to recap, evaluation of pah can be accurately accomplished by noninvasive techniques (echocardiography, multislice ct, and mri). consequently, lung biopsy and pulmonary angiography are rarely required and even v/q scanning is becoming less necessary; however, the role of right heart catheterization remains critical. connective tissue disease several connective tissue disease (ctds) are complicated by pah and they include systemic sclerosis, mixed connective tissue disease, systemic lupus erythematosus, and, rarely, rheumatoid arthritis, dermatomyositis, and sjögren's syndrome. the strongest association is with scleroderma, , and pah is the leading cause of mortality in patients with scleroderma. in a prospective study using a catheterization-based diagnosis of pah, ∼ % of the patients with scleroderma (n = ) were found to have pah. the mean age of the patients with pah in this study was years and the female-to-male ratio was : . because patients with scleroderma also suffer from pulmonary fibrosis, the assessment of dyspnea and the cause of pht (hypoxic pht due to lung disease versus pah) can be very difficult. a significant decrease in dlco (< %) usually suggests the presence of pah in these patients. it is also important to make sure that their pht is not secondary to left ventricular dysfunction, particularly diastolic dysfunction, which may complicate scleroderma. for all these reasons the threshold for right heart catheterization should be relatively low, since this is often the only test that will definitively determine the extent and the cause of pht. despite the fact that their histology and hemodynamics are similar to that of ipah in recent trials, patients with pah and scleroderma have worse prognosis compared with ipah patients. in a study conducted between and , their -year mortality was %, illustrating that the prognosis remains poor despite modern treatments, and perhaps challenging the notion that mechanisms of disease are homogeneous among the various forms of pah. interestingly, in contrast to the patients with ipah, the response to acute vasodilators in patients with scleroderma is not associated with improved survival. the high flow and the increased shear stress through the pulmonary circulation in congenital heart disease syndromes with significant left to right shunts, particularly if the shunt is at high pressure, causes endothelial damage and initiates proliferative remodeling in the pulmonary vessels. the histology, which can be graded using the validated heath-edwards classification, is indistinguishable from that of ipah and includes medial and intimal hypertrophy, small vessel obliteration, thrombosis, and plexiform lesions. as the pa pressure rises and exceeds systemic arterial pressure, the shunt reverses and eisenmenger's syndrome is established. the development of pah is much more common in ventricular septal defects than atrial septal defects. , if the ventricular septal defect is bigger than . cm, there is a % chance for pah, while fewer than % of patients with small defects develop pah. the lower pressure shunts of atrial septal defect are less likely to cause pah, but even here there is diversity. sinus venosus atrial septal defects are associated with a % chance for pah, whereas with ostium secundum defects the chance is less than %. patients with congenital heart disease and pah have better prognosis than patients with ipah. nonetheless, these patients are more prone to manifest significant desaturation with exercise and to have polycythemia than are ipah patients. they also may develop hemoptysis, due to the rupture of bronchial arteries. while cirrhosis without portal hypertension is not associated with pah, patients referred for liver transplant with portal hypertension have a % to % incidence of pah. , however, increased pa pressures, without elevated pvr, are found in up to % of this population. in most patients with cirrhosis, the associated increase in the cardiac output can cause elevated pap, simply due to the increased flow in the pulmonary circulation. thus, it is very important not to rely on indirect estimations of the pa pressures with tests like echocardiography, but proceed with right heart catheterization in patients with hepatic disease in whom pah is suspected. the prognosis of patients with pah and untreated portopulmonary hypertension is very poor, with an average survival of only months after diagnosis. in a small cohort of patients, significant improvement was reported with epoprostenol. the recognition and possible treatment of patients with portopulmonary hypertension prior to transplantation is critical because the perioperative mortality is very high. in a recent meta-analysis of patients undergoing liver transplantation, a mean pa pressure of more than mm hg was associated with % perioperative mortality; for mean pa pressure of to mm hg, the mortality was %; the mortality was % for mean pa pressure of less than mm hg. in selected patients, liver transplantation has reversed the pah. the role of the liver in the pathogenesis of pah is intriguing. one of the common animal models of pah is created by injecting rats with the toxin monocrotaline, derived from the plant crotalaria spectabilis. monocrotaline requires hepatic activation before the alkaloid is active and can induce pah. the first case of pah in a patient with aids was reported in , and the association between infection with hiv and pah was recognized a few years later. , in a cohort of ∼ hiv-infected patients, a . % incidence of pah was reported. the largest case control study so far has come from the swiss hiv cohort ( hiv patients followed over . years), which reported a cumulative incidence of . %. patients with hiv infection have a rate for pah to times higher than the general population. with the introduction of highly active antiretroviral therapy over the past few years and the improved prognosis, the incidence of noninfectious complications in this population has been increasing. the mechanism of pah in patients with hiv infection remains unknown. the virus, to date, has not been isolated for the pulmonary arteries, leading to the unconfirmed hypothesis that the disease is caused by activated mediators or cytokines that result from the infection or the immune reaction to the infection. the mortality of hiv-infected patients is significantly higher compared to the hiv-infected patients without pah, although it is similar to that of ipah patients. , univariate analysis indicates that a cd lymphocyte count of more than cells mm and the use of combination antiretroviral therapy and epoprostenol infusion were associated with better survival. interestingly, another retrovirus, human herpes virus (hhv ), was isolated from out of patients with ipah. this is intriguing because hhv causes kaposi's sarcoma, a tumor with endothelial abnormalities that show impressive similarities with the plexogenic lesions in ipah. the anorexigens aminorex, fenfluramine, and dexfenfluramine are modified amphetamines that enhance serotonin release and inhibit serotonin reuptake in the brain, resulting in appetite suppression and a % to % weight loss. between and , there was an outbreak of pah in europe related to the anorectic agent aminorex that resolved with withdrawal of the drug. a similar pah epidemic ensued in the s and s with the use of fenfluramine and dexfenfluramine. although use of these appetite suppressants for months was associated with a -fold increase in the risk of developing pah, the annual incidence of pah in the population as a whole remained very low ( . per million). only a small proportion of the patients exposed to anorexigen developed pah, suggesting a requirement for one or more predisposing conditions. endothelial dysfunction, acquired or genetic, is almost certainly a predisposing factor. patients with anorexigen-induced pah tended to be older and frequently had known risk factors for endothelial dysfunction (cigarette use or obesity). indeed, compared with ipah patients, those with anorexigen-associated pah have decreased lung no production, and their pvr is inversely related to no production. despite repeated attempts, it was not possible to create an animal model of pah by feeding different species with large amounts of the various anorexigens, again suggesting the need for genetic or other predisposing factors. the conventional view of the toxicity related to these agents is that it relates to elevation of serotonin, and certainly the "carcinoid-like" valve disease, which ultimately led to their withdrawal, may relate to disordered serotonin metabolism. however, it has been shown that potassium channel inhibition and membrane depolarization partially accounts for the pulmonary and systemic vasoconstriction that these agents induce. although only weak pulmonary vasoconstrictors are seen in normal lungs, inhibition of no synthase exposes the constrictor potency of the anorexigens, which supports the notion that endothelial dysfunction predisposes to this form of pah. it has been proposed that the anorexigens are in reality kv channel blockers that cause their intended (appetite suppression) and their unintended (altered platelet function and increased vascular tone) effects through their control of membrane potential and cytosolic ca + levels. , indeed, the anorexigens do inhibit heterologously expressed kv . and kv . channels, channels that control the membrane potential of pasmcs and whose expression is decreased in pah. in this rare disease, obliterative fibrotic lesions are seen in pulmonary veins and venules. these lesions are characteristically patchy and result in focal increase in the wedge pressure. because of the patchy nature of the disease, the wedge pressure might be increased in one pulmonary artery branch but not in another. when this disease is suspected, wedging the catheter in several pulmonary artery branches is recommended during right heart catheterization. a ct scan may be helpful, showing septal thickening, ground glass opacities and a mosaic pattern of lung attenuation (fig. . ). the prognosis is poor, and early referral for lung transplantation is suggested. it is also important to identify pulmonary veno-occlusive disease early in the assessment of pah because administration of prostacyclin can cause acute pulmonary edema in this syndrome (as is the case in patients with impaired pulmonary venous drainage, whether due to pulmonary capillary hemangiomatosis or anomalous pulmonary venous drainage). pulmonary capillary hemangiomatosis pulmonary capillary hemangiomatosis (pch) is a rare cause of pah that occurs predominantly in young adults. it was first recognized in by wagenvoort et al. the condition is characterized by invasion of the lung with cytologically normal capillaries, and it clinically manifests as pht and impaired gas exchange. histologically, there is a proliferation of capillary-like vessels on and within the alveolar wall. pulmonary capillary hemangiomatosis can occur in familial forms, and its complications include hemothorax or clubbing. it is difficult to distinguish (without histology) from pulmonary veno-occlusive disease (pvod). a typical bilateral diffuse reticular nodular pattern is seen in the chest xray. the ct findings (bilateral diffuse, centrilobular, poorly defined nodular opacities reflecting the capillary proliferation) are similar to those of veno-occlusive disease and help differentiate these two conditions from ipah (fig. . ) . as of , only cases had been reported in the literature. a more recent review noted cases, but the prognosis remained dismal (median survival was years from the first clinical manifestation). interestingly, there have been reports of improvement using interferon. early recognition of pulmonary capillary hemangiomatosis is important because there are anecdotal reports of pulmonary edema occurring in response to epoprostenol. early referral for lung transplantation is recommended. persistent pulmonary hypertension of the newborn (pphn) is a complex syndrome with multiple causes, with an incidence of . to . / live births. it occurs in both idiopathic and secondary forms (associated with meconium aspiration, respiratory distress syndrome, pulmonary hypoplasia, and congenital diaphragmatic hernia). it causes severe hypoxemia and has a % to % mortality. survivors have high morbidity in the forms of neurodevelopmental impairment, cognitive delays, hearing loss, and a high rate of rehospitalization. persistent pulmonary hypertension of the newborn is characterized by a failure of transition of the hypoxic fetal pulmonary circulation from a high resistancelow flow bed to a low resistance-high flow neonatal circulation. it results in heart failure and persistent hypoxemia due to impaired maturation, vasoconstriction, and obstruction of the pulmonary vascular bed. the mechanisms that cause pphn are uncertain, and it is likely that there are many etiologic factors, including impaired angiogenesis, downregulation of smooth muscle cell potassium channels, and elevated shear stress, , persistent pulmonary hypertension of the newborn can be fatal, and in severe cases mechanical ventilation/extracorporeal ventilation is required. in a landmark trial, fullterm infants with pphn were prospectively randomized to inhaled nitric oxide ( ppm) versus a control gas (nitrogen), mixed with oxygen from a ventilator. inhaled nitric oxide increased oxygenation in only % (two of ). long-term therapy with inhaled nitric oxide sustained systemic ino successfully and doubled systemic oxygenation in of pphn infants ( %), whereas with conventional therapy without oxygenation, % of the infants had initial improvement. extracorporeal membrane oxygenation was required in % of the control group and % of the nitric oxide group (p = . ). although ino has not been shown to decrease mortality in pph, the use of extracorporeal membrane oxygenation has continued to decline since this new standard of care has been accepted. abrupt discontinuation of inhaled no can cause a rebound pht, which may be more severe than prior to treatment. sildenafil is useful to facilitate weaning of ino in some pphn patients, and it avoids rebound pht. sildenafil may also be useful as an alternative therapy for pphn; clinical trials to evaluate this potential therapy are ongoing. patients with rendu-osler-weber syndrome may develop pah that is histologically indistinguishable from ipah. hereditary hemorrhagic telangiectasia (hht) is an autosomal dominant vascular dysplasia caused by mutations in two genes that encode the tgf-β receptors endoglin and activin-receptor-like kinase (alk ). these patients have arteriovenous malformations (mostly nasal, hepatic, cerebral, and pulmonary) and sometimes these lesions result in significant shunts. in addition, these patients are anemic due to the nasal bleeds that are often very difficult to manage. the shunts and the anemia result in higher cardiac outputs and an increase in the pulmonary pressures, due to high flow. for this reason right heart catheterization should be performed in patients with hht and suspected pht in order to measure cardiac output and calculate pvr. pulmonary hypertension of some degree has been reported in up to % of patients with β-thalassemia, but the diagnosis was made with echocardiography and not right heart catheterization. the high cardiac output that complicates anemia could, by causing high flow, elevate pa pressures without truly causing pah (i.e., without increasing pvr). in a study of patients with sickle cell anemia who underwent catheterization, were found to have increased pa pressures. however, several of these patients had increased wedge pressures due to left ventricular diastolic dysfunction. in a study of consecutive patients with sickle cell disease, pht (defined as tricuspid regurgitant jet velocity of > . m/ sec) was found to be an independent and strong index of mortality. the destruction of circulating no by the free hemoglobin in the blood of patients with hemolytic anemias has been proposed to contribute to the development of pah in these patients. thyroid disease both hyperthyroidism and hypothyroidism have been associated with pht. in patients with severe hyperthyroidism, the large increases in cardiac output can cause pht due to high flow in the pulmonary circulation. there are several reports in the literature in which treatment of the hyperthyroid crisis completely reversed the pht. , however, the association with hypothyroidism is more interesting than high-flow pht, which explains most of the apparent hyperthyroid pht. in a single-center cohort of patients with ipah, nine patients were found to have hypothyroidism, which is significantly higher that the expected incidence in the general population. an autoimmune pathogenetic link between hypothyroidism and ipah has been proposed. in this regard, the lung and the thyroid gland have the same embryologic origins. moreover, it is very interesting that the thyroid hormone has been shown to regulate the expression of kv . in the myocardium. hypothyroid rats have decreased expression of kv . in their hearts. exogenous triiodothyronine (t ) restores channel expression within hour of treatment, a reflection of the very short half-life of kv . , the k + channel that is downregulated and potentially involved in the pathogenesis of experimental and human pah. the possibility that hypothyroid patients might also be deficient in pulmonary artery kv . , predisposing them to develop pah is an intriguing, but untested, hypothesis. it was not until that the first evidence-based practice guidelines were published and endorsed by the accp (see the july supplement of chest, volume ). randomized controlled trials (rcts) have only recently been performed for pah treatments (table . ) , and still a number of recommended treatments lack support from rcts. these treatments are discussed in general measures, below. following the discussion of specific food and drug administration (fda)-approved and experimental treatments currently in use, we discuss the approach to the patient with pah and the treatment options according to the stage of the disease. conditions that can exacerbate the pathophysiologic process, such as pregnancy, high altitude, and air travel, should be avoided if possible. similarly, medications that can potentiate pulmonary vasoconstriction, such as sympathomimetics used for allergic symptoms, or vasoconstrictor prostaglandins used as abortifacients, should not be used. since oral contraceptives may exacerbate pht in susceptible patients by increasing their risk for a thromboembolic event, other methods of birth control should be utilized. lastly, all patients with pah should be immunized against influenza and pneumococcal pneumonia and evolving respiratory tract infections should be treated aggressively. in addition to maximizing oxygen delivery, supplemental oxygen therapy reduces the component of pht that is due to active hpv. patients with an arterial po of less than torr at rest or an arterial oxygen saturation of less than % with ambulation, measured while breathing ambient air, are candidates for continuous home oxygen therapy. oxygen is most effective in this setting when it is used continuously. however, despite mild hypoxemia, most pah patients do not usually manifest hemodynamic improvement with supplemental oxygen therapy. in patients with pah due to congenital heart disease and right-to-left shunting, arterial oxygenation does not usually improve with supplemental oxygen, although patients may experience some symptomatic relief with its use. in a recent controlled study of patients with eisenmenger's syndrome, oxygen therapy did not alter hematologic parameters, quality of life, or survival. diuretics are useful for the treatment of right heart failure, but aggressive diuresis should be avoided because it can compromise cardiac output by excessively reducing preload. furosemide in doses of to mg per day is usually sufficient for patients with mild to moderate degrees of right heart failure. patients refractory to furosemide may require the addition of more potent diuretics, such as metolazone or bumetanide. the potassium-sparing aldosterone antagonists, such as spironolactone, are a useful adjunct to loop diuretics for patients with refractory edema or ascites. serum potassium and sodium levels should be monitored frequently when these agents are used. the effectiveness of digitalis in patients with pah has not been studied. digitalis is sometimes used in the treatment of refractory right ventricular failure, particularly when this is associated with left ventricular dysfunction or atrial arrhythmias. the role of anticoagulants in nonthromboembolic pht is controversial. patients with pulmonary vascular disease appear to be at increased risk for thromboembolic events because of their physical inactivity, right heart dilatation, and sluggish pulmonary blood flow. in addition, they develop small thrombi in situ within their diseased arteries. sudden death due to pulmonary thromboembolism can occur and large thrombi are particularly common in patients with eisenmenger's physiology. in both a retrospective and a prospective study, survival in ipah was significantly enhanced in patients who received anticoagulant therapy. the prospective study showed that the patients who benefit the most from warfarin are the ones who do not respond to ca + channel blockers. however, this study was not designed to assess the effects of anticoagulation, and the therapy was not randomly assigned nor assessed in a blinded manner. thus, this study provides nondefinitive support only for the prescription of warfarin. warfarin was used only in the presence of an abnormal v/q scan, and it is therefore possible that these patients had simply a higher likelihood of survival. adjusting anticoagulant medications may be particularly difficult in patients prone to altered drug metabolism due to hepatic congestion, and bleeding complications can occur even in the face of therapeutic degrees of anticoagulation. some of the drugs currently completing phase iii rcts, like sitaxsentan, have a significant interaction with warfarin, requiring a significant decrease in the warfarin dose. warfarin is the preferred drug, with the dose adjusted to achieve an inr of . to . at this time, warfarin therapy is indicated in all patients with ipah (recommendation: evidence level b). some centers extrapolate the ipah data on other subsets of pah, while others do not. the risk/benefit ratio for each patient has to be carefully considered. for example, some patients with pah due to scleroderma or portal hypertension might be at increased risk of gastrointestinal bleeding due to esophagitis or varices, respectively. the role of low molecular weight heparin and new oral direct thrombin inhibitors (e.g., melagatran) in pah is unknown. until recently, calcium channel blockers (ccbs) were the only option in the treatment of pah. rich et al. used high doses of ccbs in patients with ipah and followed them for years. seventeen patients ( %) responded initially with an acute decrease in the pvr of > %. after years, % of these responders were alive, whereas only % of the nonresponders were alive (fig. . ). although this prospective trial was not placebo controlled, it remains one of the longest follow-up trials in pah so far. unfortunately, less than % of pah patients respond to vasodilators acutely, and are therefore candidates for long-term ccb therapy. furthermore, a number of these patients are unable to tolerate the high doses required (e.g., nifedipine to mg per day or an equivalent dose of a dihydropyridine), mainly because of systemic hypotension and peripheral edema. flolan® is the first treatment to show a substantial improvement in hemodynamics, functional capacity, and survival in patients with pah ( fig. . ). in a landmark -month prospective open-label rct, flolan and conventional therapy (n = ) was compared to conventional therapy alone (n = ) in patients with ipah nyha class iii or iv. the flolan group showed greater improvement: mean pulmonary arterial pressure (mpap) − % vs. + %, pvr − % vs. + %, and -minute walk + m vs. − m. while eight patients died in the conventional treatment arm, there were no deaths in the flolan group (p < . ). a weakness of this study was that the baseline -minute walk performance in the flolan group ( m) was significantly better than that of the conventional treatment arm ( m). the fact that the conventional group patients were sicker than the flolan treatment group might have contributed to both the survival and the -minute walk differences. there were four episodes of sepsis and one of thrombosis attributed to the catheter in the flolan group. in a similar rct in pah due to scleroderma, flolan was shown to have similar beneficial effects in hemodynamics and functional capacity, but it did not improve survival. several studies have shown that the beneficial effects of flolan on both hemodynamics and functional class can be sustained for years. [ ] [ ] [ ] [ ] survival with flolan treatment at , , and years was shown to be %, %, and %, respectively, significantly higher than the %, %, and % reported from historical survival data (fig. . ). flolan was originally used as a bridge to transplantation, but it was soon realized that due to the substantial improvement, most patients were removed from transplant lists. recently, four cases were reported in which long-term flolan treatment was successfully tapered off and discontinued, replaced by the newly introduced oral therapies bosentan and sildenafil. although at this point these are exceptions, as combination therapies become more common it is likely that more patients might be able to be weaned off flolan and maintained on oral therapies. on the other hand, some patients do not respond to flolan and some criteria have been proposed to identify these patients early on and refer them for transplantation. multivariate analysis in a long-term (> years) follow-up study of patients with ipah nyha class iii or iv showed that poor long-term outcome is predicted by baseline nyha class iv, baseline -minute walk < m, baseline right atrial pressure > mm hg, and, paradoxically, with mpap < mm hg. in addition, poor outcome could be predicted if at months after initiation of flolan, the functional class had not improved and the total pvr had not increased by % or more. due to its very short half life (< minutes) and its instability in acidic ph and in room temperature, the drug has to be given intravenously via a pump and kept cold at all times with ice packs. also, due to its effects on small veins, it can only be given through central venous, tunneled catheters. a dose is initiated at low levels ( - ng/kg/min) and is slowly increased to a level just below the threshold for the many dose-dependent side effects; these include jaw pain, flushing, headache, diarrhea, an erythematous rash, and leg pains. the maximum dose tolerable varies significantly among patients. excessive doses can lead acutely to hypotension and chronically to high-output cardiac failure. interruption of the flolan infusion may cause a rebound increase in pap and systemic blood pressure. in experimental models this rebound hypertension is due to activation of the renin-angiotensin system and can be prevented by angiotensin ii receptor blockade. deaths have occurred when infusion catheters become disconnected or crimped. patients having problems with the pump need to visit the emergency room immediately and be monitored until a new pump or a new access is established. most patients carry an extra pump at all times. lastly, perhaps the most serious side effect with long-term use is the catheter-related infections, from cellulitis to fatal sepsis. the cost of flolan (over $ , /year) and the intrusive nature of administration have restricted its use to class iv patients and this leaves room for development of oral or inhaled therapies. in addition, the demands of flolan therapy require a compliant patient. it is also noteworthy that this drug is not curative. in patients with conventional congestive heart failure due to left heart disease, flolan appears to be harmful. the flolan international randomized survival trial (first), which assessed the effects of flolan in patients with class iiib and iv congestive heart failure trial was terminated early because of a strong trend toward decreased survival in the patients treated with epoprostenol. in addition, chronic intravenous epoprostenol therapy did not improve in distance walked, quality of life, or morbid events. by extrapolation flolan should not be used in forms of pht associated with left ventricular dysfunction. treprostinil is a prostacyclin analogue with a half-life of hours, which is stable at room temperature. it has recently been introduced as an alternate to flolan, and is delivered subcutaneously continuously via a pump. this pump is much smaller than the flolan pump (like an insulin infusion pump-roughly the size of a pager) and there is no need for ice packs. the drug is offered premixed in a syringe and the patient does not have to prepare it sterilely every day as with flolan. because of the longer half-life, acute discontinuation of the drug is much less dangerous than it is with flolan. unfortunately, the efficacy of treprostinil is at best modest, and its use is limited by the often severe pain at the site of injection. a large multicenter rct trial on the use of treprostinil was recently reported, in which patients were randomized to either treprostinil plus conventional therapy or placebo (continuous subcutaneous infusion of vehicle) plus conventional therapy for weeks. there were significant differences in the design of this trial compared to the previous trial on epoprostenol. for the first time, class ii patients were enrolled (n = ), and patients with congenital heart disease and scleroderma were also enrolled. the primary end point was the -minute walk, which improved in the treprostinil group and did not change in the placebo arm (difference of m, p < . ). the ipah group improved by m. several secondary end points including hemodynamics and quality of life indices improved. however, % of the patients reported infusion site pain. the -m improvement in the -minute walk, although statistically significant, is likely to be clinically insignificant. this poor efficacy, at least compared to epoprostenol, might be explained by differences in the disease severity and pah types enrolled. for example, the class ii patients improved only by m (whereas the patients in class iii improved by m and in class iv by m), and the patients with congenital heart disease did not improve at all. iloprost is a prostacyclin analogue with a half-life of minutes, available for iv, oral, and inhaled administration (fig. . ). iloprost is used in the treatment of pah in europe, and was approved in april in the united states. it is mostly delivered via the inhaled route, since this mode of delivery allows for selective effects on the resistance pulmonary arteries. these small pas are surrounded by the alveoli, and some drugs, depending on their lung absorbance, can be delivered as an aerosol, with sparing of the systemic circulation, thereby limiting peripheral side effects. unfortunately, multiple inhalations (six to nine per day) are required to achieve sustained clinical benefit, and each inhalation takes from minutes (using ultrasonic nebulizers) to minutes (using jet nebulizers). following two promising open-label uncontrolled studies of iloprost in pah for months and year, a -month double-blind placebo-controlled rct was reported of patients with class iii to iv ipah as well as pah due to collagen vascular disease and inoperable thromboembolic disease. iloprost ( . or μg) six or nine times a day (max dose μg/day) prolonged the -minute walk by m in the overall population relative to placebo (p < . ). in the ipah group, the improvement in the -minute walk was m. there were also statistically significant improvements in nyha functional class and quality-of-life indices. importantly, statistically significant improvement was also seen in pulmonary hemodynamics. interestingly, this improvement was unchanged when measured before and after iloprost inhalation, suggesting some sustained positive effect on vascular remodeling, rather than reversible effects on pulmonary vascular tone. iloprost did not improve survival (one death in the iloprost group, four deaths on placebo, p = ns). only mild and transient side effects were reported. beraprost is the first orally available prostacyclin analogue with a half-life of minutes after oral administration. it has been used since in japan for the treatment of ipah, based on positive effects from several animal and small, open-label uncontrolled studies. to date, two large doubleblind, placebo-controlled rcts have studied beraprost for weeks and for year. in the -week trial, patients with nyha class ii and iii with the full spectrum of pah diseases were studied. the overall improvement in -minute walk was m; however, the ipah patients improved by m. however, the -month study showed that the small benefit in the -minute walk at and months (+ m and + m from baseline) was lost at months. tolerance was suspected, especially since the significant side effects improved after the early dose titration phase. neither beraprost study showed any significant improvement in hemodynamics or survival. beraprost in now under evaluation at the european agency for the evaluation of medicinal products, and there are no plans for application to the fda. the first trial of bosentan, a nonselective endothelin antagonist, aimed to study the safety of the drug on patients with severe pah as well as explore its effects on functional capacity and hemodynamics. eligible patients were those with nyha class iii and iv with ipah and scleroderma-pah in a double-blind, placebo-controlled manner. interestingly, although class iv patients were eligible, they were not enrolled. inclusion required patients to have been on stable standard treatment for a month prior to inclusion and not on epoprostenol. thirty-two patients were randomized to bosentan or placebo ( : ratio). patients received bosentan . mg b.i.d. × weeks followed by mg b.i.d., for a total of weeks. bosentan caused a median increase of m in the minute walk from baseline, versus − m in the placebo group. bosentan increased the cardiac index (mean improvement l/min/m in favor of bosentan). pulmonary vascular resistance was decreased in the bosentan group while it was increased in the placebo group, and functional class improved in the bosentan group as well. asymptomatic increases in aminotransferases occurred in two bosentan patients, but they normalized subsequently without discontinuing or decreasing the dose. these encouraging results led to a larger rct, which now enrolled patients, equally randomized into mg b.i.d. or mg b.i.d. for a minimum of weeks. again patients with class iii and iv and ipah or scleroderma-pah were eligible. the placebo and bosentan groups were well matched, and after weeks bosentan improved the primary end point (the -minute walk) by m, versus − m deterioration seen in the placebo group. the improvement was more pronounced in the mg b.i.d. group compared to the mg b.i.d. group (+ vs. + m). abnormal liver function tests, syncope, and flushing were more frequent in the bosentan group. the increase in the liver function tests was dose dependent ( % vs. % in the vs. mg dose, respectively). two patients in the mg group and five patients in the mg group were found to have increased liver enzymes to more than eight times the normal levels. these abnormalities were not reversible in three of the patients in the mg group, and these patients had to be withdrawn from the study. three patients died during the study: two in the placebo group and one in the mg bosentan group. based on this trial bosentan was approved by the fda for the target dose of mg po b.i.d. however, the fda requires that liver function tests be performed monthly for patients taking the drug. strict precautions for pregnancy have to be followed due to the teratogenic effects of bosentan. young males have to carefully consider the use of the drug, given the concerns that endothelin blockers as a class cause testicular atrophy with prolonged use. in contrast to bosentan, which is a nonselective eta and etb receptor, sitaxsentan is a selective eta receptor. in theory, this could be advantageous since the vasoconstrictive and mitogenic signaling comes from the eta receptor in the smooth muscle cells. in contrast the etb receptor in the endothelial cells is mainly responsible for a no-mediated vasodilatation and clearance of the circulating et- . in , the first placebo-controlled rct on sitaxsentan was reported, in which patients with class ii, iii, and iv and with ipah, scleroderma pah, or congenital heart disease-pah were randomized into placebo versus sitaxsentan mg versus mg po qd for weeks. sitaxsentan improved the -minute walk by m ( mg group) and m ( mg group). the nyha class improved in % of the patients in the mg group and in % of the patients in the mg group. the pvr and cardiac index improved in a similar manner in both groups. this trial suggested that the -mg dose was associated with a saturation of the receptors and, furthermore, was associated with higher incidence of abnormal liver function tests ( % versus % for the -mg dose). interestingly, in an earlier pilot study, even higher doses of sitaxsentan ( mg b.i.d.) were associated with two fatal cases of hepatitis. a significant increased in inr occurs in patients taking sitaxsentan, due to inhibition of the cyp c p- enzyme that metabolizes warfarin. a larger double-blind placebocontrolled rct has just been completed and the results are expected to be announced within a few months. a recent cochrane review concludes that in the short term ( weeks) there is evidence that these drugs improve hemodynamics, dyspnea, and exercise capacity in pah. the endothelin antagonists offer benefits to patients with moderate pah but are not curative and suffer from a relative lack of efficacy. they have no proven benefit on mortality and have not been adequately studied in class ii or class iv pah. it is noteworthy that hepatotoxicity is a class effect, possibly related to bile salt accumulation, and careful observation is required as the liver toxicity can be fatal. in another cautionary note, these agents were unsuccessful as therapy for congestive heart failure and systemic hypertension, although endothelin levels are increased in these conditions, as they are in pah. in the pulmonary circulation, no causes vasodilatation in part by the opening of large conductance, ca + -sensitive k + channels and bk ca channels via a cgmp-dependent kinase mechanism. at any given time, the cgmp levels in the pasmcs reflect the balance between production (due to the tonic effects of the endothelium-derived or exogenous no) and breakdown [by phosphodiesterase type (pde- ), which is relatively specifically expressed in the pulmonary and the penile/clitoral circulation]. therefore, there is synergism between both endogenous and exogenous no and the pde- inhibitors. this synergism occurs at all levels of the cgmp pathway, from the electrophysiology (opening of bk ca channels) to the final vasodilatation. the oral pde- inhibitor sildenafil (viagra®, pfizer) is a very attractive drug to be tested in pah because of extensive prior clinical use and good safety profile. sildenafil's most important side effect (systemic hypotension) is largely restricted to patients who ignore the absolute contraindication and concomitantly use systemic nitrates for the treatment of angina. the use of sildenafil for the treatment of conditions other than erectile dysfunction is not complicated by inappropriate erections since it only facilitates erections when arousal increases the levels of no in the penile tissue. in a cohort of patients with pah, a single dose of sildenafil ( mg) decreases pvr to a similar extent as the maximal doses of ino ( ppm) (fig. . ). most importantly, sildenafil significantly increases cardiac output and, in contrast to ino, decreases pulmonary artery wedge pressure. like ino, sildenafil does not decrease systemic arterial pressure. finally, the combination of ino and sildenafil is well tolerated acutely and is superior to ino in reducing pvr. this suggests that pde- inhibitors might be safe alternatives to ino in the evaluation of patients with pah. in a small ipah cohort, chronic therapy with sildenafil mg po t.i.d. was well tolerated and resulted in improved pvr, right ventricular hypertrophy as well as in a significant increase in the -minute walk (+ m increase from baseline) (fig. . ) . we have been following these patients for almost years now. while several have a sustained improvement, some patients slowly returned to their baseline level of hemodynamics, although almost all maintain the improvement in the -minute walk that they showed at months. the significance of this observation as well as the role of possible tolerance to this drug is unknown at this point. a large industry-sponsored placebo-controlled month trial has been completed and will soon be published. although this trial will give a more definitive answer on the safety and efficacy of sildenafil, more trials extending to or more months will be needed in the future. of course, this is true for all rcts in pah, most of which have been quite short ( to months). sildenafil has already found an "offlicense" role in the treatment of patients with pah. a recent study prospectively compared sildenafil ( mg po t.i.d.) with bosentan in patients with ipah and scleroderma-pah (nyha class iii) in a double-blind fashion. patients on sildenafil improved their -minute walk by m while the patients on bosentan improved only by m (fig. . ). most importantly, sildenafil caused a significant reduction in the rv mass, measured by mri, while bosentan failed to improve rv mass (fig. . ). during the study period ( weeks) there was one death in the sildenafil group that the authors did not associate with sildenafil. this important trial was sponsored by the british heart foundation and did not have any industry support. the newer pde- inhibitors might also prove to be useful in pah. ghofrani et al. recently compared the acute hemodynamic effects of sildenafil, tadalafil, and vardenafil in ipah patients undergoing right heart catheterizations ( ) leads to improvements in the -minute walk and hemodynamics, without affecting system arte-rial pressure. in the mri example shown, note that the abnormal septum position due to the rv pressure overload is normalized after sildenafil therapy (arrows). . ) . their research indicates that not all pde- inhibitors are selective to the pulmonary circulation. for example, vardenafil caused a much higher systemic vasodilatation and, in comparison to sildenafil or tadalafil, failed to decrease the pvr to systemic vascular resistance (svr) ratio. in small series, sildenafil has also been suggested to be beneficial in preventing rebound in pah patients treated with inhaled no, pht associated with pulmonary fibrosis, pah due to veno-occlusive disease, and pah in children. although pde inhibitors have promise in therapy for pah, further study is required, and there is not currently an fda-approved pah indication for this therapy. nonetheless, the pde inhibitors appear to be well tolerated and, if one excludes patients with connective tissue disease, may offer relatively larger increases in functional class and -minute walk than other therapies. in addition, phosphodiesterase inhibitors are significantly less expensive and less toxic than endothelin antagonists, the only other oral therapy available, and are less diffi cult to administer than flolan or iloprost. patients with severe pah may be considered for either combined heart-lung or lung transplantation. although there is no consensus at present regarding the preferred procedure for most patients with pulmonary vascular disease, patients with pah due to complex congenital heart disease should undergo combined heart-lung transplantation. single lung transplantation has been performed successfully in patients with ipah and pht due to chronic obstructive pulmonary disease and fibrotic lung disease. the major complications of transplantation surgery for pulmonary vascular disease are organ rejection and opportunistic infection. bronchiolitis obliterans occurs in % to % of transplant patients, and may result in serious respiratory embarrassment or death. data from the international society for heart and lung transplantation ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) show that the -year survival for ipah after transplantation is approximately % for lung transplantation (total patients) and % for heart-lung transplantation (total patients). access to this therapy is, and will remain, severely limited by the availability of donors. in addition, as therapy for pah improves, there will be reluctance to transplant patients before all medical options are exhausted, as the year survival for patients following lung transplantation is not substantially better than the prognosis of patients with class ii to iii pah on medical treatment. because of the diverse conditions that lead to pah and the often complicated and expensive therapies, patients with pah should be referred to multidisciplinary clinics in tertiary care centers. as an example, in our pah clinic at the university of alberta (www.pulmonaryhypertension.ca), patients are evaluated by teams that include cardiologists, congenital heart disease specialists, pulmonologists, rheu-matologists, and endocrinologists. cases are discussed by teams that include radiologists and pharmacologists, and patients are often also seen by social workers and psychologists. the grim prognosis and the predisposition of young women of reproductive age for this disease explain the often severe social and psychological challenges in the management of these patients. in this model, patient care is coordinated by a highly trained nurse practitioner. figure . is an evidence-based algorithm for the treatment of pah, based on the discussion above. since class i or ii patients have not been studied in the pah rcts, no evidence-based recommendations can be made for these patients. several rcts are also currently under way, and within the next years additional short-term as well as long-term trials will be available to strengthen this algorithm. although flolan and iloprost offer major benefits in pah and are the current drugs of choice in north america and europe, respectively, for class iv pah, they are not curative and have major adverse effects and cost implications. unfortunately, the new oral and subcutaneous analogues suffer from a relative lack of efficacy. currently sildenafil and bosentan are useful for class iii patients, although the sildenafil therapy must be viewed as an "off-label" indication at the time of writing. it is likely that as with hiv-aids or tuberculosis, combination therapy for pah will be required. this presumably would be targeted to optimize function, pvr, and bnp levels. all pah patients should be followed in a multidisciplinary pah clinic. a study of ibn nafis selected readings in the history of physiology harvey's perfusion of the pulmonary circulation of man depulmonibus observations anatomiae; bologna, catheterization of the right heart ueber slerose der lungenarterien uber die genuine arteriosklerose der lungenarterie primary pulmonary hypertension. clinical and hemodynamic study primary pulmonary hypertension: a vascular biology and translational research "work in progress potassium channels regulate tone in rat pulmonary veins spontaneous 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glucocorticoids and bronchodilators, have significant therapeutic effects; however, they also cause side effects, including infection and immunosuppression. here we reviewed the pathogenesis and progression of copd and elaborated on the effects and mechanisms of newly developed molecular targeted copd therapeutic drugs. among these new drugs, we focussed on thioredoxin (trx). trx effectively prevents the progression of copd by regulating redox status and protease/anti-protease balance, blocking the nf-κb and mapk signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the camp-pka and pi k/akt signalling pathways. the mechanism by which trx affects copd is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses. in addition, trx also improves the insensitivity of copd to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (mif). taken together, these findings suggest that trx may be the ideal drug for treating copd. chronic obstructive pulmonary disease (copd) is a slow-developing, incurable lung disease characterised by a sustaining airflow limitation that further develops into common diseases such as pulmonary heart disease and respiratory failure. copd is caused by a complex interaction between genes and the environment. cigarette smoking is the leading environmental risk factor for copd. fewer than % heavy smoker develop copd, it indicates that genetics may play a role in regulating the risk of copd in smokers. besides genetics, other risk factors are also involved in the development of copd, such as age and gender, , lung growth and development, , exposure to particles, - socioeconomic status, , asthma and airway hyper-reactivity, , chronic bronchitis , and infections. gender may effect whether a person smoke or experiences certain occupational or environmental exposures; socioeconomic status may be related to lung growth and development, and then influence on susceptibility to developing the disease; and long live will allow greater lifetime exposure to risk factors. asthma may be a risk factor for the development of copd. airway hyper-responsiveness is the second risk factor for copd, but airway hyper-responsiveness, as an independent predictor of copd can exist without asthma, suggesting inflammatory profiles of copd different from asthmatic subjects. the pathogenesis of copd remains unclear and has been generally suggested to be related to inflammation, oxidative stress, protease/anti-protease imbalance and decreased immunity. smoking, biofuel smoke-induced oxidative stress and excessive protease production are major factors in copd pathogenesis that cause alveolar cell death, destruction of the extracellular matrix in the alveolar region and loss of alveolar structure. , the primary manifestations in the respiratory tract include airway wall remodelling and mucus retention, and further development leads to a serious decline in the lung function. currently, the main approach is to deal with symptoms of the airflow limitation caused by the above-mentioned symptoms to improve the resulting dyspnoea through medication, oxygen treatment and rehabilitation therapy. however, there is currently no way to prevent the disease progression. drug treatment includes bronchodilators and glucocorticoids, with the main types of bronchodilators including the β receptor agonists and anticholinergic drugs; however, both have many adverse effects. for example, the main side effects of the β receptor agonists are rapid heartbeat, muscle tremors and metabolic disorders. the side-effects of anticholinergic drugs include dry mouth, blurred vision, urinary retention, postural hypotension, cognitive problems and cardiac rhythm disturbance. long-term use of glucocorticoids induces and exacerbates infections, cause hyperglycaemia, osteoporosis and even mental disorders. [ ] [ ] [ ] therefore, a series of new molecular targeted therapeutic drugs to block copd progression is under development. this article introduces the pathogenesis of copd and pharmacology of related anti-copd drugs. specifically, there is a focus on the effective role and mechanism of the small molecule secretory protein thioredoxin (trx) that is widely expressed in lung tissues such as the type ii alveolar cells, macrophages and bronchial epithelium. the occurrence and development of copd is a complex pathological process involving a variety of inflammatory cells, inflammatory mediators and related cell signalling pathways. copd also regulates the goblet cell proliferation, mucoprotein (muc) synthesis and mucus secretion. in recent years, molecular biology has revealed new insights regarding the pathogenesis of copd (fig. ). copd and oxidant/antioxidant imbalance oxidative stress is an important factor in copd pathogenesis. an increased oxidative burden occurs in the lungs of patients with copd, and oxidative stress may be involved in various the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases and enhancing lung inflammation through activation of redox-sensitive transcription factors. copd patients suffer from oxidative stress caused by the inhalation of cigarette smoke (cs) or harmful substances which causes an accumulation of pulmonary inflammatory cells (neutrophils, macrophages), leading to large numbers of reactive oxygen species (ros). excessive ros production leads to an oxidative inactivation of anti-proteases, alveolar epithelium damage, increased neutrophil retention and increased expression of various inflammatory mediators in the pulmonary microcirculation, aggravating the development of copd. [ ] [ ] [ ] in addition, ros-activated inflammatory cells, now acting as activated inflammatory cells, also generate ros to further aggravate oxidative stress in tissues. oxidant-generating systems, such as xanthine/xanthine oxidase, can cause airway epithelial mucus secretion. oxidative stress, generated by tobacco smoke and augmented by ros generated from both inflammatory cells and mitochondrial activity by cells resident in the respiratory tract, regulate mucous cell metaplasia and mucin gene expression such as muc ac and muc b. oxidants are also involved in the signalling pathways for epidermal growth factor, which has an important role in mucus production. a relative deficiency of anti-proteases, such as α -antitrypsin, because of their inactivation by oxidants from cigarette smoke or released from inflammatory leucocytes, causes a protease/ anti-protease imbalance in the lungs. cigarette smokeinduced oxidative stress plays role in enhancing inflammation by regulating redox-sensitive transcription factors, such as nuclear factor kappa-b (nf-κb) and activating protein (ap- ), the extra-cellular signal-regulated kinase (erk), c-jun n-terminal kinase (jnk), and p mitogen-activated protein kinase (p mapk) pathways. ros also decrease the activity of histone fig. the pathogenesis of copd is complex and diversified. oxidative stress may participate in various the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases and enhancing lung inflammation through activation of redoxsensitive transcription factors. under the stimulation of cigarette smoke, pathogen infection and other factors, oxidative stress is induced and the pulmonary inflammatory cells (neutrophils, cd t lymphocytes, macrophages) accumulate, resulting in a large number of reactive ros. the inflammatory cells are activated by the nf-κb, p mapk and pi k signalling. inflammatory cells (mainly neutrophils) migrate from the circulation to the inflammatory site under sequential regulation involving cytokines and adhesion molecules such as selectin. proteases are involved in tissue remodelling, inflammation and ecm degradation, thereby participating in the pathological process of copd. inflammatory cytokines and chemokines, such as ltb , il- and tnf-α, and other mediators are secreted into the lungs to aggravate the lung tissue damage and promote inflammatory responses. pde decreases camp levels in inflammatory cells and promotes inflammatory cell activity and the release of inflammatory factors. chronic inflammation stimulates the increase of egfr and tgf-β . activated egfr is involved in the proliferation of the airway epithelial goblet cells and mucus production. tgf-β chemoattracts neutrophils, macrophages and mast cells, and activates pi k/akt and/or p mapk signalling to induce pulmonary fibrosis and emt. endothelin- (et- ) produced by endothelial cells, stimulates the contraction and proliferation of vascular smooth muscle cells and the liver to produce more crp, and it also induces the synthesis of vegf. b-type natriuretic peptide (bnp) antagonises renin angiotensin aldosterone system, dilates blood vessels and reduces peripheral vascular resistance, and c-type natriuretic peptide (cnp) dilates blood vessels and inhibits the proliferation of vascular smooth muscle cells deacetylase (hdac) which recoil dna of the histone core to stop transcription, , and probably increase the activity of histone acetyltransferase, which uncoils dna from the histone core to allow transcription. this leads to the further recruitment of inflammatory cells, specifically the neutrophils and macrophages in the alveolar spaces. in addition, oxidative stress extends beyond the lung, contribute to several of the systemic manifestations. peripheral blood neutrophils of copd release more ros than in normal subjects and this is enhanced still further in exacerbation. products of lipid peroxidation are also increased in plasma in smokers with copd, particularly during exacerbations, resulting in dna damage and airway epithelial cell senescence and apoptosis. in addition, the reactive aldehydes such as acrolein and -hydroxy- -nonenal ( -hne) formed from lipid peroxidation cause damage to the epithelial cells, acrolein is unstable and toxic, whereas -hne in high concentrations is capable of inducing caspase (a major promoter of cell apoptosis). , nuclear factor e -related factor (nrf ) is a transcription factor that regulates many antioxidant genes and plays an important role in the body's antioxidant stress. normally, nrf is fixed in the cytoplasm by kelch-like ech-associated protein (keap- ). under oxidative stress, nrf and keap- dissociate, and nrf is transported to the nucleus, activating the transcription of antioxidant genes. , however, the level of nrf in copd patients is reduced, resulting in a reduction of endogenous antioxidants and weakening the body's protection against oxidative stress. sirtuins (sirt ) and sirt are also related to the redox state. sirt is a redox-sensitive protein with a wide range of biological functions, such as inhibition of autophagy, cell aging, emphysema and fibrosis, and inflammation. , , yao et al. demonstrated that sirt can resist the inflammatory response of cigarette smoke to lung cells caused by oxidative stress. inhibition of inflammation may be through deacetylation of nf-κb. , sirt is also associated with redox status and inhibits cell aging and fibrosis. , copd and protease/anti-protease imbalance the pathogenesis of copd is closely related to the imbalance of protease/anti-protease, which leads to the destruction of the elastin framework. proteases are involved in tissue remodelling, inflammation and degradation of the extracellular matrix (ecm) components and the pathology of copd. , in addition, the products of ecm decomposition, such as collagen and elastin, are themselves chemokines of inflammatory cells and cause persistent respiratory system inflammation in copd patients, even leading to systemic autoimmune diseases. elastase is an enzyme that hydrolyses peptides and other proteins, and there are three main types in lung disease: serine proteases, caspases and matrix metalloproteinases (mmps). among them, mmps are a highly conserved family of endopeptidases, consisting of known members, that depend on zinc and calcium ions. macrophages and their macrophagederived mmps may be the dominant factor in the formation of smoking-related emphysema and copd. among the mmps, mmp- and mmp- are most involved in emphysema. mmp- plays an influential role in severity of copd. mmps also play a role in vascular remodelling by modulating the migration and proliferation of smooth muscle cells and endothelial cells and mediating the release of the smooth muscle cell mitogens and growth factors, increasing the risk of copd pulmonary hypertension. [ ] [ ] [ ] [ ] the endogenous inhibitors of mmps are tissue inhibitors of metalloproteinases (timps). timps are a family of low-molecular-weight proteins with four known members. timp- inhibits active mmps, including mmp- , mmp- and mmp- . it has been reported that changes in mmp- poorly correlated with disease intensity and progression in copd. timp- binds to pro-mmp- to prevent the activation of pro-mmp- . however, neutrophil elastase acts by dissociating the binding of timp- to pro-mmp- , which allows mmp- to activate pro-mmp- to become mmp- . in serine proteases, neutrophil elastase (ne), cathepsin g and proteinase- destroy lung tissue by degrading ecm components, and induces epithelial cells and endothelial cells to release a variety of inflammatory factors to activate and chemoattract neutrophils to produce lung inflammation. , alpha-antitrypsin is a protease inhibitor synthesised by liver cells, which control over the proteolytic activity of ne, proteinase- , cathepsin g and neutrophils serine protease- . evidence from experimental models of emphysema and from individuals with genetic deficiency of alpha- antitrypsin provides strong evidence that an imbalance between the enzymes and inhibitors is important in tissue damage and the pathogenesis of copd. protease-anti-proteases imbalance during airway inflammation and airflow restriction may be an important factor affecting airway remodelling and airflow restriction. copd and inflammatory cells, cytokines and chemokines copd pathology is characterised by airway remodelling and inflammatory cell infiltration by the neutrophils, cd t lymphocytes and activated macrophages. neutrophils have been implicated in copd pathogenesis and the extent of neutrophilic infiltration in lung tissues correlates with copd severity. , inflammatory factors play a major role in the onset and development of copd. under the stimulation of cigarette smoke or other harmful substances, the respiratory tract epithelium secretes inflammatory cytokines and chemokines, such as leukotriene b (ltb ), interleukin- (il- ), il- (cxcl ) and tumour necrosis factor-α (tnf-α), and other mediators in the lungs. these inflammatory mediators aggravate the lung tissue damage and promote inflammatory responses. ltb is a lipid mediator derived from arachidonic acid by the sequential action of -lipoxygenase ( -lox), -lipoxygenase-activating protein (flap) and lta hydrolase (lta h) to stimulate leucocyte functions such as cytokines, chemokinesis, lysosomal enzyme release, superoxide anion production, adhesion to endothelial cells, generation of ros and so on. il- activates neutrophils, causing neutrophil infiltration at the inflammatory sites, inducing neutrophils to release elastase and various oxygen free radicals, destroying alveolar surfactants, increasing pulmonary vascular permeability and inducing pulmonary oedema. activated by il- , which is higher in bronchoalveolar lavage fluid (balf) and sputum of copd patients. il- has a similar effect and induces neutrophil migration to the airway and affects degranulation produced by various cell types. tnf-α stimulates the pulmonary microvascular endothelial cells to promote the accumulation, adhesion and migration of the polymorphonuclear leucocytes by inducing the expression of il- and upregulating endothelial adhesion molecules, causes release of lysosomal enzymes, elastase and large quantities of ros; and damages the endothelial cells and alveolar epithelium. tnf-α together with il- β has been identified as a key cytokine that is able to initiate inflammatory cascades during exacerbations of copd. monocyte chemotactic protein (mcp- , ccl- ), macrophage inflammatory protein- α (mip- α, ccl- ) are cc-chemokines, which act as chemoattractants for inflammatory cells like macrophages, lymphocytes. neutrophil-derived ccl- and ccl- are involved in macrophage recruitment into inflamed tissue. in patients with copd, several cc-chemokines like ccl- , ccl- are upregulated to attract specific inflammatory cells, like macrophages, neutrophils and cd (+) t-lymphocytes into the airway, suggesting the contribution of their respective receptor in the pathogenesis of the disease. copd and adhesion factors the inflammatory process of copd is characterised by a continued migration of inflammatory cells (mainly neutrophils) from the blood vessel to the lungs. neutrophil migration is a carefully regulated series of events involving cytokines and adhesion molecules including the selectins (l-, p-and e-selectin), intercellular adhesion molecule- (icam- ) and vascular cell adhesion molecule- (vcam- ). the migration has been described as a multistep process including slow rolling, adhesion strengthening, intraluminal crawling and finally paracellular or transcellular migration through the endothelium. the initial rolling is mediated by l-selectin (cd l) expressed on neutrophils, and eselectin and p-selectin expressed on the endothelium. the main ligand for these selectins is the p-selectin glycoprotein ligand (psgl)- (cd ) expressed on neutrophils and certain endothelial cells. furthermore, e-selectin binds e-selectin ligand (esl- ) and cd on the neutrophil surface, cause the slow rolling of the neutrophil. next, firm adhesion is mediated through, for example, the macrophage antigen- (mac- /cd b) expressed on neutrophils and its ligand icam- expressed on the endothelium. after the neutrophil has been fully arrested, the adhesion of the neutrophil to the endothelial surface is strengthened. stable binding of ligand to vla- (a b -integrin) is rapidly increasing neutrophil infiltration of the inflamed tissue, implicating that internal signals are required for increased adhesion. the third step, intravascular crawling, involves cd b and other β -integrins. prior to the final step, transendothelial migration, vcam- and icam- form the so-called docking structures on the endothelial cells. for the final transendothelial migration, the interaction between two platelet/ endothelial cell adhesion molecules (pecam)- , expressed at the endothelial cell boundary and on neutrophils, is essential for the ultimate transendothelial migration. , selectin l, e and p have been found in copd. psgl- levels were higher in all stable copd patients than those in in healthy controls. increased eselectin and serum icam- have also been reported in copd patients. , during migration, the neutrophils release substantial amounts of proteinases and ros. this process is known as obligate proteolysis and is an important cause for bystander tissue damage in copd. the epidermal growth factor (egf) is a single-chain polypeptide growth factor that promotes the division of epithelial cells and other cells by binding to a specific epidermal growth factor receptor (egfr) on target cells to stimulate and maintain a series of cell growth, proliferation and transformation processes. chronic inflammation increases levels of egfr and its ligands. the expression and activation of egfr are positively correlated with the airway epithelial goblet cell proliferation and mucus production. in the airways, activated neutrophils and their secretions play an important role in an egfr-dependent mucus production. activated neutrophils secrete tnf-α, which upregulates the egfr expression in airway epithelial cells and directly stimulates muc synthesis. the expression of egfr was higher in copd patients than in smokers with normal lung function, which indicated that copd was related to the overexpression of egfr. egfr and its ligand egf binding are the main causes of squamous cell metaplasia, and the growth of epithelial cells is most significant in smokers and copd. these indicate that egfr levels in the small airways of copd patients were associated with decrease in airway functionality. the transforming growth factor-β (tgf-β) family regulates cell proliferation, differentiation and the extracellular matrix synthesis. tgf-β is a chemoattractant for the neutrophils, macrophages and mast cells. tgf-β expression is significantly increased in the airway epithelial cells of copd patients, and an active tgf-β signalling is involved in copd pathogenesis. in copd patients, tgf-β promotes a fibrotic airway remodelling, which can further contribute to a diminished lung function. loss of the alveolar parenchymal tissue may be caused in part by an up-regulation of mmp expression in response to tgf-β signalling, leading to an ecm degradation. , in copd, epithelial to mesenchymal transition (emt) which is associated with airway remodelling and obliteration is activated by canonical pathways such as tgf-β, which induce expression of nuclear transcription factors psmad / and reduced inhibitory smad / expression. , tgf-β also induces and promotes the increased expression of egf, egfr and its related signalling pathways, and their synergism induces emt-related phenotypic changes. , copd and camp cyclic adenosine monophosphate (camp) is a ubiquitous secondary messenger that regulates a variety of essential processes in diverse cell types via camp-dependent effectors such as protein kinase a (pka) and/or the exchange proteins directly activated by camp (epac). epac and pka inhibit the human airway smooth muscle induced by a cigarette smoke extract (cse) by blocking the activation of the nf-κb and erk, respectively, and by releasing neutrophil chemokine il- , which together exert anti-inflammatory effects. camp also mediates the airway smooth muscle relaxation. , camp plays a key role in the functions of many airway cells including controlling ciliary beat frequency (critical for mucus clearance) in airway epithelial cells. in copd, increases in camp levels, activation of pka and enhanced protein phosphorylation have the potential to reduce inflammation and immunomodulation, relax airway smooth muscle, inhibit chemotaxis and abnormal release of inflammatory and cytotoxic mediators, and reduce proliferation and migration of inflammatory cells. phosphodiesterases (pdes) are the only way to degrade cyclic nucleotides in the body, thereby ending the biochemical effects conducted by these second messengers (camp or cgmp). in the balf from copd patients, camp levels are decreased while pde levels are increased. these indicate that camp is regulated via pdes, and two direct downstream effectors of camp (pka and epac). copd and peptide factor copd also includes a gradual increase in pulmonary arterial pressure, and - % (depending on the definition, severity and measurement of copd) have developed pulmonary hypertension. endothelin- (et- ) is an effective vasoconstrictor produced by endothelial cells, which can stimulate the contraction and proliferation of vascular smooth muscle cells. the synthesis and secretion of endothelin in patients with copd increase, and during the exacerbation of copd, the level of endothelin further rises and participates in the formation of pulmonary hypertension. , et- can also stimulate the liver to produce more c-reactive protein (crp) by up-regulating il- . crp further stimulates the release of a variety of biologically active substances, such as endothelin- , il- , etc. amplify the inflammatory effect. , in addition, et- can also participate in the pathological process of copd by inducing the synthesis of vascular permeability factor (vegf). the family of natriuretic peptides includes a-type natriuretic peptide, b-type natriuretic peptide (bnp) and c-type natriuretic peptide (cnp). bnp and cnp play a major role in the occurrence and development of copd. bnp antagonises the renin-angiotensin-aldosterone system, dilates blood vessels and reduces peripheral vascular resistance. cnp also has a strong vasodilator effect and inhibits the proliferation of vascular smooth muscle cells. cnp can block the synthesis of vegf induced by hypoxia and endothelin at the transcriptional level, thereby inhibiting vegf-mediated hyperplasia of endothelial cells. it may play an important role in the development of pulmonary hypertension. copd and the nf-κb pathway the transcription factor nf-κb is studied in systemic inflammation and has been noticed in copd patients. in an inactivated state, nf-κb is located in the cytosol and is complexed with the inhibitory protein inhibitor kappa b (iκb). there are a number of different iκb proteins such as iκbα, iκbβ, iκbγ, iκbɛ and bcl- . iκbβ is only phosphorylated by certain stimuli including lps (lipopolysaccharide) and il- β, whereas iκbα phosphorylation is triggered by most nf-κb activators. when a variety of extracellular stimuli act on receptors of the respiratory epithelium, iκb kinase (ikk) is activated. ikk, in turn, phosphorylates iκbα, resulting in ubiquitination and dissociation of iκbα from nf-κb. nf-κb (p and p ) is then translocated into the nucleus where it binds to specific sequences of dna to cause an inflammatory response. , nf-κb activates proinflammatory genes encoding cytokines and chemokines, such as il- β, il- and tnf-α. the cytokines produced by nf-κb pathway play essential roles in inflammatory cell migration and strengthen oxidative stress during copd development, further aggravating the condition. , both passive smoking and an intratracheal infusion of lps induce copd in rats via the nf-κb signalling pathway. in respiratory tract biopsies from copd patients, activated nf-κb levels were significantly higher than that of normal people, while the level of iκb in the lung tissue from smokers or copd patients was significantly lower than that of non-smoking healthy individuals. overexpression of ikk-β in mouse airway epithelial cells results in an increase in inflammatory mediators and neutrophilic inflammation that is reminiscent of the copd airway following bacterial challenge. in addition, inhibition of ikk-β in vivo and in vitro reduced tnf-α induced muc ac production. this indicates that the nf-κb pathway plays an important role in the occurrence and development of copd. copd and the p mapk p mapks are members of the mapk family activated by a variety of environmental stresses and inflammatory cytokines. it seems to be the most effective mapk, in stabilising, at post-transcriptional level, the mrnas for cytokines and chemokines relevant to copd pathogenesis. p mapks are divided into four subtypes: p α, p β, p δ and p γ. different subtypes are expressed in different tissues, and p α is most abundant in inflammatory cells. cs, lps, inflammatory factors and oxidative stress activate the p mapk pathway. in the airways and sputum of patients with copd, p mapk was significantly increased, and its activation was related to the severity of copd. in addition, the common pathogenic bacteria of copd, nontypeable haemophilus influenzae, contains cytoplasmic proteins that up-regulate human muc ac mucin transcription via a positive p mapk pathway and a negative phosphoinositide -kinase-akt pathway. the activation of p mapk associated with the degree of lung function impairment and alveolar wall inflammation. bacterial or viral infection is a common trigger for copd exacerbations, and exposure to lps induces p mapk activation in rat peritoneal macrophages and dendritic cells as well as an increase expression of inflammatory mediators. , glucocorticoid resistance in copd patients may also be related to the p mapk pathway through phosphorylated glucocorticoid receptor (gr) reducing gr translocation into the nucleus and dna binding, impairing the gr function. , the anti-inflammatory effects of corticosteroids are mediated by gr, and functional impairment of gr is an important mechanism of glucocorticoid resistance. copd and the pi k/akt pathways the phosphatidylinositol kinase (pi k) pathway is a major pathway regulating cell growth, proliferation, metabolism, survival and angiogenesis. serine/threonine kinase (akt), also known as protein kinase b, is an enzyme consisting of a ph domain, a kinase catalytic domain, and a regulatory domain that covalently attaches atp-phosphate groups to the serine/threonine of protein substrates to alter target protein activity. activated pi k phosphorylates phosphatidylinositol diphosphate to produce the secondary messenger phosphatidylinositol , , triphosphate, which binds the ph domains of akt and phosphoinositide dependent kinase- . akt undergoes a conformational change and is transferred to the plasma membrane, leading to akt activation. activated akt regulates cellular functions by phosphorylating various downstream factors including enzymes, kinases and transcription factors. , dysregulation of akt activity impacts on all these essential cellular processes, such as cell growth, survival and inflammation. the pi k/akt signalling pathway plays an important role in copd by regulating inflammatory cell activation, inflammatory mediator release and airway remodelling. the regulation of pi k/akt pathway in neutrophil restore some key copd neutrophil responses. pi k/ akt pathway regulates macrophage polarisation in emphysematous mice generated by cs exposure combined with intraperitoneal injection of cse. ecm proteins promoted proliferation, migration and adhesion of airway smooth muscle cells form rat models of copd through activation of the pi k/akt signalling pathway. ros activates pi k, initiating the pi k/akt signalling pathway. pi k/akt pathway plays an important role in the activation of nrf , which regulates oxidative stress and inflammation in copd. the persistent airway and lung inflammation of copd is related to a decreased histone deacetylase activity (mainly hdac ) caused by oxidative stress. up-regulation of pi kδ/akt signalling reduces the hdac activity, promoting the transcriptional activation of inflammatory genes. another study found that down-regulation of hdac is associated with glucocorticoid resistance. as the inflammatory signalling pathways closely associated with copd development have been elucidated, most candidate therapeutic drugs developed in recent years are molecular drugs targeting these signal transmitting substances. the following sections outline new copd treatment strategies (fig. ). oxidative stress plays a crucial role in the pathogenesis of copd. in the exhaled breath condensate of copd patients, the levels of oxidative stress markers such as hydrogen peroxide (h o ) and isoprostaglandin ( -ip) are significantly increased. through in vivo experiments, antioxidants have been shown to inhibit copd onset. n-acetylcysteine (nac) and other glutamines have been clinically tested in this regard. despite evidence of the beneficial role of nac in copd, its therapeutic efficacy in clinical management of copd has remained controversial due to its reduced bioavailability in an oral form and its acidic nature prohibiting its use in an inhaled form. in addition, the lack of assurance that there is an effective concentration of glutathione in the lung is another major reason for not achieving the desired therapeutic effect. other antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, have good antiinflammatory effects on smoking-induced lung inflammation in animal models, and clinical trials are underway. copd is also affected by oxidative stress and nitrosative stress. therefore, nitric oxide synthase inhibitors being developed for acute diseases may also be suitable to treat copd. the antioxidant transcription factor nrf downregulates inflammation-associated production of ros and reactive nitrogen species. nrf -deficient mice exposed to cs had more extensive emphysema and more pronounced airway inflammation than wild-type mice. as a small molecule nrf activator, sulforaphane increased the gene expression of nrf , reduced the level of ros, and prevented the damage of cse-treated alveolar epithelial cells. the natural product sulforaphane activated nrf in alveolar macrophage isolated from copd patients denitrify hdac and restore the sensitivity to the glucocorticoid dexamethasone in a glutathione-dependent manner. unfortunately, sulforaphane applied for weeks to patients with copd did not induce the expression of nrf genes or have an effect on oxidative stress, airway inflammation or lung function. resveratrol is a natural sirt activator. in the rat model of copd treated with resveratrol, serum il- and il- levels were decreased and lung inflammation was inhibited. in addition, resveratrol activation of sirt also downregulates the activity of mmp in fibroblasts in copd. in recent years, it has been found that srt is a compound that can activate sirt , which can improve lung function and reduce lung damage caused by cs (table ) . regulating the imbalance between proteases and their inhibitors has attracted much attention as a treatment for copd. mmps which degrade elastin are a target for drug development. nonspecific mmp inhibitors are mainly developed as anticancer agents, but they have been reported to cause side effects such as arthritis, so long-term use as a copd treatment drug may have hidden dangers. mmp- is a member of the mmp family and its endogenous inhibitor is timp- , which binds the carboxyl terminal of the catalytic centre of mmp- to form an enzyme-inhibitor complex through noncovalent bonding. both are key enzymes regulating ecm degradation and synthesis, and changes in their concentrations are closely related to an airway inflammation damage. through culturing balf cells of copd patients with healthy individuals, it was found that mmp- release by macrophages in copd patients was significantly increased while healthy control macrophages released more timps. selective inhibitors of mmp- are also being developed and have proven to be effective in treating copd in animal models, but have not been effective in clinical trials of copd. ne inhibitors are also a valuable potential therapeutic drug, which can not only protect the lung from ne-mediated tissue damage, but also control the exuberant inflammatory response. japan approved sivelestat (ono- ) for the treatment of ali and ards. however, many countries have not approved siveles for clinical use, due to the uncertainty of the randomised doubleblind trial results. other promising ne inhibitors have also been stopped for various reasons. azd ( weeks) combined with budesonide/formoterol has no effect on lung function, quality of life and lung function in copd patients (table ) . the levels of il- β, il- , tnf-α and il- are significantly increased in the sputum and serum of copd patients. they may also be a therapeutic target for copd. as a human anti-il- β monoclonal antibody, canakinumab ( -week treatment) showed no statistical analysis provided for lung function changes. the receptor inhibitor tocilizumab is an available il- inhibitor with confirmed efficacy in rheumatoid arthritis, fig. new molecular targeted drugs. based on the molecular mechanism of copd, many new molecular targeted drugs have been developing in recent years. antioxidants scavenge ros and inhibit oxidative stress in the lungs and reduce cellular damage and inflammation. protease inhibitors restore the balance between protease and anti-protease by inhibiting. proteases. cytokine and chemokine inhibitors play an important role in reducing the inflammatory response. adhesion molecule inhibitors can block inflammatory cells, which continuously migrate from the blood vessels to the tissue. pde inhibitors inhibit pde production to increase the camp activity in cells. in the occurrence and development of copd, the signalling molecules, such as nf-κb, mapk, pi k and vip help regulate inflammation and airway remodellings, and represent plausible targets for the development of therapeutic candidates. candidate drugs include inhibitors of p mapk, nf-κb and pi k, and vasoactive intestinal peptide (vip). the inhibitor of egfr reduces internalisation of egfr but does not reduce mucin stores. tgf-β inhibitor reduces a fibrotic airway remodelling and downregulates mmp expression, endothelin inhibitors prevent the progression of pulmonary hypertension in copd. adenosine a a receptor inhibits neutrophil superoxide production, phagocytosis, adhesion and cytokine release. macrolides reduces the inflammation of copd by regulating the pi k/akt-nrf pathway and control transcription factors such as nf-κb and ap- to inhibit the production of inflammatory cytokines. ppar agonists exert antioxidant and anti-inflammatory effects by downregulating nf-κb and other pro-inflammatory transcription factors but clinical trials in copd require further study. endogenous tnf-α plays an important role in the development of pulmonary fibrosis and causes a secondary interstitial lung disease. as anti-tnf-α therapies, the tnf-α antibody (infliximab) and soluble tnf-α inhibitor (etanercept) have been used as clinical drugs, mainly to treat inflammatory diseases such as rheumatoid arthritis; and the same clinical dose of the tnf-α antibody used in rheumatoid arthritis has a definite effect on bronchial asthma, but has not been confirmed in copd. in contrast, copd patients had significantly increased incidence of airway tumours and lung infections caused by tnf-α antibodies, presenting a difficult problem to be overcome with future anti-tnf-α treatments. inhibitors of the il- receptor cxc chemokine receptor (cxcr ) effectively block neutrophil infiltration in the lung tissue in animal models and clinical trials. cxcr inhibitors block neutrophil invasion and inhibit mucus production and airway remodelling. however, it should be noted that cxcr inhibition triggers side effects similar to those exhibited by the use of glucocorticoids, such as promoting bacterial/ fungal infection and delaying wound healing. currently, there are clinical trials in progress for the cxcr receptor antagonists in copd, bronchial asthma and cystic fibrosis. ccr has an affinity for multiple chemokines, including (mip- α/ ccl ) and regulated on activation, normal t-cell expressed and secreted (rantes/ccl ), which are both elevated in lungs of copd patients. , ccr antagonists have been developed and are in clinical trials for autoimmune diseases. ccr which is the only receptor for (mcp- /ccl recruits inflammatory cells to lungs in copd, and increases synthesis of muc ac and muc b. the levels of both ccr and mcp- /ccl mrna were increased in bronchial epithelium of copd patients. mcp- /ccl production upon cigarette smoke exposure were increased in a mouse model of copd, ccr inhibitors for copd have been studied, but statistical analysis not released. ltb is elevated to some extent in the balf, sputum, serum and lung tissues of copd patients, and is positively correlated with the copd severity. several inhibitors are under development, one of which has entered clinical trials, but no effective anti-inflammatory effect has been demonstrated. in recent years, a -lox inhibitor upstream of ltb has been under development for bronchial asthma, but current -lox inhibitors have problems such as lack of selectivity, structure-activity relationships, methaemoglobin formation, and poor efficiency and oral availability. it should be noted that inhibiting ltb biosynthesis at the level of -lox or flap removes the lta intermediate. however, the latter molecule is an important intermediate in the biosynthesis of anti-inflammatory lipoxins, potentially reducing the net anti-inflammatory effect. in addition, some lta h inhibitors are also being developed , because these have been suggested to block ltb production while preserving lta , allowing shunting into lipoxin a . this features may make lta h inhibitors superior therapeutic molecules as compared with -lox or flap inhibitors (table ) . in the inflammation process of copd, selectins are essential for the migration of inflammatory cells from the bloodstream into the pulmonary tissue. therefore, targeting these molecules may inhibit the inflammatory process of copd. although several selectin inhibitors have been tested in clinical trials for bronchial asthma protect the lung from ne-mediated tissue damage and control the exuberant inflammatory response azd ( weeks) combined with budesonide/ formoterol has no effect on lung function, quality of life and lung function in copd patients patients, they have not proven to be effective. bimosiamose, a pan-selectin antagonist, blocks the adhesion of neutrophils, eosinophils and lymphocytes in vitro, and has anti-inflammatory effect in animal models of lung inflammation. bimosiamose inhalation has good safety and tolerance for copd patients. it reduces the levels of il- and mmp- in the sputum and reduces the number of neutrophils, reduces airway inflammation and improves the lung function, thus warranting further testing. el is an antiselectin monoclonal antibody that recognises specific positions on the e and l selectins to inhibit cell adhesion. el is currently being developed as a therapeutic drug for acute exacerbation of copd. it is clear that further studies are required to demonstrate the true clinical benefits of bimosiamose and el in copd patients. because e, l, p selectins recognise and bind to epitopes containing the carbohydrate sle x of glycoprotein or glycolipidon on a cell surface. a clinical study of -o, -o desulfated heparin (odsh or pgx- ) which is a carbohydrate-based drug was performed in phase ii for copd. however, the trial has been terminated because the interim analysis showed that odsh had no effect on the safety of patients with acute exacerbation of copd (table ) . egfr and tgf inhibitor egfr regulates mucin stores in airway epithelium, which are significantly increased in copd. bibw is the inhibitor of egfr, and inhalation of bibw ( -week treatment) reduced internalisation of egfr but did not reduce mucin stores. inhibition of tgf-β signalling may also be a useful therapeutic strategy in copd. the bone morphogenic protein and activin membrane-bound inhibitor (bambi) is a transmembrane glycoprotein, which acts as a negative regulator of tgf β signalling. bambi is induced by members of the tgf family-²-catenin, smad and smad , acting as a pseudoreceptor. bambi expression as significantly stronger in copd patients and that increased plasma bambi levels in copd patients displayed excellent correlations with enhanced plasma tgf-β levels. the because the mechanisms regulating bambi expression are poorly understood, the clinical trail of bambi is not developed. in addition, small molecule antagonists which inhibit tgf-β receptor kinase or tgf-β activated pathways were studied, , although the long-term safety of such drugs might be a problem, particularly as tgf-β affects tissue repair and is a potent anti-inflammatory mediator (table ) . pde inhibitors pde inhibitors have a selective inhibitory effect on pde specifically expressed in inflammatory, airway smooth muscle and epithelial cells. its main biological effects are selective inhibition of pde , leading to increased camp levels in inflammatory cells, regulating the activity of inflammatory cells and regulating the release of inflammatory factors to exhibit antiinflammatory effects. they have been developed as new antiinflammatory drugs for copd and asthma since the s. the pde inhibitor roflumilast has been approved by the food and drug administration as a copd treatment. it was shown roflumilast reduced the diffuse emphysema induced by cs in mice as compared with that in the control group. other studies have found that roflumilast inhibits bleomycin-induced pulmonary fibrosis in rats and reduces pulmonary vascular remodelling. , clinical trials have proven that roflumilast relieves the symptoms of dyspnoea in copd patients and reduces the frequency of acute attacks. once-daily administration of roflumilast significantly improves forced expiratory volume in s and decreases exacerbations, particularly in patients with severe disease, , but has side effects such as nausea, vomiting and headache. there are mainly four subtypes of pde , a to d. in recent years, the antiinflammatory effect of pde inhibitors has been shown to be mainly related to pde b while pde d is related to side effects such as digestive tract symptoms. the development of new pde b subtype-specific agents is expected, and inhalants that reduce systemic side effects are also being developed. in addition, oher pde inhibitors is being developed now [ ] [ ] [ ] [ ] (table ) . endothelin signalling plays a major role in pulmonary hypertension secondary to copd. endothelin antagonises bosentan (treatment for months) can alleviate the condition of copd patients and prevent the progression of pulmonary hypertension. this effect is more significant in gold iii and iv patients. but for copd patients without pulmonary hypertension, bosentan will aggravate their hypoxaemia. at present, further research on the role of bosentan in patients with gold iii or iv copd and pulmonary hypertension in the acute exacerbation phase is ongoing, but its status is unclear (table ) . vasoactive intestinal peptide vasoactive intestinal peptide (vip) has been characterised as a vasodilatory peptide. it exerts a wide range of biological actions, such as bronchodilation, anti-inflammatory effects, via binding its receptor vpac or vpac to increase significantly camp, adenylate cylase and phospholipase c, which cause different downregulation on a variety of transcription factors. vpac receptor mrna is abundant in lung and t lymphocytes. vpac receptor is mainly distributed in the smooth muscle layer and the base of mucosal epithelium in lung. vpac was particularly elevated in alveolar macrophages of copd patients. vpac receptor was activated by vip, and inhibited the cseinduced cytotoxicity of rat lung alveolar l cells. increased serum vip levels are associated with acute exacerbation of copd patients. vip has significant therapeutic potential in the treatment of copd. how, it clinical application might be limited because of the short half-life of plasma after intravenous administration and the difficulty of routes. (table ) . adenosine a a receptor agonist adenosine is a natural purine nucleoside that is ubiquitous in human tissues and plays a key role in many biological processes, such as energy production and protein metabolism. at present, four subtypes (a , a a , a b and a ) of adenosine receptors have been cloned. the anti-inflammatory effect of adenosine is mainly attributed to occupancy of camp-elevating gs-protein-coupled , [ ] [ ] [ ] [ ] [ ] bosentan blocks endothelin receptor. bosentan ( months) can alleviate the condition of copd patients and prevent the progression of pulmonary hypertension. this effect is more significant in gold iii and iv patients. but for copd patients without pulmonary hypertension, bosentan will aggravate their hypoxaemia. , solithromycin decrease the production of proinflammatory cytokines and chemokines by epithelial and immune cells a macrolide antibiotic. no data of solithromycin ( days) collected for this outcome due to early termination of the trial (nct ) ppar agonists regulates function of multiple cells of the immune system. pparγ agonists includes troglitazone, rosiglitazone, and pioglitazone. pparα agonists includes clofibrate and fenofibrate. patients who took more than two thiazolidinediones ( . % rosiglitazone) had significantly less copd deterioration than patients receiving other diabetes drugs. results information of clinical trail (february, months) has been submitted to clinicaltrials. gov by the sponsor or investigator, but is not yet publicly available on clinicaltrials.gov (nct ) , a a-receptors. the key molecular mechanism is the suppression of nf-κb pathway activated by cytokines such as tnf-α and il- β. a a receptor plays an anti-inflammatory role in specific cells and various inflammation models. knockout of the a a receptor gene will cause mucus production, airway destruction and lung inflammation. currently, several adenosine a a receptor agonists have been proven effective in copd models, but there are cardiovascular side effects. a phase , randomised, double-blind study (nct ) assessed the safety of the selective adenosine a a receptor agonist, regadenoson, compared with placebo in subjects with asthma or copd, and the result showed randomised did not modify repeated forced expiratory volume in s (fev ) when compared to placebo. uk , , which is beneficial in the lungs of anaesthetised guinea pig without any obvious cardiovascular sideeffects. phosphorylated a a receptor agonists are under development to reduce adverse effects such as hypotension (table ) . macrolide antibiotics are secondary metabolites of a variety of actinomycetes bacteria. the molecule contains a - -membered macrolide structure, which has a wide range of functions. it has not only antibacterial function, but also anti-inflammatory effect, inhibition of mucus secretion and immune regulation. , the anti-inflammatory and immunomodulatory functions are mainly -ring and -ring. clinically, they are used for long-term treatment of chronic inflammatory lung diseases such as copd. the anti-inflammatory mechanism of macrolide antibiotics is complex and has not been fully elucidated. it may reduce the inflammation of copd by regulating the pi k/akt-nrf pathway and control transcription factors such as nf-κb and ap- to inhibit the production of inflammatory cytokines. animal models provided further evidence that clarithromycin has an inhibitory effect on the development of emphysema, and its dose is almost the same as the clinical dose. the potential benefit of a new antibiotic, solithromycin was studied for the long-term treatment of copd, but due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis. other macrolides without anti-bacterial activity are being developed as anti-inflammatory drugs and clinical trials are expected in the future (table ) . ppar agonists peroxisome proliferator activated receptors (ppars) are ligandactivated nuclear hormone receptors belonging to the steroid receptor superfamily, including three recognised subtypes (pparα, pparγ and pparδ). the activation of pparγ and pparα may have anti-inflammatory and immunomodulatory effects. pparγ exert antioxidant and anti-inflammatory effects by down-regulating nf-κb and other pro-inflammatory transcription factors. cigarette smoke will down-regulate the expression of pparγ, and the level of pparγ in the lung tissues of copd patients is significantly lower than that of normal people. pparγ agonists, such as the thiazolidinediones, rosiglitazone and pioglitazone, have been shown to reduce lung inflammation in mouse models of tobacco smoke, and studies have found that treating model mice with thiazolidinedione can reverse emphysema. , in addition, pparγ agonists can also inhibit pulmonary fibrosis, which is expected to be a drug to prevent small airway fibrosis in copd. a retrospective epidemiological study showed that diabetes patients treated with pparγ agonists have a significantly reduced risk of copd exacerbation, but their risk of cardiovascular risk events has also increased. in addition, only large doses of thiazolidinediones can produce anti-inflammatory effects, which leads to speculation about the correlation of pparγ stimulation in copd. non-thiazolidinedione pparγ ligands are currently being studied to reduce potential cardiovascular risks. pparα agonists, such as fenofibrate, may have therapeutic potential in the treatment of systemic symptoms of copd (table ) . a japanese drug discovery company is developing a compound code named imd- , which is an ikk β inhibitor developed for the treatment of copd, but has no follow-up information posted since april . it is unclear whether study was performed. bms- is a highly selective ikk inhibitor with good pharmacokinetic characteristics. in the human airway smooth muscle cells, co-incubation with bms- markedly inhibited the nf-κb nuclear translocation induced by tnf-α and il- . ps- induce a dose-dependent inhibition of phosphorylated ikbα and nf-κb activation, and then reduces the expression of adhesion molecules, cytokines and chemokines on airway smooth muscle cells. a small molecule ikk inhibitor is under development as a therapy for inhibiting the nf-κb activity. the effectiveness of ikk inhibitors has been verified in animal models of copd; and clinical trials of ikk inhibitors in patients with bronchial asthma and joint rheumatism have also been conducted. ikk inhibitors are expected to be used as a new therapeutic drug for copd in the future following in-depth research. further developments include nf-κb "decoy" oligonucleotides and antisense and small interfering rna agents. , in addition, nf-κb-deficient mice have been reported to be more prone to sepsis, hence complications such as immunosuppression and infection susceptibility caused by long-term nf-κb inhibition must be considered (table ) . as a new type of anti-inflammatory drug, p mapk inhibitors have attracted much attention from researchers. currently, various small-molecule p mapk inhibitors have been developed and verified in animal models of smoking-induced pneumonia, proving their beneficial anti-inflammatory effects. inhibiting p mapk activation has been found to reduce the cs-induced airway smooth muscle cell proliferation, suggesting that p mapk inhibitors may reduce the progression of copd airway remodelling. p mapk inhibitors also reduce cytokine production by alveolar macrophages. in addition, there is evidence that corticosteroids cannot inhibit p mapk activation, and that p mapk inhibitors combined with corticosteroids enhance the inhibitory effect of corticosteroids on cytokines produced by macrophages in patients with copd mediated by lps. p mapk inhibitors have a unique advantage in patients with a poor hormone response. a days trial of p mapk inhibitor sb in patients with moderate stable copd reduced sputum neutrophils and plasma fibrinogen with improvement in forced vital capacity. the patients with moderate to severe copd receiving p mapk inhibitor ph for week decreased serum crp levels, and induced a significant increase of fev and a concomitant improvement in dyspnoea score. each subtype of p mapk has unique functions due to differential expression across tissue types and different regulatory kinases and downstream genes, hence their targeting comes with adverse effects. although some clinical trials are in progress, due to severe side effects such as those caused by an undesired pharmacological activity, suppression of the innate immune response to viral and bacterial infections, and damage to the central nervous system and liver, , these drugs remain challenging for a clinical application. there is a need to develop inhaled formulations and selective inhibitors of the α-δ subgroups. the inhaled narrow spectrum kinase (p α + src family) inhibitor (jnj /rv ) in patients with moderate to severe copd decreased serum crp levels as well as improved trough fev and dyspnoea index scores. however, p αmapk inhibitors block the upstream mapk kinase kinases, leading to hyperactivation of the transforming growth factor-activated kinase- and mixed-lineage kinase which then hyperactivate the jnk. therefore, other drugs that target more downstream substrates should be also developed (table ) . pi k inhibitors pi k is divided into three categories, namely classes i, ii and iii, among which class i pi k is most widely studied. class i pi k is a heterodimer composed of a regulatory subunit (p ) and a catalytic subunit (p ). there are four types of catalytic subunits: p α, p β, p δ and p γ, and while δ and γ subunits are limited to white blood cells, α and β subunits are widely distributed in various cells. pi k, especially pi k δ and γ subtypes, are closely related to a copd inflammation. pi k inhibitors reduce nitric oxide production by inhibiting carbon monoxide synthase. studies have shown that interruption of the pi k pathway improves severe copd protease imbalance. aerosolized tg - , a compound that selectively blocks pi kγ and pi kδ, inhibits pulmonary neutrophils induced by intranasal lps and smoke in mice with chronic obstructive pulmonary disease. as is a selective inhibitor of pi kγ, which reduces the migration of polymorphonuclear leucocytes in vitro and the infiltration of polymorphonuclear leucocytes in the lungs of mice with lps induced lung injury. the interventional therapy of tg - was successful even in steroid resistant copd induced by smoking in mice. various pi k inhibitors are currently being used in clinical trials, primarily for malignant tumours. , in recent years, inhaled pi kγ/δ inhibitors have been reported to inhibit pneumonia caused by smoking in animal models and have been especially effective and safe for patients with glucocorticoid contraindications. specific pi kδ inhibitors, gsk and rv are being developed, and studies on the effects of such inhibitors in copd are in progress. efficacy data remain limited. , in contrast, even selective p k subtype inhibitors have the risk of immunosuppression and secondary bacterial infections, and reducing the occurrence of side effects will be an important issue (table ) . trx is a multifunctional protein consisting of amino acids with a molecular weight of kda and a highly conserved cys-gly-pro-cys active site. trx exists in two forms: oxidised (trx-s ) and reduced (trx-(sh) ). trx-s can be reduced to trx-(sh) by the exchange reaction of -ss-and -sh under the action of thioredoxin reductase (trxr) and nicotinamide adenine dinucleotide phosphate (nadph). trx cooperates with trxr and nadph to form the trx system. trx catalyses the reduction of disulphide bonds and quenches ros by coupling with trx-dependent peroxidases or peroxiredoxins. in addition to its antioxidant effects, trx has a crucial role in the redox regulation of cellular signalling and activation. trx is involved in various redox-dependent cellular processes such as gene expression, signal transduction, cell growth, apoptosis and interacts with various target molecules. , under stress conditions, trx is released into the extracellular space where it exerts a cytoprotective effect and cytokine-like activities. trx expression in the sputum of copd patients is positively correlated with the degree of hypoxia. mice that overexpress human trx can effectively inhibit a cs-induced emphysema and pulmonary inflammation. intraperitoneal injection of trx suppress a smoke-induced murine pulmonary inflammation by inhibiting the production and release of cytokines, inflammatory mediators, chemokines and ros. trx inducer increases the trx expression in murine lung tissue and improves lung injury. recent research has also shown that inhaled trx also reduces a smoke-induced chronic lung injury. currently, clinical trials targeting acute lung diseases have entered the preparation stage. at the same time, as a pre-clinical trial of copd, intravenous infusion therapy for acute exacerbations, protein inhalation therapy for stable phase, and oral administration of inducers are also underway. adenosine a a receptor exert anti-inflammatory effect by enhancing camp regadenoson group ( months) occurred with higher incidence of dyspnoea, and unable to modify repeated fev when compared to placebo ((nct ). uk , is beneficial in the lungs of anaesthetised guinea pig without any obvious cardiovascular sideeffects. but uk- ( -week inhaled treatment) in dbpcrt showed no significant improvement in fev and quality of life parameters (nct ). , , progress in the mechanism and targeted drug therapy for copd wang et al. adjusting the redox balance trx plays an important role in maintaining the body's redox balance. trx can be used as an electron donor to reduce h o and tertiary butyl hydroperoxide. in addition, when the body's peroxidase reduces hydrogen peroxide, trx is also needed to provide a certain reduction equivalent. further, there are other redox systems similar to the trx system in the body, such as the glutathione (gsh) system. the trx system and the gsh system jointly control the redox system. the equilibrium state of the environment, and the trx and gsh systems cross each other to provide electrons and serve as a compensation system. , in addition, trx and thioredoxin-interacting protein (txnip), a negative regulator, constitute a redox-like protein compound (redoxisome) that regulates a variety of redox-sensitive signals and is essential for maintaining the intracellular and extracellular redox balance and monitoring inflammatory responses. without an oxidative stress, txnip is in a bound state with trx. when the intracellular ros content increases, trx and txnip are dissociated, and trx bind to ros. dissociated txnip combines with and activates the nlrp inflammasome to induce il- β expression in a nlrp -asc-caspase- -dependent manner, thus causing inflammatory reactions. this signalling complex may be a key regulatory mechanism for the body to regulate cellular redox balance and prevent the progression or exacerbation of stressinduced diseases. regulating the protease balance both endogenous and exogenous trx inhibit and improve a protease-induced emphysema. mmp- and mmp- play important roles in copd. oxidative stress upregulates the mmp- expression while trx inhibits mmp- via its antioxidant properties. , the mechanism may be inhibition of p mapk and jnk. in addition to inhibiting mmp, trx also inhibits its inhibitor, timp. studies have found that trx has a differential inhibitory effect on mmp- , mmp- , timp- and timp- , thereby regulating the mmp/timp balance. trx suppresses mmp and timp by reducing their activity but not degrading timp and mmp. , the activity of timp- , timp- or mmp- was not inhibited by a version of trx lacking a disulphide reductase activity or trx with a trxr deficiency. , this indicates that trx regulates the mmp/timp balance by differentially inhibiting the activities of timp and mmp, and this process depends on the redox active sites of trx and trxr. regulating inflammatory cells, cytokines and chemokines trx inhibits the migration and activation of inflammatory cells such as neutrophils, reduces the release of inflammatory factors, and reduces the inflammatory response. both in vivo and in vitro studies have shown that trx inhibits the chemotaxis of macrophages, lymphocytes, and neutrophils. , during copd development, the neutrophils and alveolar macrophages are activated to produce various inflammatory mediators, including il- β, il- , il- and tnf-α. trx significantly inhibits the production and release of il- β, il- , il- and tnf-α induced by lps in the human monocyte-derived macrophages. this is achieved by trx blocking the nf-κb pathway or inhibiting an inflammatory signal activation by cell surface molecules. , the specific mechanism of action has been thoroughly explained in our previous article. regulating adhesion factors and growth factors l-selectin (cd l) is a shedding molecule on neutrophils that plays a vital role in guiding neutrophils to adhere to the vascular endothelium and penetrate the blood vessels. trx inhibited the lpsinduced downregulation of l-selectin exfoliation on neutrophils and reduced the l-selectin attachment to endothelial cells whereas double-mutant trx c s/c s did not inhibit neutrophil adhesion to the endothelial cells. in a rat model of lps-induced inflammation, systemic trx significantly reduced neutrophil infiltration in the bronchus and lung tissues, but did not directly reduce the increased lps-induced icam- present on the endothelial cells. trx undergoes oxidation in response to egf. the local and specific oxidation of trx occurs during the ros signalling produced by egf stimulation. egfr signal transduction requires a special endoplasmic reticulum trx to control receptor expression on the cell surface. intracellular trx inhibits egfr synthesis and activation. tgf-β activates smad / , pi k/akt, erk / , gsk- β and/ or p mapk signalling to induce pulmonary fibrosis and emt. , trx inhibits the mpk -induced tgf-β function in a phosphorylation-dependent mannerm. trx inhibits bleomycininduced skin fibrosis by down-regulating tgf-β. trx overexpression inhibits airway remodelling by inhibiting tgf-β and egfr. regulating camp camp plays a protective role in copd inflammation through its effector proteins epac and pka. in animal models of brain injury, trx protected the astrocytes by activating camp-pka and inhibiting astrocyte apoptosis. down-regulating the trx gene inhibits the camp-pka pathway to cause apoptosis, exacerbating astrocyte damage caused by an oxygen-glucose deprivation/ reoxygenation in vitro. trx is necessary for the nerve growth factor (ngf) signalling through its camp responsive element to drive expression of c-fos, which has been hypothesised to be critical for the function of ngf. pka activity is inhibited by the hydrogen peroxide formed by insulin but activated by trx, which restores the newly formed -ss-bond of pka to the -sh group. we suggest that trx may also protect lung cells by acting on the camp-pka pathway in copd. regulating the nf-κb and mapk pathways trx suppresses the inflammatory response by regulating the nf-κb and mapk pathways. trx modulates nf-κb activity and plays different roles extracellularly and intracellularly. inhibiting the nuclear trx blocks the nuclear activities of nf-κb and ap- dependent transcription factors and reduces neutrophil invasion and tnf-α production. extracellular trx inhibits the production of p and p and promotes iκb synthesis by acting on cell membrane surface receptors to limit nf-κb activation and translocation into the nucleus, thereby blocking the nf-κb pathway. trx inhibits eotaxin-induced phosphorylation of extracellular signal-regulated kinase / and p by reducing the activation of erk / and p mapks. under normal conditions, trx binds to the n-terminal region of the apoptosis signal-regulating kinase (ask ). ask is a member of the mapk kinase family and elicits a wide variety of cellular responses to various types of stress by activating the jnk and p mapk pathways. under oxidative stress, trx separates from ask , activating ask . this indicates that trx acts as an upstream inhibitor of ask , and trx/ask signalling is an upstream modulator of p mapk. trx suppresses p mapk activation in the lps-stimulated neutrophils. in addition, ros exacerbates airway inflammation by activating inflammatory mediators and transcription factors, such as nf-κb, mapk and ap- . this suggests that trx regulates the p mapk pathway by removing ros. adjusting the pi k/akt signalling pathway the pi k/akt signalling pathway is a classic signalling channel that can be activated by various extracellular signals including growth factors, cytokines, and oxidative stress, and plays an important role in copd. trx inhibits the indomethacin-induced ros production and inhibits the expression of phosphorylated akt in rat gastric epithelial cells. in addition, trx deficiency reduces the expression of akt and pakt by no. the main activation signals of pi k/akt signalling are inhibited by trx, and downstream akt phosphorylation was also inhibited by trx. therefore, we suggest that trx likely plays an important role in the pi k/akt signalling pathway. improving glucocorticoid resistance copd is relatively resistant to modulation by corticosteroids; even high doses of glucocorticoid (gc) do not delay or inhibit copd progression. one mechanism of gc resistance is the impairment of gc sensitivity by the macrophage migration inhibitory factor (mif) via map kinase phosphatase- (mkp- ) inhibition. mif is part of a class of pleiotropic immunomodulatory factors with a unique structure that functions similar to chemokines and promotes inflammatory responses, directed cell migration, and release of other cellular inflammatory factors. mif may play a key role in the pathogenesis of airway inflammation. [ ] [ ] [ ] mif has at least two catalytic activities: tautomerase and oxidoreductase activities. the oxidoreductase activity of mif is closely related to the trx family. , - mkp- is an archetypal member of the dual specificity phosphatase family that inactivates the mapk activity in response to pro-inflammatory stimuli. - mkp- is induced by gc to mediate gc inhibition of erk, jnk and p mapk activities and cytokine production induced by proinflammatory stimuli such as lps or il- . [ ] [ ] [ ] it has recently been demonstrated that mif inhibits the gc-induced leucine zipper (gilz) expression via a unique set of effects on transcription factor expression and phosphorylation, and regulation by mif of mkp- and mapk activation are mediated through gilz (fig. ). fig. trx improves gc through mif. one gc resistance mechanism impaired by the mif is the loss of gc sensitivity via inhibition of mkp- . mkp- is induced by gc to mediate gc inhibition of erk, jnk and p mapk activities and cytokine production. mif inhibits gilz expression via a unique set of effects on transcription factor expression and phosphorylation. mkp- and mapk activation are regulated by mif via gilz. both intracellular and extracellular trx bind to mif and form a heterodimer to prevent the mif entry into cells and mif-induced glucocorticoid resistance fig. trx prevents and relieves copd pathogenesis through multiple molecular mechanisms. trx eliminates mif to improve glucocorticoid resistance and eliminates ros and inhibits neutrophil infiltration by regulating adhesion molecules to suppress the production of cytokines to reduce oxidative stress and inflammation. trx exerts its anti-oxidative and anti-inflammatory effects by regulating the nf-κb, mapk, pi k/akt and camp-pka pathways. trx also inhibits the airway neutrophil recruitment by down-regulating the expression of neutrophil l-selectin on circulating neutrophils. trx is subtle in regulating the balance between protease and antiprotease. trx has inhibitory effect on both, but it is asymmetric in its inhibition. trx has stronger inhibitory effects on over-generated proteases, thus maintaining the balance of the protease-antiprotease system. moreover, trx down-regulates the expression of egfr and tgf in the airway to reduce mucus secretion, airway remodelling and pulmonary fibrosis trx regulates mif expression levels and inhibits inflammation caused by mif. , in a mouse asthma model, transgenic overexpression of trx significantly reduced mif expression in the airway epithelial cells and reduced the number of mif-positive inflammatory cells in the lung parenchyma. trx inhibits mif production in human monocytes. mif has a specific affinity for trx; extracellular mif is internalised into cells exclusively by binding to trx on the cell membrane. exogenous trx and intracellular trx combine with mif to form a complex which affects the mif-induced inflammatory response. in addition, some studies have also demonstrated that trx directly bind to glucocorticoid receptor and enhance the cell's response to glucocorticoids. , although there are not the evidence showing the effect of trx on hdac , we suppose that trx may increase hdac activity by regulating cellular redox signalling, and we would like to prove this attractive hypothesis in our next studies. effects on the immune system trx has no inhibitory effect on the immune system while regulating inflammatory responses in various inflammation models. , , there is no significant difference in the population and differentiation of immune cells such as the mast cells, dendritic cells, and lymphocytes between trx overexpression and wt animals. oxidative stress promotes the th type immune response by inducing th cell apoptosis and th cell differentiation, breaking the th /th balance, and causing th airway inflammation. , after the ova challenge, il- expression in balf of trx-tg mice was significantly lower than that in wt mice, while serum levels of il- were comparable. this shows that trx inhibits local th cells to push the balance towards th and suppress local inflammation while having no effect on the th / th balance of the systemic immune system. bronchial ln (bln) cells isolated from the trx-tg mice produced an equal amount of th cytokines il- , il- and il- as the bln cells of wt mice after leaving the high trx environment. this shows that trx does not directly affect the th /th proliferation and differentiation, but rather inhibits inflammation by regulating the production and release of th /th cytokines. copd pathogenesis is mainly related to the overexpression of inflammatory mediators and cytokines, the activation of inflammatory signalling pathways, the protease/anti-protease imbalance, and the oxidation-antioxidation imbalance. these factors are interrelated and it is difficult to achieve the desired treatment results through a single target. owing to the overlapping function of molecular targeted inflammatory signals, the degree to which pathogenesis of copd can be prevented if only one pathway is inhibited remains unknown. at present, some drugs have been proven to be effective in animal tests; some are challenging to be used in clinical trials due to significant side effects while others continue to be in the hypothetical stage and have not been proven effective in treating copd. therefore, further studies of the functions and mechanisms of various target molecules are necessary, and their effectiveness 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effects of the p mapk inhibitor sb- on blood biomarkers of inflammation in copd patients efficacy and safety of the oral p inhibitor ph- in chronic obstructive pulmonary disease: a randomised clinical trial phosphoinositide -kinase delta (pi kδ) in leukocyte signaling and function emerging pharmaceutical therapies for copd present status and tasks for future of point of care testing il- induces translocation of nf-kappab in cultured human bronchial smooth muscle cells we deeply appreciate prof. takashi inamoto for pointed advice and discussion for writing up this paper. competing interests: the authors declare no competing interests. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons. org/licenses/by/ . /. key: cord- -ouvn r authors: chow, michael y.t.; qiu, yingshan; lam, jenny k.w. title: inhaled rna therapy: from promise to reality date: - - journal: trends pharmacol sci doi: . /j.tips. . . sha: doc_id: cord_uid: ouvn r rna-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. the largest obstacle in its clinical translation remains identifying a safe and effective delivery system. studies investigating rna therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of rna therapeutics to the target site of action while minimizing systemic exposure. in this review, we highlight recent developments in pulmonary rna delivery systems with the use of nonviral vectors. we also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside. michael y.t. chow, , , yingshan qiu, , and jenny k.w. lam , * rna-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. the largest obstacle in its clinical translation remains identifying a safe and effective delivery system. studies investigating rna therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of rna therapeutics to the target site of action while minimizing systemic exposure. in this review, we highlight recent developments in pulmonary rna delivery systems with the use of nonviral vectors. we also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside. the diverse roles of rna in the body have led to the emergence of different approaches to harnessing rna for therapeutic use. rna therapeutics can be broadly divided into three functional classes: (i) inhibition of gene expression [e.g., small interfering rna (sirna; see glossary), microrna (mirna), and antisense oligonucleotide (aso)]; (ii) protein encoding (e.g., mrna); and (iii) protein targeting (e.g., rna aptamers) [ ] . despite their diverse mechanisms of action, it is no secret that the biggest barrier to all types of rna therapeutic is delivery; that is, to bring therapeutic rna molecules into the target cells effectively in a safe and reproducible manner. with the us food and drug administration (fda) approval of the first two sirna therapeutics, patisiran and givosiran, both of which target hepatic disorders, the field of rna therapy is ready to look for applications beyond the liver [ , ] . there is an increasing number of studies that report the potential of rna in treating a range of lung diseases including asthma [ ] , cystic fibrosis (cf) [ ] , lung cancer [ ] , and respiratory infections [ ] . inhalation of aerosol is an efficient way to deliver rna to the lung by maximizing local concentration while minimizing systemic exposure. aln-rsv , designed to treat respiratory syncytial virus (rsv) infection, was the first sirna candidate to be delivered through the pulmonary route in clinical trials in [ , ] . since then, several clinical trials on inhaled rna therapy have been initiated (box ). however, no inhaled rna therapeutic has yet been approved for use in clinics. naked rna for inhalation rna is a negatively charged, hydrophilic macromolecule that is incapable of permeating the cell membrane. it is vulnerable to degradation before reaching the target sites due to the abundance of rnase in the body. therefore, it has to rely on delivery vectors to protect it from premature degradation and facilitate its cell entry. interestingly, it has been known for over a decade that naked rna, including both sirna and mrna, can be transfected in the lung following pulmonary delivery, as shown in many in vivo studies [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . given that the lung comprises various cell types with distinct functions, it is crucial to understand which cell types are susceptible to naked rna transfection for effective clinical translation. to address this issue, ng et al. carried out a comprehensive investigation on the distribution and activity of naked sirna in the lung of mice following intratracheal administration [ ] . the silencing activity of naked sirna was most prominent in lung epithelial cells, dendritic cells, and alveolar macrophages. similar observations were reported by other groups in which the activity of naked sirna was primarily found in lung epithelial cells but not the endothelial cells [ ] , making it attractive for use in lung conditions affecting these cell types without systemic exposure, for example in rsv infection and cf. ng et al. stressed that chemical modification is crucial for naked sirna to induce effective gene silencing by improving metabolic stability and reducing immunostimulation [ ] . using modified naked mrna, tiwari et al. successfully developed a mrna-based approach to express neutralizing antibodies in the lung via intratracheal delivery to prevent rsv infection in mice [ ] . the authors also compared naked mrna with the use of polyethyleneimine (pei, a synthetic cationic polymer discussed later) derivatives as delivery vectors and noticed that the transfection efficiency of naked mrna was either better than, or comparable to, these polymers. despite the promising effect of pulmonary naked rna delivery, the exact mechanism of how naked rna crosses the cell membrane barrier in the lung remains unclear, although it has been suggested that the pulmonary surfactant has a significant role in facilitating rna uptake [ , ] . some studies also showed that the use of delivery vectors could significantly improve rna transfection compared with naked rna in the airways [ ] [ ] [ ] [ ] [ ] . the development of safe and effective inhaled delivery systems in parallel is paramount currently. with the recent success of sirna in the clinic and the intensive investigation of mrna in clinical trials, including mrna vaccines against coronavirus disease (covid- ) [ , ] , we believe that these two rna candidates are likely to be the first to enter the clinic for treating lung diseases. therefore, in this review, we focus on the pulmonary delivery of sirna and mrna. we glossary aerosol: suspension of solid particles or liquid droplets in gas. in humans, drug delivery via the pulmonary route has to be administered in the form of an aerosol. antisense oligonucleotide (aso): short single-stranded dna or rna (~ nucleotides in length) that binds to a target mrna through complementary base pairing, activating rnase h that leads to degradation of mrna, thereby preventing the translation of mrna into protein. cell-penetrating peptide (cpp): short cationic or amphipathic, natural or synthetic peptide (usually < amino acids) that is developed to deliver large cargoes, such as proteins, peptides, and nucleic acids, into cells by promoting cellular uptake. chemical modification: strategy to improve the stability and/or reduce immunogenicity of rna by modifying the structure of rna while maintaining the biological activity of the molecules (e.g., methylation of the ribose '-oh group; alteration of the bases; modification of phosphodiester backbone, etc.). intratracheal administration: introduction of substances directly into the trachea, either through the oral cavity via intubation or through a surgical procedure that creates an incision in the trachea (tracheotomy). microrna (mirna): a short rna (~ - nucleotides in length) that is partially complementary to multiple messenger rna (mrna), preventing the translation of mrna into protein through the rna interference mechanism. mrna vaccine: mrna that encodes the target antigen to elicit immune responses in the body. naked rna: rna that is not associated with any delivery vectors or transfection agents, such as polymers and lipids. nebulization: conversion of liquid medications into a spray of fine droplets that can be breathed in by the patient. nonviral vector: agent or vehicle that transports nucleic acids into the cells without involving the use of viruses. parenteral: nonoral route of drug administration; usually refers to injection or infusion of drug directly into the body, bypassing the skin and mucous membranes. rna aptamer: singled-stranded rna oligonucleotide that serves as ligand and binds to specific targets (e.g., proteins aln-rsv is a naked sirna targeting the rsv nucleocapsid protein for the treatment of the associated viral respiratory infection. it was the first sirna investigated for pulmonary delivery in clinical trials. rsv causes significant illness in immunocompromised patients following lung transplantation, and bronchiolitis obliterans syndrome (bos) is the major cause of morbidity and mortality in these patients [ ] . the phase i clinical trial (nct ) started in and demonstrated that aln-rsv was well tolerated following intranasal administration. the phase iib clinical trial (nct ) showed that aerosolized aln-rsv was effective in reducing the incidence of new or progressive bos in lung transplant patients with rsv infection following inhalation. although aln-rsv failed to progress to a phase iii trial, it marked an important milestone of inhaled rna therapy [ , [ ] [ ] [ ] . excellair is an sirna targeting spleen tyrosine kinase (syk), which is involved in the inflammatory response in the lung epithelium [ ] . it was investigated for the treatment of asthma by inhalation. the phase i trial began in . there was little information published about the outcome of the study, although it was reported that the drug was well tolerated in patients with asthma. the phase ii trial was discontinued in [ ] . eluforsen is a single-stranded rna aso targeting cf transmembrane conductance regulator (cftr) for inhalation to patients with f del cf. the phase i clinical trial (nct ) initiated in showed that cftr activity was restored after intranasal administration of eluforsen. the phase ib clinical trial (nct ) was completed in and demonstrated that inhaled eluforsen was safe, well tolerated, and improved respiratory symptoms in patients with f del cf [ , ] . however, no further clinical development is planned for this candidate. mrt is the first inhaled mrna candidate for cf and delivers mrna encoding fully functional cftr protein. the phase i/ii clinical trial was initiated in may to test the safety and tolerability of mrt . patients with cf received mrna encoding fully function cftr protein through nebulization. interim results were encouraging, showing that mrt was well tolerated at low and mid-dose levels ( - mg) with no serious adverse events reported at any dose level (up to mg). there was a marked improvement of lung function in patients after single dose of mrt at the middose level ii . in early , the fda granted fast track and rare pediatric disease designations for mrt for the treatment of cf iii,iv . discuss and highlight the recent advances of nonviral vector-based pulmonary rna delivery systems development, gather what we have learnt from these studies, and identify the major gaps of knowledge. with these, we provide insights and direction to move the field forward. many rna delivery vectors have been developed for pulmonary delivery and their major functions are to facilitate the uptake of rna by target cells and to protect rna from premature degradation. selected recent studies with different rna delivery vectors that have demonstrated in vivo transfection in animal models are summarized in table . we highlight some important studies in each category and discuss them in more detail herein. lipid-based delivery systems due to their high transfection efficiency, ease of synthesis, and low batch variability, lipids were popular as transfection agents during the early years of gene therapy studies for various routes of administration [ , ] . the transfection efficiency and toxicity of lipid-based systems are affected by the composition of lipids and the ratio of lipids to rna. typically, cationic lipids, such as n-[ -( , -dioleyloxy)propyl]-n,n,n-trimethylammonium chloride (dotma) and , -dioleoyl- -trimethylammonium-propane chloride salt (dotap), are used to form lipoplexes with, or encapsulate, rna [ ] . the addition of neutral helper lipids, such as dioleoyl phosphatidylethanolamine (dope) and cholesterol, in the lipoplexes provide the ability to facilitate rna complexation, increase stability of the lipoplexes, and reduce toxicity [ , ] . one major problem associated with lipid-based systems for pulmonary delivery is their poor structural stability because they readily fuse with pulmonary surfactants in the airways [ ] , leading to premature release of rna before cellular uptake. lipid nanoparticles (lnps), which comprise cationic lipids, cholesterol, and polyethylene glycol (peg), have been developed to improve the structural stability of lipid-based systems [ , ] (table ) . with proper design and engineering, they can encapsulate rna efficiently. lnps are already in use in the clinic for parenteral injection of sirna [ ] and also are in an ongoing clinical trial to deliver mrna (mrt ) to the lung through nebulization for the treatment of cf, with encouraging early results (box ). there are two main categories of polymers: natural and synthetic polymers. natural polymers have the advantages of excellent biocompatibility, biodegradability, and safety profiles [ ] . derived from the shells of crustaceans, the natural polymer chitosan is commonly investigated for pulmonary delivery due to its mucoadhesive and mucopermeable properties, enabling it to cross the mucus layer in the airways efficiently [ ] . it can be used to form polyplexes with rna or as a coating layer on the surface of nanoparticles [ , ] (table ) . however, chitosan is limited by its poor solubility at physiological ph and relatively low transfection efficiency [ ] . to overcome these problems, water-soluble chitosan derivatives, such as piperazine-substituted chitosan, were developed and found to be efficient for pulmonary sirna delivery in healthy mice [ ] (table ) . furthermore, inhalable chitosan/sirna dry powder formulations were successfully prepared by supercritical drying [ ] and spray-freeze drying [ ] (table ) . both studies demonstrated a gene-silencing effect of the powder formulations in lung tissues following intratracheal administration in mouse models of lung cancer, taking these delivery systems one step closer to clinical application. among the synthetic polymers, pei is extensively studied due to its high cationic charge density, good aqueous solubility, and wide ph-buffering capacity [ ] . its high versatility allows it to be functionalized to achieve specific targeting. for example, transferrin-pei was used to target activated t cells in the lung, particularly t helper cells, as potential therapy for asthma by reducing and nucleotides) with high affinity and specificity. small interfering rna (sirna): short double-stranded rna (~ - nucleotides in length with two 'overhang nucleotides) in which the antisense strand binds to the target mrna through complementary base pairing, preventing the translation of mrna into protein via rnai. transfection: a process of introducing nucleic acids into cells artificially. (table ) . however, the relatively high toxicity of this nonbiodegradable polymer remains a considerable concern, even with a low-molecular-weight pei, rendering it difficult to be translated for clinical application. thus, biodegradable synthetic polymers were developed to address this issue. for example, in a recent study, hyperbranched poly(beta amino esters) (hpbaes) [ ] were used to deliver mrna through nebulization, with promising gene expression observed in the lung epithelium of mice without local or systemic toxicity after repeated dosing (table ) . to enhance rna delivery efficiency for lung cancer therapy, yan et al. used a combinatorial library of functional polyester and high-throughput screening to identify matching cancer cells for specific targeting [ , ] (table ) . after screening a library of > polyester candidates, synthetic amine a modified polyester pe k-a was found to be potent for sirna delivery to mice with lung tumors [ ] (table ) . cell-penetrating peptides (cpps) have attracted increasing attention for rna delivery due to their versatility and cell entry ability [ ] . the design of peptide sequence can be inspired by natural peptides, proteins with known functions, or by computational simulation [ , ] . the sequence of amino acids determines the properties of peptides, such as structure, charges, solubility, and polarity, which further affect the interaction with rna, cellular uptake, toxicity, and transfection efficiency. one of the drawbacks of cpps is the lack of cell specificity, which can be addressed by introducing cell-targeting sequences [ ] . furthermore, natural l-amino acids are susceptible to protease degradation; although strategies such as replacing l-amino acids with d-analogs has been proposed, this approach may lower the efficiency of the peptides [ ] . although many cpps appeared to be promising candidates for delivering rna to the lung, only a few have shown in vivo transfection. welch et al. developed disulfide-constrained cyclic amphipathic peptides that form complexes with sirna with good transfection efficiency because the disulfide bond reduction in the cytosol facilitated the release of the cargo as well as proteolytic clearance. efficient gene knockdown was also observed in lung tissues of healthy mice following pulmonary delivery [ ] ( [ , ] . the pegylated kl peptide was also used to formulate mrna as inhalable dry powder by spray-drying and spray-freeze drying techniques, with efficient gene expression observed in the lung of healthy mice [ ] (table ) . to overcome the limitations of a single class of delivery vector, hybrid delivery systems, which are defined as the combination of two or more delivery vectors into a single entity, have been investigated and developed. this formulation strategy aims to increase the strengths of these delivery vectors while decreasing their disadvantages, with lower toxicity compared with their precursors [ ] . the combination of lipids with polymers intends to address the problems of poor structural stability associated with lipids and the low biocompatibility of polymers. thanki et al. developed lipid-polymer nanoparticles (lpns) comprising a poly(lactic-co-glycolic acid) (plga) matrix core coated with lipidoid, with sirna localized in both the core and the shell [ ] . this design compensated the low sirna-loading capacity of plga by introducing cationic lipidoids while controlling the rate of sirna release through degradation of the polymer. enhanced lung retention upon pulmonary administration of the sirna-loaded lpns was observed in animal studies, suggesting their potential for controlled sirna delivery in the lung (table ) (table ). this hybrid system demonstrated effective gene silencing in animal models of pulmonary fibrosis with good stability and low toxicity. another common hybrid strategy is to combine lipids with peptides, with the latter serve as a hydrophilic group and facilitate cellular uptake and transportation. for example, cationic liposomes comprising dotma/dope were blended with epithelial-targeting peptides to deliver sirna to the lung of healthy mice, leading to successful silencing of the epithelial sodium channel at the airway epithelium [ , ] (table ). the results demonstrated the potential application of this hybrid system for cf therapy. similar to lipid-peptide hybrids, the major aim of combining polymers with peptides is to enhance the cellular transport efficiency. polymers are usually conjugated covalently with the peptides. feldmann et al. developed a polymer system called viper (virus-mediated polymer for endosomal escape), which comprised a cationic methacrylated-based copolymer for sirna binding and a membrane lytic peptide melittin, to facilitate endosomal escape [ ] ( table ). the hybrid system demonstrated more effective gene-silencing effects in the lung of healthy mice compared with the unmodified polymer system. guan et al. developed a multimodular synthetic peptide with anchor, cationic, and targeting moieties that can form complexes with biocompatible poloxamine-based copolymers and mrna via self-assembly [ ] (table ) . these ternary complexes showed excellent mrna expression in the lungs of mice with cf with negligible toxicity, making them an attractive gene delivery system for cf and other lung diseases. functionalized nanoparticles in addition to the aforementioned conventional delivery vectors, inorganic metal-based nanoparticles have also been evaluated for the pulmonary delivery of rna. however, these nanoparticles cannot act as transfection vectors by themselves due to their lack of rna-binding ability. therefore, they are usually functionalized on the surface to enhance the transfection efficiency. for example, gold nanoparticles are attractive delivery vectors because of their ease of synthesis and conjugation as well as their superior stability [ ] . gold nanoparticles were conjugated with sirna through gold-thiol bonds and functionalized with m pep, a peptide that selectively targets tumor associated macrophages [ ] (table ) . specific gene-silencing effects were observed in targeted macrophages following intratracheal administration in a mouse lung tumor model. it has been suggested that pulmonary surfactant facilitates the delivery of polymer-based delivery systems in the lung [ ] . to take advantage of this phenomenon, pulmonary surfactant and surfactant protein b-coated dextran-based nanoparticles were developed for sirna delivery, with successful gene-silencing effects observed in healthy mice and in a model of acute lung injury (ali), respectively, following pulmonary administration [ , ] (table ) . exosomes are extracellular vesicles secreted in many cell types. they are involved in communication through the transfer of substances, such as lipids, proteins, and nucleic acids, between cells [ , ] . they have many desirable features for rna delivery, including high biocompatibility with low inherent toxicity and immunogenicity [ ] . zhang et al. presented a new approach to delivering small rna to the lung with the use of exosomes. sirna was loaded into serum-derived exosomes via calcium-mediated transfection. following intratracheal administration, the sirnaloaded exosomes were successfully taken up by lung macrophages to achieve specific gene silencing in a mouse model of ali [ ] (table ) . we carried out a survey of studies published between and early that reported sirna or mrna transfection following pulmonary delivery in animals ( figure ) . a pubmed search was performed using the search terms 'sirna' or 'mrna', 'pulmonary delivery', 'intratracheal', 'inhalation', 'nebulization', and with the filters 'last years' (publication date) and 'other animals' (species) . in total, articles were included in the survey [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . each article was categorized manually according to the type of rna delivery vector used or naked rna; the animal model (disease or healthy); the method of administration to animal; and the type of rna (sirna or mrna). while polymer was the most commonly used rna delivery vector due to its high versatility and ease of preparation, the hybrid delivery system is gaining popularity, many of which include a targeting peptide to improve specificity. with the successful transfection of naked rna in the lung and the technological advances in chemical modifications that greatly enhance the stability and reduce the immune activation of rna [ , ] , many researchers opt for the use of naked rna to transfect lung tissues due to its simplicity ( figure a ). this approach can also eliminate the risk of toxicity and immunogenicity associated with the delivery vectors. it is particularly popular when researchers are interested in examining the biological function of a particular protein rather than its therapeutic potential, such as the role of yes-associated protein (yap), ribosomal protein s (rps ), and pi k/sgk pathway in ali [ , , ] . nevertheless, the successful use of naked rna should not lead us to discard the use of delivery vectors for clinical applications. the transfection efficiency of naked rna may not be robust enough for therapeutic use. also, as mentioned earlier, the cellular uptake mechanism of naked rna in the airways is still unclear. it has been speculated that lung lining fluid and pulmonary surfactants have a critical role in facilitating the transportation of rna into cells [ ] . the composition of lining fluids could vary substantially among patients and pathological conditions. indeed, it has already been observed that pulmonary surfactant protein and lipid composition change significantly as a result of aging [ ] . lung diseases, such as cf, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease (copd), are also associated with surfactant deficiency and altered lipid compositions [ ] [ ] [ ] . consequently, the transfection efficiency of naked rna could be easily influenced by the age and disease status of the patients, leading to problems of reproducibility. moreover, naked rna lacks active targeting ability. given that the lung tissues contain a variety of cell types, it would be desirable to use a delivery vector with a targeting moiety to enhance specificity while reducing transfection in unintended cell types. the potential of rna therapeutics to treat a range of lung diseases prompts us to examine the possibility of developing a universal delivery platform that can be adopted by different rna therapeutics for different conditions. while such a system would accelerate the clinical translation of inhaled rna therapy, delivery barriers could be unique to a specific physiological condition. in that case, it would be more effective to have a carefully designed system to overcome these specific sets of barriers. for example, patients with cf have thick and excessive mucus in the airway; hence, a delivery vector with excellent mucus penetration ability would be favorable. moreover, in preclinical studies, healthy animals are sometimes used to evaluate the efficiency of a delivery vector, with the use of reporter or housekeeping genes as the rna target ( figure b) . this approach may run into a similar problem in that a delivery vector may perform differently in a healthy animal versus a disease model due to the different delivery barriers in the airways. furthermore, a non-disease rna target (which is generally used to evaluate the efficiency of a delivery vector) does not provide any information regarding the pharmacodynamics properties of the proposed therapy. even if a disease model is used, there is still the challenge of the clinical translation because many lung disease models have limitations that prevent their direct translation to human disease [ ] [ ] [ ] [ ] . for instance, asthma is a complex condition that is observed exclusively in humans. the most common model used in preclinical studies is murine allergic airway inflammation. however, the distribution of lung inflammation in mice is different from human asthma, and the animals develop tolerance after repeated allergen exposure [ ] . therefore, a collaborative approach between formulation scientists, pharmacologists and clinicians will facilitate the development of a clinically relevant delivery system for inhaled rna therapy. many studies have focused on the development of rna delivery vectors, but the translation of these vectors into suitable dosage forms for clinical application is currently lacking. here, we summarize the critical steps for the development of successful pulmonary rna delivery system ( figure , key figure) and discuss the areas/factors that should be focused on. in general, it is desirable to use delivery vectors that exhibit cell-targeting properties with the ability to overcome the specific barriers associated with the disease concerned. delivery vectors that are nonbiodegradable or with a low rna-loading capability would be less attractive. a thorough understanding of the excretion pathway is required to ensure that the delivery vectors would not accumulate in the body, especially when synthetic or nonbiodegradable materials are used. vectors with high loading capacity could avoid the use of excessive excipients, thereby minimizing the risk of toxicity. moreover, to evaluate the in vivo efficacy of the delivery system, rna is often administered intratracheally to the lung of animals either as large droplets instilled by pipette or as a fine spray aerosolized by a microsprayer or similar device ( figure c ). clearly, these administration methods are impractical for human use. for clinical practice, rna drugs can be delivered either as liquid aerosols through nebulization or as dry powder for inhalation ( figure ). while the former can deliver high doses of liquid formulations over a period of time (typically~ - min, depending on the dose), the latter is more portable and convenient to use. however, there are stringent requirements for particles to be suitable for inhalation in clinical settings and animal studies cannot reflect the 'inhalability' of a formulation. surprisingly, only a few studies have evaluated the aerosol performance of rna formulations designed for inhalation [ , , ] (box ). a good understanding of the aerosol properties of the formulation could boost the chance of successful clinical translation ( figure ). moreover, nebulizers or dry powder inhalers are needed to generate aerosol for inhalation. given that both devices could damage the fragile rna molecules (especially single-stranded mrna) due to the high shear stress during aerosolization, it is essential to examine the rna integrity, in terms of physical structure and biological activity, in the aerosolized particles ( figure ). it is unclear whether the rna dose is optimized in in vivo preclinical studies because the doseresponse relationship of rna following pulmonary delivery is often not reported. dose trends optimization is critical for clinical translation not only for maximizing the therapeutic efficacy, but also for the practicality of administration. the amount of excipient (which may be included in the formulation to improve stability or to enhance aerosol performance) needs to be considered carefully because this can also affect the final liquid volume or powder mass to be administered. when rna is delivered through nebulization, a high dose would increase the volume and, hence, the administration time, leading to the increased risk of rna degradation due to prolonged exertion of shear stress on the rna molecules. for dry powder formulations, there is a constraint on the amount of powder that could be inhaled by a patient each time. currently, tobi® podhaler® (tobramycin inhalation powder) approved for treating pseudomonas aeruginosa infection in patients with cf, has the highest inhaled dose of~ mg per actuation [ ] . the rna dose has to be taken into consideration during the development of an effective delivery system that is fit for purpose. another area that requires attention during development of a pulmonary rna delivery system is understanding the biodistribution and pharmacokinetic profile of the inhaled rna formulation ( figure ). many studies focus on the evaluation of gene expression in the lung tissues as a whole. while naked rna is shown to manipulate gene expression primarily in the lung epithelial cells and macrophages [ ] , the sites where nanoparticulate rna delivery vectors exert their biological activity are less clear. for delivery vectors that rely on nonspecific cellular uptake mechanisms, rna could be effectively taken up by various cell types and absorbed into the systemic circulation. therefore, it is critical that biodistribution as well as pharmacokinetic profiles are thoroughly investigated. furthermore, the long-term toxicity of the delivery system also needs to be carefully evaluated. rna therapeutics have great potential in lung diseases. here, we have discussed nonviral delivery systems developed for sirna and mrna therapeutics in the lung and briefly summarized the what is the exact cellular uptake mechanism of naked rna in the airways? what are the factors governing its uptake? what are the delivery barriers to different rna delivery systems in different respiratory diseases? is it possible to have a universal pulmonary delivery platform that can be used to deliver different types of rna therapeutics? how can we protect the integrity of rna molecules against shear and thermal stresses effectively during the aerosolization and drying process? how do we improve the translation of inhaled rna therapy from animal studies to clinical applications? the most important factor that affects the aerosol performance of an inhaled formulation is particle size, which is most suitably expressed in aerodynamic diameter. aerodynamic diameter is defined as the diameter of a sphere of density g/cm that has the same settling velocity in still air as the particle of interest. it is generally accepted that particles with aerodynamic diameter between and μm are optimal for lung deposition [ ] . larger particles tend to deposit at the back of the throat and get swallowed subsequently, whereas smaller particles are likely to be exhaled. this criterion applies to both liquid and powder aerosol [ ] . the aerodynamic particle size distribution of an aerosol is often described in terms of mass median aerodynamic diameter (mmad) and geometric standard deviation (gsd) [ ] . the method of choice for measuring particle size distribution of inhaled products is the cascade impactor (ci), which operates on the principle of inertia impaction [ ] . ci comprises multiple stages and separates particles according to their aerodynamic diameters. large particles with high inertia are unable to follow the airstream and impact on earlier stages, whereas small particles remain in the airstream and flow to the next stage, where the process is repeated. the two parameters commonly reported from ci are emitted dose and fine particle dose. the former refers to the total dose that has exited the dispersion device, while the latter represents the amount of aerosol with an aerodynamic diameter below a certain threshold (typically μm) [ ] . these can also be expressed in fractions relative to the loaded dose or recovered dose. an important feature with the use of ci for measuring particle size is that a dispersion device (a nebulizer for liquid dosage forms or a dry powder inhaler for solid dosage forms) needs to be connected to generate the aerosol [ ] . given that the choice of device can have a dramatic impact on the aerosol properties of formulations, it is crucial to identify a suitable device to maximize the aerosol performance of a given formulation. there are different designs of ci, but only three are currently listed in both european pharmacopoeia and united states pharmacopoeia: the andersen cascade impactor (aci), the next generation impactor (ngi), and the multi-stage liquid impinger (msli) [ ] . current preclinical and clinical state of the field. currently, it appears that the development of mrna therapeutics is lagging behind that of sirna therapeutics ( figure d ), possibly because of the relatively poor stability of the long single-stranded rna molecule. with technological advances in rna modification that improve the stability, specificity, and safety of rna therapeutics [ , ] and the recent success of sirna therapeutics, we believe that both sirna and mrna will enter the clinic for the treatment of respiratory diseases in the near future. however, some crucial questions remain to be addressed before a successful rna inhalation delivery system can be realized (see outstanding questions). in light of the current covid- pandemic, development of an inhaled version of mrna vaccine is an area that deserves more attention. currently, there are several clinical studies (clinical trial no i .-nct ; nct ; nct ; nct ; and nct ) that demonstrate the safety and efficacy of mrna vaccines for the treatment of and protection against lung cancer and influenza, respectively [ , ] . mrna vaccines for covid- are being explored in several different clinical trials (clinical trial no.: nct ; nct ; nct ; nct ; nct ; nct ; and nct ). these mrna vaccine candidates are designed to be administered through parenteral injection. if any of these are successful, we believe that an inhaled version of the successful mrna vaccine will be an area to explore because it will provide a non-invasive route of administration with the possibility of self-administration, especially dry powder formulations, which show superior stability. the challenges of manufacture and scale-up, including the production of rna, delivery vectors, and the loading of rna into the vectors without losing their physicochemical properties and biological activities, also need to be overcome. overall, a safe and efficient rna delivery system to the lung remains the key to successful clinical translation. rna therapies explained gene-silencing technology gets first drug approval after -year wait givosiran: first approval t-cell targeted pulmonary sirna delivery for the treatment of asthma new approaches to genetic therapies for cystic fibrosis overcoming multiple drug resistance in lung cancer using sirna targeted therapy advancements in nucleic acid based therapeutics against respiratory viral infections aln-rsv for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients rna interference therapy in lung transplant patients infected with respiratory syncytial virus intratracheal administration of small interfering rna targeting fas reduces lung ischemiareperfusion injury mrna-mediated gene supplementation of toll-like receptors as treatment strategy for asthma in vivo ribosomal protein s gene silencing protects against experimental allergic asthma insulin ameliorates pulmonary edema through the upregulation of epithelial sodium channel via the pi k/sgk pathway in mice with lipopolysaccharide induced lung injury yes-associated protein (yap) signaling regulates lipopolysaccharide-induced tissue factor expression in human endothelial cells duox mediates persistent epithelial egfr activation, mucous cell metaplasia, and airway remodeling during allergic asthma small interfering rna targeting nf-kappab attenuates lipopolysaccharide-induced acute lung injury in rats fluorescence-and computed tomography for assessing the biodistribution of sirna after intratracheal application in mice ribosomal protein s gene silencing protects against cigarette smoke-induced acute lung injury engineered mrna-expressed antibodies prevent respiratory syncytial virus infection herpes virus entry mediator (hvem) expression promotes inflammation/organ injury in response to experimental indirect-acute lung injury intratracheal administration of sirna triggers mrna silencing in the lung to modulate t cell immune response and lung inflammation establishment of an evaluation method for gene silencing by serial pulmonary administration of sirna and pdna powders: naked sirna inhalation powder suppresses luciferase gene expression in the lung blockade of endothelial, but not epithelial, cell expression of pd-l following severe shock attenuates the development of indirect acute lung injury in mice expression of therapeutic proteins after delivery of chemically modified mrna in mice from pulmonary surfactant, synthetic kl peptide as effective sirna delivery vector for pulmonary delivery nanocarrier lipid composition modulates the impact of pulmonary surfactant protein b (sp-b) on cellular delivery of sirna aerosol delivery of stabilized polyester-sirna nanoparticles to silence gene expression in orthotopic lung tumors functional delivery of sirna by disulfide-constrained cyclic amphipathic peptides hybrid pulmonary surfactant-coated nanogels mediate efficient in vivo delivery of sirna to murine alveolar macrophages targeted delivery of chil /chil sirna to alveolar macrophages using ternary complexes composed of hmg and oligoarginine micelles effective mrna pulmonary delivery by dry powder formulation of pegylated synthetic kl peptide tailoring mrna vaccine to balance innate/adaptive immune response an mrna vaccine against sars-cov- -preliminary report non-viral gene therapy: gains and challenges of non-invasive administration methods lipid nanoparticle systems for enabling gene therapies combinatorial treatment of idiopathic pulmonary fibrosis using nanoparticles with prostaglandin e and sirna(s) small interfering rna from the lab discovery to patients' recovery intratumoral delivery and therapeutic efficacy of nanoparticle-encapsulated anti-tumor sirna following intrapulmonary administration for potential treatment of lung cancer the lord of the lungs: the essential role of pulmonary surfactant upon inhalation of nanoparticles expression kinetics of nucleosidemodified mrna delivered in lipid nanoparticles to mice by various routes lipid nanoparticles enabling gene therapies: from concepts to clinical utility natural polysaccharides for sirna delivery: nanocarriers based on chitosan, hyaluronic acid, and their derivatives chitosan-based nanomaterials for drug delivery chitosan-based sirna delivery systems chemically modified hcftr mrnas recuperate lung function in a mouse model of cystic fibrosis water-soluble substituted chitosan derivatives as technology platform for inhalation delivery of sirna histological quantification of gene silencing by intratracheal administration of dry powdered small-interfering rna/chitosan complexes in the murine lung intratracheal administration of sirna dry powder targeting vascular endothelial growth factor inhibits lung tumor growth in mice polyethylenimine: a versatile, multifunctional non-viral vector for nucleic acid delivery targeted delivery of sirna to activated t cells via transferrin-polyethylenimine (tf-pei) as a potential therapy of asthma development of spray-freeze-dried sirna/pei powder for inhalation with high aerosol performance and strong pulmonary gene silencing activity inhaled nanoformulated mrna polyplexes for protein production in lung epithelium functional polyesters enable selective sirna delivery to lung cancer over matched normal cells versatility of cell-penetrating peptides for intracellular delivery of sirna cell penetrating peptides: the potent multicargo intracellular carriers recent advances in cell penetrating peptide-based anticancer therapies cancer targeting peptides cell-penetrating peptides: design strategies beyond primary structure and amphipathicity non-viral transfection vectors: are 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obstructive and restrictive respiratory diseases antisense oligonucleotide eluforsen improves cftr function in f del cystic fibrosis antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in f del cystic fibrosis pulmonary delivery of therapeutic sirna pulmonary drug delivery. part i: physiological factors affecting therapeutic effectiveness of aerosolized medications pulmonary drug delivery measurement of aerodynamic particle size distribution of orally inhaled products by cascade impactor: how to let the product specification drive the quality requirements of the cascade impactor key: cord- -v crgj w authors: pastores, stephen m.; dulu, alina o.; desouza, shilpa a. title: what has been learned from postmortem studies? date: - - journal: pulmonary involvement in patients with hematological malignancies doi: . / - - - - _ sha: doc_id: cord_uid: v crgj w infectious and noninfectious pulmonary diseases are commonly found on postmortem autopsy studies in patients with hematological malignancy. despite the technological advances in diagnostic testing and imaging modalities, obtaining an accurate clinical diagnosis remains difficult and often not possible until autopsy. major diagnostic discrepancies between clinical premortem diagnoses and postmortem autopsy findings have been reported in these patients. the most common missed diagnoses are due to opportunistic infections and cardiopulmonary complications. these findings underscore the importance of enhanced surveillance, monitoring and treatment of infections and cardiopulmonary disorders in these patients. autopsies remain important in determining an accurate cause of death and for improved understanding of diagnostic deficiencies, as well as for medical education and quality assurance. infectious and noninfectious pulmonary complications occur in - % of patients with hematological malignancy and recipients of hematopoietic stem cell transplantation (hsct) and are associated with signifi cant morbidity and mortality [ ] . in allogeneic hsct patients who develop respiratory failure requiring mechanical ventilation, the intensive care unit (icu) and hospital mortality rates often exceed % and %, respectively [ ] [ ] [ ] [ ] . the factors that contribute to the development of pulmonary complications in these patients include immunologic defects due to the underlying disease and its treatment, conditioning regimens, development of graft-versus-host disease (gvhd), and the type of hsct [ , , ] . the spectrum of pulmonary complications in patients with hematological malignancy and hsct recipients is changing because of recent advances in antineoplastic therapies, such as the use of monoclonal antibodies and other targeted agents, increased application of hsct for older patients, widespread use of prophylactic antibiotics and novel antimicrobial agents, and advances in supportive care [ ] . prompt investigation and diagnosis of pulmonary complications in patients with hematological malignancies are essential to improving patient survival. unfortunately, despite the technological advances in diagnostic testing and imaging modalities, obtaining an accurate clinical diagnosis in these patients remains difficult and at times is made only at the time of the postmortem autopsy examination. autopsy rates in cancer patients are much lower ( - %) as compared to general medical and surgical patients ( - %) [ ] [ ] [ ] . this probably reflects the unwillingness on the part of physicians and family members to subject the cancer patient to the same level of scrutiny applied to other major illnesses in determining the primary and contributory causes of death [ ] . additional concerns include legal issues regarding exposition of physicians' errors and non-reimbursement for postmortem examinations [ ] . this chapter will review the infectious and noninfectious pulmonary findings that have been described at autopsy in patients with hematological malignancies, including blood and bone marrow transplant recipients. in addition, we discuss the frequently noted diagnostic discrepancies between premortem clinical diagnoses and postmortem autopsy findings in these patients. finally, we highlight the difficulties in diagnosing many of these conditions antemortem and emphasize the important role of the postmortem examination in accurately establishing the cause of death. table . lists the infectious and non-infectious pulmonary disorders reported in autopsy studies of patients with hematologic malignancy, including hsct recipients. the incidence of invasive fungal infections in patients with hematologic malignancies has increased steadily over the past three decades [ ] . this has been attributed to improvements in the prevention or preemptive treatment of bacterial infections and other opportunistic pathogens, particularly candida and cytomegalovirus; increased administration of chemotherapies with profound and prolonged immunosuppressive effects on t-cell function (e.g., purine nucleoside analogs, anti-t-cell immunoglobulin, and monoclonal antibodies); and the growing number of allogeneic and nonmyeloablative transplantation procedures that carry a higher risk for chronic gvhd [ ] . patients with hematologic malignancies, especially in the neutropenic state after aggressive chemotherapy or hsct and hsct recipients with gvhd, are particularly susceptible to invasive fungal infections [ ] . approximately - % of patients with hematological malignancies and hsct recipients have evidence of invasive fungal infections at autopsy [ ] . these include invasive aspergillosis and fungal infections due to candida spp., zygomycetes spp., trichosporon spp., fusarium spp., and various chaetomium species. in neutropenic patients with acute leukemia, the histopathological pattern of invasive pulmonary aspergillosis (ipa) is characterized by scant inflammation, hyphal angioinvasion with a high fungal burden, and extensive coagulative necrosis [ , ] . in contrast, among hsct recipients with gvhd, the histopathological findings consist of severe lung inflammation and less abundant aspergillus burden. several autopsy [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in recent years, treatment of ipa with voriconazole has led to better responses, improved survival rates, and fewer side effects than amphotericin b [ ] . autopsy studies have assisted in describing and confirming the immune reconstitution inflammatory syndrome (iris) in patients with ipa who are recovering from the neutropenia [ ] . when clinical and radiologic worsening coincides with neutrophil recovery, it is usually assumed that this deterioration is related to progressive aspergillosis, prompting changes in patient man agement. however, its temporal relation with neutrophil recovery suggests that it may be caused by iris. the patients who died during the first month had no evidence of aspergillosis at autopsy. finally, autopsy studies have proved helpful in documenting the efficacy of systemic antifungal therapy and surgery for ipa [ ] . since the early s, the incidence of invasive candidiasis (candidemia and/or hepatosplenic candidiasis) has continued to decrease due to effective antifungal prophylaxis and empirical treatment of high-risk patients with echinocandins and voriconazole [ ] . mucosal damage is a risk factor for invasive candidiasis among patients receiving antineoplastic therapy. hsct recipients who received conditioning regimens with total body irradiation and patients treated with chemotherapy regimens containing high-dose cytarabine or an anthracycline have an increased risk of developing invasive disease. in recent years, there has been an increase in bloodstream infections caused by non-albicans candida species such as candida glabrata and c. krusei. the diagnosis of invasive candidiasis is difficult to prove due to the lack of specific clinical features and the low sensitivity of blood cultures to isolate candida, especially in patients receiving fluconazole prophylaxis [ ] . difficult-to-treat opportunistic molds, such as zygomycetes, trichosporon spp., and various chae tomium spp., including c. atrobrunneum, c. strumar ium, c. globosum, c. perlucidum, and c. cinereus are being described with increasing frequency on autopsy studies in patients with hematologic malignancies [ , [ ] [ ] [ ] [ ] [ ] [ ] . pulmonary involvement with these mold infections is characterized by tissue necrosis from angioinvasion and subsequent thrombosis. as with many fungal infections, diagnosis of these infections is often not possible until autopsy. treatment modalities usually involve lipid-based amphotericin b formulations and surgical debulking or debridement in selected cases [ ] . pneumocystis jiroveci pneumonia (pcp) remains a serious infection in patients with acute and chronic leukemias, myelodysplastic syndrome, and hsct recipients [ ] . however, diagnosis of pcp is frequently obtained by bronchoalveolar lavage with or without lung biopsy; thus, the diagnosis is made on autopsy in only a minority of cases. bacterial pneumonias caused by pseudomonas aerugi nosa, streptococcus spp., staphylococcus aureus, serratia spp., and legionella pneumophila have been described on autopsy studies in patients with hematologic malignancy and hsct recipients [ ] . as the majority of these patients commonly receive empiric antimicrobial therapy during the initial diagnostic workup for infection, very few autopsy studies report unusual bacterial infections. a single center autopsy series of patients with hematological malignancies found multidrug-resistant strains such as enterococcus faecium to be very prevalent [ ] . two coagulasenegative staphylococcus epidermidis strains were also noted. a few autopsy case reports have also described lethal pulmonary hemorrhage due to stenotrophomonas maltophilia [ ] . the incidence of autopsy-proven cytomegalovirus (cmv) pneumonia in patients with hematologic malignancy and hsct recipients has been decreasing in recent years as a result of improvements in early diagnosis and treatment and more effective preventive strategies [ ] . however, it is also possible that the declining rate of autopsies may account for the decrease in the number of reported cmv pneumonias. other etiologies of viral pneumonias that have been described in autopsy reports include infection due to herpes simplex virus, respiratory syncytial virus (rsv) [ ] , and measles virus [ ] . reactivation of latent toxoplasmosis is a rare but wellrecognized opportunistic infection in immunocompromised patients. besides encephalitis, the other common presentation with toxoplasma gondii infection is interstitial pneumonitis. because of its non-specific clinical and radiological presentation and its lethal outcome, toxoplasmosis is often misdiagnosed and only revealed at autopsy [ ] . toxoplasmic pneumonitis follows the same pathogenetic mechanism, but occurs less frequently than either toxoplasmic encephalitis or other opportunistic pneumonias, such as pcp. diagnosis is based upon a high degree of clinical suspicion and demonstration of t. gondii in bal fluid and/or lung biopsy specimens. widely disseminated necrotic areas with numerous cysts of toxoplasma gondii are commonly reported in autopsy cases. noninfectious pulmonary complications account for up to % of autopsy findings in patients with hematologic malignancies, particularly in hsct recipients. the most common complications are diffuse alveolar damage (dad) and diffuse alveolar hemorrhage (dah) [ ] . diffuse alveolar damage (dad) is a nonspecific finding at autopsy often in association with various infectious and noninfectious etiologies, such as shock, aspiration, alveolar hemorrhage, peri-engraftment respiratory distress syndrome, drug toxicity, and radiation therapy. it is characterized by the presence of alveolar injury and the absence of active lower respiratory tract infection. dad has been reported at autopsy in . % of patients with treated leukemia and lymphoma and close to % among hsct patients [ , ] . infections as the cause of dad are identified on autopsy in only a third of hsct patients, while approximately % have dah. in over % of patients with dad, no etiology is determined, and these patients are considered as having idiopathic pneumonia syndrome (ips). it is possible that empirically treated previous infections could have caused the histological changes noted in patients classified as having ips. only one third of the cases of dad are diagnosed antemortem [ ] . given that almost half of the cases of dad may be secondary to ips, the role of corticosteroids may need to be furthered studied. diffuse alveolar hemorrhage (dah) is a clinical syndrome characterized by the acute onset of alveolar infiltrates, bloody bronchoalveolar lavage, and hypoxemia in the absence of infection [ , ] . the incidence of dah ranges from - % to - % in autologous and allogeneic hsct recipients, respectively [ ] [ ] [ ] . a few case reports have been described in patients with acute leukemia more commonly in association with chemotherapy [ ] [ ] [ ] . dah has also been described in patients undergoing an umbilical cord hsct [ , ] . the majority of patients with dah develop severe respiratory failure with high mortality rates. vascular damage and inflammation from chemotherapy and radiation therapy used in the con ditioning regimen and immune-mediated events including gvhd have been implicated in the pathogenesis of dah [ , , ] . wojno et al. reported that % of allogeneic hsct patients who underwent autopsies had extensive pulmonary hemorrhage, which was thought to have led to severe respiratory failure and death [ ] . these patients were subdivided into those with significant acute gvhd and those without. of the patients with acute gvhd, % died of acute respiratory failure secondary to dah compared with % of those without gvhd. pulmonary hemorrhage was also independently found to be associated with pre-transplant total body irradiation. although pulmonary and systemic infections cause alveolar damage through similar mechanisms [ ] . infection-associated alveolar damage has traditionally been excluded from analyses of dah. autopsy studies have shown that pulmonary infections are frequently underdiagnosed in hsct recipients; thus, patients with alveolar hemorrhage and underlying undetected infections can be misclassified as having dah [ , , ] . because inflammation is thought to play a role in the pathogenesis of post hsct-dah, high-dose steroids have been used for its treatment, based on anecdotal case reports and small retrospective series [ , ] . other treatment modalities that have been used for dah in hsct recipients include epsilon aminocaproic acid and recombinant factor viia [ , ] . unfortunately, the mortality from dah in hsct recipients remains high because of misdiagnosis and lack of effective treatments. primary pulmonary lymphomas are very uncommon, especially those arising from bronchus-associated lymphoid tissue (balt) and have a low mortality. they represent % of the extranodal non-hodgkin's lymphomas (nhls) and only . % of all primary pulmonary malignant neoplasms and less than % of lymphomas. eighty percent of the cases are low-grade b-cell lymphomas, which are slow growing and respond well to therapy. autopsy case reports suggest that pulmonary balt lymphoma can remain restrictive to the thorax for long periods before dissemination, but tend to relapse frequently. lymphomatous involvement of the lung is common and occurs in % and %, respectively, of patients with hodgkin's lymphomas (hl) and nhl [ ] . typical findings in the lung include peribronchialperivascular, nodular, alveolar, interstitial, and pleural involvement. peripheral t-cell lymphomas also involve the lung frequently, % at diagnosis and a further % during the course of the disease. the nodular pattern is a characteristic of lung infiltration in hl, but no differences could be detected in the subtypes. pulmonary parenchymal involvement by multiple myeloma cells is very rare and described on autopsy in few case reports. the antemortem diagnosis of lung involvement by myeloma is difficult to make as infections and alveolar hemorrhage can have the same radiologic features. leukemic infiltration of the lungs may occur in - % of hyperleucocytic patients with acute myeloid leukemia (aml). pulmonary infiltrates are usually microscopic and invariably associated with hyperleukocytosis. there are autopsy case reports of pulmonary leukemia as a cause of pulmonary infiltrates, even in non-hyperleukocytosis aml patients with low blast counts. radiographically, patients present with an airspace disease with a diffuse interstitial reticular pattern in cases of hyperleukocytosis similar to cases of infectious pneumonia. pulmonary leukostasis syndrome involves the occlusion of small blood vessels in the lungs and typically occurs with a wbc count of greater than , per ml. the increased number of wbcs causes blood viscosity to rise due to the decreased deformability of the abnormal leukocytes, resulting in cell clumping and stasis in the microvasculature, leading to severe hypoxemic respiratory failure. autopsy studies reveal extensive infiltration by leukemic cells in the pulmonary vasculature; pulmonary infarction with hemorrhage is also noted. [ ] rarely, lung involvement by intravascular large b-cell lymphoma (ivlbcl) is noted on autopsy [ ] . early diagnosis is difficult as neither computed tomography nor -gallium scintigraphy can detect lung involvement. however, -fluro-deoxyglucose positron tomography (fdg-pet) may be a powerful tool for the early diagnosis of ivlbcl with pulmonary involvement [ ] . autopsy studies show that pulmonary thromboembolism (pte) infrequently complicates the course of patients with acute leukemia and severe thrombocytopenia, and hsct recipients with an incidence rate ranging from % to . % [ ] . [ ] patients with acute leukemias commonly have clinically silent haemostatic abnormalities, but some may show clinical manifestations, including venous thromboembolism, pulmonary embolism, disseminated intravascular coagulation, and life-threatening thrombohemorrhagic syndrome. the pathogenesis of pte is complex and multifactorial and may involve tumor cell-derived procoagulant, fibrinolytic or proteolytic factors, and inflammatory cytokines, which affect clotting activation. chemotherapy and anti-angiogenic drugs also increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. infectious complications are another important factor: endotoxins from gram-negative bacteria induce the release of tissue factor (tf), tumor necrosis factor (tnf), and interleukin- (il- ), and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor xii. needleman et al. reviewed consecutive autopsies in leukemia patients and found three patients with previously undiagnosed pte, all of whom had been severely thrombocytopenic. however, candida forms were abundant in the thromboemboli in all three patients, with some containing septate hyphal forms consistent with mucor or aspergillosis. no vessel wall invasion or necrosis was noted, and fungus was not shown to be present in pulmonary vessels in segments of the lung not involved with thromboembolism [ ] . leukemic patients may also be affected by other prothrombotic factors, including hyperleukocytosis, increased tf expression and activation, and the prothrombotic properties of therapeutic agents, such as all-trans retinoic acid and l-asparaginase, which can induce thrombosis involving multiple organs. a higher index of suspicion may lead to the diagnosis, but the signs and symptoms of pte in patients with hematologic malignancy are variable and nonspecific as with pte in other populations. the majority of patients with hematological malignancies who develop organizing pneumonia (boop) have been exposed to various chemotherapeutic agents, including cytarabine and anthracyclines as well as radiation therapy. [ , ] in one autopsy series, sharma et al. reported on patients who had undergone hsct, of whom % had bo and % had boop [ ] . unusual histological variants have also been described, including a case report of acute fibrinous and organizing pneumonia following hsct in a patient with aml [ ] characterized by prominent intraalveolar fibrin deposition and organizing pneumonia. the radiographic presentation revealed patchy consolidation in the lower lobes and a diffuse miliary pattern. clinically, these cases can have subacute presentations similar to cryptogenic organizing pneumonia or have more rapid progression with clinical features similar to ards. boop and bo are rare autopsy findings, which may be because infections are being treated aggressively, and often patients not responding to antibiotics and with no clinical evidence of infections are given a trial of corticosteroids. yokoi et al. reported bronchiolitis obliterans (bo) on autopsy in of patients who underwent allogeneic bmt with aml or all. all patients received conditioning regimens with total body irradiation and cyclophosphamide with or without busulfan or cytosine arabinoside. immunosuppressive therapies were administered to all patients after bmt, including methotrexate with or without cyclosporine. the onset of respiratory symptoms was - days after bmt, and the symptoms were non-productive cough, dyspnea, fever, chest pain, and pneumothorax. seven patients died of progressive respiratory failure and one of relapsed leukemia. coexistent infections included cmv, varicella zoster, mycobacterium tuberculosis, and aspergillus [ ] . paz pulmonary veno-occlusive disease (pvod) is a rare cause of pulmonary hypertension that is characterized histopathologically by intimal proliferation and fibrosis of the pulmonary venules and small veins leading to progressive vascular obstruction [ ] . the etiology of pvod remains unclear. it has been reported as an unusual complication of both myeloablative allogeneic, autologous and cord hsct, suggesting that it might be regimen-related toxicity [ ] [ ] [ ] [ ] [ ] [ ] . surgical lung biopsy provides definitive diagnosis [ ] . pvod carries a poor prognosis, with most reported patients experiencing progressive disease and death within years of diagnosis [ ] . autopsy findings reveal intimal fibrosis of most of the pulmonary veins, with no significant intraluminal thrombi or arterial changes [ ] . treatment recommendations are anecdotal. steroids and heparin have been reported to possibly improve outcomes [ ] . autopsy studies in patients with hematologic malignancy (particularly with myelodysplastic syndrome) and following hsct have revealed rare cases of secondary pulmonary alveolar proteinosis (pap) characterized by intra-alveolar accumulation of surfactant components and cellular debris, with minimal interstitial inflammation or fibrosis [ ] [ ] [ ] . secondary pap is frequently noted among patients with hematologic malignancies who develop fungal infection, especially pulmonary aspergillosis. kl- protein is produced by type ii alveolar pneumocytes and can be helpful in establishing an early diagnosis of pap [ , ] . the standard therapy for pap with hematological malignancy has not yet been firmly established. the administration of gm-csf has been suggested to activate the alveolar macrophages and increase the rate of surfactant clearance [ ] . case reports indicate that the prognosis of pap with leukemia is very poor because of the high frequency of superinfections in the affected alveoli [ , ] . several autopsy series have reported diagnostic discrepancies between premortem clinical diagnosis and postmortem autopsy findings ranging from % to % in patients with hematologic malignancy and hsct recipients (table . ) [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the goldman criteria are commonly used to categorize discrepancies between clinical and pathological diagnoses or causes of death [ ] . class discrepancies are defined as missed major diagnoses with potential adverse impact on survival and would have changed management. class ii discrepancies are missed major diagnoses with no potential impact on survival and that would have not changed therapy. class iii discrepancies are defined as missed minor diagnoses related to terminal disease, but not related to the cause of death, and class iv are other missed minor diagnoses. gerain et al. reported a % major discrepancy rate in cancer patients who were admitted to a medical oncological icu over an -month period. [ ] the majority of major discrepancies were due to complications of the cancer itself or its treatment (such as non-cardiogenic pulmonary edema, acute hemorrhage, and pulmonary embolism) rather than infection. pastores et al. reported a major missed diagnosis rate of % in autopsies performed on cancer patients who died in a medical-surgical icu [ ] . of the patients, ( %) had undergone hsct, ( %) had either leukemias or lymphomas, ( %) had solid tumors, and ( %) were surgical cancer patients. among the patients with discrepancies % had class i discrepancies, % had class ii discrepancies, and % had both class i and class ii discrepancies. of the discordant cases, had hematological malignancies and underwent hsct. opportunistic infections due to viral, fungal, bacterial, and parasitic organisms and cardiac complications were the most common class i discrepancies. the majority of class ii discrepancies were accounted for by cardiopulmonary complications due to pulmonary embolism and thrombotic endocarditis. the study was limited by the retrospective study design and selection bias that may have occurred as physicians and family members of patients with premortem diagnostic uncertainty would have been more likely to pursue an autopsy. xavier et al. reported a class i discrepancy rate of . % in autopsies of patients with hematological malignancies or severe aplastic anemia [ ] . the most common diagnoses causing these discrepancies were hematological disease, pneumonia, and gastrointestinal hemorrhage. class i discrepancies were more common in elderly patients (> years) and in patients who had not received previous specific treatment for the hematological malignancy, had not been treated with bone marrow or peripheral blood hsct, or had not been treated in a specialized hematology unit. seftel et al. reported a discrepancy rate of % ( % major, % minor) in autopsies of patients who underwent hsct (blood and bone marrow) [ ] . infectious complications, including pulmonary aspe rgillosis, candidiasis, and infective endocarditis, accounted for the majority of the major discrepancies. hoffmeister et al. found a % discrepancy rate ( % major, % minor) in autopsies of patients who had undergone hsct [ ] . in contrast, al saidi et al. found a pneumonia - significant concordance between the clinical and postmortem diagnoses in critically ill hsct patients [ ] . ten ( %) of the twenty eight patients had discrepancies uncovered on autopsy; only two discrepancies would have influenced patient management, and none would have altered patient outcome. most of the unexpected diagnoses were infections, and the rest included non-infective endocarditis, gvhd, and gastrointestinal and neurologic diagnoses. the authors concluded that clinical diagnosis alone might be appropriate for withdrawal of care decision-making in these patients. infectious and noninfectious pulmonary diseases are commonly found on postmortem autopsy studies in patients with hematological malignancy and hsct recipients. despite the technological advances in diagnostic testing and imaging modalities, obtaining an accurate clinical diagnosis remains difficult and is often not possible until autopsy. major diagnostic discrepancies between clinical premortem diagnoses and postmortem autopsy findings have been reported in patients with hematologic malignancy. the most common missed diagnoses are due to opportunistic infections and cardiopulmonary complications. these findings underscore the importance of enhanced surveillance, monitoring, and treatment of infections and cardiopulmonary disorders in these patients. autopsies remain important in determining an accurate cause of death and for improved understanding of diagnostic deficiencies, as well as for medical education and quality assurance. the goldman classification of diagnostic discrepancies was applied. major discrepancies included two categories (class i referred to missed diagnoses that would have led to a change in management with possible increased survival or cure; class ii referred to major missed diagnoses that would not have impacted survival because no treatment was available, treatment was given even though the diagnoses was unknown, or the patient refused further treatment). minor discrepancies included two categories (class iii referred to missed minor diagnoses related to the terminal disease process but not directly related to the cause of death, and class iv referred to missed minor diagnoses that did not contribute to the cause of death but ultimately may have been significant had the patient survived the major illness) congestive heart failure - acute pancreatitis - pulmonary embolism - invasive pulmonary aspergillosis - pulmonary edema - class ii ( . %) pneumonia - hematological disease - invasive pulmonary aspergillosis - pulmonary hemorrhage - other forms of aspergillosis - pulmonary candidiasis - class iii ( . %) hemosiderosis - secondary malignant neoplasm of kidney and renal pelvis - pleural effusion in conditions classified elsewhere - secondary malignant neoplasm of other unspecified digestive organ - pulmonary hemorrhage - class iv ( . %) pulmonary hemorrhage - pulmonary edema - gastrointestinal hemorrhage - nontraumatic intracerebral hemorrhage - pleural effusion in conditions classified elsewhere - secondary malignant lung neoplasm - chronic tubulo-interstitial nephritis - outcome of critically ill allogeneic hematopoietic stem-cell transplantation recipients: a reappraisal of indications for organ failure supports identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation pulmonary complications after bone marrow transplantation: an autopsy study from a large transplantation center pulmonary complications in adult blood and marrow transplant recipients: autopsy findings causes of deaths in an oncology unit pathologists request autopsy revival trend reversal in the frequency of mycoses in hematological neoplasias: autopsy results from to invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a -year period epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients pulmonary aspergillosis in an unselected autopsy series relationship between premortem and postmortem diagnosis in critically ill bone marrow transplantation patients fungal infections in cancer patients: an international autopsy survey auto psyidentified infections among bone marrow transplant recipients: a clinico-pathologic study of patients. bone marrow transplantation team trends in the postmortem epidemiology of invasive fungal infections at a university hospital clinical and radiologic predictors of invasive pulmonary aspergillosis in cancer patients: should the european organization for research and treatment of cancer/mycosis study group (eortc/msg) criteria be revised? clinical applicability of the new eortc/msg classification for invasive pulmonary aspergillosis in patients with hematological malignancies and autopsy-confirmed invasive aspergillosis bronchobronchiolitis obliterans as a complication of bone marrow transplantation: a clinicopathological study of eight autopsy cases voriconazole versus amphotericin b for primary therapy of invasive aspergillosis pneumocystis carinii pneumonia in patients with malignant haematological diseases: years' experience of infection in gimema centres successful treatment of invasive mould infection affecting lung and brain in an adult suffering from acute leukaemia effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving patients with haematological malignancy invasive mycotic infections caused by chaetomium perlucidum, a new agent of cerebral phaeohyphomycosis mucormycoses in patients with hematologic malignancies: an emerging fungal infection autopsy case of disseminated trichosporon inkin infection identified with molecular biological and biochemical methods fatal pulmonary infection in a leukaemic patient caused by hormographiella aspergillata mucormycosis in hematologic malignancies: an emerging fungal infection successful management of cerebral and pulmonary mucormycosis with liposomal amphotericin b in a -year-old woman with acute lymphoblastic leukemia patients at high risk of invasive fungal infections: when and how to treat pulmonary complications in patients with haematological malignancies treated at a respiratory icu frequent detection of multidrug-resistant pneumonia-causing bacteria in the pneumonia lung tissues of patients with hematological malignancies lethal pulmonary hemorrhage caused by a fulminant stenotrophomonas maltophilia respiratory infection in an acute myeloid leukemia patient fatal cytomegalovirus pneumonia in patients with haematological malignancies: an autopsy-based case-control study cytologic manifestations of respiratory syncytial virus pneumonia in bronchoalveolar lavage fluid: a case report diagnosis of measles viral pneumonia in a patient with hodgkin's disease by reverse transcription-polymerase chain reaction of serum toxoplasmosis with hemophagocytic syndrome after bone marrow transplantation: diagnosis at autopsy diffuse alveolar hemorrhage syndromes diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow transplantation: cryptic etiology and uncertain therapy diffuse alveolar hemorrhage: an evolving problem pathogenesis of massive pulmonary hemorrhage in acute leukemia diffuse alveolar damage and hemorrhage in acute myelogenous leukemia treated with corticosteroids diffuse alveolar hemorrhage as a complication in patients with hematologic malignancies after chemotherapy: report of two cases and literature review diffuse alveolar hemorrhage after unrelated cord blood transplantation autopsy findings in umbilical cord blood transplant recipients pulmonary hemorrhage as a cause of death in allogeneic bone marrow recipients with severe acute graft-versus-host disease inflammatory response to infectious pulmonary injury diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. a postmortem study corticosteroid therapy for diffuse alveolar hemorrhage in autologous bone marrow transplant recipients corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation diffuse alveolar hemorrhage after allogeneic hematopoietic stemcell transplantation: treatment with recombinant factor viia diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid histologic patterns of lung infiltration of b-cell, t-cell, and hodgkin lymphomas pulmonary leukostasis mimicking pulmonary embolism intravascular large b-cell lymphoma (ivlbcl): a clinicopathologic study of cases with special reference to the immunophenotypic heterogeneity of cd intravascular large b-cell lymphoma with fdg accumulation in the lung lacking ct/( )gallium scintigraphy abnormality pulmonary embolism in patients with acute leukemia and severe thrombocytopenia organizing pneumonia in patients with hematologic malignancies: a steroidresponsive lesion bronchiolitis obliterans organizing pneumonia in cancer: a case series acute fibrinous and organizing pneumonia following hematopoietic stem cell transplantation bronchiolitis obliterans after autologous bone marrow transplantation pulmo nary veno-occlusive disease following reduced-intensity cord blood transplantation pulmonary venoocclusive disease following bone marrow transplantation pulmonary venoocclusive disease accompanied by microangiopathic hemolytic anemia year after a second bone marrow transplantation for acute lymphoblastic leukemia pulmonary veno-occlusive disease following allogeneic peripheral blood stem cell transplantation for chronic myeloid leukaemia pulmonary veno-occlusive disease after bone marrow transplantation pulmonary veno-occlusive disease in an adult following bone marrow transplantation. case report and review of the literature pulmonary venoocclusive disease pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients a case of myelodysplastic syndrome complicated by pulmonary alveolar proteinosis with a high serum kl- level pulmonary alveolar proteinosis and disseminated atypical mycobacteriosis in a patient with busulfan lung difference in sero-diagnostic values among kl- -associated mucins classified as cluster causes of deaths in an oncologic intensive care unit: a clinical and pathological study of autopsies premortem clinical diagnoses and postmortem autopsy findings: discrepancies in critically ill cancer patients missed diagnosis in hematological patients -an autopsy study autopsy diagnoses of malignant neoplasms. how often are clinical diagnoses incorrect hodgkin's disease: correlation between causes of death at autopsy and clinical diagnosis high rate of discordance between clinical and autopsy diagnoses in blood and marrow transplantation clinical utility of autopsy after hematopoietic stem cell transplantation the value of the autopsy in three medical eras key: cord- -i l mtx authors: el fakiri, karima; draiss, ghizlane; rada, noureddine; bouskraoui, mohammed; hamdaoui, abderrachid; oulad saiad, mohamed title: hydropneumothorax revealing a pneumoblastoma in children date: - - journal: case rep pediatr doi: . / / sha: doc_id: cord_uid: i l mtx pneumoblastoma is a rare primary childhood tumor. we report the observation of an infant aged years and months who presented with dry cough and dyspnea. the physical examination found mixed pleural effusion syndrome on the right. the chest x-ray revealed a right pneumothorax. biology has shown leukocytosis at , /mm( ). the ct scan revealed parenchymal air cystic lesions affecting the outer segment of the middle lobe mimicking a pulmonary malformation. thoracic drainage brought back ml of the fluid. two months later, when a pyopneumothorax appeared, a medium lobectomy was performed. pathological study specimen showed a high-grade type ii pneumoblastoma the extension assessment identified a secondary hepatic location. chemotherapy has been indicated. this observation illustrates the diagnosis challenge of pneumoblastoma in children. pneumoblastoma (pb) is an extremely rare primary malignant tumor in children. it represents . to . % of all lung tumors [ ] with a very serious prognosis. classically, there are three types of pb [ ] : type i is a purely cystic, bullous lesion, type ii combines solid and cystic plaques, and type iii is exclusively solid. e clinical features of pb are usually nonspecific encompassing pneumothorax or respiratory distress [ ] sometimes leading to delayed diagnosis. x-ray images are often confused with those of a congenital lung defect. metastasis from pb can affect the central nervous system, bone, and liver. treatment is based on surgery and neoadjuvant chemotherapy. here, we report an unusual observation after the consent of the parents of a hydropneumothorax revealing pneumoblastoma in a girl mimicking pulmonary malformation. we report a case of a -year- -month-old female without parental consanguinity. she was vaccinated up to date according to the national immunization program. no known recent tuberculosis or personal atopy and no family history of tumors were found. she was referred for a dry cough, becoming wet, dyspnea, and chest pain with fever. e clinical examination found a conscious patient with fever at . °c tachypnea at breaths per minute, normal heart rate closer to beats per minute. her oxygen saturation was % at room air. her body weight was kilograms, and her size was cm. e pleuropulmonary examination found signs of respiratory distress, such as intercostal, subcostal, and supraclavicular retractions and decrease in vocal resonance. on auscultation, there was absence of breath sounds and tympanism in the right chest. e chest x-ray showed a right pneumothorax ( figure ) that was drained. e laboratory data showed leukocytosis at , /mm , predominantly neutrophilic at , /mm , hemoglobin at . g/dl, and crp at mg/dl, and the blood culture was sterile. e patient was treated by amoxicillinclavulanic acid without much clinical and radiological improvement. a thoracic ct scan searching an underlying pathology revealed overdistension of the right hemithorax with parenchymal air cystic lesions involving the external segment of the middle lobe conducting to a malformation cystic adenomatoid, a fairly abundant right hydropneumothorax responsible for a compressive effect on the adjacent pulmonary parenchyma, and inflammation of the pleura ( figure ). e patient has been scheduled for surgery; however, she was lost because of covid- pandemic and social distancing, so she missed her scheduled surgery. two months later, she presented with pyopneumothorax that was drained. e drain brought back ml of yellow ladle liquid with lumps of pus. bacteriological examination of pus isolated pseudomonas aeruginosa and klebsiella pneumoniae. a right middle lobectomy was performed because we suspected a cystic adenomatoid malformation of the right middle lobe. rough an open thoracotomy, we found a gelatinous component in the right chest originated from the middle right lobe extending to the pleura and diaphragm; a middle lobectomy was performed with resection of the gelatinous component ( figure ). e specimen weighed g and measured cm. cytological finding confirmed macroscopically multiple fragments with polypoid cerebroid and necrotic component and rare cystic wall.-microscopically, the tumor proliferation had the double epithelial ( figure ) and sarcomatous component ( figure ). we conducted type ii of pneumoblastoma. e extension assessment found secondary hepatic localization. adjuvant chemotherapy has been indicated in addition to surgery, and the child was referred to the pediatric oncology unit. six months after the surgery, the patient developed a local recurrence that is still being treating by chemotherapy. pulmonary blastoma is an uncommon tumor. is rare and very aggressive tumor has unspecific clinical and radiological characteristics which often delay the diagnosis. in general, respiratory symptoms such as cough, chest pain, dyspnea, and hemoptysis are most common in pb patients. other clinical presentations, including pneumothorax, fever, hemothorax, and pleural effusion, may also be encountered [ ] . chen et al. reported a case of a large pulmonary blastoma in a -year-old girl whose initial presentation was progressive dyspnea and productive cough [ ] , which was similar to our case who had cough dyspnea, and the pulmonary blastoma was revealed by pneumothorax. in fact, radiological images are being often confused with those of a congenital lung defect. regarding the localization, the right lung is more frequently affected by pulmonary blastoma than the left, which is consistent with a previous study involving adult patients [ ] . from a cytological point of view, it is an embryonal tumor of the lung with epithelial and mesenchymal components. e solid regions in types ii and iii were histologically similar, displaying a mixed, sarcomatous pattern. ese sarcomatous cells may include interspersed foci of anaplasia, features of embryonal rhabdomyosarcoma, chondrosarcoma, or necrosis [ ] [ ] [ ] . pb types and had areas very similar to congenital pulmonary airway malformation type ; however, the latter has no immature/ malignant components. cytogenetically, these are completely different lesions. our patient had large foci of tumor necrosis. in fact, the biologic behavior of the tumor was unpredictable. however, no sensitive and specific serum tumor marker was available for its diagnosis. formerly, controversy existed regarding whether a pulmonary malformation could degenerate into a pb [ ] [ ] [ ] . however, detailed genetic and immunohistochemical explorations have confirmed that distinct pathogenic mechanisms exist between these two disease entities [ , ] . in fine, we concluded that the pathology is mandatory to confirm pulmonary blastoma diagnosis. knight et al. reported that types ii and iii may metastasize most often to the brain but rarely to the liver and bone [ ] , which contrasts with our patient because she metastasized to the liver. overall, our management was surgery with chemotherapy. e european cooperative study group for pediatric rare tumors has children with a threshold of tumor's size, and tumors were large at cm in maximum diameter as a reasonable cutoff point, above which up-front biopsy followed by neoadjuvant chemotherapy is a reasonable approach [ ] . in our case, neoadjuvant chemotherapy was used in order to minimize the radical surgical approach needed to achieve local control. surgical resection of type ii and type iii ppb may require a wedge resection lobectomy or pneumonectomy to achieve negative margins if possible. when performing a lobectomy for type ii or iii ppb, involved pleural surfaces should be resected with the primary tumor and involved pulmonary lobe. for large type ii or iii ppb with extensive pleural spread, an extrapleural pneumonectomy may be required to achieve local control [ ] . in our case, the surgery was not initially carried out for cancer purposes, so neoadjuvant chemotherapy was used in order to minimize the radical surgical approach needed to achieve local control. in addition, we emphasize the importance of completing surgical excision because it appears as an important prognosis factor. significant correlation occurred between the ppb type and survival which is type i at %; type ii at %, and type iii at % [ ] . in our case, the factors of bad prognosis were the sarcomatous component with local recurrence and hepatic metastasis. case reports in pediatrics finally, pulmonary blastoma is a rare tumor which must be in mind even if we have no specific signs. erefore, we have to think about in front of a pulmonary malformation and also a pneumothorax. a few cases have been reported presenting as a spontaneous pneumothorax, even in the absence of any demonstrable solid mass [ , ] . further studies focusing on the pathway to this rare disease are mandatory to provide new treatments' insights. pneumoblastoma in children is a rare, aggressive tumor that shows up with nonspecific clinical and radiological signs which may often delay diagnosis, so the prognosis may be so bad. pathological confirmation is mandatory. biphasic pulmonary blastoma: an unusual presentation with chest wall, rib and pleural involvement pleuropulmonary blastoma. a unique intrathoracic pulmonary neoplasm of childhood pleuropulmonary blastoma a retrospective analysis of the clinicopathological and molecular characteristics of pulmonary blastoma pulmonary blastoma in children: report of a rare case and review of the literature clinical analysis of patients with adult-type pulmonary blastoma pleuropulmonary blastoma pleuropulmonary blastoma: a report on central pathologyconfirmed pleuropulmonary blastoma cases by the international pleuropulmonary blastoma registry dicer mutations in familial pleuropulmonary blastoma is congenital cystic adenomatoid malformation a premalignant lesion for pleuropulmonary blastoma? pleuropulmonary blastoma in childhood. a malignant degeneration of pulmonary cysts pulmonary cysts in early childhood and the risk of malignancy prenatal and postnatal management of congenital pulmonary airway malformation fgf signaling differences between type i pleuropulmonary blastoma and congenital cystic adenomatoid malformation current management of pleuropulmonary blastoma: a surgical perspective treatment and prognostic factors in pleuropulmonary blastoma: an expert report extrapleural pneumonectomy for advanced pleuropulmonary blastoma pneumothorax preceding pulmonary blastoma in a child critical presentation of pleuropulmonary blastoma e authors declare that they have no conflicts of interest. all authors read, contributed, and approved the final version of the manuscript. key: cord- -toam r y authors: franquet, tomás; chung, johnathan h. title: imaging of pulmonary infection date: - - journal: diseases of the chest, breast, heart and vessels - doi: . / - - - - _ sha: doc_id: cord_uid: toam r y the spectrum of organisms known to cause respiratory infections is broad and constantly increasing as new pathogens are identified, and an increasing number of patients have impaired immunity due to disease or medications. the radiographic manifestations of a given organism may be variable depending on the immunologic status of the patient and the presence of pre- or coexisting lung disease. moreover, the clinical data and radiographic findings often fail to lead to a definitive diagnosis of pneumonia because there are an extensive number of noninfectious processes associated with febrile pneumonitis. this chapter describes and illustrates the characteristic imaging manifestations of the most common community- acquired pneumonias, nosocomial pneumonias, and the various infections seen in both immunocompetent and immunocompromised patients. community acquired pneumonia refers to an acute infection of the lung in patients who did not meet any of the criteria for hcap, presenting select clinical features (e.g., cough, fever, sputum production, and pleuritic chest pain) and accompanied by an acute infiltrate on a chest radiograph. pulmonary opacities are usually evident on the radiograph within h of the onset of symptoms [ ] . although the imaging findings do not allow a specific etiologic diagnosis, cap diagnosis and disease management most frequently involve chest radiography, and other imaging modalities are not usually required [ ] . the spectrum of causative organisms of cap includes gram-positive bacteria such as streptococcus pneumoniae (pneumococcus), haemophilus influenzae, and staphylococcus aureus, as well as atypical organisms such as mycoplasma pneumoniae, chlamydia pneumoniae, or legionella pneumophila and viral agents such as influenza a virus and respiratory syncytial viruses [ ] . however, many community-acquired pneumonias are still commonly caused by s. pneumoniae and are lobar in appearance. the radiographic patterns of cap are often related to the causative agent. infection of the lower respiratory tract, acquired by way of the airways and confined to the lung parenchyma and airways, typically presents radiologically as one of three patterns: (a) focal nonsegmental or lobar pneumonia, (b) multifocal bronchopneumonia or lobular pneumonia, and (c) focal or diffuse "interstitial" pneumonia. microorganisms responsible for vap may differ according to the population of patients in the icu, the durations of hospital and icu stays, and the specific diagnostic method(s) used. the spectrum of causative pathogens of vap in humans is staphylococcus aureus, pseudomonas aeruginosa, and enterobacteriaceae [ ] . chest radiograph is most helpful when it is normal and rules out pneumonia. however, pulmonary opacities were detected by computed tomography (ct) scan in % of cases with a normal portable chest x-ray. when infiltrates are present, the particular pattern is of limited value for differentiating among cardiogenic pulmonary edema, noncardiogenic, pulmonary edema, hemorrhage, atelectasis, and pneumonia. when pneumonia is associated with healthcare risk factors such as prior hospitalization, dialysis, residing in a nursing home, and immunocompromised state, it is now classified as a healthcare-associated pneumonia (hcap). the number of individuals receiving healthcare outside the hospital setting, including home wound care or infusion therapy, dialysis, nursing homes, and similar settings, is constantly increasing [ ] . a clinical diagnosis of pneumonia can usually be readily established on the basis of signs, symptoms, and chest radiographs, although distinguishing pneumonia from conditions such as left heart failure, pulmonary embolism, and aspiration pneumonia may sometimes be difficult. differentiation of etiologies based solely on the radiograph is not reliable, yet the pattern of abnormalities should be very useful in formulating a differential diagnosis of the nature of disease [ ] . chest radiographs are of limited value in predicting the causative pathogen but are of good use to determine the extent of pneumonia and to detect complications (i.e., cavitation, abscess formation, pneumothorax, pleural effusion), to detect additional or alternative diagnoses, and, in some cases, to guide invasive diagnostic procedures. the most common radiographic manifestations of respiratory infection are foci of consolidation, ground-glass opacities, or reticulonodular opacities. other less common radiographic findings include hilar and mediastinal lymphadenopathy, pleural effusion, cavitation, and chest wall invasion [ , ] . computed tomography, particularly high-resolution ct (hrct), has been shown to be more sensitive than the radiograph in the detection of subtle abnormalities and may show findings suggestive of pneumonia up to days earlier than chest radiographs. ct is recommended in patients with clinical suspicion of infection and normal or nonspecific radiographic findings, in the assessment of suspected complications of pneumonia or suspicion of an underlying lesion such as pulmonary carcinoma. pneumonias are usually divided according to their chest imaging appearance into lobar pneumonia, bronchopneumonia, and interstitial pneumonia. in lobar pneumonia the inflammatory exudate begins in the distal airspaces adjacent to the visceral pleura and then spreads via collateral air drift routes (pores of kohn) to produce uniform homogeneous opacification of partial or complete segments of the lung and occasionally an entire lobe. • pneumonia is the leading cause of death due to infectious disease. • a variety of organisms that may present with similar clinical symptoms result in similar radiographic manifestations. • the radiographic manifestations of a given organism may be variable depending on the immunologic status of the patient. as the airways are not primarily involved and remain patent, there is little to no volume loss, and air bronchograms are common. some pneumonias present as spherical-or nodularshaped consolidations. bronchopneumonia (lobular pneumonia) is characterized histologically by peribronchiolar inflammation manifesting radiologically as patchy airspace nodules with poorly defined margins. radiologically a bronchopneumonia is characterized by large heterogeneous, scattered opacities which only later, with worsening of disease, become more homogeneous. an air bronchogram is usually absent. the most common causative organisms of bronchopneumonia are s. aureus, h. influenzae, p. aeruginosa, and anaerobic bacteria [ ] . characteristic manifestations of bronchopneumonia on hrct include centrilobular ill-defined nodules and branching linear opacities, airspace nodules, and multifocal lobular areas of consolidation [ ] . the term atypical pneumonia (interstitial pneumonia) was initially applied to the clinical and radiographic appearance of lung infection not behaving or looking like that caused by s. pneumoniae [ ] . today, when new diagnostic techniques such as direct antigen detection, polymerase chain reaction, and serology (elisa) have moved beyond the initial diagnostic methods, a debate with regard to the appropriate use of the term "atypical pneumonia" is open [ ] . radiographically focal or diffuse small heterogeneous opacities are seen uniformly distributed in the involved lung. frequently these opacities are described as reticular or reticulonodular. the usual causes of interstitial pneumonia are viral and mycoplasma infections [ ] . streptococcus pneumoniae, a gram-positive coccus, is the most common bacterial cause of cap among patients who require hospitalization. risk factors for the development of pneumococcal pneumonia include the extremes of age, chronic heart or lung disease, immunosuppression, alcoholism, institutionalization, and prior splenectomy. the characteristic clinical presentation is abrupt in onset, with fever, chills, cough, and pleuritic chest pain. the typical radiographic appearance of acute pneumococcal pneumonia consists of a homogeneous consolidation that crosses segmental boundaries (nonsegmental) but involves only one lobe (lobar pneumonia) ( fig. . ) . occasionally, infection is manifested as a spherical focus of consolidation that simulates a mass (round pneumonia). complications, such as cavitation and pneumatocele formation, are rare. pleural effusion is common and is seen in up to half of patients. pneumonia caused by s. aureus usually follows aspiration of organisms from the upper respiratory tract. risk factors for the development of staphylococcal pneumonia include underlying pulmonary disease (e.g., copd, carcinoma), chronic illnesses (e.g., diabetes mellitus, renal failure), or viral infection. the clinical presentation of staphylococcal pneumonia is changing and of particular importance is the dramatic increase of the incidence of methicillinresistant staphylococcus aureus (mrsa) infections in recent years. increasingly, previously healthy young people without traditional risk factors for s. aureus disease are presenting with severe necrotizing infection and high mortality. fever, cough, and purulent sputum are prominent symptoms in cases of post-aspirative staphylococcal pneumonia. severe pneumonia caused by community-associated methicillin-resistant staphylococcus aureus (mrsa) carrying genes for panton-valentine leukocidin has been described in immunocompetent young adults. the characteristic pattern of presentation is as a bronchopneumonia (lobular pneumonia) that is bilateral in % of patients. the radiographic manifestations usually consist of bilateral patchy areas of consolidation. air bronchograms are uncommon. other features are cavitation, pneumatoceles, pleural effusions, and spontaneous pneumothorax ( fig. . ). pneumatoceles are seen especially in children [ ] . thoracic actinomycosis is a chronic suppurative pulmonary or endobronchial infection caused by actinomyces species, most frequently actinomyces israelii considered to be a gram-positive branching filamentous bacterium. pulmonary infection is characterized pathologically by bronchopneumonia with focal or multifocal abscess formation. actinomycosis has the ability to spread across fascial planes to contiguous tissues without regard to normal anatomic barriers. on ct, parenchymal actinomycosis is characterized by airspace consolidation with cavitation or central areas of low attenuation and adjacent pleural thickening. endobronchial actinomycosis can be associated with a foreign body (direct aspiration of a foreign body contaminated with actinomyces organisms) or a broncholith (secondary colonization of a preexisting endobronchial broncholith by aspirated actinomyces organisms). nocardia is a genus of filamentous gram-positive, weakly acid fast, aerobic bacteria that affects both immunosuppressed and immunocompetent patients. nocardia asteroides is responsible of % of infections by this organism in man. pulmonary nocardiosis can be an acute, subacute, or chronic disease. nocardiosis usually begins with a focus of pulmonary infection and may disseminate through hematogenous spread to other organs, most commonly to the cns. imaging findings are variable and consist of unifocal or multifocal consolidation and single or multiple pulmonary nodules [ ] . nocardia asteroides infection may complicate alveolar proteinosis. gram-negative pneumonias are chiefly caused by klebsiella pneumoniae, enterobacter sp., serratia marcescens, escherichia coli, proteus sp., and pseudomonas aeruginosa. patients affected are invariably debilitated by a chronic medical or pulmonary disease. the lower lobes contrast-enhanced ct image shows a mixed opacity of consolidation (arrow) and ground-glass opacity (small arrows) consistent with lobar pneumonia tend to be affected, and the radiographic pattern is similar to that seen with s. aureus infections in adults. klebsiella pneumoniae is among the most common gramnegative bacteria accounting for . - . % of all cases of pneumonia. these features are bulging fissures, sharp margins of the advancing border of the pneumonic infiltrate and early abscess formation. ct findings consist of ground-glass attenuation, consolidation, and intralobular reticular opacity, often associated with pleural effusion. complications of klebsiella pneumonia include abscess formation, parapneumonic effusion, and empyema. axial contrast-enhanced ct shows a cavitary mass within the right lower lobe (arrow) and a mass in the left upper lobe demonstrating surrounding ground-glass opacity (halo sign) (arrows) escherichia coli accounts for % of cases of cap and - % of cases of hap or hcap. it occurs most commonly in debilitated patients. the typical history is one of abrupt onset of fever, chills, dyspnea, pleuritic pain, and productive cough in a patient with preexisting chronic disease. the radiographic manifestations usually are those of bronchopneumonia; rarely a pattern of lobar pneumonia may be seen. pseudomonas aeruginosa is a gram-negative bacillus that is the most common cause of nosocomial pulmonary infection. it causes confluent bronchopneumonia that is often extensive and frequently cavitates (fig. . ) . the radiologic manifestations are nonspecific and consist most commonly of patchy areas of consolidation and widespread poorly defined nodular opacities [ ] . chlamydia pneumoniae is the most commonly occurring gram-negative intracellular bacterial pathogen. it is frequently involved in respiratory tract infections and has also been implicated in the pathogenesis of asthma in both adults and children. symptoms include sore throat, headache, and a nonproductive cough that can persist for months if treatment is not initiated early. chest radiographs tend to show less extensive abnormalities than are seen with other causes of pneumonia. on ct, c. pneumoniae pneumonia demonstrates a wide spectrum of the most common rickettsia lung infection is sporadic or epidemic q-fever pneumonia caused by coxiella burnetii, an intracellular, gram-negative bacterium. infection is acquired by inhalation from farm livestock or their products and occasionally from domestic animals. imaging findings consist of multilobar airspace consolidation, solitary or multiple nodules surrounded by a halo of "groundglass" opacity and vessel connection, and necrotizing pneumonia. tularemia is an acute, febrile, bacterial zoonosis caused by the aerobic gram-negative bacillus francisella tularensis. it is endemic in parts of europe, asia, and north america. primary pneumonic tularemia occurs in rural settings. humans become infected after introduction of the bacillus by inhalation, intradermal injection, or oral ingestion. chest radiographic findings are scattered multifocal consolidations, hilar adenopathy, and pleural effusion. haemophilus influenzae is a pleomorphic, gram-negative coccobacillus that accounts for - % of cap in patients in whom an organism can be identified successfully. factors that predispose to haemophilus pneumonia include copd, malignancy, hiv infection, and alcoholism. the typical radiographic appearance of haemophilus influenza pneumonia consists of multilobar involvement with lobar or segmental consolidation and pleural effusion. legionella is a pathogenic gram-negative bacterium with at least species. it is one of the most common causes of severe community-acquired pneumonia in immunocompetent hosts. human infection may occur when legionella contaminates water systems, such as air conditioners and condensers. risk factors for the development of l. pneumophila pneumonia include immunosuppression, posttransplantation, cigarette smoking, renal disease, and exposure to contaminated drinking water. patients with legionella pneumonia usually present with fever, cough, initially dry and later productive, malaise, myalgia, confusion, headaches, and diarrhea. thirty percent of patients develop pleuritic chest pain. imaging findings include peripheral airspace consolidation similar to that seen in acute s. pneumoniae pneumonia. in many cases, the area of consolidation rapidly progresses to occupy all or a large portion of a lobe (lobar pneumonia) or to involve contiguous lobes or to become bilateral. cavitation is uncommon in immunocompetent patients, and pleural effusion may occur in - % of cases. moraxella catarrhalis (formerly known as branhamella catarrhalis) has emerged as a significant bacterial pathogen of humans over the past two decades. it is an intracellular gram-negative coccus now recognized as one of the common respiratory pathogens [ ] . m. catarrhalis causes otitis media and sinusitis in children and mild pneumonia and acute exacerbation in older patients with copd. it is currently considered the third most common cause of community-acquired bacterial pneumonia (after s. pneumoniae and h. influenzae). the majority of patients with pneumonia ( - %) have underlying chronic pulmonary disease. chest radiographs show bronchopneumonia or lobar pneumonia that usually involves a single lobe. m. pneumoniae is one of the most common causes of community-acquired pneumonia. it accounts for up to % of cap in persons treated as outpatients. patients with copd appear to be more severely affected with m. pneumoniae than normal hosts. the radiographic findings in m. pneumoniae are variable and in some cases closely resemble those seen in viral infections of the lower respiratory tract. chest radiograph shows fine linear opacities followed by segmental airspace consolidation [ ] . • a "tree-in-bud" pattern is a characteristic ct manifestation of infectious bronchiolitis. • focal areas of consolidation secondary to infection in immunocompromised patients are most commonly due to bacterial pneumonia. • interstitial and/or mixed interstitial and airspace opacities in cap are typically due to viruses or m. pneumoniae. mycobacterium tuberculosis accounts for more than % of pulmonary mycobacterial infections. other mycobacterial species, m. kansasii and m. avium-intracellulare complex (mac), account for the remainder. factors that contribute to the large number of cases seen worldwide are human immunodeficiency virus (hiv) infection, inner city poverty, homelessness, and immigration from areas with high rates of infection. other predisposing conditions are diabetes mellitus, alcoholism, silicosis, and malignancy. this form is seen in infants and children. with improved control of tuberculosis in western societies, however, more people reach adulthood without exposure, and primary patterns of disease are being seen with increasing frequency in adulthood and represents about - % of all adult cases of tuberculosis. although primary tuberculosis typically presents with radiographic manifestations, chest radiograph may be normal in % of cases. lymphadenopathy is the most common manifestation of primary tuberculosis in children and occurs with or without pneumonia. in adults hilar or mediastinal lymphadenopathy is less common declining to about % of cases in the older population. pleural effusion occurs in children, who usually have parenchymal or nodal disease, or in teenagers and young adults, when it is frequently isolated. most cases are due to reactivation of quiescent lesions, but occasionally a new infection from an exogenous source occurs. pathologically, the ability of the host to respond immunologically results in a greater inflammatory reaction and caseous necrosis. the radiological manifestations may overlap with those of primary tuberculosis, but the absence of lymphadenopathy, more frequent cavitation, and a predilection for the upper lobes are more typical of postprimary tuberculosis. a rasmussen aneurysm is a rare life-threatening complication of cavitary tuberculosis caused by granulomatous weakening of a pulmonary arterial wall. endobronchial spread can occur with or without cavitary disease and is similar to that seen with primary tuberculosis leading to the appearance of the typical images of "tree-inbud" [ , ] . after antituberculous treatment healing results in scar formation. the fibrosis produces well-defined, upper lobe nodular and linear opacities, often with evidence of severe volume loss and pleural thickening. residual thin-walled cavities may be present in both active and inactive disease. although classically a manifestation of primary disease, miliary tuberculosis is now more commonly seen as a postprimary process in older patients. multiple small ( - mm) discrete nodules are scattered evenly throughout both lungs. a tuberculoma may occur in the setting of primary or postprimary tuberculosis and represents localized parenchymal disease that alternately activates and heals. it usually calcifies and frequently remains stable for years [ ] . as mentioned above, - % of pulmonary mycobacterial infections are caused by agents other than m. tuberculosis: usually m. avium-intracellulare complex (mac) and less commonly m. kansasii. patients are often predisposed by reason of underlying debilitating disease, immune compromise, chronic airflow obstruction, previous pulmonary tuberculosis, or silicosis and following lung transplantation [ ] . clinically, mac may be an indolent process with symptoms of cough, with or without sputum production. more commonly, mac presents with a radiological pattern that does not resemble that of postprimary tuberculosis. it consists of multiple nodules, with or without small ring opacities, showing no specific lobar predilection and bronchiectasis particularly in the lingula and right middle lobe. the most typical form of pulmonary nontuberculous mycobacteria (ntmb) infection is frequently associated to elderly men with underlying lung disease and to elderly white women without underlying lung disease (lady windermere syndrome). radiological findings consist of mild to moderate cylindrical bronchiectasis and multiple - mm diameter centrilobular nodules. fungi involved in pulmonary infections are either pathogenic fungi, which can infect any host, or saprophytic fungi, which infect only immunocompromised hosts. pathogenic fungi include coccidioidomycosis, blastomycosis, and histoplasmosis. saprophytes include pneumocystis, candidiasis, mucormycosis, and aspergillosis. pulmonary fungal infections may be difficult to diagnose, and a definitive diagnosis of pulmonary fungal infections is made by isolating the fungus from tissue specimen. aspergillosis is a fungal disease caused by aspergillus species, usually a. fumigatus that can take different forms depending on an individual's immune response to the organism. classically, pulmonary aspergillosis has been categorized into saprophytic, allergic, and invasive forms [ , ] . aspergillus mycetomas are saprophytic growths which colonize a preexisting cavity in the lung (e.g., from sarcoidosis or tuberculosis). most cavities and thus mycetomas are in the upper lobes or superior segments of the lower lobes. allergic bronchopulmonary aspergillosis (abpa) describes a hypersensitivity reaction which occurs in the major airways. it is associated with elevated serum ige, positive serum precipitins, and skin reactivity to aspergillus. the radiographic appearances consist of nonsegmental areas of opacity most common in the upper lobes, lobar collapse, branching thick tubular opacities due to bronchi distended with mucus and fungus, and occasionally pulmonary cavitation. the mucus plugs in abpa are usually hypodense, but in up to % of patients, the mucus can be hyperdense on ct (fig. . ) . angioinvasive aspergillosis is seen in immunocompromised hosts with severe neutropenia. this form is characterized by invasion and occlusion of small-to-medium pulmonary arteries, developing necrotic hemorrhagic nodules or infarcts. the most common pattern seen in ct consists of multiples nodules surrounded by a halo of ground-glass attenuation (halo sign) or pleural-based wedgeshaped areas of consolidation [ ] . candida species has been increasingly recognized as an important source of fungal pneumonia in immunocompromised patients, particularly in those with underlying malignancy (acute leukemia and lymphoma), intravenous drug abuse, and acquired immune deficiency syndrome a b c fig. . (a, b, c) allergic bronchopulmonary aspergillosis: (a) posteroanterior chest radiograph demonstrates basilar branching opacities suggestive of mucus-filled bronchiectasis (arrows). (b) axial ct image confirms the presence of left basilar bronchiectasis, mucus-filled airways (arrows). (c) hyperdensity of mucus-filled airways on axial mip image (arrows) from chest ct is diagnostic of allergic bronchopulmonary aspergillosis (aids), and following bone marrow transplantation. the most common thin-section ct findings of pulmonary candidiasis consist of multiple bilateral nodular opacities often associated with areas of consolidation and groundglass opacity [ ] . pneumocystis jiroveci a unique opportunistic fungal pathogen that causes pneumonia in immunocompromised individuals such as patients with aids, patients with organ transplants, and patients with hematologic or solid organ malignancies who are undergoing chemotherapy. in % of patients with pneumocystis jiroveci, pneumonia chest radiographs show diffuse bilateral infiltrates in a perihilar distribution ( fig. . ) . the most common high-resolution ct finding in pneumocystis jiroveci pneumonia is diffuse ground-glass opacity [ ] . mucormycosis is an opportunistic fungal infection of the order mucorales, characterized by broad, nonseptated hyphae that randomly branch at right angles. the most common radiographic findings consist of lobar or multilobar areas of consolidation and solitary or multiple pulmonary nodules and masses with associated cavitation or an air-crescent sign [ ] . viruses can result in several pathologic forms of lower respiratory tract infection including tracheobronchitis, bronchiolitis, and pneumonia. viral infections predispose to secondary bacterial pneumonia. organizing pneumonia, a nonspecific reparative reaction, may result from a variety of causes or underlying pathologic processes including viral infections [ ] . influenza type a is the most important of the respiratory viruses with respect to the morbidity and mortality in the general population. in recent years, both influenza and parainfluenza viruses have been recognized as a significant cause of respiratory illness in immunocompromised patients, including solid organ transplant recipients. the predominant high-resolution ct findings are ground-glass opacities, consolidation, centrilobular nodules, and branching linear opacities. adenovirus accounts for - % of acute respiratory infections in infants and children but for less than % of respiratory illnesses in adults. swyer-james-macleod syndrome is considered to be a post-infectious bronchiolitis obliterans (bo) secondary to adenovirus infection in childhood. respiratory syncytial virus (rsv) is the most frequent viral cause of lower respiratory tract infection in infants. the major risk factors for severe rsv disease in children are prematurity (< weeks gestation), congenital heart disease, chronic lung disease, immunocompromised status, and multiple congenital abnormalities. ct findings consist of small centrilobular nodules, airspace consolidation, ground-glass opacities, bronchial wall thickening, and "tree-in-bud" opacities ( fig. . ). primary infection with ebv occurs early in life and presents as infectious mononucleosis with the typical triad of fever, pharyngitis, and lymphadenopathy, often accompanied by splenomegaly. mild, asymptomatic pneumonitis occurs in about - % of cases of infectious mononucleosis. the ct manifestations of ebv pneumonia are similar to those of other viral pneumonias. the findings usually consist of lobar consolidation, diffuse and focal parenchymal haziness, irregular reticular opacities, and multiple miliary nodules or small nodules with associated areas of ground-glass attenuation ("halo"). varicella is a common contagious infection in childhood with increasing incidence in adults. clinically presents in two forms: varicella (chickenpox) representing a primary disseminated disease in uninfected individuals and zoster (shingles) representing reactivation of latent virus (unilateral dermatomal skin eruption). pneumonia, although rare, is the most serious complication affecting adults with chickenpox. the thin-section ct appearances in varicella pneumonia reflect the multicentric hemorrhage and necrosis centered on airways. common findings include numerous nodular opacities measuring - mm in diameter, some with a surrounding halo of ground-glass opacity, patchy ground-glass opacities, and coalescence of nodules. cytomegalovirus pneumonia is a major cause of morbidity and mortality following hematopoietic stem cell (hsct) and solid organ transplantation and in patients with aids in whom cd cells are decreased to fewer than cells/mm . this complication characteristically occurs during the post-engraftment period ( - days after transplantation) with a median time onset of - days posttransplantation. ct features of cmv pneumonia consist of lobar consolidation, diffuse and focal ground-glass opacities, irregular reticular opacities, and multiple miliary nodules or small nodules with associated areas of ground-glass attenuation ("halo"). severe acute respiratory distress syndrome (sars) caused by sars-associated coronavirus (sars-cov) is a systemic infection that clinically manifests as progressive pneumonia. severe acute respiratory distress syndrome was first detected in the guangdong province of china in late , with major outbreaks in hong kong, guangdong, singapore, and toronto and vancouver, canada. over people were affected, with a mortality rate of %. the typical clinical presentation consists of an incubation period of - days, early systemic symptoms followed within - days by dry cough or shortness of breath, the development of radiographically confirmed pneumonia by day - , and lymphocytopenia in many cases. histologically, acute diffuse alveolar damage with airspace edema is the most prominent feature. the imaging features consist of unilateral or bilateral ground-glass opacities, focal unilateral or bilateral areas of consolidation, or a mixture of both [ , ] . mers is a viral disease caused by a coronavirus (mers-cov), with most of the infections believed to have originated in saudi arabia and the middle east. most patients develop a severe acute respiratory illness. ct may depict groundglass opacities, consolidation, interlobular thickening, and pleural effusion. during the subsequent weeks, other findings may be present, such as centrilobular nodules, a "crazypaving" pattern, obliterative bronchiolitis, peribronchial air trapping, and organizing pneumonia [ ] . in the spring of , an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza a (h n ) virus, widely known as swine flu, in mexico. on june , , the world health organization declared the first pandemic of the twenty-first century caused by swine-origin influenza virus a (h n ). the predominant ct findings are unilateral or bilateral ground-glass opacities with or without associated focal or multifocal areas of consolidation. on ct, the ground-glass opacities and areas of consolidation have a predominant peribronchovascular and subpleural distribution, resembling organizing pneumonia [ ] . • primary tb occurs most commonly in children. • the most typical form of pulmonary ntmb infection is frequently associated to elderly non-smoking white women without underlying lung disease (lady windermere syndrome). • with respect to the morbidity and mortality, influenza type a is the most important of the respiratory viruses in the general population. vap: the diachronic linguistics of pneumonia community-acquired pneumonia admission chest radiograph lacks sensitivity in the diagnosis of community-acquired pneumonia community-acquired pneumonia re-evaluation of the etiology and clinical and radiological features of community-acquired lobar pneumonia in adults ventilator-associated pneumonia health care-associated pneumonia (hcap): empiric antibiotics targeting methicillin-resistant staphylococcus aureus (mrsa) and pseudomonas aeruginosa predict optimal outcome imaging infection imaging of community-acquired pneumonia high resolution ct findings in community-acquired pneumonia atypical pneumonia atypical pneumonia--time to breathe new life into a useful term? radiology of bacterial pneumonia ct findings of pulmonary nocardiosis moraxella catarrhalis: from emerging to established pathogen mycoplasma pneumoniae pneumonia: radiographic and high-resolution ct features in patients ct of pulmonary tuberculosis treein-bud pattern at thin-section ct of the lungs: radiologic-pathologic overview tuberculosis: a radiologic review update on the epidemiology of pulmonary nontuberculous mycobacterial infections spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings the spectrum of pulmonary aspergillosis pulmonary candidiasis after hematopoietic stem cell transplantation: thinsection ct findings pneumocystis jiroveci pneumonia: high-resolution ct findings in patients with and without hiv infection pulmonary mucormycosis: radiologic features at presentation and over time imaging of pulmonary viral pneumonia thin-section ct of severe acute respiratory syndrome: evaluation of patients exposed to or with the disease severe acute respiratory syndrome (sars) middle east respiratory syndrome coronavirus: what does a radiologist need to know? ct utilization in the prospective diagnosis of a case of swine-origin influenza a (h n ) viral infection /), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license and indicate if changes were made. the images or other third party material in this chapter are included in the chapter's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the chapter's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use key: cord- - dq oe authors: greaves, peter title: respiratory tract date: - - journal: histopathology of preclinical toxicity studies doi: . /b - - / - sha: doc_id: cord_uid: dq oe the chapter describes different aspects of the respiratory tract. in preclinical safety studies, pathologies of the respiratory system can be a result of an intercurrent disease or can be induced by systemically administered drugs. intranasal or inhalation modes of therapy pose particular challenges in terms of the formulations and technologies required to administer a drug. a complex technology is developed to support the assessment of adverse effects of inhaled substances in rodent and nonrodent species, and the extrapolation of experimental findings to humans. the nasal chambers are the structures that are first to be subjected to the effects of inhaled substances, whether microorganisms or chemical substances. in rodents, the relatively small size of the nose and nasal sinuses facilitates a histological examination. findings show that infectious agents cause inflammation in the nose and nasal sinuses, and this may be associated with inflammation in the conjunctiva, the middle ear, and the oral cavity. it has been observed that a particular response of the rodent nasal mucosa to some irritant substances, including pharmaceutical agents, is the formation of rounded eosinophilic inclusions in the cytoplasm of sustentacular cells of the olfactory epithelium, and to a lesser extent in respiratory and glandular epithelial cells. by far and away the most important pulmonary diseases in humans are related to the smoking of tobacco. however, occupational lung diseases caused by inhalation of industrial chemicals, particulate matter and antigens, are also important causes of morbidity and mortality. for this reason, considerable effort has been directed to the examination of airborne pollutants over recent years, including study of their effects in laboratory animals when administered by the inhalation route. extensive study has shown that a complex array of defensive mechanisms protects the lung against the adverse effects of airborne substances and pathogenic organisms. aerodynamic factors prevent access of particles larger than |im diameter for these are deposited on the walls of the nasal passages. particles measuring between and (im diameter tend to be trapped by the mucus-covered ciliated epithelium lining the bronchial tree and removed by mucociliary transport aided by the cough reflex. smaller particles may reach the alveoli where they are ingested and transported by pulmonary macrophages.^ considerations of airborne delivery to the lungs are also important in the development of therapies to be administered via the respiratory tract. whilst the inhalation route has been used for many years for volatile anaesthetic gases, the respiratory tract is increasingly being employed for delivery of therapy in not only for asthma and other lung diseases but also as a means of systemic delivery of polypeptides such as insulin. in contrast to the adverse pulmonary effects of cigarette smoke and industrial pollutants, therapeutic agents remain a relatively minor cause of pulmonary toxicity in humans although actual incidence is difficult to ascertain. however, drug-induced pulmonary disease appears to be an increasingly frequent clinical problem and the drugs associated with parenchymal pulmonary injury in humans continue to increase.^ although it is difficult to assess in the context of the underlying disease process, it has been suggested that about % of patients receiving wellestablished anticancer drugs develop various forms of pulmonary toxicity some novel antineoplastic therapies may have a similar liability.^ drug-induced toxicity usually occurs after exposure of lung tissue via the circulation to parent drug or metabolites, although increasingly the adverse effects of direct administration of drugs to the lungs needs consideration in preclinical studies. in patients a number of drugs have been associated with pulmonary toxicity which can occur through different mechanisms and take different forms.^"^ through their specific pharmacological action drugs can produce excessive effects on bronchial calibre or pulmonary function. drugs mediate allergic reactions in the bronchi or lungs. they may also produce a variety of obscure, diffuse pulmonary alveolar conditions including a pulmonary syndrome resembling systemic lupus er ^hematosis. as the respiratory tract is a major route by which microorganisms gain entry into the body, opportunistic pulmonary infections with bacteria, viruses, fungi or protozoa are consequences of immunosuppression or broad-spectrum antibacterial therapy. as in other organs, drugs that disturb coagulation may precipitate pulmonary thromboembolism or haemorrhage. localized lung lesions also result from accidental, diagnostic or therapeutic inhalation of xenobiotics. mucociliary clearance is also sensitive to therapeutic agents that affect the secretion of mucus and fluid, ciliary activity and transport.^ treatment with antacids or histamine h blockers can also increase the risk of pneumonia developing in patients in intensive care units through increasing gastric ph, which leads to an overgrowth of gram-negative bacteria in the stomach and retrograde pharyngeal colonization.^ in preclinical safety studies, pathology of the respiratory system can be the result of intercurrent disease or be induced by drugs administered systemically. intranasal or inhalation modes of therapy pose particular challenges in terms of the formulations and the technologies required to administer drug. the different anatomical and physiological characteristics of the airways also influence drug toxicity, disposition and metabolism. the development of drugs to be administered by inhalation or intranasal routes is particularly difficult because of the perceived risks of high local drug concentration in respiratory tissues and their use in potentially vulnerable patients with pulmonary disease.^ a complex technology has been developed to support the assessment of the adverse effects of inhaled substances in rodent and non-rodent species and the extrapolation of the experimental findings to humans.^'^ in order to administer drugs by inhalation, it is necessary to generate aerosols (suspensions of particles in a gas) with a well-defined composition, particle size and shape. they must be delivered to the respiratory tract of laboratory animals in a way that parallels the likely human exposure. in case of therapeutic agents, this should avoid non-respiratory pathways through the skin and food. when aerosols are inhaled, various fractions of the particles are deposited at different locations in the respiratory tract. site of deposition depends primarily on particle size, but variability in the sites of deposition occurs among different laboratory animal species and humans by virtue of the differences in the size and shape of the respiratory passages as well as breathing patterns. ^^ in addition, there are different types of inhalers used in human therapy to consider in the assessment, which can deliver different materials to the lungs, for example nebulizers, propellant-driven metered dose inhalers and dry powder inhalers for asthma treatment. ^^ the subsequent fate of inhaled particles depends not only on their size but also their shape, chemical nature, and solubility in body fluids. soluble substances are absorbed into the blood stream and are removed by the pulmonary circulation. they may also undergo metabolism by enzymes present in the cell populations of the respiratory tract and reactive metabolites may cause local pulmonary damage. insoluble, inert particles are removed primarily by the mucociliary transport system of the trachea and bronchi or through phagocytosis by macrophages. overload of the lung by even relatively inert, nonfibrous particles such as titanium dioxide or carbon black may impair alveolar macrophage-mediated particle clearance. ^^ this may lead in turn to accumulation of dusts over time with eventual fibrotic and tumorigenic responses, particularly in rats.^^ measurements of respiration rate, tidal volume, airway resistance, pulmonary gas exchange and the disposition of the inhaled substances have an important place in the evaluation of chemically induced lung damage in laboratory animals.^"^'^^ however, the key component of the evaluation of the adverse effects of inhaled substances is careful morphological assessment of the fixed tissues. even though there are novel and very sensitive physiological methods for the characterization of oedema following lung injury in rodents, light and electron microscopy of lung tissue provides vital qualitative evidence of the nature of injury. ^^ the nasal chambers are the structures which are first to be subjected to the effects of inhaled substances, whether microorganisms or chemical substances. although these chambers are not usually examined in great detail in conventional toxicity studies in which substances are administered orally or by parenteral routes, they are carefully examined histologically when drugs are administered by inhalation. study of nasopharyngeal silicone rubber casts has shown considerable species differences in the anatomy of this part of the airway. ^^"^^ relative to total nasal length, the nasopharynx is longest in rats and shortest in humans with the dog in an intermediate position. maxilloturbinates are relatively simple structures in man and non-human primates but highly complex in dogs and rodents. as a consequence, regional nasal airflow and disposition patterns vary considerably and this influences the distribution of lesions produced by inhaled xenobiotics in the nasal cavity.^^ however, comparison of the nasal cavity of rhesus monkey and humans using magnetic resonance imaging and nasal casts have shown that many similarities in structure exist in these species. ^^ the anterior nares are lined by stratified squamous epithelium. in other zones the sinuses are covered either by respiratory or olfactory epithelium with a zone of transitional epithelium at the junction between the two types. respiratory epithelium is similar to that found elsewhere in the respiratory passages being composed of ciliated cells, serous and mucous cells, brush cells, intermediate cells and progenitor basal cells. it represents a cellular system engaged in mucociliary clearance carrying surface secretions to the nasopharynx to be cleared by swallowing. although this epithelium is similar to that lining the other large airways, key differences are the particularly rich complement of secretory cells and the complex vasculature of the nose which can modulate capillary, arterial and venous blood flow through the mucosa.^^ mucins may be particularly important. it has been postulated that they not only have a physical protective function but also possess antioxidant properties by virtue of the scavenging behaviour of their high proportion of sugar groups. ^^ the proportion of the nose lined by olfactory mucosa is variable between species, being disposed over a much larger area in dogs and rodents than in primates. ^^ however, it is structurally similar in humans and rodents. it is located in more dorsal or posterior regions of the nasal passages out of the direct line of airflow during normal respiration. olfactory mucosa is a pseudostratified columnar epithelium composed of basal cells, sustentacular cells and sensory cells with mucus-secreting bowman's glands situated in the lamina propria. basal cells are composed of two distinct types, light and dark cells. the light type represents the primitive, stem cell population. sustentacular or supporting cells are non-ciliated, columnar cells possessing microvilli that extend into the overlying layer of mucus. cell bodies of olfactory sensory neurons are situated in the middle layer of the epithelium between sustentacular and basal cells. their dendritic processes extend above the epithelial surface to end in a ciliated expansion referred to as the olfactory vesicle that is believed to be the receptor of odour perception. olfactory axons extend from the cell body, penetrate the basement membrane in bundles to become surrounded by schwann cells and eventually join with the olfactory bulb. the olfactory system is of importance in toxicology for it can be selectively damaged by xenobiotics, including therapeutic agents, presumably as a result of its high metabolizing capacity. the superficial location of neural cells in the olfactory epithelium also provides a model system for the study of the effects of xenobiotics on neural cells. submucosal mucous glands have been well characterized in the rat, hamster and dog, where they are divided into lateral nasal glands and maxillary recess glands. these are both situated in the posterior parts of the nasal cavity and composed of mucus-secreting cells.^^"^^ immunocytochemical study using antisera raised against the major isoenzymes of rat hepatic microsomal cytochromes p induced by ( -napthoflavone, -methylcholanthrene, phenobarbitone and pregnenolone- -a-carbonitrile as well as nadph-cytochrome p reductase, epoxide hydrolase and glutathione s-transferases b, c and e, has shown their presence in rat nasal mucosal cells.^^ cyp a enzymes appear to be expressed at high levels in the respiratory tract mucosa.^^"^^ this suggests that the nasal mucosa not only has a capacity for metabolizing and activating xenobiotics by oxidation, but also for hydration and inactivation of potentially toxic epoxides and conjugating electrophilic, reactive metabolites with reduced glutathione. it has been shown that the distribution of immune-reactive enzymes is different in olfactory and respiratory mucosa.^^ xenobiotics can be metabolized within both olfactory and respiratory mucosa but the olfactory regions appear to possess greatest capability for oxidative metabolism. consequently, regional differences in nasal toxicity and tumour formation from inhaled materials may not only be a response to different water solubility and deposition patterns but also differences in the formation of reactive metabolites.^'* another feature of this metabolizing activity is that it can be induced by systemically administered xenobiotics and this can alter the distribution of enzyme activity in the nasal mucosa.^^ studies of the mouse olfactory mucosa have shown that whilst typical hepatic inducers of cyp a do not significantly change its expression in the mucosa, olfactory toxicants can alter the pattern of enzyme distribution.^^'^^ like many other tissues exposed to external environmental agents, the nasal mucosa possesses aggregates of lymphoid tissue in the underlying lamina propria. in rats these areas, characterized by follicles containing both t and b cell areas, are located in the ventral aspects of the lateral walls of the nasal airways at the opening of the nasopharyngeal duct.^^'^^ like the gutassociated lymphoid tissue, these nasal follicles have been shown in the rat to be covered by specialized epithelium with islands of cells with microvilli, socalled m or membranous cells. little is known of any toxicity occurring in this tissue despite its strategic position in the respiratory tract.^^ in rodents, the relatively small size of the nose and nasal sinuses facilitates histological examination. usually this area is sectioned transversely into several standardized blocks following decalcification.^^ there have been a number of detailed publications describing the histological preparation and assessment and recording of pathology of the rodent nasal cavity.^^"^^ careful standardized histological sections, careful recording of lesions with the use of diagrams of the rodent nasal cavity are useful in the assessment of lesions in the nasal cavity found in inhalation studies."*^ in larger species, particularly dogs and primates, sectioning and blocking is more complex. although dissection is required, a similar procedure following decalcification can be adopted. careful examination of haematoxylin and eosin stained sections remains paramount in the assessment of the nasal cavity, although special stains may be helpful. examination of cytokeratin expression in the respiratory mucosa has been used as a marker of epithelial differentiation in the respiratory tract>^ a test system that relates to the innervation of the nasal mucosa is that proposed by alarie.^^ the trigeminal nerve endings in the nasal mucosa of mice mediate the response to sensory irritants and this can be measured by a decrease in respiratory rate. it has been shown that a good correlation exists between the decrease in respiration rate in mice exposed to airborne chemicals and the nasal irritancy potential of the chemicals in humans.^^ this enables the detection of airborne sensory irritants and the prediction acceptable levels of exposure to the upper respiratory tract in people. microbial pathogens infectious agents cause inflammation in the nose and nasal sinuses and this may be associated with inflammation in the conjunctiva, middle ear and oral cavity. murine pathogens may cause alterations in the respiratory tract that can confound the assessment of changes induced by xenobiotics.^^ in rats, microbiological agents implicated in the development of rhinitis and sinusitis include corynebacterium kutscheri (pseudotuberculosis), streptococcus pneumonia, pasteurella pneumotropica, klebsiella pneumoniae, mycoplasma pulmonis and the sialodacryoadenitis virus or rat corona virus.^^ rats infected with the sialodacryoadenitis virus show inflammation and necrosis of the upper respiratory epithelium as well as damage to salivary and lachrymal glands. the sendai virus, a paramyxovirus, also has marked tropism for the respiratory tract, including the nasal cavity, and is associated with systemic effects that can compromise studies in laboratory rodents. occasionally, fungal infections of the airways with. aspergillus fumigatus are reported.^^ a variable that has been shown to influence the severity of the rhinitis produced by mycoplasma pulmonis is the strain of rat. following housing of lewis and fischer strains together to eliminate microbial and environmental differences it was shown that the lewis strain developed a more severe rhinitis following inoculation with mycoplasma pulmonis than fischer rats, although the reason for the difference was unclear."^^ rats exposed to ammonia, a common pollutant of the air in laboratory animal cages, have also been shown to develop lesions of the dorsal meatus, dorsal nasal septum and prominence of the turbinates.^^ these lesions are characterized histologically by swelling or mild degeneration of the epithelium. it appeared that ammonia exposure potentiated the acute inflammatory response of the nasal cavity to microbiological pathogens. a microorganism reported in the nasal cavity of rhesus monkeys employed in inhalation studies is the nematode of the genus anatrichosoma.^^ sections of this nematode are found in the squamous epithelium of the nasal vestibule and are associated with acanthosis and hyperkeratosis of the epithehum and a multifocal or diffuse granulomatous inflammation in the submucosa. administration of toxic or irritant substances to laboratory animals by the inhalation route produces degenerative, inflammatory and reactive changes in the nasal mucosa. the range of histological features is similar to those found in other mucosal surfaces damaged by other exogenous agents. whilst therapeutic agents administered by the inhalation route do not usually produce a severe degenerative or inflammatory responses in the nasal mucosa, at least at therapeutic doses, the simple categories proposed by hardisty and colleagues in recording of degenerative and reactive lesions following exposure to volatile chemicals are useful.'^^ categories suggested are: degeneration, regeneration, atrophy (postdegenerative), respiratory metaplasia and basal cell hyperplasia and inflammation. degeneration is usually the earliest morphological change characterized by loss of sensory and sustentacular cells resulting in a thinner mucosa. bowman's glands and nerve bundles, individual cell necrosis may be seen in more severe cases. regeneration is characterized by proliferation of basal cells associated with an epithelium that loses its regular structural features. post-degenerative atrophy usually follows severe damage and is characterized by loss of sensory and sustentacular cells. respiratory metaplasia is a process whereby the normal olfactory mucosa is replaced by pseudostratified epithelium of respiratory type often with cilia. basal cell hyperplasia represents a longer term effect where the proliferating basal cells form a distinct layer of cells below the respiratory epithelium. an example of the type and distribution of the degenerative and inflammatory conditions which can be induced by inhaled irritants is provided by the study in which swiss-webster mice were given various irritants by inhalation for periods of hours per day for days at concentrations that produced a % decrease in respiratory rate (alarie test). although the degree of histological changes varied with different agents, the changes were broadly similar in type and distribution.^^ most agents examined produced little or no alteration in the squamous mucosa lining the anterior part of the nose apart from some mild increase in thickness of the squamous layers. principal sites of damage were shown to be the anterior respiratory epithelium adjacent to the vestibule and the olfactory epithelium of the dorsal meatus. there was a distinct decrease in severity in posterior regions. histologically, the lesions in respiratory epithelium ranged from mild loss of cilia and small areas of epithelial exfoliation to frank erosion, ulceration and necrosis of the epithelium and underlying tissues including bone. variable polymorphonuclear cell infiltration was also found. in some cases, early squamous metaplasia developed on the free margins or the naso-maxillo-turbinates. changes to the olfactory epithelium varied from focal to extensive loss of sensory cells associated with damage to sustentacular cells. in severe cases, complete loss of olfactory epithelium occurred. although the degree of histological change was shown to vary with different agents, lesions induced by the more water-soluble chemicals tended to remain localized in the anterior part of the nasal cavity whereas agents with relatively low water solubility produced lung lesions in addition. it was suggested that these findings demonstrated the powerful 'scrubbing' action of the nasal cavity for water soluble, airborne xenobiotics.^^ inflammatory alterations have been induced in the nasal cavity of rodents treated with therapeutic agents at high doses by inhalation. significantly irritant substances do not make viable therapies. however, the precise relevance of such changes for human therapy by the inhalation route are sometimes questionable when the nasal damage is limited to high doses and it is not associated with alterations in other parts of the respiratory tract. in the case of tulobuterol, a -adrenergic receptor agonist, it was argued that the nasal inflammation induced in rats in a one month inhalation toxicity study was the result of a particularly high exposure of the nasal epithelium to drug, not representative of the likely human exposure to tulobuterol by inhalation, where little or no nasal exposure would occur.^^ rp [ cyclopentyloxy)-ar-( , -dichloro- -pyridy)- -methoxybenzamide], a novel type iv phosphodiesterase inhibitor which was being developed for the treatment of asthma and rheumatoid arthritis, was also reported to produce degeneration of the olfactory epithelium in rats but neither dogs nor mice after single and repeated oral doses and by inhalation.^^ histologically, the olfactory epithelium showed necrosis of the superflcial epithelial layers including the sustentacular and sensory cells, with sparing of the basal cell layer. there was also damage to bowman's glands. the development of proliferative lesions and ultimately tumours of principally neuroectodermal origin followed chronic treatment. as rp was highly metabolized and the nasal lesions could be inhibited by treatment of rats with metyrapone, a non-speciflc inhibitor of cytochromes p , it was postulated that the changes were the result of p mediated activation in the olfactory tissues, not linked to its pharmacological phosphodiesterase activity.^^ nasal epithelial degeneration and necrosis has also been reported in both rats and dogs treated with another candidate anti-inflammatory drug ci- by the intranasal route. this agent affected olfactory epithelium more than respiratory mucosa, suggesting that metabolism was important in the generation of this toxicity^^ although the nasal cavity has not been often examined histologically in great detail in toxicity studies conducted on drugs administered orally or by parenteral routes, damage to the nasal mucosa can be induced by drugs administered by these routes. one example is methimazole, a thioureylene antithyroid drug used in clinical practice where oral doses of . - mg/kg/day are employed and abnormalities of taste and smell have been described.^^ administration of methimazole at relatively high doses to long-evans rats by single oral ( mg/kg) or intraperitoneal ( mg/kg) routes was shown to produce damage to the sustentacular and sensory cells with sparing of the basal cells and basement membrane.^^ bowman's glands were also involved. methimazole is metabolized by the flavin-containing monooxygenase system and it is employed as a model substrate for this enzyme in vitro. the presence of flavin-containing monooxygenase isoforms in olfactory mucosa of long-evans rats suggested that reactive intermediates may be responsible for the nasal toxicity ^^ similar changes have been reported in mice where depletion of glutathione in the olfactory mucosa has been demonstrated also suggesting formation of local reactive metabolites.^^ histological examination has also shown that intravenous administration of a single dose of vincristine to mice damages the olfactory epithelium.^^'^^ vincristine is a vinca alkaloid derivative used in cancer therapy which has antimitotic activity and binds to tubulin. cell death was noted in olfactory cells - days after dosing with a peak of cell proliferation at days and repair after about days. these features resemble those that can be seen in other proliferating tissues after single doses of antimitotic drugs. the risk of damage to human olfactory cells from agents with these effects in rat nasal mucosa often remains uncertain because an understanding of relative exposure and metabolism in different species and a better understanding of the metabolic potential of human olfactory mucosa is required. a particular response of the rodent nasal mucosa to some irritant substances, including pharmaceutical agents, is the formation of rounded eosinophilic inclusions in the cytoplasm of sustentacular cells of the olfactory epithelium and to a lesser extent in respiratory and glandular epithelial cells.^^'^^ these inclusions are pas-negative and ultrastructural examination shows that they are membrane-bound, ellipsoid bodies containing homogenous electron dense matrix. their significance remains uncertain. a consensus classification for the variety of proliferative, non-neoplastic changes and atypical epithelial lesions and neoplasms found in the rat nasal cavity has been defined by schwartz and colleagues.^^ the classification of the international agency for research on cancer provides a similar perspective for rats and mice.^^'^^ proliferative lesions may be occasionally seen in untreated rodents in carcinogenicity studies but are much more commonly induced by administration of xenobiotics in inhalation carcinogenicity studies. spontaneous nasal tumours are uncommon but most often squamous in type in rats whereas in mice spontaneous squamous tumours are extremely rare and haemangiomas and respiratory adenomas predominate.^^'^^ the generally agreed categories are described below: mucous (goblet) cell hypertrophy and hyperplasia affects the nasal respiratory epithelium and are characterized by the presence of enlarged mucus-filled goblet cells, some of which form clusters suggestive on intraepithial glands. squamous cell hyperplasia is seen in the stratified squamous epithelium of the nares and is characterized by a focal increase in the number of cell layers. cells may show atypia with irregular enlarged, pleomorphic nuclei and nucleoli. squamous metaplasia occurs to respiratory epithelium under conditions of chronic damage. it is characterized histologically by the presence of three or more layers of epithelial cells with eosinophilic cytoplasm and clear cell boundaries whereas advanced lesions show typical keratinization and formation of intercellular bridges. cellular atypia may also be seen and should be characterized when found. respiratory epithelial metaplasia (of the olfactory epithelium) represents atrophy and degeneration of the olfactory epithelium with loss of sensory cells and in advanced cases loss of sustentacular cells with replacement by ciliated and non-ciliated respiratory epithelium. it may be seen as a spontaneous focal lesion in aged rats. epithelial hyperplasia with cellular atypia (atypical hyperplasia, basal cell hyperplasia, dysplasia) is a term used to embrace proliferative lesions in the respiratory and olfactory mucosa in the nasal cavity in which there is varying degrees of altered differentiation and atypia. there is perturbation of the growth pattern of the epithelium such that the changes are not those found in the normal regenerative response to transient mucosal damage. adenomas (polypoid or villous adenoma, adenomatous or villous polyp) usually develop in the anterior part of the nasal cavity and are usually exophytic lesions that develop from respiratory epithelium or nasal glands. adenomas of respiratory epithelium may be papillary in form but are, by definition, well circumscribed with minimal cellular pleomorphism and atypia. they may very occasionally occur spontaneously in aged rats.^^ adenomas of nasal glands usually show an acinar pattern. squamous cell papillomas develop in the squamous epithelium of the nares or in areas of squamous metaplasia in respiratory or olfactory epithelium. they are exophytic lesions with limited connective tissue stroma. they may develop spontaneously in aged rats.^^ carcinomas of either squamous or glandular differentiation develop in the nasal mucosa. histologically, they have similar characteristics to those in other epithelial tissues. they are rare spontaneous lesions in aged laboratory rodents but may be induced by xenobiotics administered by inhalation, orally or by the parenteral route. squamous carcinomas have been reported to develop in a small number of untreated fischer rats used in carcinogenicity studies in association with point mutations in the c-h-ras and c-k-ras gene.^^ olfactory neuroblastoma (ethesioneuroblastoma, olfactory neuroepithelioma, olfactory neuroepithelial carcinoma) show olfactory differentiation and arise from olfactory epithelium. they do not seem to occur as spontaneous lesions in rats or mice and only rarely induced.^^'^^ cells are arranged in lobules or in solid sheets with scanty stroma. cells are relatively uniform with scanty cytoplasm with round or oval hyperchromatic nuclei. true rosettes with lumens or pseudorosettes are also seen. poorly differentiated tumours of this type may require ultrastructural study for diagnosis. olfactory neuroblastomas typically show the presence of electron-dense neurosecretory granules, neurofilaments or axons. as there is no detailed understanding of the biological behaviour of these neoplasms in laboratory rodents, the generic term olfactory neuroblastoma is usually preferred. they are almost always invasive tumours.^^ olfactory carcinomas forming glands, follicles and rosettes have been occasionally reported in aged syrian hamsters.^^'^^ mesenchymal neoplasms may be seen in the nasal cavity, particularly after exposure to potent carcinogens. their histological features are similar to those in the soft tissues and bone elsewhere in the body (see chapter ). the mucosa lining the larynx and trachea becomes involved as part of an upper or lower respiratory tract infection. for instance, in rats, an acute laryngitis or tracheitis has been shown to accompany experimental infection with mycoplasma pulmonis and the sialodycroadenitis virus."^^'^^ a spontaneous degenerative condition of tracheal and laryngeal cartilage of uncertain pathogenesis associated with granulomas has been reported in fischer rats.^^ the condition increases in severity and incidence with advancing age although it is seen in rats as young as weeks of age. tracheal cartilage rings may also show alterations in genetically engineered animals, such as the c bl/ j-tgn(c -l-tag)cjeg (tag) mice that have generalized defects in cartilage development.^^ the larynx of rodents is also susceptible to the effect of inhaled substances, notably tobacco smoke but also pharmaceutical agents and propellants.^^'^^ in view of the localized nature of induced lesions in the larynx, standardized histological sectioning techniques have been proposed for rats, mice and hamsters using anatomical landmarks.^^"^^ the target site is located on the ventral floor of the larynx near the base of the epiglottis cranial to the ventral laryngeal diverticulum. lesions tend to occur in the ventrolateral region, which is covered by respiratory epithelium and the inner aspect of the arytenoid processes which is lined by squamous mucosa. the larynx responds to inhaled irritants by inflammatory, degenerative and regenerative changes in a manner similar to other regions of the respiratory tract. these include disruption of the epithelial cells, inflammatory cell exudates and infiltration, goblet cell hyperplasia and squamous metaplasia.^^ however, these changes are not specific to inhaled irritants but also occur as a response to natural respiratory tract pathogens in conventionally housed rats.'^^ the pseudostratified ciliated and non-ciliated mucosa of the trachea may also show pathological alterations in inhalations studies, although sites at the bifurcation (carina) are those often first affected. consequently, the carina should be systematically included in examination of the respiratory tract for induced lesions.^^'^^ as in the nasal passages a range of proliferative lesions including squamous hyperplasia, mucous cell hyperplasia, as well as papilloma, carcinoma and mesenchymal tumours are occasionally reported in the airways in laboratory rodents. in humans and laboratory animals, the trachea terminates at the bifurcation giving rise to two main bronchi which serve left and right lungs. depending on species, the main bronchi subdivide into further branches that enter the different lobes. various forms of branching are recognized. bronchi may arise as side-branches from a parent or stem bronchus (monopodial). the parent bronchus can divide into two equal daughter bronchus (dichotomous) or several daughter bronchi ipolychotomous)j^ study of silicone rubber casts of the respiratory tract has shown that the bronchial trees of humans and non-human primates are essentially dichotomous, in contrast to the monopodial pattern of rodents.^^ the comparatively long trachea of the dog gives rise to dichotomous upper airways but monopodial branching develops peripherally within each lobe. the size of the lungs is generally dependent on size and weight of the different species. auometric studies have shown that lung volume, alveolar surface area and diffusing capacity increase proportionally with body weight across a broad range of mammalian species, although cell size and surface area appear to be more determined by cell function rather than species size.^^ dogs have comparatively smaller body mass and higher airway dimensions compared to humans.^^ the number of lobes is species-dependent. the human lung possesses an upper and lower left lobe and an upper, middle and lower right lobe. this contrasts with the upper, middle and lower left lobes and a fourth, azygos right lobe in rhesus monkeys and baboons.^^ the dog has three lobes on both right and left sides. rats, mice and hamsters show cranial, middle, caudal and postcaval right lobes with a single, left lobe in mice and rats and a superior and inferior lobe on the left side in hamsters. cell types lining the bronchi are generally similar between species.^ the majority of cells are the ciliated cells that are accompanied by variable but relatively smaller proportions of basal cells, intermediate cells, mucous or goblet cells, serous cells, neuroendocrine and brush cells. in addition, mucous cells line the adjacent bronchial glands.^^ unlike the tracheal mucosa, which is pseudostratified, the mucosa of intra-pulmonary bronchi is non-stratified. ciliated cells are tall, columnar cells attached to basal and intermediate cells by desmosomal junctions. tight junctions exist between adjacent specialized cells at the apex. each cell possesses or more cilia that are engaged in mucociliary clearance.^^ the superficial cell surface also shows a pronounced glycocalyx. the cytoplasm of ciliated cells contains scattered profiles of rough endoplasmic reticulum, a supranuclear golgi and numerous mitochondria particularly near the apex where a prominent cytoskeleton is also found. mucous or goblet cells are typical mucus-secreting cells representing about % of the bronchial mucosa cell population in man but less than % in pathogenfree rats.^ the serous cell is a cylindrical or pyramidal cell containing small, round, closely packed serous granules.^^ basal cells are compact, pyramidal cells resting on the basement membrane. they are believed to be progenitor stem cells with the intermediate cells representing an intermediate stage of cell differentiation. the mucus-secreting and ciliated cells form the cellular basis for the mucociliary clearance mechanism of the main conducting airways. the epithelium is covered by a mucous blanket that is fairly complete in humans and rabbits but patchier in rats.^ the mucous layer is segregated into an upper layer or gel phase separated from epithelial cells by a serous layer or sol phase. the complex carbohydrates of the glycocalyx and secreted mucosubstances show species-related differences in their sugar residues, which can be demonstrated histochemically by the use of labelled-lectins.^^ mucociliary clearance mechanisms are sensitive to the effects of many therapeutic agents, particularly those that alter mucins, fluid or electrolyte balance and ciliary activity. anaesthetic gases, barbiturates, narcotics and alcohol depress clearance function. by contrast, topical, oral or parenteral administration of ( -adrenergic agonists, isoprenaline and adrenalin, produce a dose-dependent stimulation of mucociliary transport by an effect on ciliary beat frequency, probably mediated by increasing levels of cyclic adenosine monophosphate in ciuated cells rather than through vascular changes. although basal mucociliary function is dependent on normal vagal tone, parasympathomimetic agents can affect mucociliary transport. acetylcholine and cholinergic agents stimulate ciliary activity whereas anticholinergic drugs, atropine and hyoscine, inhibit ciliary activity and mucociliary transport. these substances may alter deposition of inhaled particles in the lung.^ clara cells or non-ciliated bronchiolar cells located in the bronchiolar epithelium, first described by clara in , are small and cylindrical in shape with highly infolded nuclei, surface microvilli, well developed golgi, abundant endoplasmic reticulum and characteristic oval, homogeneous electron-dense granules in the apical cytoplasm. in rats, rabbits and humans the granules are pas-positive, although they are usually considered pas-negative in hamster and mouse.^^ clara cells have high metabolic activity. they contain cytochrome p -dependent enzymes and secrete a variety of proteins.^^"^^ clara cell secretory protein is the major component of their cytoplasmic granules and they have been shown to produce mucin following antigen challenge.^^ in most laboratory rodents, the conducting airways terminate abruptly at the non-cartilaginous terminal bronchiole that opens directly into an alveolar type airway, the alveolar duct which in turn communicates with the alveoli.^^ squamous epithelial or type i cells form only about % of all lung cells but they line over % of the alveolar surface, by virtue of extremely long cytoplasmic extensions. the principal gas exchange takes place across this cell. in the rat, the typical thickness of this barrier is nm for a cytoplasmic extension of a type i pneumocyte, nm for basal lamina and nm for an endothelial cell.^^ the type i cell contains juxtanuclear mitochondria and the long smooth cytoplasmic extensions contain many ribosomes and pinocytotic vesicles. the anatomical configuration and function of type i cells render them highly vulnerable to inhaled gases and particles. the other main alveolar lining cell is the granular pneumocyte or type ii cell which constitutes about % of all lung cells, but which covers only about % of the alveolar surface.^^ this cell does not possess the long cytoplasmic processes typical of type i cells and it shows many microvilli on its luminal surface. the cell cytoplasm contains rough endoplasmic reticulum, golgi apparatus, some mitochondria and characteristic oval, osmiophilic lamellar inclusions. surfactant, a microaggregate of phospholipid and protein which modifies alveolar surface tension at low inflation volumes, is secreted by type ii alveolar cells. ultrastructural immunocytochemistry has shown the presence of surfactant apoproteins in the synthetic organelles and in the lamellar bodies of these cells, in agreement with the concept that the surfactant apoproteins are synthesized in the rough endoplasmic reticulum, glycosylated in the golgi and are stored in lamellar bodies.^^ type ii cells are more resistant to the damaging effects of xenobiotics and unlike type i cells they retain the ability to undergo mitotic division. following damage to type i cells, increased numbers of mitoses are evident in type ii cells which results in the appearance of large undifferentiated epithelial cells which ultimately differentiate into type i and type ii cells.^^ the lung also contains a dense neural network and a population of endocrinelike cells believed to be important in lung function.^^ these neurosecretory cells (kultschitsky or apud cells) are scattered sparsely in the epithelial surface of the larynx, trachea bronchi, bronchioles and alveoli. these cells are oval or cuboidal with oval nuclei, and argyrophilic cytoplasm which electron microscopic examination shows to contain dense core granules. the role of neuroendocrine cells in the lung is uncertain but immunocytochemical study has shown them to contain a number of neuroendocrine substances including neurone-specific enolase, synaptophysin, chromogranin and a variety of other peptides similar to vasoactive intestinal peptide, bombesin, calcitonin, serotonin, leu-encephalin, p endorphin and acth.^^'^^ cells lining the bronchi, bronchioles and alveolar walls are capable of metabolizing xenobiotics. immunocytochemical study has shown the presence of immune-reactive cytochromes p , nadph cytochrome p reductase, epoxide hydroxylase and glutathione s-transferase in bronchial epithelial cells, ciliated bronchiolar cells, clara cells, type ii and possibly type i pneumocytes in the rat lung.^^ different cell populations contain different amounts of enzymes, clara cells containing the greatest concentrations of the phenobarbitoneinducible isoenzyme of cytochrome p , nadph-cytochrome p reductase and epoxide hydrolase. studies of microsomal enzyme activities suggest that lung tissue contains fewer p isoenzymes than liver, principally forms cyplal cyp b , cyp a and cyp bl^^ whereas p enzyme activity is highly concentrated in specific cell types, overall microsomal enzyme activity is low compared with liver on the basis of microsomal protein weight.^^ other important cells are the pulmonary alveolar macrophages and lymphocytes. lymphocytes are found in the epithelium of the airways, in the interstitium of alveoli and as part of follicles in bronchial walls. pulmonary macrophages form part of the specific immune defence system of the lung, involving, as elsewhere in the body, antigen presentation. in the rat and mouse, distinctive populations of pulmonary macrophages have been described based on enzyme activities and reactivity to monoclonal antibodies against monocyte and macrophages surface determinates.^^'^^ bronchus associated macrophages in rat and mouse have more acid phosphatase and less non-specific esterase activity than the populations found in the pulmonary alveoli and interstitial tissues. an important aspect of the immune system is the bronchus-associated lymphoid tissue or balt, which forms part of the mucosal lymphoid system found in other epithelia. the morphology of balt is a useful guide to the nature and degree of immune stimulus in the lung. balt is organized in a way that is characteristic of other peripheral lymphoid organs. it is structurally similar in the laboratory rat, mouse, rabbit, guinea pig as well as in man but its size and prominence is species and strain-dependent as well as a function of the degree of antigenic stimulus^"^"^^. in the rat, the balt is composed of lymphoid aggregates or fouicles located mostly between a bronchus and artery with a zone of lymphocytes situated immediately under the bronchial epithelium. as in other peripheral lymphoid tissue, balt is organized into b and t cell zones but in no predetermined manner. immunocytochemical staining has shown that b and t lymphocyte zones differ in location from one aggregate to another. there are about two t lymphoc ^es for every three b cells compared with a ratio of : in rat peyer's particles.^^ the ratios may be different in other species. quantitative observations of t cell subsets using monoclonal antibodies have also shown that rat balt normally contains twice as many t-helper as t-suppressor/cytotoxic lymphocytes.^^ the t cells are confined to one or two discrete zones with a light scattering of t cells within the b cell zones and immediately under the bronchial epithelium. in common with lymph nodes, interdigitating cells are also found. the epithelium overl dng balt shows anatomical modifications. it is composed of ciliated and non-ciliated cells covered by microvilli. in conventional, untreated laboratory rats, balt shows little activity and germinal centres are usually absent, although balt may be more prominent in some rat colonies in association with non-specific inflammatory lesions in lungs.^^'^^ in one colony of young wistar rats germinal centres were not seen in balt in untreated animals but they developed following the administration of a single intratracheal dose of lipopolysaccharide, a t cell-independent antigen.^^^ single intratracheal doses of t cell dependent antigens such as horseradish peroxidase, bovine serum albumin and bcg have been shown to produce only minor morphological changes which include expansion of the zone of lymphocytes immediately under the epithelium and infiltration of the bronchial epithelium overlying balt by lymphocytes.^^^ in addition, perivascular, peribronchial or alveolar infiltrates of small and large lymphocytes and macrophages were observed in the lungs of rats given bcg. immunoc ^ochemical study of the rat balt following intratracheal challenge with horseradish peroxidase showed that the majority of cells that infiltrated the bronchial epithelium were t helper (cd positive) lymphocytes. ^^^ furthermore, la antigen expression of the epithelial cells overlying the balt was shown to increase, associated with an increase in the number and size of microvilli, a more pronounced glycocalyx and a decrease in number and size of cilia. immunocytochemical study of the balt tissue in c b / mice using monoclonal antibodies to lymphoid and macrophage populations has demonstrated quite similar arrangements of cells to those in the rat with the majority of t cells belonging to the t helper (cd positive) class.^^ the pulmonary lymphatic system drains into mediastinal or cervical lymph nodes. although among rat strains differences in the location of lymph nodes and their drainage occur, tracer studies in the fischer rat using colloidal carbon have shown that the lung lymphatics drain mainly into posterior mediastinal lymph nodes and those in the tracheal wall drains primarily to the internal jugular and posterior cervical nodes.^^^ although a variety of fixation, embedding and staining procedures are available for light and electron microscopic examination of lung tissue, there is no substitute for initial, careful visual inspection of the lungs at autopsy. uneven collapse of lungs on opening the thoracic cavity, discoloration or alteration in texture of the pleural or cut surface, congestion and presence of fluid in the larger airways may indicate structural damage. in rodent lungs, small pulmonary adenomas may be detectable by inspection in good light. fresh lung weight is also a helpful measure in lung assessment, although passive vascular engorgement can significantly affect this value. nevertheless, studies in the normal fischer rat have shown that after exsanguination, wet lung weights show a close relationship to body weight and that dry weight of lungs consistently represents about % of the wet weights regardless of age or body weight. ^^^ an increase in wet weight over dry weight appears to be a good index of pulmonary oedema. ^^ various methods of fixation have been employed although simple immersion fixation in formalin for conventional light microscopy has the virtue of simplicity and it avoids the risk of translocation or removal of exudates from airways and alveoli. mixtures of formaldehyde, paraformaldehyde and glutaraldehyde are used in initial fixation for electron microscopy.^^ the best overall appreciation of lung architecture is achieved by instillation of fixative via the trachea under an appropriate constant pressure or by perfusion fixation of the pulmonary arteries that is less liable to dislodge intra-alveolar exudate. in a review of methods employed routinely in rodent toxicity studies, instillation of fixative via the trachea was the preferred method in most laboratories because its advantages were seen to outweigh its disadvantages.^^ the sampling procedure is an important aspect of histological examination of the bronchi and lungs, particularly those of large laboratory animals. the extent of histological sectioning in conventional toxicity studies should be modulated to take account of lesions found by macroscopic examination, the type of study and the nature of the test substance. the bronchi should be carefully sampled to allow assessment of any alterations in bronchial epithelium. morphometric analysis represents a sensitive tool of value in the evaluation of drug-induced lung changes, but it requires particularly rigorous sampling and evaluation procedures.^^^'^^^ a tiered, multiple stage or cascade sampling technique is normally considered the most appropriate for morphometric studies.^^'^ this involves dividing the lung into a series of homogeneous compartments or strata from which randomly selected samples can be examined by appropriate light or electron microscopic techniques. conventional special stains for reticulin and collagen as well as pas and alcian blue for mucins are helpful in the characterisation of lung damage and changes to the respiratory epithelium. immunocytochemistry and enzyme cytochemistry are also useful in the study of the heterogeneous cell population of the lung. xenobiotic metabolizing activity can be studied both by enzyme cytochemical methods as well as by immunocytochemical techniques using antisera specific for pulmonary monooxygenases and related enzymes.^^ important structural components, particularly collagen and laminin can be studied both at light and ultrastructural level with immunocytochemical methods.^^^ cytokeratin immunocytochemistry can be used as a method for the characterization of changes to epithelial cells.^^ clara cells can be localized by the presence of clara cell secretory protein and ciliated cells by the presence of tubulin.^^ endocrine cells are visualized by immunocytochemistry using antibodies to general neuroendocrine markers such as chromogranin and synaptophysin or regulatory peptides.^^ other useful antigens, which can be demonstrated in the lung, include surfactants, lysozyme, immunoglobulins and those of microorganisms that infect the lung.^^^ electron microscopy is particularly useful for the detailed characterization of injury to the cells of the alveolar epithelium and endothelium ( figure . ). pulmonary oedema is a component of many inflammatory conditions of the lung, including those induced by infectious agents. however, the term oedema is reserved for a poorly cellular exudate characterized by the presence of pale, homogenous eosinophilic material in the alveoli, sometimes associated with a similar exudate in the lung septae and perivascular connective tissue. it occurs in a number of spontaneous conditions such as in congestive cardiac failure, metastatic pulmonary neoplasms or as an agonal change in association with pulmonary congestion and haemorrhage. drugs may induce cardiogenic pulmonary oedema as a consequence of pulmonary hypertension or impaired ventricular contractility. cardiogenic oedema is often associated with vascular congestion and red blood cells and haemoglobin may leak into airspaces. this can give rise to the presence of haemoglobin crystals within the oedema fluid in formalin-fixed tissue sections. most importantly, pulmonary oedema may be a manifestation of acute lung injury. inhalation or systemic administration of toxic chemicals may produce acute pulmonary oedema (see figure . ). some substances such as phenylthiourea and a-naphlythiourea produce massive pulmonary oedema in laboratory animals when administered orally, principally as a result of damage to the endothelium of pulmonary capillaries and venules. ^^^ over drugs have been reported to produce non-cardiogenic pulmonary oedema in humans, either directly or through poorly understood immunogenic mechanisms.^ another form of pulmonary oedema involves the main airways. allergic reactions in sensitized airways of asthmatic individuals is believed to result from cross-linking of ige and activation of mast cells that degranulate and release inflammatory mediators. ^^^ this has been reproduced in the main airways of rats sensitized to ovalbumin and then challenged with ovalbumin by the intratracheal route. ^^^ this treatment leads to rapid accumulation of bronchial exudate, degranulation of mast cells and the development of mucosal oedema, most marked immediately below the respiratory epithelium. congestion and haemorrhage is a frequent finding in the lungs of laboratory animals, where it is usually related to certain modes of death. it can be associated with administration of drugs and chemicals that have adverse effects on cardiac function or on the coagulation system. administration of heparin to rats produces a characteristic extravasation of blood into the air spaces.^^^ lower respiratory tract infection is generally not a major health hazard among laboratory animals but it is nevertheless an ever-present threat that can cause overt respiratory disease within a colony or develop following administration of xenobiotics. subclinical pulmonary infections and infestations can also produce histological alterations in the bronchial airways or pulmonary parenchyma which mimic changes induced by inhaled irritants or systemically administered drugs.^^'^^ furthermore, some respiratory pathogens alter immune defences and exacerbate the effects of inhaled substances. ^^^ a range of bacterial and viral pathogens may produce inflammatory lung changes.^^ typically, bacterial pathogens such as steptococcus pneumoniae produce acute bronchitis associated with a variable degree of acute inflammation of the lung parenchyma (bronchopneumonia) or a confluent lobar pneumonia. viral agents are generally associated with histological features of bronchiolitis and interstitial pneumonia, characterized by an increase in mononuclear cells in the respiratory bronchioles and alveolar septa. the histological features are variable for they depend on the particular pathogen, species and strain, immune status, presence or absence of secondary infection and the particular stage at which the infection is examined. respiratory infections are frequently mixed. changes due to secondary bacterial infection are frequently superimposed on those induced by viruses. sequential histopathological examination of the lungs of laboratory animals following inoculation with respiratory tract pathogens has been able to characterize the evolution of pathological changes produced by individual organisms. for instance, following inoculation with mycoplasma pulmonis, one of the more important respiratory pathogens among laboratory rodents both lewis and fischer rats were shown to develop upper and lower respiratory tract inflammation. in the lewis strain this was characterized after days by a variable acute inflammatory exudate in bronchi and bronchioles with focal bronchiectasis, inflammation and hyperplasia of the epithelium with a predominantly macrophage infiltration of the alveoli and alveolar walls.^^'^^^ these changes were associated with marked hyperplasia of the bronchusassociated lymphoid tissue (balt), which extended down the airways and blood vessels towards the periphery of the lungs. although the lymphoid hyperplasia was also found in inoculated fischer rats, it was less marked and accompanied by little or no mucopurulent exudate or active inflammation of the bronchial walls. this disparity in response suggested that differences were related to the degree of lymphocyte activation in the two strains, an imbalance in regulation of lymphocyte proliferation in lewis rats, or both.^^^ other studies have been conducted in both rats and mice infected with another important respiratory pathogen of laboratory rodents, the sendai virus (parainfluenza type ). sequential studies showed that the initial damage to bronchial and bronchiolar epithelium is associated with polymorphonuclear and lymphocytic inflammation (bronchiolitis). immunocytochemical and ultrastructural studies revealed the presence of viral antigen in the mucosa.^^^ hyperplastic and multinucleated syncytial epithelial cells develop in the hyperplastic terminal bronchiolar epithelium and the inflammatory process extended to involve peribronchial or peribronchiolar parenchyma with infiltration of alveolar walls by mononuclear cells, macrophages and neutrophils. a similar cell population accompanied by cell debris and oedema fluid develops in air spaces. pulmonary arteries show only minor involvement with inflammatory cells and focal reactive hyperplasia of the endothelium. immunocytochemistry and ultrastructural examination suggested that virus replication takes place in alveolar type i and type ii epithelial cells and macrophages but not in endothelial or interstitial cells of the alveolar septae.^^^ it was shown that when repair occurs there may be residual distortion of bronchiolar and alveolar walls by collagen and hyperplastic cuboidal epithelium may line the thickened alveolar septa. air spaces may also contain enlarged macrophages with pale vacuolated cytoplasm.^^^ strain differences in susceptibility have also been demonstrated to this virus. there is differential pulmonary interleukin (il- ) gene expression between virus-susceptible brown norway rats and resistant fischer rats and il- treatment provides protection from virus-induced chronic airway inflammation and remodelling. moreover increased tumour necrosis factor a (tnfa) expression has been shown to be an important regulatory factor in the development of sendai virus-induced bronchiolar flbrosis in infected rats.^^^ virus-inoculated brown norway rats had increased tnfa pulmonary mrna levels and increased numbers of bronchiolar macrophages and fibroblasts expressing tnfa protein compared with virus-inoculated f rats.^^^ the corona virus, which causes sialodacryoadenitis in many rat colonies, also produces lower respiratory tract inflammation. this is characterized by acute bronchitis and bronchiolitis with focal extension into lung parenchyma. thickened oedematous, hypercellular alveolar walls infiltrated by monocytic cells are found.^^ immunocytochemistry has shown the presence of viral antigen in bronchial and bronchiolar epithelial cells. there is also peribronchial lymphocytic infiltration and increased prominence of balt. ultimately complete resolution occurs. viruses remain a potential source of spontaneous respiratory disease in laboratory dogs. canine adenovirus type , parainfiuenza sv , canine herpes virus, coronavirus and parvovirus have all been isolated from laboratory dogs developing respiratory disease.^^^ the syndrome of visceral larva migrans also incites focal inflammation, granulomas and fibrosis in the lungs of species such as dog and primate in which parasites are prevalent. the syndrome of visceral larva migrans is usually defined as that which results from the migration of nematode larvae into the viscera. it has been well described in the beagle dog lung where it results from the larvae of toxocara species or metastrongyloid nematodes.^^^'^^^ the precise identification of parasites is not always possible in tissue sections. histological appearances of infested lungs are highly variable. nematodes surrounded by granulomas and granulomatous inflammation, mostly in a subpleural location, may be visible in sections. in affected lungs there may be perivasculitis and active arteriolitis, bronchiolitis and peribronchiolitis. pleural involvement by the inflammatory process can be marked, particularly in regions overlying granulomas. scarring develops and pleural and sub-pleural fibrosis is frequently associated with epithelial hyperplasia and squamous metaplasia of the associated airways ( figure . ).^^^ the lesions may sufficiently severe to resemble those induced by high doses of anticancer drugs such as bleomycin (see below). pulmonary acariasis is a common infestation of many species of non-human primates caused by various species of the mite pneumonyssus. reproduction of the mites appears to take place in the terminal bronchioles. pneumonyssus simicola is the recognized form found in rhesus monkeys.^^^ although it is most prevalent in wild caught primates, the disease is not easily eliminated during breeding in captivity. ^^^ even when eliminated by ivemectin the lesions of chronic bronchiolitis, bronchiectasis and pigmentation may persist as an incidental finding. ^^^ as the mite can produce significant destructive pulmonary pathology and render animals susceptible to secondary pulmonary bacterial infections, it can disrupt or confound the interpretation of toxicity studies performed in primates. the lesions are located most frequently in cranial lobes and are characterized by the presence of bullae distending the pleural surface, parenchymal cysts, nodules and scar tissue.^^^'^^^ histologically, there is a wide range of inflammatory activity. fully developed lesions are characterized by granulomatous bronchiolitis and peribronchiolitis with involvement of immediately adjacent alveoli. cystic lesions involving the bronchiolar walls develop around the parasites giving rise to the appearance of walled-off cysts composed of highly cellular granulation tissue, associated with neutrophils, lymphocytes, macrophages, multinucleated giant cells and various pigments (see below). in less active lesions, dilated, cystic airways with walls composed of thick bands of smooth muscle and lined by squamous or cuboidal epithelium are found. pneumocystis carinii is an important cause of pneumonia in patients with the acquired immunodeficiency syndrome (aids) as well as in other immunocompromised patients, including those treated with immunosuppressive drugs.^^"^ the natural habitat of pneumocystis carinii is pulmonary alveoli and it is widely encountered in the human population without being associated with overt disease. both clinical and experimental evidence suggests that impaired cellular immunity is much more important as a predisposing factor than impaired humoral immunity. ^^^ as in humans, laboratory animals may have latent pneumocystis infection that becomes clinically evident following immunosuppression. it has been shown in the rat that chronic administration of various regimens of adenocorticosteroids, low protein diets, cyclophosphamide and other immunosuppressive drugs with concomitant antibiotic administration to prevent other infections gives rise to typical pneumocystis pneumonia. ^^^ rodents with genetically deficient cellular immunity also develop pneumocystis pneumonia. the importance of pneumocystis pneumonia in toxicology is that it can be considered as a sentinel of chronic immune depression. in haematoxylin and eosin stained sections, pneumocystis pneumonia is characterized in both humans and rodents by the presence of alveoli filled with foamy eosinophilic material containing a few macrophages and indistinct nuclei of pneumocystis (figure . fe). ovoid or crescent-shaped structures of the organisms become clearly visible with gomori methenamine silver or toluidine blue stains. ultrastructural study of rats with pneumocystis pneumonia shows that trophozoites attach themselves most frequently to type i pneumocytes by altering their morphology to the contours of the pneumocytes rather than by a process of invasion. ^^^ systemically administered therapeutic agents may produce histological changes within the lung parenchyma that mimic components of the normal response to respiratory pathogens. however, there is no sharp separation between agents that produce pulmonary oedema with those that are associated with acute inflammatory changes and histological features overlap because an acute inflammatory process is often accompanied by exudate within airspaces. an example of drug-induced pulmonary inflammation in laboratory animals and humans is reported following the administration of interleukin (il- ). il- is a glycoprotein lymphokine, molecular weight kda, which is normally produced by activated t cells and mediates immunoregulatory responses. it has been produced in large quantities by recombinant dna technology for use in tumour immunotherapy. however, high doses have been associated with a number of adverse effects, notably the 'vascular leak' syndrome, characterized clinically by pulmonary oedema, pleural effusions and ascites. ^^^ the vascular leak syndrome has been reported in laboratory animals given high doses of this agent. histological examination of the lungs of b d f mice developing this syndrome following administration of il- showed infiltration of the alveolar walls with large lymphocytes and intra-alveolar proteinaceous exudate containing large lymphocytes, macrophages and red blood cells.^^^'^^^ pulmonary venules and arterioles showed the presence of lymphocytes attached to or lying beneath the endothelium, infiltrating vessel walls or in a perivascular location where they were accompanied by oedema fluid or red blood cells. similar, but less severe changes have been demonstrated in rats given il- .^^^ in addition, treated rats showed an infiltration of pulmonary vasculature with eosinophils probably secondary to an eosinopoietic cytokine produced by il- stimulated lymphocytes. immunocytochemical evaluation of the lymphoid infiltrate in mice showed that most of the cells were thy . positive (cd ) lymphocytes. furthermore, co-administration of asialo gml (ganglio-n-tetrosyl-ceremide) with il- not only abrogated the clinical signs but also reduced the number of asialo gml-positive lymphocytes in the tissue sections. as lymphoid cells expressing lyt- (cds, suppressor/cytotoxic t cells) were unaffected by asialo gml treatment, it was postulated that the vascular leak syndrome (but not antitumour efficacy) in these mice was mediated by an endogeneous subset of il- stimulated lymphocytes or lymphokine-activated killer cells. ^^^ corresponding changes were also observed in liver and lymphoid tissue. immunocytochemical and detailed electron microscopic studies in rats have supported the concept that il- induces cytotoxic vascular damage that is mediated both directly by lymphokine-activated killer cells and cytotoxic t lymphocytes with secondary release of inflammatory cytokines.^^^ as in humans, severe chronic pulmonary inflammatory disease in laboratory animals may compromise pulmonary function and lead to secondary alterations in other organs. although the mechanisms were not explored in detail, a diffuse interstitial pulmonary inflammatory process with lung haemorrhage was induced in rats treated for two years with prizidilol (skandf -a ), an antihypertensive agent with both vasodilator and ( adrenoceptor blocking properties.^^^ affected animals developed dyspnoea associated with reduction in lung volume, deformity of the thoracic spinal column and marked cardiac hypertrophy. inflammation with granulomas develops in the lungs of laboratory animals under a variety of different circumstances, which have been alluded to above. a common cause in rodents is granulomatous pulmonary inflammation resulting from aspiration of stomach contents or food particles (aspiration pneumonia). this is sporadically observed in aged rodent where it is associated with general ill health, particularly resulting from pressure effects of large pituitary adenomas and subsequent disturbance of pharyngeal or laryngeal reflex mechanisms. ^^^ histologically, the lungs show peribronchial and peribronchiolar granulomatous inflammation with macrophages and foreign body cells associated with fragments of refractive vegetable matter. the associated bronchial mucosa may also show reactive changes including goblet cell hyperplasia in long-standing cases. as dogs and primates are more liable to be infested by parasites, granulomatous inflammation in response to pulmonary larvae is more common in these species. pulmonary tuberculosis represents a potential problem among non-human primate colonies in view of its insidious onset and its liability for transmission from monkeys to humans. ^^^ pathological findings are similar to those so well known in the human disease. the disease is characterized by the presence of granulomas in lung parenchyma and lymph nodes. in florid cases there may be caseation surrounded by epithelioid and multinucleated giant cells and variable numbers of lymphocytes, plasma cells and flbroblasts. diffuse granulomatous pneumonia as a result of tuberculosis is also reported in non-human primates. granulomatous pneumonitis is also produced in laboratory animals by the intravenous injection of bcg. twenty-eight days following intravenous injection of bacille calmette-guerin (bcg), the lungs of c b / mice contained numerous granulomas composed of histiocytes and round cells which were surrounded by alveoli with thickened walls and associated with mild interstitial pneumonitis. ^^^ these histological changes were associated with an increase in the number of thy . -positive (cd ) cells, especially lyt- (cds) positive lymphocytes. the histological changes were abrogated by treatment with cyclosporin a suggesting an important role for cd -positive lymphocytes in the development of the granulomas. discrete granulomas occur in the lungs of experimental animals in response to intra-tracheal or intravenous injection of certain relatively insoluble substances (figure . ) . intra-tracheal administration of insoluble polymerized dextran and latex micro-particles to mice showed that the morphology and the systemic effects of granulomas depends on the nature of the injected substances. it has been shown that large granulomas develop rapidly in the pulmonary parenchyma around dextran particles that subsequently regress quickly, whereas latex particles produce small, discrete stable granulomas. ^^^ although both forms of granulomas are of foreign body or non-immunological in type, those produced by dextran but not latex beads, are associated with anergy-like immunosuppression, probably caused by release of soluble factors from the granulomas. it has been reported that granuloma formation after instillation of sephadex beads is associated with increases in the interleukin -(il- ) like activity in the lung.^^^ studies comparing the effects of inhaled crystalline silica and titanium dioxide have shown a correlation between the release of the macrophage derived cytokine il- and granuloma formation, suggesting that il- might be a useful biomarker for granuloma formation. ^^^ localized, angiocentric granulomas of foreign body type, clustered around pulmonary arteries and arterioles and occasionally alveolar capillaries and venules also develop following intravenous injection of relatively insoluble polysaccharides or other polymers. ^^^ characteristic epithelioid and large, foreign body type giant cells efface the smaller vessels although overt necrosis is not usually observed (figure . ) . haemosiderin-laden macrophages accumulate in the alveou of laboratory animals in association with chronic pulmonary congestion and haemorrhage. similar changes occur in patients in congestive cardiac failure where the haemosiderin-laden macrophages are termed 'heart failure' cells. the lungs of non-human primates are especially liable to contain alveolar, perivascular and peribronchial aggregates of macrophages laden with various brown pigments. iron-containing pigments have been associated with the inflammatory changes produced by simian lung mites (pneumonyssus simicola) which are prevalent in many non-human primates. in addition, lungs from some primate colonies may show perivascular and peribronchial collections of brown-grey macrophages containing highly refractive spicules and plates composed of high concentrations of silica.^^^'^^^ it has been shown that in old world primates including rhesus and cynomolgus monkeys, this pigment contains fossil diatomaceous material, compatible with the concept that the animals inhale dusts containing diatoms and other silicon fragments to which they are exposed in their semi-arid, natural habitats.^^^ chronic lung injury from a variety of different causes is frequently associated with the development of pulmonary fibrosis characterized by the replacement of the normal pulmonary structure by a thickened collagenous matrix with consequent reduction in the capacity for gas exchange. regardless of the inciting agent, the fibrogenic process appears to be generally characterized by disruption of the normal alveolar-capillary structure, leakage of exudate from the vascular compartment into the airspaces, subsequent invasion by infiammatory cells and fibroblasts associated with excess matrix formation. studies in laboratory animals with different fibrogenic agents as well as in humans have suggested that central to pulmonary fibrogenesis is increased production of tnfa by macrophages.^^'^^^'^^^"^^^ this cytokine is a not only a mitogen for fibroblasts but also a potent activator and chemo-attractant for macrophages, capable of stimulating release of other cytokines and inducing expression of adhesion molecule expression on endothelial cells. moreover, it has been shown that tnfa receptor knockout mice appear protected from the fibroproliferative effects of inhaled asbestos. ^^^ pulmonary fibrosis is a common sequel of chronic lower respiratory tract inflammation. it may be associated with, or preceded by interstitial pneumonitis, characterized by infiltration of lymphocytes, plasma cells and macrophages with scattered polymorphonuclear cells. ^^^ focal pulmonary fibrosis occurs spontaneously in laboratory animals, although this is usually most prevalent in dogs and non-human primates as a response to chronic infestation by parasites, which are not easily eliminated during breeding. in humans, conditions leading to pulmonary fibrosis vary widely. they include infections, shock lung syndrome, ionizing radiation, inhalation of irritant particulate matter, exposure to antigens or excessive amounts of oxygen as well as the results of the toxicity of paraquat and a range of both cytotoxic and noncytotoxic therapeutic agents which cause pulmonary parenchymal injury.^'^^^ the principal therapeutic agents that produce pulmonary fibrosis in both humans and laboratory animals are anticancer drugs. bleomycin, a glycopeptide preparation derived from streptomyces verticillus, is the best known example but pulmonary fibrosis is also associated with the clinical use of a number of other anticancer agents, including l, -bis-( -chloroethyl)-l-nitrosourea (bcnu or carmustine), cyclophosphamide, busulphan, mitomycin c and methotrexate. ' , - the precise mechanisms involved in the induction of pulmonary fibrosis by antineoplastic drugs in humans are poorly understood. the true incidence for a particular drug is difficult to estimate because of confounding factors in cancer patients, such as concomitant administration of several drugs, radiation and oxygen therapy, diffuse pulmonary cancer and opportunistic infections. it is probable that drug-induced fibrosis is accentuated by concomitant administration of several antineoplastic agents, radiation therapy, hyperoxia, preexisting pulmonary damage and age of the patient. severity is often related to total dose of drug received.^^^ novel antineoplastic drugs may also produce lung toxicity.^ bleomycin is associated with the development of interstitial pneumonia and pulmonary fibrosis in clinical use and this can be reproduced in experimental animals. the histopathological appearances of bleomycin-induced pulmonary fibrosis in patients are in many instances different from those seen in laboratory animals because the lungs of patients treated with bleomycin are modified by the primary neoplastic disease, smoking, multiple drugs, radiation therapy and secondary pulmonary infections, interstitial pneumonitis and fibrosis.^^^ it has been postulated that tnfa is an important mediator in the development of bleomycin-induced fibrosis. ^'^ in the preclinical evaluation of bleomycin beagle dogs were given cycles of drug by the intravenous route for periods of up to weeks. ^^^ dogs developed anorexia, weight loss, a variety of epithelial lesions as well as focal interstitial pneumonia and fibrosis. the focal lung lesions were characterized by increased elastic fibres, reticulin, collagen and acid mucosubstances. the lesions were situated predominantly in the pleural and subpleural zones, suggestive of a potentiating effect of friction between the pleural surfaces. histologically the lesions resembled those produced by larvae migrans in the dog (see figure . a). similar histological changes have also been described in both rats and mice treated with bleomycin by both the intravenous and intratracheal route.^^^'^^^ as fibrosis is such a consistent change, bleomycin-treated rodents have been extensively employed as a model for pulmonary fibrosis. early changes include mild, diffuse increases in interstitial lymphocytes, macrophages, polymorphonuclear cells and perivascular or interstitial oedema. after about a week, interstitial infiltrates also comprise fibroblasts with early collagen deposition, associated with proliferation of macrophages and type ii pneumocytes.^^^'^^^ subsequently, the amount of interstitial collagen increases, with eventual scarring and collapse of lung tissue in proportion to the cumulative dose given. ^^^ immunohistochemical and ultrastructural study of rats and mice treated with bleomycin shows a large accumulation of immune-reactive laminin and reduplication of the basement lamina within the thickened alveolar walls. ^^^ in bleomycin-treated rats three-dimensional scanning electron microscopy shows drug-induced capillary remodelling comprising irregular alveolar and pleural capillaries with increased diameter and decreased branching. ^^^ certain strains of mice have been shown to possess greater sensitivity to bleomycin fibrogenesis. the c bl/ strain produces a greater fibroblastic response than dba/ and swiss mice and the balb/c strain demonstrates a particularly poor fibroblastic response. ^^^ therapeutic use of cyclophosphamide is also occasionally associated with the development of pulmonary interstitial fibrosis.^^^'^^^ it appears to be associated with two forms of pathology: an early-onset pneumonitis and a late onset progressive pulmonary fibrosis. ^^^ similar changes have been less easy to reproduce in laboratory animals. when mice were sequentially examined for periods of up to one year after a single intravenous dose of loomg/kg of cyclophosphamide, only slight pulmonary interstitial thickening and hypercellularity was observed in association with progressive multifocal accumulation of intra-alveolar macrophages. ^^^ however, these changes were also accompanied by a progressive increase in pulmonary hydroxyproline content and a decrease in pulmonary compliance with time in treated animals compared with controls. the changes were amplified by exposure to % ambient oxygen. the bronchiolitis, alveolar septal infiammation and fibrosis induced by gold therapy in patients with rheumatoid arthritis is probably immune-mediated. this condition is associated with peripheral eosinophilia and drug-induced alterations to the immune system.^^^ emphysema is characterized by abnormal, permanent enlargement of airspaces distal to terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis. three principle types, centriacinar, panacinar and distal acinar emphysema, are recognized in humans. enlargement of air spaces as a result of congenital factors or fibrous scarring are grouped separately and not regarded as emphysema. ^^^ emphysema has been reported as an age-related spontaneous change in laboratory rats.^^^ however, several experimental rodent emphysema models have been developed, using intratracheal instillation of proteolytic enzymes papain, pancreatic and neutrophil elastase. this gives rise to histological appearances resembling panacinar emphysema in humans.^^^ irritant gases, notably oxides of nitrogen, are also capable of inducing changes in the lungs of laboratory rats and hamsters following long term exposure which resemble mild human, centrilobular emphysema.^^^'^^^ a variety of different names have been applied to membrane-bound, acid phosphatase-positive cytoplasmic inclusions with a lamella or crystalloid ultrastructural matrix. these include myeloid bodies, myelinoid bodies, myelin figures or myelinosomes. these lysosomal inclusions are seen in small numbers in a variety of normal cell types but they accumulate in various organs in laboratory animals following administration of a wide variety of drugs of diverse therapeutic classes.^'^^^"^^^ the generalized accumulation of these lysosomal cytoplasmic bodies is generally called phospholipidosis, a term coined to describe the tissue accumulation of phospholipids. ^^^ at the light microscopic level, phospholipids are characterized by the increase in the number of foam cells in the airspaces. examples of drug-induced phospholipidosis include the anorectic drug chlorphentermine, tricyclic antidepressants, inhibitors of cholesterol biosynthesis such as triparanol, the antihistamine chlorcyclizine and its analogues, the selective oestrogen receptor antagonist tamoxifen, chloroquine and the cardiovascular drugs amiodarone, , 'diethylamino-ethoxyhexestrol and perhexiline.^^^'^^^'^^^ many tissues and organs may develop the cytoplasmic inclusions, including lymphoid cells, liver, pancreas, endocrine tissue, nervous system, muscle cells, eyes and particularly lungs. aminoglycoside antibiotics may produce laminated phospholipid inclusions in the renal tubular cell and imidazol antifungals in hepatocytes (see under liver and kidney, chapters and ). many drugs that induce phospholipidosis usually share structural features, notably a hydrophilic cationic side chain, a primary, secondary or tertiary amine and a hydrophobic region that is usually an aromatic ring or ring system. as this structural pattern renders these molecules amphiphilic, these drugs probably bind with polar lipids by means of electrostatic and hydrophobic forces.^^"^ this leads to formation of drug-lipid complexes which are poorly degraded by lysosomal enzymes and which accumulate in the cell cytoplasm to form the inclusions described above. as the binding is not covalent, its reversibility depends on the dissociation rate constant under the particular intracellular conditions and drug concentration achieved. predictions of this activity based on molecular structure have shown reasonably good correlation with the ability of compounds to produce phospholipidosis in cultured rat peritoneal macrophages. more recently other cell based systems have been proposed for screening for phospholipidosis.^^^'^^^ however these perform less well in the prediction of in vivo potency, presumably because of differences in drug disposition in blood and tissues. it should be underlined that the accumulation of foamy macrophages in the alveolar spaces may also be a spontaneous change in laboratory animals. it has long been recognized as a spontaneous alteration in ageing rats.^^^ it may also be found in lung tissue distal to bronchial lesions that impede clearance mechanisms. in contrast to drug-induced changes, the spontaneous lipidosis characterized by accumulation of alveolar foam cells occurs sporadically in older rats and is observed in both controls and treated animals. drug-induced phospholipidosis occurs within a period of several months during which lungs of control animals remain fairly free of foam cell accumulation. the lungs appear especially vulnerable to drug-induced phospholipidosis, possibly because macrophages are in very close proximity to blood-borne agents. phospholipidosis is also more clearly visible microscopically in alveoli whereas it can be easily overlooked in other organs. the continuous uptake of phospholipid-rich surfactant material from the alveoli by macrophages leads to excessive accumulation of phospholipids when their catabolism is impaired.^^^'^^^ the fact that lungs are commonly affected is a potentially useful diagnostic feature because in many organs phospholipidosis can be extremely difficult to recognize in haematoxylin and eosin stained sections. although the changes in the lungs are not specific for drug-induced phospholipidosis, an increase in the number of lipid-containing lung macrophages in treated animals compared with controls is relatively easy to detect and provides a simple way for the pathologist to screen for this effect. in severe generalized phospholipidosis in rats, the lungs show irregular pale grey or yellowish patches of discoloration of the pleura and parenchyma. this is a result of patchy or confluent aggregates of large, pale, foamy macrophages. they may be free lying or packed in alveoli and accompanied by granular, extracellular material. their abundant cytoplasm shows a vacuolated appearance in which fine eosinophilic granules are sometimes visible. the nuclei are rounded and centrally located structures of variable size (figure . ) . multi-laminated cells are also occasionally seen, as are vacuolated cells firmly attached to alveolar walls, probably pneumocytes. these foamy cells stain typically for phospholipids (e.g. acid haematin), although neutral lipids may also be present and stain with oil red o. semi-thin plastic-embedded sections stained with toluidine blue allow better characterization of phospholipidosis in all organs, including the lungs. the macrophages in the air spaces contain unmistakable dense, dark round cytoplasmic inclusions of variable size, some over mm diameter. ^^^ plasticembedded sections also show the inclusions in other pulmonary cells including pneumocytes attached to the alveolar walls, from which they can be seen discharging into the alveolar spaces. as in other organs affected by phospholipidosis, ultrastructural examination reveals dense, multi-lamellar membranes and numerous heterogeneous dense bodies of lysosomal origin (figure . ) . these bodies need to be distinguished from membranous bodies that form as a result of fixation for ultrastructural study. lipids tend to leach out and become hydrated to form myelinoid membranes during glutaraldehyde fixation. these structures are subsequently fixed by osmium to give rise to electron-dense membranous figures both outside and inside cells, particularly in mitochondria where they may be mistaken for pathological lesions.^^^ the lamella patterns seen in phospholipidosis may be simple alternating dense and clear lines spaced at - nm, or more complex arrangements of clear and dense lines. the other typical crystalloid inclusions of hexagonal aggregates of tubular subunits seen in other organs are not usually found in the lungs. the significance of these various forms is uncertain but they probably represent the various phases in which phospholipids exist and are influenced by proportions of lipids present. electron microscopic examination reveals that not only are pulmonary macrophages affected by these changes but that inclusions may be present in pneumocytes types i and ii, pulmonary capillary endothelial cells, smooth muscle cells, bronchiolar epithelium and occasionally neutrophils.^^^"^^^ the changes are typically still visible several weeks after withdrawal from treatment with the offending agent. although the extent of pulmonary phospholipidosis in the lungs varies between dosage regimen and animal species, studies with chlorphentermine, , 'diethylaminoethoxyhexestrol and amiodarone indicate that similar cytological and ultrastructural changes occur in most laboratory animal species studied including rats, mice, hamsters, guinea pigs, rabbits and dog.^^^'^^^'^^^'^^^ safety assessment -amphiphilic drugs what are the imphcations for humans of drugs that induce phosphohpidosis in laboratory animals? novel compounds continue to be found that possess the property of producing phosphohpidosis in laboratory animals with varying degrees of severity.^^^'^^^ although not all drugs that produce phosphohpidosis in animals have been studied in humans, only very few drugs that produce phosphohpidosis in animals have been shown capable of inducing significant phosphohpidosis in human clinical practice.^ agents such as chloroquine, , 'diethylamindethoyhexestrol and amiodarone, which have been shown to produce phosphohpidosis in patients, can also induce cellular damage in the same organs. however the phenomenon of phosphohpidosis where phospholipids are packaged behind lysosomal membranes may not be causally related to cellular damage in humans. indeed the weight of evidence suggests that druginduced phosphohpidosis per se is an adaptive phenomenon and does not in itself have functional or deleterious consequences unless excessive. ^^^ hence, the finding of phosphohpidosis in animal studies with a novel drug requires careful assessment on a case by case basis with respect to its implications for the safety of humans. an example of this issue is the iodinated benzofuran derivative amiodarone, a potent antiarrhythmic drug effective against ventricular arrhythmia. lung toxicity continues to be a problem in patients treated for cardiac arrhythmias with this drug.^^"^ not only does phosphohpidosis occur in a wide variety of organs in laboratory animals treated with amiodarone,^^^'^^^ but also in liver, peripheral nerve cells, skin, lymphoid cells and lungs in patients at therapeutic doses.^^^'^^^'^^^ although pulmonary interstitial fibrosis occurs in association with phosphohpidosis in patients, amiodarone-induced phosphohpidosis in rodents is not associated with pulmonary fibrosis or significant functional alterations. several theories have been proposed for the pulmonary alveolitis and interstitial fibrosis in humans. the weight of evidence to date suggests that the accumulation of lipid-laden histiocytes is not causally related to the alveolitis or pulmonary fibrosis. ^^^ indeed, overall there is little evidence that the mere presence of phosphohpidosis is deleterious to the organism.^^^ cytotoxicity, possibly through the metabolite desethylamiodarone, has been proposed and an immune-mediated mechanism has been postulated, possibly favoured by the binding of drug to components of pulmonary tissue.^^^ it might also involve free radical formation or indirect influences on inflammatory mechanisms.^^^ it is also possible that pulmonary disease results from an interaction of several mechanisms and metabolic factors unique to particular patients. ^^^ despite undoubted differences in tissue and species sensitivity to development of phosphohpidosis, dose, drug disposition, metabolism and elimination and the degree of tissue exposure to drug are important considerations in safety assessment of drugs that produce phosphohpidosis in laboratory animals. although phosphohpidosis is more likely to occur at high doses employed in toxicity studies than at lower therapeutic doses used in patients, it has been suggested that this may be offset by faster ehmination of the drug, characteristic of small laboratory animals. ^^^ the potential for drugs to accumulate in critical tissues such as eye and heart is especially important when drugs are administered for long periods of time, particularly as tissue/plasma ratios of some amphiphilic drug may exceed , following repeated administration.^^^ consequently, although phospholipidosis may not have functional consequences, any implications for humans of drugs that induce phospholipidosis in laboratory animals can only be assessed on a case by case basis, with due consideration of mechanism, drug disposition and clinical risk-benefit analysis. it is important to underline that similar morphological changes due to the increased presence of phospholipids in lysosomes can also result from treatment with compounds that are not cationic amphiphilic structures. mechanisms include direct or indirect inhibition of lysosomal enzyme activity. this reenforces the need to understand the mechanism of any chemically induced increase of phospholipids in the lungs of laboratory animals. for example, it has been shown that when glycosaminoglycans accumulate in inherited human lysosomal disorders they inhibit other lysosomal enzymes, thereby inducing lysosomal phospholipid inclusions. ^^^ this is reflected by administration of high doses of the trypanocidal drug suramin to rats which induces intracellular storage of glycosaminoglycans associated with phospholipid inclusions in diverse organs including lungs. ^^^ although at light microscopy clear vacuoles are typically seen, electron microscopic examination shows the presence of both clear vacuoles containing glycosaminoglycans and lamellar phospholipid inclusions. a similar effect seems to have been produced in rats by elmiron®, a semi-synthetic heparin-like macromolecular carbohydrate derivative, chemically and structurally similar to glycosaminoglycans used clinically for anticoagulant effects and interstitial nephritis.^^^ another example is the induction of lysosomal inclusions in the lungs of rat and dogs by the macrolide antibiotic erythromycin.^^^ collections of foam cells were described in the lungs and lymphatic tissues of dogs and rats treated with high oral doses. foam cells in the lung showed a pattern of small whorls in vacuoles similar to that seen with other drugs that induce phospholipidosis. in vitro studies have suggested all macrolide antibiotics have the potential to cause phospholipidosis. biochemical studies suggest that drug binds to phosphatidylinositol-containing liposomes and inhibits activity of lysosomal phospholipase in close correlation with the number of cationic groups carried by each of the drugs. ^^^ hook reviewed other agents, such as oxidant gases and insoluble particles including silica, that can also increase phospholipid levels and histological appearances of phospholipidosis in the lungs.^^^ some of these agents inhibit phospholipid catabolism in the lungs giving rise to accumulation of surfactant protein a and surfactant lipoproteins and a clinico-pathological picture similar to pulmonary alveolar proteinosis in humans. studies from humans have shown that three chnically distinct forms of this condition occur: congenital, secondary or acquired. the congenital disease is caused by a diverse range of mutations in the genes encoding surfactant proteins or the ( c chain of the receptor of granulocyte-monocyte colony stimulating factor (gm-csf). the secondary form occurs in association with conditions where there is functional impairment or reduced numbers of alveolar macrophages, such as in haematological cancers, following immune suppression or inhalation of silica or toxic fumes. acquired or idiopathic alveolar proteinosis that accounts for over % of all cases ( . per persons) has been an enigma until recently. patients are at risk from infections, particularly nocardia, and the year survival rate appears to be about %. studies from transgenic mouse models and in humans have shown that autoantibodies against gm-csf are important in the development of the acquired form of the disease as this antibody causes a defect in macrophages function which impairs the catabolism of surfactant lipids and proteins. ^^^ in this context it is of interest to note that treatment with imatinib, a tyrosine kinase inhibitor of the bcr-abl tyrosine kinase constitutively expressed in philadelphia chromosome positive myeloid leukemia, has been associated with the accumulation of lamellar inclusions in pulmonary macrophages in a leukaemia patient, although this might have been a result of the primary disease. ^^^ studies in mice have suggested that imatinib mesylate actually inhibits the fibrogenic activity of transforming growth factor ( and prevents fibrosis induced by bleomycin.^^^ various forms of hyperplasia are found in the airways and lungs of laboratory animals. the mucosal surface of the bronchi may show hyperplasia of the goblet cells, squamous hyperplasia or metaplasia. the cells lining the terminal bronchiole and alveolus may also show hyperplasia and squamous metaplasia. standard classifications for the characterization of these changes in histological sections have been developed for use in rodent studies.^^"^^ goblet cell hyperplasia is a well-recognized response of the mucosa of conducting airways to chronic inflammation and inhalation of irritant substances such as cigarette smoke and sulphur dioxide.^^'^^'^^^'^^^ the degree of goblet cell hyperplasia is dictated by the severity and duration of the irritation or inflammatory process. florid cases of goblet cell hyperplasia are characterized by thickening and pseudostratification of the tracheal or bronchial mucosa by a population of tall, mucus secreting cells with abundant pale cytoplasm. in addition, goblet cells extend further down the airways than in normal animals and mucus may fill or distend the airways or impact in the alveoli. in less florid cases, a simple increase in the number of goblet cells may be found without other structural change.^^ goblet cell hyperplasia of the lining epithelium may be accompanied by an increase in size of the underlying submucosal glands. this has clearly been demonstrated in patients with chronic bronchitis and in rats where submucosal glands are normally quite prominent.^^^'^^^ species differences may exist because the airways of laboratory animals are variably endowed with goblet cells and submucosal mucous glands. the normal rat has more goblet cells lining the airways than either mouse or hamster. ^^^ the factors controlling these alterations are uncertain but is has been long suggested that increased mitotic activity as well as cell conversion, probably by metaplasia of serous or clara cells to mucous cells, is involved.^^^ it has more recently been shown in mice sensitized to ovalbumin and subject to a single antigen challenge by aerosol that clara cells in the proximal airways show great plasticity and become mucin-secreting cells.^^ pharmacological agents can induce goblet or mucous cell hyperplasia. rats given six or daily injections of isoprenaline, a non-selective ( receptor agonist showed a dose-and time-dependent increase in the number and size of alcian blue-positive goblet (mucous) cells as well as serous cells in the tracheal and bronchial mucosa. this was associated with an increase in length, width and depth of submucosal glands.^^^ similar changes were produced by pilocarpine, although both alcian blue-and pas-positive cells were increased in number following this agent, suggesting that pilocarpine induced both acid and neutral glycoprotein secretion. comparison of the distribution of these changes in the rat following isoprenaline, with those of salbutamol, pilocarpine and tobacco smoke, showed that there were regional differences in the distribution of these changes in the airways.^^'* isoprenaline produced a greater increase in secretory cells in peripheral airways than tobacco smoke, which itself produces a greater increase in mitotic activity. isoprenaline and pilocarpine produced a more diffuse change than the more selective ( agonist, salbutamol. the changes induced by these therapeutic agents are presumably the result of their pharmacological activity.^^'^ sturgess and reid showed that the changes in the rat were accompanied by hypertrophy of the pancreas, submaxillary and parotid salivary glands^^^ (see digestive system, chapter ). unlike the rat and mouse, the hamster appears predisposed to develop minor multifocal epithelial hyperplasia of the tracheal and bronchial mucosa spontaneously with advancing age. these changes are flat or polypoid in nature and are composed of clear cells and goblet cells.^^'^^ the epithelium of the bronchi shows squamous metaplasia in response to chronic irritation or injury. it is characterized by three or more layers of epithelial cells with abundant eosinophilic cytoplasm with prominent cell boundaries. it may be associated with degenerative alterations to the mucosa or goblet cell hyperplasia. squamous metaplasia can also develop in the alveolar parenchyma as a response to prolonged damage such as produced by large burden of inhaled irritant or insoluble dusts. the metaplasia is also characterized by the presence of several layers of flattened epithelial cells showing squamous differentiation. the term pulmonary keratinizing cyst has been recommended for pulmonary cystic lesions lined by non-neoplastic squamous epithelium without excessive proliferative change.^^^ hyperplasia, bronchiolo-alveolar (type ii cell hyperplasia) hyperplasia may involve the lining epithelium of the alveoli or bronchioli. this form of hyperplasia has been termed alveolar hyperplasia, adenomatosis, alveolar bronchiolization or epithelialization. it occurs spontaneously but can be induced by infections and administration of irritant xenobiotics in rats/^'^^^"^^^ j^j^g , ^^^ hamsters.^^^ histologically, the lesions consist of localized but unencapsulated foci of hyperchromatic regular, cuboidal or columnar cells investing airspaces without appreciable distortion of alveolar walls. neuroendocrine hyperplasia is well described in hamsters. although small aggregates of neuroendocrine cells (neuroepithelial bodies) are found at various levels of the bronchi and bronchioli in normal hamsters, administration of nitrosamines and -nitroquinoline -oxide produces neuroendocrine hyperplasia.^^^"^^^ hyperplastic lesions are recognizable as groups of non-ciliated cuboidal, oval or columnar cells located in the bronchial or bronchiolar epithelium. they contain argyrophilic granules that show immunoreactivity for corticotrophin (acth) and neurone-specific enolase. ultrastructural examination reveals the presence of dense-core cytoplasmic granules of apud type. proliferative changes have also been reported in other species, including rats and humans in hypoxic conditions, although it has been suggested that these changes might be a result of increased peptide content rather than cell proliferation.^^'^^^ the most frequently diagnosed neoplasm world wide is lung cancer, where it is usually caused by smoking tobacco.^^^ bronchogenic squamous carcinoma is generally the most common subtype but in north america the incidence of adenocarcinoma now exceeds that of squamous cell tumours for reasons not fully understood. some of the most aggressive subtypes are small and large cell neuroendocrine lung cancers, defined as small or large tumour cells with greater than ten mitoses per mm^.^^^ these seem to be seen almost exclusively in heavy cigarette smokers. in contrast to findings in people, squamous cell lung tumours are only occasionally seen arising spontaneously in laboratory animals. even laboratory animals -rats, mice, hamster, monkeys and dogs -exposed to tobacco smoke for long periods and at high doses fail to develop an increase in lung tumours.^^^'^^^ moreover, there appears to be no good experimental model for neuroendocrine lung cancer. thus, particular caution is merited if using animal models for prediction of lung tumorigenic potential of inhaled substances. by far the most common primary pulmonary neoplasms found in laboratory rats, mice and hamsters are adenomas and adenocarcinomas. these appear to develop from the bronchiolar or alveolar epithelium, although their precise histogenesis is somewhat disputed. although spontaneous squamous neoplasms are uncommon in rodents cystic keratinizing lesions can be induced in rats by high burdens of particulate material in the lungs.^^^ pleural mesotheliomas and mesenchymal neoplasms also occur in these species but are uncommon. they can be induced in rodents by mineral fibres.^^^ mesenchymal tumours have similar histological features to those in soft tissues and mesotheliomas may show either epithelial or mesenchymal differentiation or both. in most rat strains alveolar or bronchiolar neoplasms occur spontaneously in relatively small numbers, but morphologically identical neoplasia can be induced by administration of chemical carcinogens.^^^ the most common are classified as bronchiolo-alveolar adenoma (pulmonary adenoma) and bronchioloalveolar carcinoma. the national toxicology program database on control fischer rats used in carcinogenicity studies indicates an overall percentage of less than % of animals with bronchiolo-alveolar adenomas and less than % with bronchiolo-alveolar carcinomas.^^ however, the range of bronchioloalveolar adenomas in different studies was between and % in this series. histologically, bronchiolo-alveolar tumours are mostly small, discrete, rounded nodules located in the lung parenchyma and composed of fairly uniform cells with moderately hyperchromatic nuclei arranged in solid (alveolar), tubular, papillary or mixed growth patterns. they usually compress surrounding tissues without infiltration or metastatic spread (adenoma), although loss of differentiation, infiltration and spread to adjacent tissues can occur (adenocarcinoma). ultrastructural study of bronchiolar-alveolar neoplasia in fischer rats has shown the presence of osmiophilic, lamellated inclusion bodies similar to those found in alveolar type ii cells. therefore it has been suggested that the neoplasms are derived from this cell type.^^^ pulmonary squamous carcinoma occurs but is a very uncommon spontaneous neoplasm in the rat.^^ the large proliferative but benign cystic lesions found in the lungs of rats following accumulation of large amounts of particulate matter have been termed pulmonary cystic keratinizing epitheliomas for they have been regarded as benign neoplasms. when these lesions show evidence of tissue invasion they are regarded as pulmonary squamous cell carcinomas. similar lesions are very occasionally reported as spontaneous lesions.^^^ analogous neoplasms are found more commonly in most strains of laboratory mice used in carcinogenicity bioassays although considerable variation in incidence is reported. they are common in strain a mice where they are observed in low frequency at - months of age and incidences reach nearly % by months of age.^^^ fewer, but significant numbers are found in b c fi mice, although there is considerable inter-laboratory variation.^^^ the national toxicology program database on control b c fi mice used in carcinogenicity studies indicates an overall percentage of about % of males and % of females with bronchiolo-alveolar adenomas but only about % and . % respectively with bronchiolo-alveolar carcinomas.^^ however, the range of bronchioloalveolar tumour varied considerably between studies in this series. even in the same laboratory, mice housed under similar conditions show variation in incidence in these neoplasms with time. the incidence of lung adenomas and adenocarcinomas occurring in cd-i mice used as controls in -month carcinogenicity bioassays in the same laboratory under similar conditions for a period of years varied from between and % in males and to % in females.^^^ by contrast, some strains of mice such as the c / j strain show a very low predisposition to the development of lung adenomas.^^^ although these mouse pulmonary adenomas and adenocarcinomas do not resemble the common lung tumours in humans, strain differences have been exploited to study genetic susceptibility and resistance to pulmonary adenomas and carcinomas.^^^'^^^ histologically, pulmonary tumours of this type in mice are generally small, sharply circumscribed nodules composed of fairly uniform, closely packed columns of cuboidal or columnar cells arranged in tubular or papillary structures with scanty fibrovascular stroma ( figure . ). they may be less well differentiated, with cellular pleomorphism, and show intrabronchial growth, invade lung parenchyma and produce metastatic spread. the histogenesis of mouse pulmonary adenomas and adenocarcinomas is disputed. on the basis of sequential light and electron microscopic study of pulmonary adenomas induced in bagg-webster swiss mice by transplacental exposure to ethylnitrosourea, it has been suggested that they develop from either alveolar type ii cells or clara cells.^^^'^^^ careful, stepwise analysis using light microscopic and electron microscopic examination has suggested that adenomas can be divided into three principal groups. some are composed of solid growths of uniform cuboidal cells with expanding margins limited to alveolar septae (alveolar pattern). these cells contained concentrically arranged cytoplasmic lamellar bodies and abundant, large mitochondria similar to mitochondria found in alveolar type ii cells. tubular or papillary patterns are composed of cuboidal cells showing histological and ultrastructural features of clara cell differentiation.^^^ however, immunocytochemical studies of chemically induced and spontaneous pulmonary neoplasia in b c f , balb/c or a strain mice have shown that the majority of adenocarcinomas, including those showing papillary patterns, contain surfactant apoprotein, typical of type ii antigens, suggesting that most neoplasms show alveolar type ii differentiation.^^^ however, in view of the plasticity of clara cells, this does not exclude a clara cell origin of the tumours. immunocytochemistry of specific clara cell secretory protein expression in a transgenic mouse model of lung carcinomas developing from clara cells has shown that the protein is lost during tumour cell progression.^^^ it has also been shown in strain a mice that the proportion of tumours with papillary and solid/alveolar growth patterns varies with the inducing agent.^^^ this also suggests biological differences exist between histological subtypes. very few squamous carcinomas are reported in most series of mouse studies. a chemically induced mouse model of squamous cell carcinoma has been generated by administration of n-nitroso-tris-chloroethylurea. strain differences in susceptibility to squamous cancer development have been demonstrated in this model, with nih swiss, a/j and swr/j being highly susceptible, akr/j and c bl/ j being resistant and fvb/j and balb/cj mice showing an intermediate response to carcinogen.^^^ the high incidence and the inherent variabihty of pulmonary adenomas and adenocarcinomas in conventional mouse carcinogenicity bioassays sometimes gives rise to statistically significant differences between control and treatment groups. there is considerable risk in over-interpretation of such group differences in conventional mouse bioassays. in the analysis of group differences, consideration needs to be given to tissue sampling procedure, age-standardization, historical control incidence, effects on food intake as well as the results of mutagenicity studies and carcinogenicity bioassays in other rodent species. indeed, a considerable number of widely employed therapeutic agents of different classes have produced an increase in benign or malignant pulmonary tumours in carcinogenicity studies performed in mice without this proving of any significance to humans. davies and monro counted at least drugs of this type in the physicians' desk reference of the united states.^^^ for instance, in a carcinogenicity bioassay in which cfl mice were treated for weeks with the synthetic analgesic tilidine fumarate, a statistically significant difference (p < . ) was reported in the incidence of lung adenocarcinomas between the top dose female group ( %) and concurrent controls ( %).^^^ it was argued that group differences did not indicate tumorigenic potential of tilidine fumarate on the basis that the incidence in the high dose group was within the historical control range ( %) and that there was no tumorigenic effect in a parallel week rat carcinogenicity study. a more difficult evaluation concerned metronidazole, a nitroimidazole which is an important therapeutic agent active against anaerobic organisms and trichomonas species. administration of this compound led to an increased incidence of pulmonary adenomas and carcinomas in three separate mouse carcinogenicity bioassays.^^^'^^^ the analysis of these findings was somewhat complicated by evidence that metronidazole shows mutagenic activity in bacterial assays using some strains of salmonella typhimurium. it was argued that the risk to human patients was slight because the increase in prevalence in pulmonary tumours was likely to be a result of changes in nutritional status of the mice through the effect of metronidazole on gut fiora, as similar differences could occur between ad libitum fed mice and those fed the same but restricted diet.^^^ it was also postulated that the positive findings in bacterial mutagenesis assays were an inherent part of the antibacterial activity of metronidazole as a result of nitroreduction that does not occur in normal mammalian tissues. this conclusion was supported by negative effects in hamster carcinogenicity bioassays as well as lack of excess cancer risk in women followed up for years or more.^^^ the common occurrence of lung adenomas in strain a mice has been utilized in the development of a quantitative bioassay for carcinogenic activity. this followed the demonstration that administration of carcinogens such as -methylcholanthrene to this strain could significantly increase the incidence of pulmonary adenomas within periods of up to six months.^^^ over many years the strain a mouse pulmonary tumour assay has been used to test a large number of chemicals of different classes, including polycyclic hydrocarbons, nitrosamines, food additives, alkyl halides, metals and chemotherapeutic agents.^^^'^^^ however, as with many test systems, correlation of results in the strain a test with year carcinogenicity study data and genotoxicity results have been shown to be poor so prudence is needed in the use of this test.^^^ hamsters develop lung adenomas spontaneously in small numbers with advancing age. they are composed of uniform cylindrical cells similar to those found in bronchial epithelium or goblet cells showing distinct mucus production.^^'^^'^^^ an immunohistochemical study of similar pulmonary neoplasms induced in hamsters by n-nitrosodiethylamine showed the presence of clara cell antigen in early phase of development, but as the tumours developed they became more squamous in type and showed immunoreactivity for cytokeratins.^^^ a 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pharmaceuticals reported to be tumorigenic in rodents evaluation of chronic toxicity and carcinogenesis in rodents with the synthetic analgesic, tilidine fumarate induction of lung tumors and malignant lymphomas in mice by metronidazole toxicologic evaluation of metronidazole with particular reference to carcinogenic, mutagenic, and teratogenic potential induced pulmonary tumors in mice. ii: reaction of lungs of strain a mice to carcinogenic hydrocarbons. arc/iii;es of pathology strain a mouse pulmonary tumor test results for chemicals previously tested in the national cancer institute carcinogenicity tests animal model: spontaneous carcinoma of the lung in hamsters key: cord- -i ck oo authors: kouri, andrew; gupta, samir; yadollahi, azadeh; ryan, clodagh m.; gershon, andrea s.; to, teresa; tarlo, susan m.; goldstein, roger s.; chapman, kenneth r.; chow, chung-wai title: chest reviews: addressing reduced laboratory-based pulmonary function testing during a pandemic date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: i ck oo abstract to reduce the spread of sars-cov- , many pulmonary function testing (pft) laboratories have been closed or have significantly reduced their testing capacity. as these mitigation strategies may be necessary for the next - months to prevent recurrent peaks in disease prevalence, fewer objective measurements of lung function will alter the diagnosis and care of patients with chronic respiratory diseases. pfts, which include spirometry, lung volumes, and diffusion capacity measurement, are essential to the diagnosis and management of patients with asthma, copd, and other chronic lung conditions. both traditional and innovative alternatives to conventional testing must now be explored. these may include peak expiratory flow devices, electronic portable spirometers, portable exhaled nitric oxide measurement, airwave oscillometry devices, as well as novel digital health tools such as smartphone microphone spirometers, and mobile health technologies along integration of machine learning approaches. the adoption of some novel approaches may not merely replace but could improve existing management strategies and alter common diagnostic paradigms. with these options come important technical, privacy, ethical, financial, and medicolegal barriers that must be addressed. however, the covid- pandemic also presents a unique opportunity to augment conventional testing by including innovative and emerging approaches to measuring lung function remotely in patients with respiratory disease. the benefits of such an approach have the potential to enhance respiratory care and empower patient self-management well beyond the current global pandemic. as of june nd, there are over . million confirmed cases of covid- globally, and many countries have implemented broad and extraordinary public health strategies in hopes of "flattening the curve". one important consequence of these strategies has been the widespread suspension of non-urgent healthcare services, such as non-urgent outpatient in-person consultations and routine diagnostic testing. this has resulted in the full or partial closure of most pulmonary function testing (pft) laboratories, in keeping with guidance provided by the american thoracic society. this guidance is founded primarily on concerns that the testing performed in these laboratories, which includes spirometry, lung volume, and diffusion capacity measurement, present a higher risk of sars-cov- transmission compared to other diagnostic tests, given the potential for aerosol formation and coughing during the testing of patients with lung disease. though these and other societal measures have resulted in some success in slowing the spread of sars-cov- , modeling at both local and national levels has suggested that current policies will likely need to be maintained for as long as months in order to prevent a deadly rebound. , for pft laboratories, this implies continued closure versus limited reopening with strict pre-visit viral testing, personal protective equipment use, and cleaning protocols -either scenario leading to a significant reduction in testing capacity compared to historical norms. although the provisional diagnosis and management of chronic respiratory diseases with limited access to objective measures of lung function may be feasible in the short term, sustained reductions in testing will almost certainly lead to sub-optimal care for many. furthermore, the inability to diagnose new conditions objectively, for example occupational asthma, may worsen long term outcomes. as such, it is important to address this issue as soon as possible. as with the decrease in in-person consultations, virtual and digital technologies may play an important role going forward, but it is vital to consider the technical, administrative, ethical, and financial implications that will arise as newer technologies replace, complement or augment conventional pulmonary function testing. pulmonary function testing is essential to the care of respiratory disorders. it is used to diagnose lung disease, monitor disease course and the effect of therapeutic interventions, determine perioperative risk, and assess prognosis. reduced access to pfts over the next - months would affect the nearly half a billion children and adults worldwide who live with asthma and chronic obstructive pulmonary disease (copd), the two most common chronic respiratory conditions, as well as those who will be under-and over-diagnosed during that time period due to reduced testing. in both children and adults with asthma, respiratory symptoms correlate poorly with lung function measurements and cannot be used to infer underlying pulmonary function and pathophysiology. , the results of pfts have also been shown to change physicians' treatment plans in as many as % of patients with asthma, and are a strong independent predictor of exacerbation risk. with copd, pfts are critical for diagnosis, for assessing the impact of pharmacologic and non-pharmacologic interventions, and for prognosis, as deteriorating function is associated with increased exacerbations, hospitalization, and risk of death. pfts are equally vital in preventing misdiagnosis of asthma and copd, which can result in the unnecessary, potentially harmful, and costly use of respiratory medications in patients who will not benefit from them. [ ] [ ] [ ] as many as one third of patients receiving anti-asthma therapy in canada are found not to have the disease when objective measures of lung function are used diagnostically. the overdiagnosis and misdiagnosis of copd may be even worse, with estimates of overdiagnosis in primary care ranging from % to %. objective measurement of lung function has also been shown to reduce the problem of gender bias in copd. beyond asthma and copd, many other chronic respiratory conditions rely on the objective measurements of lung function to guide diagnosis, management, and prognostication. guidelinebased care of patients with cystic fibrosis, interstitial lung disease, and pulmonary hypertension, for example, depends on regular access to pft results. [ ] [ ] [ ] [ ] access to reliable pulmonary function data is particularly critical for lung transplant patients when weekly monitoring with spirometry is the gold standard care during the first months post-transplant when the risk of acute graft rejection is highest. though some respiratory sub-specialists have already provided guidance as to how care should be adjusted while deferring non-essential pfts, it is not yet clear how long this new paradigm of care will be effective in avoiding negative health outcomes, especially as increasing numbers of patients have their testing postponed. to prevent undue harm to both patients and technicians in communities with high prevalence of covid- , many healthcare facilities have restricted laboratory-based pfts to "essential" cases where results will influence immediate treatment decisions. however, this has the secondary effect of further limiting the information available to clinicians who must already manage patients without physical examinations, since many have now moved almost exclusively to virtual care for outpatient visits. without this information, management decisions are being made based on history alone. this may be adequate for routine follow-up of some patients with stable respiratory disease but is challenging for new patients and follow-up patients whose clinical status has changed. though pft laboratories may gradually open as covid- numbers plateau and begin to decrease, infection control requirements will likely still reduce testing capacity for a long time. similar concerns around infection control and testing capacity will also adversely affect traditional alternatives to in-laboratory testing such as office-based spirometry, as current international recommendations do not distinguish between healthcare settings when assessing the risks of aerosol generating procedures, and even the use of spirometer filters does not eliminate the need for enhanced infection control measures. , , alternatives to laboratoryand office-based pfts may be sought in existing approaches as well as innovative technologies. home measurement of peak expiratory flow (pef) using an inexpensive portable handheld device is already a guideline-recommended option to facilitate patient self-management in asthma and in the diagnosis of occupational asthma, but its role is less well defined in copd. , , many studies have investigated the potential for pef to be used as a surrogate for pfts in the diagnosis and management of patients with asthma and copd, but the results have been mixed. some research has shown that pef, in combination with other tools such as validated patient questionnaires, can be used to help diagnose copd when spirometry is not easily available, [ ] [ ] [ ] [ ] and may be helpful in copd prognostication independent of spirometry. however, other work in both diseases has shown that agreement between pef (a purely effortdependent measure) and spirometry can be highly variable, and may lead to inappropriate clinical decision making if relied on exclusively, particularly in children and in cases with either very mild or severe airway obstruction. [ ] [ ] [ ] [ ] additionally, studies in children with asthma have shown that self-recorded peak flow is often inaccurate and adherence levels low, and similar concerns may extend to adults. thus, while pef may continue to be used by patients with asthma already familiar with its measurement and tracking, it is unlikely to suffice as a long-term replacement for pfts across chronic respiratory diseases. given the potential for aerosol generation during the forced exhalation maneuver required for pef measurement, patients using this technique to monitor their respiratory status at home should also be counselled on measures to avoid infecting other members of their household while using their flowmeter. a more sophisticated alternative to pef measurement is the use of portable spirometers. as a home-based measurement, it minimizes the exposure risk of forceful expiratory measurements and cough in the laboratory or office setting. many of these devices are now commercially available and in addition to providing more accurate objective measurements of lung function compared to pef, most are now also designed to pair with and download results onto personal mobile devices or computers, facilitating transmission to and monitoring by healthcare professionals. electronic portable spirometers have been studied and found to be comparable to conventional laboratory spirometry in several chronic respiratory conditions, such as asthma and copd, cystic fibrosis, idiopathic pulmonary fibrosis, and post-lung and hematopoietic stem cell transplant monitoring. [ ] [ ] [ ] [ ] [ ] [ ] [ ] indeed, the ability of patients to monitor spirometry weekly, more frequently than is feasible using laboratory-based measurements, offers advantages in some settings where early detection of problems is important -pulmonary fibrosis monitoring and lung transplant surveillance are two established examples. , limitations of these devices include cost, which can range from $ to over a $ usd, lack of feedback on quality of the breathing maneuvers in many devices, variable reporting of accuracy levels (though some devices claim to meet american thoracic society standards for spirometry and include global lung function initiative reference equations), and the need to validate results against reference standards when starting them for new patients. additionally, most of these devices are only able to provide spirometry readings, and cannot aid in lung volume or diffusion capacity measurement. given these limitations, clinicians considering electronic portable spirometers must select the most appropriate devices available locally, ideally balancing price, accuracy, and features that support correct and safe usage. with the correct device-patient match, portable spirometers may present a valuable in-home alternative to pfts for monitoring patients with known chronic lung conditions, augmenting virtual care with important physiologic data. their use could also offload the testing demand on pft laboratories and outpatient clinics, allowing them to focus their limited capacity on new diagnoses and more urgent testing. as with flowmeter use, patients using portable spirometers at home should be counselled on measures to avoid potentially infecting other members of their household. the fraction of exhaled nitric oxide (feno) has been studied extensively in asthma, but also in other respiratory diseases, as a non-invasive biomarker that can supplement or potentially replace conventional spirometry in diagnosis and management decisions. [ ] [ ] [ ] [ ] unlike spirometry, measurement of feno does not require forceful expiratory maneuvers and is not prone to trigger cough. feno may be particularly useful in identifying asthma characterized by type airway inflammation, and may help guide treatment initiation decisions in these patients. , guidelines do not currently recommend using feno alone in either the diagnosis or ongoing management of asthma across different phenotypes. however, increased use of the technology could see revision of these paradigms. at present, laboratory-based measurements are used to diagnose asthma by demonstrating evidence of variable airflow obstruction. such an approach is fraught with difficulty, as patients with mild asthma seldom demonstrate bronchodilator responsiveness at times of randomly scheduled laboratory visits. in fact, operating characteristics of exhaled no measurement for asthma diagnosis were clearly superior to those of spirometry with bronchodilator testing in a recent review. moreover, traditional challenge studies are not only cumbersome to carry out, but also produce variable responses in different subpopulations of patients with asthma and depending on the challenge used. arguably, recognizing and managing airways inflammation is a more important treatment decision in asthma than the decision to use albuterol for symptoms, and exhaled nitric oxide has been suggested as a predictor of inhaled corticosteroid responsiveness is patients with asthma or asthma-like symptoms. institutions familiar with feno testing may thus consider using this technology as a potentially safer (i.e. less likely to generate aerosols) method in inpatient and outpatient settings for diagnosing and following patients with asthma characterised by type airway inflammation. portable handheld devices that can measure feno are also available, and could be a useful remote monitoring option in patients with eosinophilic asthma in the future, though strategies to ensure appropriate technique and quality standards will be required. however, the high cost of portable devices, requirement for patient coaching, and lack of validation for feno in different asthma phenotypes and across other chronic respiratory diseases means it is unlikely to provide an adequate long-term substitute for pfts. oscillometry is emerging as an alternative form of pulmonary function testing that offers some advantages over conventional pfts. it has been shown to be more sensitive than spirometry in early diagnosis of copd, , to correlate better with respiratory symptoms and asthma control , as well as in identifying spirometrically silent episodes of biopsy-proven acute graft rejection following lung transplant. however, there is a dearth of normal reference values for oscillometry due to its relative infancy when compared to conventional pfts, though this is anticipated to improve with recent publications of technical and interpretation guidelines. , as oscillometry is conducted under normal tidal breathing and does not require forced expiratory efforts, it may also have infection control advantages over spirometry, being less likely generate aerosol and minimizing potential sars-cov- transmission. furthermore, oscillometry can be easily conducted in the very young, the elderly and those with physical or cognitive impairment. oscillometry may also be a useful endpoint in methacholine or other challenge studies, obviating the need for forceful maneuvers (although challenge-induced cough remains a potential hazard). lastly, remote home monitoring with portable oscillometry is available and likely to provide more reliable readings than portable spirometry, as coaching, a crucial component for quality control in spirometry, is not needed for oscillometry. one barrier to the broader use of oscillometry is the high cost of the limited portable devices available (for example, the tremoflo ® device from thorasys) , though some of this may be recouped over time given the increased volume of testing permitted by oscillometry, and staff training is considerably simpler than with traditional spirometry. , [ ] [ ] [ ] novel digital health alternatives a growing body of literature is exploring the potential to turn existing mobile devices and smartphones into portable electronic spirometers using their built in microphones, supplemented with machine learning techniques. , pilot studies of these "smartphone spirometers" in healthy subjects and patients with asthma and copd have demonstrated reasonable levels of agreement between resulting values and traditional spirometry, particularly with the fev /fvc ratio. [ ] [ ] [ ] [ ] [ ] though rigorous clinical evaluation and validation of these innovative approaches against laboratory-based pulmonary function testing has not been done and they cannot be considered a current alternative during the covid- crisis, their low cost and capacity for broad dissemination and digital integration offer considerable promise. is not a direct substitute for formal pulmonary function testing but may contribute to improved management outcomes if implemented during the covid- pandemic. in asthma care, mhealth applications supporting patient self-management through education, medication reminders, symptom monitoring, and action plan provision have been shown to improve asthma control, medication and action plan adherence, and quality of life. , similar mhealth interventions for copd have been associated with decreased hospitalization risk. importantly, many mhealth self-monitoring technologies are able to facilitate the transmission of clinical data to healthcare professionals, which could enhance the virtual and remote-patient monitoring and management currently taking place. these types of mhealth solutions may be leveraged in patients with established respiratory diagnoses and relationships with mhealth-savvy health care professionals, but are likely less useful in new patient assessments or cases of diagnostic uncertainty. additionally, it is important to note that mhealth in asthma and copd is an emerging research field, and long-term studies of clinical effectiveness are still lacking. , another innovative approach to enhance remote and virtual monitoring is the use of machine learning algorithms with telemonitoring data. in copd for example, machine learning techniques have been combined with sociodemographic, clinical, and physiologic telemonitoring data to predict acute exacerbations of copd with high sensitivity and specificity. [ ] [ ] [ ] as these technologies mature, they may become particularly useful in centers with established telemonitoring programs in helping clinicians to identify which patients are at higher risk of clinical deterioration, allowing triaging of limited pft resources. however, as with all applications of machine learning with healthcare data, interpreting clinical applicability, generalizability, and the potential for algorithmic bias must be carefully addressed. our present concern is to maintain the usual management standards of patients with chronic respiratory disease until conventional lung function laboratories are able to re-open. however, as new technology is developed and validated, we may find our management strategies improved. convenience is one obvious advantage of remote patient-measured pulmonary function options. patients, especially those living in underserviced areas, may be spared the need for frequent office visits and laboratory-based studies if equally useful measurements can be generated at home. more frequently monitored lung function at home or in the workplace also offers obvious advantages in the management of difficult asthma, for example. the benefits of weekly home spirometry for monitoring patients with interstitial lung disease, post-transplant patients, and those with cystic fibrosis have already been demonstrated and seems likely to replace at least some of the quarterly clinic visits now employed. , , , additionally, many of the non-remote options reviewed such as in-laboratory feno and airwave oscillometry currently offer a lowerrisk alternative to pfts in the short-term, as they are less likely to generate aerosols, but they may also prove to be viable longer-term alternatives as more research is dedicated to their validation across respiratory conditions. one important question that remains with the proposed use of alternative and/or portable pulmonary function testing technologies is what criteria would warrant confirmation with in-laboratory testing. while some options such as feno have established cut-offs, interpretation guidelines for other options such as airwave oscillometry have only recently been published and have yet to be incorporated into computer-based interpretation algorithms. , clinicians will have to be mindful of emerging evidence when using any pft alternative and incorporate other sources of clinical information into their decision making. however, any signals of deterioration from the options suggested could equally prove useful in the triaging of limited in-laboratory pft resources. see table for a summary of reviewed alternatives and their limitations. though the covid- pandemic presents an opportunity to study and explore the potential alternatives to conventional pfts in managing the care of patients with chronic respiratory diseases, these alternatives are not without their own unique challenges. integrating many of the proposed remote alternatives into existing care workflows and electronic health records that are already struggling to cope with the massive shift to virtual care would be challenging. privacy and equity issues would need to be carefully addressed, particularly when dealing with interventions that interact with patients' personal digital devices as well as when considering the costs of various alternatives. technical support for both patients and healthcare workers may be needed with new technologies and devices. remuneration systems would need to be adjusted to recognize the technical and professional components involved in the introduction of new and advancing technologies, and to compensate for potential loses in hospital revenue associated with decreased laboratory testing. this is already occurring to some extent, as the us administration has enacted several regulatory changes to support expanded remuneration for remote patient monitoring and telehealth services. finally, the use of novel technological solutions may herald unanticipated or new medicolegal implications which will require consideration. in the face of serious limitations to the availability of conventional laboratory and office-based pulmonary function testing that are likely to persist for at least the next - months, respiratory clinicians, researchers, and administrators must begin to consider how alternatives to conventional pfts could be integrated into the care of patients with chronic respiratory diseases to provide the best possible quality of care. though no current individual alternative is sufficient to replace conventional testing in all patients, many of the options reviewed may provide acceptable and actionable physiologic information to improve clinical management. examples include the use of portable electronic spirometry and mhealth self-monitoring technologies in patients with asthma and copd, as well as portable oscillometry for monitoring patients postlung transplant. the covid- pandemic provides a unique opportunity for the respiratory community to implement existing alternatives to pfts and to engage in the rigorous clinical evaluation of new digital solutions and systems that may enhance the management of those with respiratory diseases, while being mindful of the importance of privacy and autonomy to our patients. table . summary of evidence for pft alternatives during a pandemic peak expiratory flow measurement use in asthma : -diagnosis of variable expiratory airflow limitation (diurnal variation, response to therapy, variation between visits) -diagnosis of occupational asthma and workexacerbated asthma -short-term and long-term self-monitoring (i.e. use in asthma action plans) use in copd [ ] [ ] [ ] [ ] [ ] [ ] : -diagnosis, in combination with validated patient questionnaires -prognostication results less reliable in children, and in patients with very mild or severe airways obstruction. may also be adherence issues, particularly in children but also in adults. remote follow-up in patients 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applications in self-management of patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis of their efficacy living with asthma and chronic obstructive airways disease: using technology to support self-management -an overview machine learning for copd exacerbation prediction ensemble machine learning for the early detection of copd exacerbations improving prediction of risk of hospital admission in chronic obstructive pulmonary disease: application of machine learning to telemonitoring data key challenges for delivering clinical impact with artificial intelligence trump administration makes sweeping regulatory changes to help u.s. healthcare system address covid- patient surge authors' contributions: an initial draft of this paper was prepared by a.k., and all authors contributed to the editing and final draft of the work. a.k acts as the guarantor of this work. key: cord- -s r en f authors: toom, marjolein lisette den; dobak, tetyda paulina; broens, els marion; valtolina, chiara title: interstitial pneumonia and pulmonary hypertension associated with suspected ehrlichiosis in a dog date: - - journal: acta vet scand doi: . /s - - - sha: doc_id: cord_uid: s r en f background: in dogs with canine monocytic ehrlichiosis (cme), respiratory signs are uncommon and clinical and radiographic signs of interstitial pneumonia are poorly described. however, in human monocytic ehrlichiosis, respiratory signs are common and signs of interstitial pneumonia are well known. pulmonary hypertension (ph) is classified based on the underlying disease and its treatment is aimed at reducing the clinical signs and, if possible, addressing the primary disease process. ph is often irreversible, but can be reversible if it is secondary to a treatable underlying etiology. cme is currently not generally recognized as one of the possible diseases leading to interstitial pneumonia and secondary ph in dogs. only one case of ph associated with cme has been reported worldwide. case presentation: a seven-year-old, male intact, mixed breed dog was presented with weeks history of lethargy and dyspnea. the dog previously lived in the cape verdean islands. physical examination showed signs of right-sided congestive heart failure and poor peripheral perfusion. thoracic radiography showed moderate right-sided cardiomegaly with dilation of the main pulmonary artery and a mild diffuse interstitial lung pattern with peribronchial cuffing. echocardiography showed severe pulmonary hypertension with an estimated pressure gradient of mm hg. on arterial blood gas analysis, severe hypoxemia was found and complete blood count revealed moderate regenerative anemia and severe thrombocytopenia. a severe gamma hyperglobulinemia was also documented. serology for ehrlichia canis was highly positive. treatment with oxygen supplementation, a typed packed red blood cell transfusion and medical therapy with doxycycline, pimobendan and sildenafil was initiated and the dog improved clinically. approximately weeks later, there was complete resolution of all clinical signs and marked improvement of the ph. conclusion: this report illustrates that cme might be associated with significant pulmonary disease and should be considered as a possible differential diagnosis in dogs presenting with dyspnea and secondary pulmonary hypertension, especially in dogs that have been in endemic areas. this is important because cme is a treatable disease and its secondary lung and cardiac manifestations may be completely reversible. ehrlichia canis is a pleomorphic bacterium that infects circulating monocytes and can cause canine monocytic ehrlichiosis (cme). cme results in variable nonspecific clinical manifestations and clinical signs can be subclinical, acute or chronic. most dogs present with depression, lethargy, mild weight loss, anorexia, splenomegaly, and lymphadenopathy with or without hemorrhagic tendencies [ , ] . respiratory signs are sporadically reported in dogs but are regularly described in human patients infected with human monocytic ehrlichiosis (hme) [ ] . interstitial pneumonia can have an infectious or noninfectious etiology. in dogs, reported infectious agents leading to interstitial pneumonia are angiostrongylus acta veterinaria scandinavica *correspondence: m.l.dentoom@uu.nl department of clinical sciences of companion animals, faculty of veterinary medicine, utrecht university, yalelaan , td utrecht, the netherlands full list of author information is available at the end of the article vasorum, leishmania chagasi, toxoplasma gondii, pneumocystis carinii, babesia canis, leptospira sp., mycoplasma sp, canine distemper virus and adenovirus [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in patients with interstitial pneumonia, gas exchange is often impaired due to ventilation-perfusion mismatching, intrapulmonary shunting, and decreased diffusion across the abnormal interstitium with arterial hypoxia as a consequence. in contrast to the systemic vasculature that responds with arterial vasodilation to better perfuse hypoxic tissue, the pulmonary vasculature constricts in response to hypoxia. besides pulmonary vasoconstriction, hypoxia also causes proliferation of the smooth muscle cells in the arterial wall. both phenomena lead to a decrease in luminal cross-sectional area and an increase in pulmonary vascular resistance index with pulmonary hypertension (ph) as a consequence. pulmonary hypertension is classified based on the underlying disease and its treatment is aimed at improving the clinical signs and addressing the primary disease process [ ] . although ph is often irreversible, ph is reversible in some cases if the underlying etiology is diagnosed and treated accordingly. reversibility of ph has for instance been demonstrated in dogs after successful treatment for a. vasorum [ ] . pulmonary changes consistent with interstitial pneumonia have been reported previously in humans with hme [ ] and as an atypical finding in dogs with cme [ ] [ ] [ ] [ ] . however, cme is generally not recognized as one of the possible diseases leading to interstitial pneumonia and secondary ph in dogs. only one case of ph associated with e. canis infection has been reported worldwide [ ] . consequently, cme might be underdiagnosed as a possible cause of interstitial pneumonia and secondary ph. this case report describes the clinical, radiographic and echocardiographic presentation of a dog with interstitial pneumonia and severe ph suspected to be associated with e. canis infection. a seven-year-old, intact male, mixed breed dog weighing . kg was presented to the emergency service of the department of clinical science of companion animals of the faculty of veterinary medicine, utrecht university with a weeks history of lethargy, progressive dyspnea and coughing. the dog previously lived in the cape verdean islands for approximately years and returned to the netherlands months before presentation. in the past years, the dog had showed chronic mild exercise intolerance and had a few episodes of diarrhea that resolved with symptomatic therapy. the dog was up-to date with his vaccinations and anthelminthic treatments. physical examination showed generalized weakness and decrease mental state. cardiovascular examination revealed tachycardia, weak peripheral pulses, pale mucous membranes, prolonged capillary refill time, jugular distensions and venous pulses, and a grade three out of six systolic murmur with the point of maximal intensity over the right cardiac apex. the dog was also severely dyspneic and demonstrated harsh lung sounds on auscultation. the abdomen was distended and positive undulation was detected. these findings were consistent with pulmonary disease, right-sided heart failure and poor peripheral perfusion. complete blood count (cbc) showed a moderate microcytic, hypochromic anemia, moderate leukocytosis with a marked left shift and a severe thrombocytopenia. biochemistry showed severe hyperproteinemia, hyperglobulinemia and a mild hypoalbuminemia. serum protein electrophoresis showed a polyclonal peak in the gamma globulin region. arterial blood gas analysis showed a severe hypoxemia with hypocapnia. urinalysis showed mild hemoglobinuria, glucosuria and proteinuria. blood samples were submitted for serological and molecular biological testing. immunofluorescence antibody test (ifat) for e. canis (megafluo ehrlichia canis ® , mega cor diagnostik gmbh, hörbranz, austria) was positive (igg titer > ), but polymerase chain reaction (pcr) amplification for ehrlichia genus (realtime pcr, light cycler ® . , roche diagnostics gmbh, mannheim, germany, primers used as described previously [ ] ) was negative. serology for leishmania sp. (dog-dat ® , leishmania specific antibody detection kit, koninklijk instituut voor de tropen, amsterdam, the netherlands) and b. canis. (megafluo babesis canis ® , mega cor diagnostik gmbh, hörbranz, austria) and antigen snap tests for a. vasorum (angio detect ™ test, idexx laboratories) and dirofilaria immitis (snap ® heartworm rt test, idexx laboratories) were also negative. laboratory results are summarized in table . on thoracic radiographs, a mild diffuse increase in pulmonary opacity with an interstitial lung pattern and mild peribronchial cuffing was seen, which was most accentuated in the caudodorsal lung lobes. thin pleural fissure lines were noted between all lung lobes. the cardiac silhouette showed signs of right-sided cardiomegaly (vertebral heart score (vhs): . , reference interval < . ± . ) and a main pulmonary artery knuckle was present on the dorsoventral view ( fig. ) . echocardiography showed dilation of the right ventricle and the pulmonary artery, septal flattening and a severe tricuspid regurgitation. the left ventricle was severely under filled (fig. ) . congenital defects and left heart disease were excluded. the maximal tricuspid systolic velocity was . m/s, indicating a peak tricuspid gradient of approximately mm hg which is graded as severe ph (reference < mm hg, severe > mm hg) [ ] , (fig. ) . to address the severe hypoxemia and ph the dog was placed in an oxygen cage with an inspired concentration of oxygen between and %. the clinical signs of the dog did not improve markedly with the extra oxygen supplementation. because anemia could have contributed to the cardiovascular signs and the poor tissue oxygenation, a typed packed red blood cell transfusion was administered. based on the travel history, the abnormalities within the cbc and biochemical analysis and the positive serology for e. canis, an infection with cme was suspected. treatment with doxycycline ( mg/ kg, orally twice daily) (doxoral ® , ast farma, oudewater, the netherlands), pimobendan ( . mg/kg, orally twice daily) (cardisure ® flavour, eurovet animal health bv, bladel, the netherlands) and sildenafil ( . mg/kg, orally twice daily) (viagra ® , pfizer, new york, usa) was initiated. the hematocrit increased from to % after the blood transfusion and the dog's clinical condition improved remarkably. however, the dog remained moderately dyspneic and severely hypoxic (pao : . mm hg, reference interval: . - . mm hg). the dyspnea gradually improved and the dog seemed comfortable outside the oxygen cage after days of treatment, although the improvement of the hypoxemia was only minimal (pao : mm hg, reference interval: - . mm hg, table ). because of financial limitations of the owner, the dog was discharged with the above-mentioned therapies at that time. seventeen days after initiation of treatment, the dog was admitted via the cardiology polyclinics of the same university and re-examined. at that time, there was complete resolution of all clinical signs and physical examination was completely unremarkable. cbc showed normal platelet counts and leukogram, with only a very mild microcytic hypochromic anemia. biochemical analysis again showed severe hyperproteinemia and hyperglobulinemia. the ) . thoracic radiography showed marked improvement with resolution of cardiomegaly (vhs: . , reference interval . ± . ) and only a very mild interstitial pattern of the caudodorsal lung lobes and a very mild dilation of the pulmonary artery (fig. ) as remaining abnormalities. echocardiography also showed a remarkable improvement. tricuspid regurgitation was no longer present and only a very mild uniform dilation of the pulmonary artery was still present (fig. ) . therapy with pimobendan and sildenafil were discontinued and the treatment with doxycycline was continued for another weeks. the dog was reevaluated weeks later and was clinically doing very well. nevertheless, the dog again developed mild anemia and the hyperproteinemia persisted. proteinuria had resolved at that time (table ) . doxycycline therapy was continued for another weeks and another re-examination was advised. unfortunately, the dog was lost to follow-up at that time. interstitial pneumonia with secondary ph was suspected in this dog based on the presentation on thoracic radiography and the severe hypoxemia on arterial blood gas, but the etiology was initially unclear. however, cme was suspected based on the travel history of the dog, the results of cbc, biochemical analysis and a positive serology result for e. canis. exposure to e. canis was demonstrated with the ifat for anti-e. canis igg antibodies. igg titers > are considered positive for e. canis exposure [ ] . in right lateral (a) and dorsoventral (b) thoracic radiographs weeks after discharge. radiographs demonstrating resolution of cardiomegaly (vertebral heart score: . , reference interval < . ± . ) and reduction of the dilation of pulmonary arteries and the diffuse interstitial pattern this case, the igg titer was high (> ), which strengthened the suspicion of an active infection [ ] . however, definite active infection at the time of presentation could not be proven, because pcr amplification for ehrlichia genus was negative and anti-ehrlichial igg antibodies persist for several months to years after elimination of the parasite [ ] . a negative result from a pcr test can occur when organisms in circulation are below the level of detection, as may happen when infections are chronic. it has been demonstrated that dogs can be pcr negative on blood samples, but pcr positive on splenic aspirates [ ] . it is hypothesized that the e. canis are sequestered in splenic macrophages to avoid immune elimination. unfortunately, in the present case, the owners declined fine needle aspirates of the spleen due to the potential risks and stress involved, e.g. internal bleeding, aggravation of the dyspnea. paired serology samples can also provide useful information about antibody kinetics, which may point to current status of infection. a fourfold increase in igg antibodies over time is suggested to be evidence for an active infection [ ] . antibody titers will decrease gradually after appropriate treatment, but may persist for months to years even after full clinical recovery [ , ] . in this case, the ehrlichia igg titer was still very high days after initiation of doxycycline therapy, probably due to the short time between start of the treatment and retesting; ifat was unfortunately not repeated on day . although doxycycline therapy generally results in fast clinical improvement and improvement of most laboratory abnormalities, persistence of hyperglobulinemia is generally observed for a longer period. most studies have shown normalization of serum protein electrophoresis results after - months of therapy [ , ] . this explains the persistence of hyperglobulinemia at the re-examinations of the dog at days and . in human medicine, respiratory signs are commonly described as a consequence of hme infection [ ] and acute respiratory distress syndrome (ards) has also been reported as a severe, although uncommon, finding in hme [ ] [ ] [ ] . both cme and hme animal models also revealed prominent mononuclear cellular infiltration in the interalveolar septa, endothelial damage and vasculitis in the lungs [ , ] . this could explain the pulmonary changes found in this dog and the clinical and radiographic improvement after treatment with doxycycline. however, recently, acute resolution of patchy pulmonary alveolar infiltrates has been described after sildenafil therapy in dogs with idiopathic ph and ph secondary to idiopathic lung fibrosis [ ] . therefore, sildenafil therapy might also have contributed to the improvement of the radiographic changes in this case. another explanation for the radiographic abnormalities and the improvement on doxycycline therapy that cannot be excluded is that the dog suffered from a bacterial pneumonia. furthermore, an important possible factor that might have contributed to the hypoxemia and ph in this dog is pulmonary thromboembolism (pte) [ ] . pte can occur as complicating sequelae in patients with ph or can be the primary cause of ph [ ] . in people, it is increasingly recognized that patients with pulmonary arterial hypertension have dysregulated coagulation and antithrombotic homeostasis, which may contribute to a prothrombotic state [ ] . unfortunately, we did not perform diagnostic investigations such as d-dimer concentration [ ] , computed tomography pulmonary angiography [ ] or thromboelastography (teg) [ , ] to investigate if the dog suffered from pte or a prothrombotic state. however, to the author's knowledge, pte has never been associated with cme in veterinary literature. only two cases of aortic and portal vein thrombosis have been described in dogs with cme [ , ] . treatment of ph is aimed at eliminating or improving the underlying disease process. if the ph is not controlled by primary disease therapy or if the ph is idiopathic, treatment with pulmonary arterial dilators may be implemented. in veterinary medicine currently, only phosphodiesterase inhibitors are used. sildenafil is a highly selective phosphodiesterase five inhibitor that has been used in veterinary medicine with encouraging results [ , ] . pimobendan, a calcium-sensitizing agent with phosphodiesterase three inhibiting actions has also been used, especially when left heart disease is a contributing cause [ ] . in the present case, a dual therapy with pulmonary arterial dilators was initiated, because we hoped this would ameliorate the very severe ph and clinical signs faster than a monotherapy with sildenafil. although recovery has been described in a similar case with just a monotherapy with doxycycline [ ] , we believe that the symptomatic support with pulmonary vasodilators was justified in this dog. mild to moderate improvement of tricuspid regurgitation gradient by sildenafil therapy has been described in some dogs with ph [ ] , but not in others [ ] . consequently, we cannot rule out that the improvement of the echocardiographic changes could also be partially explained by the use of the vasodilating drugs. ideally, another echocardiogram should have been performed after discontinuation of the vasodilator therapy. however, the improvement was so dramatic, that we do not believe that this could be solely explained by the vasodilator therapy. this case report illustrates that cme might be associated with significant pulmonary disease and that it should be considered as a possible differential diagnosis in dogs presenting with dyspnea and secondary pulmonary hypertension, especially in dogs that have been in endemic areas. this is important because cme is a treatable disease and its lung and cardiac manifestations may be completely reversible. guideline for veterinary practitioners on canine ehrlichiosis and anaplasmosis in europe ehrlichiosis and anaplasmosis in dogs and cats epidemiologic, clinical, and laboratory findings of human ehrlichiosis in the united states interstitial pneumonia in 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hypertension cv performed the initial clinical investigations of the dog and was responsible for the care and treatment of the dog during admittance at the intensive care unit. eb was responsible for the serological and molecular biological diagnostic testing. mdt also performed clinical investigations of the dog and performed and evaluated the echocardiograms of the dog during hospitalization and at follow-up. td performed and evaluated the initial echocardiogram of the dog at presentation and was responsible for the interpretation of the thoracic radiography. the manuscript was drafted by mdt and finalized jointly by all authors. all authors read and approved the final manuscript. the authors declare that they have no competing interests. submit your next manuscript to biomed central and we will help you at every step: key: cord- -i hbx pz authors: matthews, abigail a.; ee, pui lai rachel; ge, ruowen title: developing inhaled protein therapeutics for lung diseases date: - - journal: mol biomed doi: . /s - - -z sha: doc_id: cord_uid: i hbx pz biologic therapeutics such as protein/polypeptide drugs are conventionally administered systemically via intravenous injection for the treatment of diseases including lung diseases, although this approach leads to low target site accumulation and the potential risk for systemic side effects. in comparison, topical delivery of protein drugs to the lung via inhalation is deemed to be a more effective approach for lung diseases, as proteins would directly reach the target in the lung while exhibiting poor diffusion into the systemic circulation, leading to higher lung drug retention and efficacy while minimising toxicity to other organs. this review examines the important considerations and challenges in designing an inhaled protein therapeutics for local lung delivery: the choice of inhalation device, structural changes affecting drug deposition in diseased lungs, clearance mechanisms affecting an inhaled protein drug’s lung accumulation, protein stability, and immunogenicity. possible approaches to overcoming these issues will also be discussed. biological drugs are revolutionising the treatment and management of many serious illnesses including cancer, autoimmune disorders, and rare genetic diseases, with about a third of all new drug approvals by the food and drug administration (fda) consisting of biological drugs [ ] . however, over the past decades, the development of inhaled therapeutics for the treatment of respiratory diseases has largely been focused on small molecules (corticosteroids, β agonists, and muscarinic antagonists), with only one inhaled protein biologic drug pulmozyme® being approved by the fda to date [ ] . in the treatment of lung diseases via inhalation therapy, biological drugs such as proteins/polypeptides offer many advantages over small molecule drugs. proteins delivered via the pulmonary route could accumulate in the lungs while having a poor ability to traverse the airblood barrier due to their large molecular weight. this would result in higher target site accumulation (airway epithelial cells, alveolar macrophages, neutrophils etc) and minimise systemic toxicity, as compared to small molecule drugs that would pass easily into the systemic circulation after reaching the lungs [ ] [ ] [ ] . in addition, protein therapeutics display higher potencies (picomolar to femtomolar range) than small molecules (nanomolar range), as well as highly specific receptor binding to reduce off-target effects [ ] . notably, although peptide drugs (< kda or < - amino acids in length) share some of the characteristics with protein/polypeptide drugs such as both are composed of amino acids linked via peptide bond and both having high target specificity, most of peptide drugs are much smaller in sizes, conferring them with some distinct differences including less enzyme stability, higher tissue penetration ability etc. in addition, many peptide drugs harbour chemical modifications in the form of peptidomimetics and/or cyclization, and some have direct cell membrane penetrating ability. these peptide drugs are not covered in this review. protein therapeutics are conventionally administered via the systemic route, although this has proven to be an inefficient approach for drug delivery to the lung, not mentioning the additional danger of exposing the rest of the body vulnerable to toxicity [ , ] . for instance, monoclonal antibodies (mabs) are found at higher levels ( - , times more) in serum than in bronchoalveolar lavage (bal) fluid following intravenous administration, a trend that has been demonstrated in all species [ ] . by the same token, protein therapeutics delivered via the airways also pass poorly from the lungs into the systemic circulation. for example, only low amounts of anti-vegf-a g - mab ( . %) and cetuximab ( %), an anti-egfr mab, were present in the serum after aerosol delivery in mouse models of lung cancer [ , ] . this means that high concentrations of the protein drug can be attained in the lung via pulmonary delivery, suggesting that lower doses of inhaled protein can have an equivalent or even superior therapeutic effect for lung diseases when compared to the higher doses that would be needed from systemic administration [ ] . indeed, it was reported that the nebulised effective dose of avidinox-anchored biotinylated cetuximab was / , of the intravenous effective dose in a mouse model of advanced metastatic lung cancer [ ] . although higher pulmonary levels of protein therapeutics can be achieved through inhalation compared to systemic administration, this could be offset by the short residence time of proteins in the lung compared to plasma. proteins and antibodies are mostly cleared from the lungs within h, while plasma half-lives of full-length antibodies following intravenous injection can reach weeks and more [ ] . nevertheless, there are strategies that can be employed to increase the local residence time of protein therapeutics in the lungs, and these will be discussed in detail later on in this review. besides improving pharmacokinetic and toxicity profiles of protein therapeutics, the inhalation route is non-invasive and allows for self-administration, which could improve patient compliance [ , , ] . in , pulmozyme® (dornase alfa/deoxyribonuclease i), was introduced for the treatment of cystic fibrosis [ ] . it has been almost three decades since then, and no other inhaled protein therapeutics for topical treatment of a lung disease has reached the market, despite the aforementioned advantages that inhaled proteins possess. presently, and to the best of our knowledge, ten inhaled protein therapeutics are being assessed in clinical trials for the treatment of a range of lung diseases including asthma, cystic fibrosis, lung cancer, copd and covid- (table ) [ ] [ ] [ ] [ ] [ ] [ ] . there are also protein therapeutics such as mabs that are in the preclinical stages [ , ] . in order to drive more of these therapies into clinical development and eventually to the market, it is crucial to take into account the challenges unique to the development of these agents into potential treatments so that they may be utilised successfully for pulmonary delivery. in this review, we will discuss the challenges in developing an inhaled protein therapeutic for lung diseases, as well as approaches that could help to circumvent these issues. the focus of this review is on the pulmonary delivery of protein drugs for local action in the lung, however, examples of inhaled proteins for systemic action will be mentioned wherever relevant. challenges and considerations in the development of protein therapeutics for local lung delivery choice and limitations of drug delivery device there are mainly three classes of inhalation devices namely dry powder inhalers (dpis), nebulisers, and metered dose inhalers (mdis). dpis deliver drug as a solid aerosol, and powder formulations possess inherent stability and shelf life benefits [ , ] . however, the temperature and shear stress during the manufacturing processes needed to produce powders (e.g. freeze drying, spray drying) could lead to protein degradation [ ] . dpis have been used for the marketed inhalable insulin formulations exubera® (approved in , but was discontinued after year due to large device size, high pricing, and safety concerns) and afrezza® (still commercially available) [ ] . moreover, dpis have shown promising results in studies assessing their use for inhaled protein formulations. for example, weers et al. ( ) showed that dry powder formulations of csj (antithymic stromal lymphopoietin (tslp) mab fragment) could achieve a total lung dose (tld) of about % of the delivered dose (dd) with the use of particle engineering techniques such as via the introduction of surface corrugation through the addition of trileucine [ ] . nebulisers (jet, ultrasonic, and mesh) generate aerosol droplets from a liquid solution of the drug [ ] . the first and only inhaled protein formulation approved for pulmonary delivery to date, pulmozyme®, is administered via jet nebuliser. nebulised formulations are less expensive to produce and test, because the manufacturing process for these formulations does not include extra drying steps. nevertheless, prolonged storage of proteins in liquid solutions can lead to protein instability through degradation pathways (i.e. deamidation and hydrolysis), temperature and ph changes, and aggregation (through agitation of the aqueous carrier) [ ] . furthermore, across all nebuliser types, the process of nebulisation exposes the protein to physical stresses such as shearing forces and heat, as well as the large air-liquid interface (ali) that could alter protein conformation and/or structure through denaturation, chemical modifications (oxidation, deamidation), and aggregation [ , ] . device-specific limitations such as the shear forces generated by jet nebulisers, and the temperature increases that occur in ultrasonic nebulisers, can also lead to protein degradation. jet and ultrasonic nebulisers actually recycle % of the primary aerosol, and a molecule would typically be subjected to - cycles of nebulisation before leaving the nebuliser as a secondary aerosol [ ] . this subjects the molecules to high shear stress in these devices, resulting in the denaturation of proteins, with the extent of protein denaturation and degradation varies depending on the characteristics of the individual protein [ ] . for example, for jet nebulizer delivery of ldh and urease, there is a log-linear degradation with a fraction of protein degraded with every recirculation [ , ] . in contrast, igg and g-csf has a rapid initial decline in native proteins in the first - min [ , ] . for ultrasonic nebulizers, heating resulting from ultrasonic radiation in addition to aerosol recirculation generated various protein denaturation and degradation in different proteins [ ] . for example, the degradation of ldh with ultrasonic nebulizer presented a sigmoidal progression instead, indicating different denaturation process and factors involved from jet nebulizers [ ] . by comparison, vibrating mesh nebulisers employ single-pass technology, ensuring that there is no recirculation of droplets into the reservoir; they do not alter solution temperature, and produce less shear forces inside the drug reservoir during nebulisation, making them more suitable for the delivery of protein therapeutics [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in fact, several studies have reported that jet and ultrasonic nebulisers produce lower levels of activity, lower amounts of protein monomers (because of partial degradation), and more aggregates (with or without excipients). on the other hand, mesh nebulisers appear to maintain protein integrity to a greater extent than other nebulisers [ ] . safe aerosolisation with mesh nebulisers has already been demonstrated in several studies of labile drugs including proteins and mabs [ ] [ ] [ ] [ ] [ ] [ ] . the detailed designs and comparisons of various types of nebulizers have been reviewed previously and we will not elaborate further here [ , [ ] [ ] [ ] ] . recently, nanoengineered particles using metal-phenolic networks (mpns) with highly defined physical properties have been used to encapsulate both small molecule and macromolecules including proteins for pulmonary delivery via nebulisation. intratracheal nebulization delivery of fitc-labelled bovine serum albumin (bsa, kda) in mice demonstrated that these capsules are biocompatible and biodegradable, showing > % of the capsules in the lung after h, while only < % remaining after days without causing obvious lung inflammation or toxicity. although still in early stage of development, these mpn particles may revolutionize the nebulization delivery of protein drugs and provide a more protected environment for effective pulmonary delivery [ ] . moreover, new generation nebulisers are being developed such as surface acoustic wave (saw) nebulisers and the more recent hydra (hybrid resonant acoustics) nebulisers that provide new platforms for inhaled drug delivery. saw use surface waves to generate aerosols which can preserve macromolecule integrity that has been shown to be efficient in aerosolising proteins [ ] . hydra uses a hybrid combination of surface and bulk sound waves to generate the aerosol droplets, and can overcome the low nebulisation rate of saw nebulisers and conventional nebulisers, while also avoiding the potential damage to proteins due to high shear (jet nebulisation) or cavitation (ultrasonic nebulisation). the first human lung deposition study using a prototype hydra nebuliser has been reported recently, indicating successful lung deposition of a radiolabelled small molecule [ ] . it is probable that hydra nebulisers may be developed for pulmonary protein drug delivery. mdis deliver drug through an aerosol burst, and allow for the controlled delivery of specific amounts of drug to the lungs [ , ] . however, as with nebulisers, the use of aqueous solutions is not ideal for protein storage [ ] . there are also concerns that the hydrofluoroalkane (hfa) propellants used in mdis could denature proteins [ , ] . despite this concern, there are examples of studies showing that proteins can remain stable in hfa-containing mdi formulations. quinn et al. ( ) utilised raman spectroscopy to analyse the secondary conformations of lysozyme in the hfa propellants tetrafluoroethane (hfa a) and heptafluoropropane (hfa ), demonstrating that structural integrity of lysozyme was preserved in both hfas, and that there is potential for proteins to be developed as mdi formulations without compromising their conformational stability [ ] . moreover, liao et al. ( ) demonstrated that spray-dried lysozyme and catalase that were stabilised with excipients (sugars and/or % polyvinyl alcohol) and then stored in hfa a at room temperature for months showed retention of biological activity [ ] . when choosing an inhalation device, it is important to be cognisant of the fact that not all devices in the same category are equivalent. for instance, although it is generally accepted that there is minimal heating of the drug reservoir in vibrating mesh nebulisers, and that heating occurs to a lesser degree than in ultrasonic nebulisers, considerable temperature increases have been reported in some brands of vibrating mesh nebulisers (pari eflow®, akita apixneb®, and aeroneb go), with temperatures of up to °c being reached towards the end of nebulisation [ ] . therefore, it is essential to choose the inhalation device carefully, bearing in mind that the best device type is the one that confers the most stability to the protein drug formulation. soft mist inhaler (smi), which also generate aerosols from liquid, is the newest type of inhaler which does not use any propellent. as only one medicine respimat uses smi, its suitability for protein drug delivery is not clear. another factor to consider is the aerodynamic diameter of aerosol particles, which is critical to control where the particles will be deposited in the respiratory track after inhalation. to be therapeutically effective, the drug containing particles need to be deposited into the correct location within the respiratory track. for example, for therapeutics for copd, drugs need to be delivered to the deep lung (the alveolar space) for which it requires the aerodynamic diameter of the particles to be between and μm. larger size particles will generally be deposited in the oropharyngeal region and be ingested, while small particles < μm may be exhaled during the next breathing cycle. thus, suitable aerosol particle sizes need to be selected for precise drug delivery into the lung to enhance drug efficacy while simultaneously reducing harmful side effects [ ] . the respiratory tract comprises of a series of branching airways, which can be categorised into two parts: the conducting zone and the respiratory zone. the conducting zone consists of the trachea, bronchi, bronchioles, and terminal bronchioles. the airway wall in the conducting zone is too thick for diffusion and this region does not contain alveoli. as such, no gas exchange takes place here, and the purposes of the conducting zone include transmitting air to the respiratory zone, as well as to warm, moisture and cleaning the inspired air. the respiratory zone consists of respiratory bronchioles, alveolar ducts, and alveolar sacs, and facilitates gas exchange between the air and the bloodstream. alveoli can occasionally be found in the walls of the respiratory bronchioles, and are abundant in the alveolar ducts and alveolar sacs [ , ] . given the branched structure of the lungs, it is not only important to achieve high deposition rates, but also to obtain an appropriate deposition pattern for the respiratory disease in question i.e. the protein therapeutic would not only need to reach the lung, but would also need to reach the correct target site within the lung. for instance, a therapeutic for asthma would have to reach the large airway, as asthma mainly affects the bronchi, while a drug for emphysema in copd would need to go deeper and reach the small airways of the lung because emphysema affects the alveolar region [ ] . the amount and pattern of lung deposition is not only affected by the device and the characteristics of the inhaled drug (particle size and physicochemical properties of the formulation), but also by factors that are influenced by the specific disease state, including breathing patterns, lung geometry (i.e. airway diameter, number of alveoli) and structure, and nasal, oral, and pharyngeal anatomy [ ] . these factors need to be considered, and if possible, alterations to the drug formulation can be made to address these issues. for example, in certain lung pathologies (for instance cystic fibrosis, copd, and chronic sinusitis), the airway mucus becomes thicker. it has been reported that the thickness of the mucus layer ranges from to μm in normal lungs to more than μm in cystic fibrosis and other obstructive airway diseases [ ] . this presents a physical barrier that the protein drug would need to penetrate to reach its target site in the lung and exert its effects. the addition of anti-adhesive molecules (e.g. polyethylene glycol, peg) in the formulation may help to promote the translocation of the protein drug through the thickened mucus, although it should be noted that the adhesive properties of peg depend on peg molecular weight (mw) [ ] . while high mw pegs display mucoadhesive properties, low mw pegs are able to prevent mucoadhesion, with pegs of mw up to kda able to provide effective mucus penetration [ ] [ ] [ ] . notably, as macromolecules, proteins have a relatively poor ability to penetrate the epithelial layer to reach the deep parenchyma lung. however, depending on the molecular weight and aerosol characteristics, a portion of the proteins would be able to reach the abluminal side of the epithelium or the air-blood interface in the thin alveolar wall, triggering local or even systemic immune signalling that may provide beneficial therapeutic effect in some cases [ ] . a good lung deposition pattern would be worthless if the protein therapeutic cannot withstand the lung's clearance mechanisms. inhaled proteins would be subjected to clearance by three mechanisms. the first clearance mechanism is mucociliary clearance (mcc), which is the coordinated beating of cilia lining the nasal cavity, trachea, and bronchi, in order to move the mucus towards the larynx/pharynx, thereby pushing dust, microorganisms, and insoluble particles that are trapped in the mucus out of the lungs and into the upper airways to eventually be swallowed [ ] . the surface lining of the airways in normal lungs consists of an aqueous layer adjacent to the epithelium and a surfactant containing film layer at the air-liquid interface. the peri-ciliary aqueous layer has a relatively low viscosity, while the surfactant film layer is more viscous. the surfactant film plays an important role in the displacement of airway particles towards the epithelium where they will be immersed and retained. the extent of particle immersion depends on the surface tension of the film. the lower the surface tension, the greater the immersion of particles into the aqueous layer adjacent to the epithelium [ , ] . it is possible that some protein monomers could quickly reach the stagnant aqueous layer and not be subjected to mcc. on the other hand, some protein monomers would become aggregated during the inhalation delivery process and the aggregates may stay with the surfactant film layer at the air-liquid interface for some time for mcc to take effect. anti-adhesive formulations (achieved by using lower mw pegs for example) could be used to circumvent mcc clearance of inhaled therapeutics, thus increasing their lung accumulation. the mucus-penetrating ability of such pegs has already been demonstrated in multiple studies [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the second clearance mechanism is macrophage uptake, which is the primary clearance mechanism in the alveoli. proteins are taken up by alveolar macrophages in the deep lung via pinocytosis, and the uptake of particles is size dependent [ , , ] . large proteins (≥ kda) would have more time to be engulfed by alveolar macrophages by virtue of their slower transport and absorption across the alveolo-capillary barrier, while small proteins and peptides (≤ kda) are absorbed rapidly from the airspaces and thus, may not be impacted by alveolar macrophage uptake as much. in essence, pinocytosis by alveolar macrophages could become significant for macromolecules with mw > kda [ ] . the use of excipients can help to reduce clearance of large proteins by alveolar macrophages. for example, koussoroplis et al. ( ) showed that pegylation conferred increased residence time to antibody fragments anti-il- a f (ab ′) and anti-il- fab′ (unconjugated f (ab′) was kda and unconjugated fab′ was kda), and that the effect was due to mucoadhesion as well as evasion of alveolar macrophage uptake [ ] . protein pegylation may potentially also alter its deposition pattern in the respiratory track, due to changes in molecular weight, hydrophilicity etc. however, systemic analyses of the effect of pegylation on protein deposition pattern in the respiratory track are still needed in order to know if a consistent deposition pattern and behaviour can be reached based on how pegylation is achieved. the third clearance mechanism is absorption into the systemic circulation. after deposition in the alveolar region, aerosol drug particles may dissolve in pulmonary epithelial lining fluid if the drug is water-soluble, and become available for systemic absorption and clearance [ ] . for the purpose of topical lung treatment, the goal would be to minimise systemic absorption, which is greatly influenced by protein mw. the bioavailability of a protein after absorption from the lung decreases as protein mw increases. small peptides are absorbed rapidly from the lungs with - % of the bioavailability for subcutaneous injection [ ] . proteins with mw of - kda exhibit moderate absorption, with bioavailability ranging from to %, although it should be noted that pulmonary absorption studies in animals may lead to an overestimation of bioavailability. for example, systemic bioavailability after aerosol administration in animals for growth hormone (gh) and interferon α (ifnα) was % and % respectively, compared to only - % in humans [ , ] . large mw antibodies (~ kda) are not significantly absorbed across the lung, and bioavailability is negligible (<< %) unless an active transport system is included [ ] . apart from high protein mw, the presence of obstructive lung diseases (e.g. asthma, copd, cystic fibrosis) can also reduce systemic absorption and bioavailability of proteins and other drugs [ ] . for example, henry et al. ( ) reported that healthy subjects had significantly higher area under the curve (auc) and mean maximum concentration (c max ) after insulin inhalation than asthma patients, indicating that less insulin was absorbed into the systemic circulation in asthma patients [ ] . in addition, diderichsen et al. ( ) reported that the c max of an inhaled long acting β agonist (pf- ) was found to be reduced by % and % for copd and asthma patients respectively, compared to healthy volunteers [ ] . additional possibility for the lower systemic absorption of drugs in lung disease patients could be due to altered drug deposition pattern in the diseased lung, for which further studies are needed. regardless the underlying mechanisms, effective local lung retention of protein drugs may not be a major issue for the successful inhalation treatment of obstructive lung diseases, since the protein can be relatively well retained in the lungs. inhaled protein therapeutics may undergo various degradation mechanisms during production, processing and/or storage. these degradation pathways may be physical (denaturation and non-covalent aggregation) or chemical (mainly covalent aggregation, deamidation, oxidation and/or glycation). denaturation is the result of physical stresses including low/high temperatures, high salt concentrations, organic solvents, and air/water or ice/water interfaces. removal of the stressor may be spontaneously reversible (for some single domain proteins), but is usually irreversible for most of the larger multi-domain proteins [ ] . surface-induced aggregation is one of the common mechanisms of non-covalent aggregation, and one example of when it occurs is during the process of nebulisation [ , ] . as most proteins are amphiphilic and surface active, they have a tendency towards adsorption at the ali. upon adsorption, conformation changes may occur, exposing hydrophobic residues to the interface to avoid contact with water, thus leading to aggregation and unfolding, which are the main factors contributing to protein instability [ , ] . chemical degradation of proteins (deamidation, oxidation, glycation) may also cause aggregation (either covalent or non-covalent) [ ] . aggregation has been extensively studied but chemical modifications have not, despite having implications on biological activity and immunogenicity [ , ] . aggregation can result from both physical and chemical pathways; therefore, it is useful to also evaluate chemical changes in inhaled proteins. most studies assessing stability of inhaled protein formulations focus on formation of aggregates, while studies that also examine chemical changes are few and far between. one study did, however, consider chemical changes when evaluating the technical feasibility of delivering dornase alfa using perforated vibrating membrane devices for nebulisation. in this study, besides detecting protein aggregates, stability was also evaluated by measuring the percent deamidation of dornase alfa at asn (the main chemical change for the protein), which was shown to be inversely proportional to dornase alfa potency [ ] . another study looked at methionine oxidation [met(o)] of nebulised insulin-like growth factor- (igf-i), and how that correlated with aggregate formation and bioactivity. highly aggregated samples displayed a complete loss of bioactivity, while samples with complete oxidation but minimal aggregation showed partial retention of bioactivity. limited met(o) formation and no aggregation was observed following delivery with air-jet or vibrating mesh nebulisers [ ] . bandi et al. ( ) conducted a study to compare the effects of deamidation and oxidation on interferon alpha- a (ifna a), as deamidation of asparagine and glutamine residues, and oxidation of methionine residues are two of the most common chemical alterations that occur in pharmaceutical proteins that could compromise their efficacy and safety [ ] . these findings revealed that deamidation destabilised ifna a and enhanced its tendency to aggregate under stressful conditions, and reduced its function to a greater extent than oxidation. this is the first study that quantitatively compared the effects between deamidation and oxidation of a therapeutic protein [ ] . it would be a good strategy to conduct such studies early on in the development of therapeutic protein candidates in order to identify the chemical modifications that a particular protein would be susceptible to, and to test out various excipients that could resolve specific stability issues. the protein therapeutic also needs to remain stable after reaching the lung, which can be challenging due to the high numbers of serine proteases and aminopeptidases present in the lung mucosa [ ] [ ] [ ] [ ] . these proteases could degrade protein drugs even before they reach their target sites within the lung. the use of appropriate excipients in the formulation such as peg, could help to enhance protein resistance to proteolysis by these lung proteases. for example, zhang et al. ( ) evaluated the stability of fibronectin (fn) preferentially pegylated at lysine residues using different mw pegs [ kda (peg ), kda (peg ) or kda (peg )] against the protease α-chymotrypsin. they showed that pegylation protected fn from proteolysis and that peg mw positively correlated with proteolytic stability (i.e. after min of proteolysis, %, %, % and % of the starting amounts of native fn, fn-peg , fn-peg and fn-peg respectively were remaining) [ ] . one must also be aware of the possibility of protein aggregates forming in the lungs. lasagna-reeves et al. [ ] demonstrated that mice exposed to inhaled insulin (exubera®) in a chamber twice daily for week developed amyloid aggregates of insulin in both the proximal and distal airways, as well as the lung parenchyma (epithelium and muscle layer of the bronchi, bronchioles, and in the alveolar lining cells). the formation of insulin aggregates coincided with a significant decrease in respiratory flow rates, and also with caspase- activation. previous studies investigating the link between changes in pulmonary function and inhaled insulin use focused on formation of anti-insulin antibodies, or pulmonary inflammation and subsequent airway remodelling, but none of the published works before this looked at insulin aggregation in the lungs as a contributor to pulmonary dysfunction after inhaled insulin use [ ] . indeed, exu-bera® was reported to cause cough, dyspnea, increased sputum and epistaxis [ ] . this example highlights the possibility of inhaled proteins forming aggregates in the lungs, and thus the need for toxicity testing and safety studies examining this possibility to be done early on in the development of an inhaled protein candidate, during preclinical studies. in addition, proteins and other macromolecules have the potential to induce immunogenicity, with the production of anti-drug antibodies (adas) as the main immune response [ ] . the development of adas in patients can alter pharmacokinetics, drastically reduce efficacy, and can also lead to severe adverse events or even lethal consequences [ ] . immunogenicity is also linked to protein stability, as the presence of aggregates can render the protein immunogenic. as aggregates are typically composed of denatured molecules, they would exhibit no or decreased activity, but at the same time, aggregates are usually immunogenic leading to adas with important clinical implications [ ] . aggregates are believed to be recognised and processed via non-specific uptake by antigen presenting cells and specific uptake by b cells. they may unmask neo−/cryptic/repetitive epitopes, and these differences may influence the mechanism by which they activate the immune system [ ] . currently, only a few excipients have been approved by the fda for inhalation due to a dearth of toxicological studies for inhaled excipients [ , ] . there is also very limited number of excipients that are approved by fda for biologics, rendering formulators limited choices to improve protein formulations when excipients are searched on the fda's inactive ingredient database guidance. furthermore, very few novel excipients have been investigated for biologic products; most are cyclodextrin-based excipients [ ] . as such, there is a need for more extensive toxicity testing to identify novel excipients for pulmonary delivery. for excipients already known to increase protein stability, a trial and error approach needs to be taken in determining their suitability for a particular protein formulation, as an excipient may work for one protein but not for another for various reasons including sequence differences [ ] . excipients that are commonly used in liquid formulations (nebulisers and mdis) include buffering or ph adjusting agents, and surfactants, and those that are commonly used in dry powder formulations (dpis) include sugars, polyols, and amino acids [ , ] . buffering or ph adjusting agents such as sodium chloride, sodium citrate, hydrochloric acid, sodium hydroxide, and citric acid, are added to maintain the ph of the formulation. it is important to choose the right buffering agent at an appropriate concentration, as most proteins in solution only remain stable within a narrow ph range. different buffer systems and concentrations can also affect the aggregation pattern of proteins [ ] . kim et al. [ ] analysed the stability of a fusion protein, etanercept (marketed enbrel®), with changing ph and buffer concentrations. increasing the ph of etanercept from ph . to . resulted in a decrease in protein size and increase in aggregation. under high buffer concentrations ( mm tris buffer), changes in protein size was reduced and irreversible aggregation was not observed, while in lower buffer concentrations ( mm tris buffer), larger aggregates (~ μm) were observed across the ph range [ ] . surfactants (polysorbates, sorbitan esters, oleic acid, and soy lecithin) are frequently used to prevent aggregate formation, and they work by displacing protein molecules from the ali [ , ] . polysorbates are the most commonly used surfactants, and are already being used to preclude aggregation in formulations of intravenously administered antibodies [ ] . polysorbate has been reported to lead to stabilisation in various inhaled protein formulations including those for granulocyte-colony stimulating factor (g-csf), lactate dehydrogenase (ldh), tissue plasminogen activator (t-pa) and aviscumine (recombinant mistletoe lectin) [ ] . the ability of polysorbates and other surfactants to stabilise a protein and hinder aggregate formation is contingent on the protein-to-surfactant ratio. respaud et al. [ ] examined the effects of various antibody and surfactant (polysorbate ) concentrations to optimise the protein-to-surfactant ratio for a nebulised antibody formulation. the authors determined that high concentrations of either surfactant or protein could minimise the formation of medium and large-sized aggregates, without significantly affecting the volume mean diameter (vmd) of the aerosol cloud, ensuring suitability for inhalation. therefore, including surfactants and raising protein concentration to enhance the stability of inhaled protein formulations is a viable strategy, although it should be noted that this approach needs to be evaluated and optimised for each drug and device pairing being developed into an inhaled protein formulation [ ] . sugars (sucrose, trehalose, raffinose and lactose) and polyols (mannitol) stabilise proteins through the preferential hydration of proteins via steric repulsion of sugar/ polyol molecules from the native protein [ , ] . lactose is often used as a drug carrier in dpis, however, it may not be suitable for proteins because it is a reducing sugar, and it could interact with amino groups in proteins (maillard reaction) [ ] . on the other hand, non-reducing sugars such as sucrose, trehalose and raffinose would not undergo the maillard reaction with proteins, and thus could be used as alternatives to lactose [ ] . sellers et al. [ ] demonstrated that sucrose could help to improve the stability of a dry powder formulation of ldh. supercritical fluid (scf) drying of ldh without excipients lead to irreversible loss of activity (only % recovered after rehydration). inclusion of % (w/w) sucrose during dehydration lead to an increase in activity recovered (to~ %), and there was almost complete retention of activity when polysorbate was added in addition to sucrose [ ] . trehalose and raffinose are currently not approved for any administration routes, but have been evaluated in experimental studies with promising results. for instance, Ógáin et al. [ ] incorporated lysozyme into nanoporous microparticles of trehalose and raffinose. lysozyme showed good retention of specific activity after storage for weeks at either °c ( . ± . % for lysozyme:trehalose and . ± . % for lyzosyme:raffinose) or °c ( . ± . % for lysozyme:trehalose and . ± . % for lyzosyme:raffinose) [ ] . mannitol was used as an excipient in the formulation of exubera® (table ) [ ] . small amino acids (histidine, arginine, alanine, glycine, lysine, isoleucine) are also used as stabilisers, and they work by the "water substitution mechanism" in which the amino acids hydrogen bond with the protein during drying to preserve the native protein structure in the dried state [ , ] . ajmera and scherlieβ [ ] screened different amino acids and their combinations for their ability to stabilize catalase during spray drying. when various ratios of arginine, glycine and histidine were mixed with catalase, some formulations were able to maintain close to % catalase activity [ ] . despite encouraging results in studies such as this one, there is a lack of data on the local toxicity of the various amino acids following inhalation, which could limit their use. however, as they are endogenous substances, they may not present major safety issues for local lung delivery [ , ] . the polyol, peg, could be used for both liquid and powder formulations of inhaled proteins. small mw pegs (< kda) are often used as excipients in oral, intravenous and nasal formulations. larger pegs (up to kda) may be used in pegylated biopharmaceuticals, and safety testing for these formulations are done during development on a case-by-case basis [ ] . pegylation is a commonly used method to enhance solubility and stability, as well as to decrease immunogenicity of bioactive drugs including but not limited to proteins, peptides, antibody fragments, and enzymes, and is achieved by the covalent or noncovalent conjugation of peg to the biomolecule [ , ] . pegylation can also help to reduce clearance and increase lung accumulation and residence time of inhaled protein therapeutics. for instance, conjugation of a peg chain to two antibody fragments (anti-il- a f (ab′) and anti-il- fab′) increased their levels in mouse lungs following intranasal administration. fortyeight hours post-administration, levels of unconjugated antibody fragments in the lungs had dropped to % and % of the original deposited dose of f (ab′) and fab′ respectively, while this value was % for both pegylated fragments [ ] . furthermore, conjugation of a peg chain to an anti-il- a fab' antibody fragment increased pulmonary retention in all three species tested (mice, rats, and rabbits) following intratracheal administration. unconjugated fragments were cleared from the lungs within h while large amounts of pegylated fragments still remained for up to h [ ] . the two biggest challenges in developing particle systems for pulmonary drug delivery are to maintain colloidal stability during aerosolisation and to achieve high delivery efficacy. encapsulation of proteins in carriers could provide multiple benefits such as protection from enzymatic degradation and specific targeting to the site of action through targeting ligands [ ] . furthermore, carriers may also be used to provide sustained drug release, accumulating in the lungs and releasing therapeutic levels of the protein drug over extended periods of time. this would enhance efficacy while averting peaks in local drug concentrations that could cause pulmonary toxicity [ ] . proteins, including insulin, calcitonin, and igg, have already been loaded into various carriers such as microparticles, liposomes, and solid lipid nanoparticles [ , ] . indeed, afrezza® uses techno-sphere® technology, in which fumaryl diketopiperazine (fdkp), an excipient added into the formulation, selfassembles into microspheres, entrapping the insulin. upon reaching the alveolar zone of the lung, the tech-nosphere® particles rapidly dissolve in the ph-neutral environment and release the insulin for systemic absorption [ ] . although this approach has not been extensively explored for topical lung delivery of proteins, and more work needs to be done on the use of carriers for the purpose of systemic delivery of proteins through the lungs, some promising results have been reported that support further development of this approach. tawfeek et al. [ ] encapsulated a model mucinolytic enzyme, αchymotrypsin (which is very sensitive to unfolding and formulation conditions), in a novel biodegradable pegco-polyester microparticle carrier. the encapsulated αchymotrypsin exhibited retention of enzymatic activity and the results indicated suitability of the carrier for potential use in the delivery of macromolecules as dpi formulations for the treatment of lung diseases [ ] . in another study by osman et al. [ ] , various surface modifications were made to dnase i loaded microparticles using different excipients in order to provide higher lung deposition, enzyme stability and biological activity. surface modifying the microparticles with polyglutamic acid (pga) or dextran was found to provide high inhalation indices (emitted fraction (ef), respirable particle fraction (rp), and effective inhalation index (ei)) and increased mucolytic activity in cystic fibrosis sputum. this could be explained by the resulting surfaces of the particles after modification with pga (rough dented surfaces) or dextran (dimpled surfaces). compared to spherical particles with similar physical properties, corrugated particles have surface asperities that could reduce the true contact area between particles, decreasing powder cohesiveness and enhancing aerosol performance [ ] . advancements in drug-loaded capsules for pulmonary delivery have been made in both inhalable dry powder or liquid drug formulations [ ] [ ] [ ] . for dry powder drug particles, precise control of the particle size has been reported using the particle replication in nonwetting templates (print) technology [ , ] . for control of aerodynamic particle size in liquid aerosols such as in nebulized liquid formulation, the recently reported mpns have presented promising possibilities. mpnbased drug-loaded capsules with highly defined physical properties can be generated for both macromolecular protein drugs and small molecule chemical drugs [ ] . these new developments may transform inhalation drug delivery in the near future. one drawback with the use of carriers is their rapid uptake by alveolar macrophages [ , ] . phagocytosis of carriers by alveolar macrophages can result in fast clearance and reduced residence time, limiting the therapeutic efficacy of the carrier-associated drug. this would be an issue for the treatment of chronic lung diseases such as asthma and copd, where the goal of using a carrier system would be to achieve controlled and continuous drug release over an extended period of time. however, various formulation design strategies may be employed to reduce the uptake of particulate carriers by alveolar macrophages including modulation of particle size, shape, surface charge and surface coating [ ] . studies on the use of various polymer coatings demonstrate reduced alveolar macrophage uptake of coated carriers. for example, jones et al. [ ] showed that respirable microspheres coated with dipalmitoyl phosphatidylcholine (dppc; a major component of lung surfactant) were able to significantly reduce phagocytic uptake by nr in cultured alveolar macrophages compared to uncoated microspheres. the uptake of dppc coated microspheres was found to be only . ± . %, . ± . % or . ± . %, of the uptake of uncoated microspheres for ratios of , or excess microspheres per nr cell respectively [ ] . furthermore, shen et al. [ ] demonstrated that surface coating of hydrogel nano-and microparticles with peg showed significantly reduced uptake by alveolar macrophages both in vitro (in mh-s cells) and in vivo (in mice) compared to unpegylated particles of the respective size. at h post-dose, the fold difference between pegylated and unpegylated × nm, . μm, and μm particles in bronchioalveolar lavage fluid (balf), was . , . and . respectively [ ] . on the other hand, drug-loaded particles may be advantageous for anti-tuberculosis drugs as efficient uptake of drugs into alveolar macrophages could potentially enhance the drug's efficacy to kill the parasitic mycobacterium tuberculosis that hide inside the cells [ ] . if the usage of a carrier is to be included in the protein formulation, it should be noted that the formulation (i.e. combination of protein and carrier) would need to be optimised together with the choice of device, as the chosen carrier may not work well with all inhalation device types. for instance, liposomes may be delivered to the lungs either by dry powder inhalation or nebulisation of a liposome suspension. however, nebulised solutions of liposomes may cause instability as nebulisation has been reported to disrupt liposomal structure, leading to the release of loaded drug. these issues can be avoided with the use of dry powders of liposomes instead [ ] . hence, although this review has presented a general overview for the various aspects of protein formulation design (such as choice of device, excipients), it is important to test out the formulation and device together to determine which combination works best. this review analyses the various obstacles that an inhaled protein drug would need to overcome in order to reach the lungs and exert its therapeutic effects. these obstacles include the physical and chemical stresses experienced by the protein during production/storage/ aerosolisation, the need to overcome mucociliary clearance and physical barriers arising from disease conditions in order to reach target sites within the lung, and the need to remain stable in spite of the presence of abundant proteases, and to evade clearance by alveolar macrophages after reaching the lungs (fig. ) . all of these threats to the integrity of the protein need to be carefully considered, so that pre-emptive measures can be taken while designing the protein formulation to ensure its therapeutic efficacy. nevertheless, although the information provided here may serve as general considerations in developing pulmonary protein therapeutics, empirical testing of the formulation together with the device should still be performed to determine the best combination for a particular protein. several key areas will require further investigation in order to support the development of more successful inhaled protein therapies, and maintaining the stability of the inhaled protein is of paramount importance. firstly, more studies could look at other instability issues beyond protein aggregation. in depth studies on the specific chemical modifications that a protein would be susceptible to, such as the one conducted by bandi et al. ( ) , could be carried out on therapeutic protein candidates so that they may be developed into stable and effective treatments [ ] . moreover, the scarcity of fdaapproved excipients for inhaled therapeutics further limits drug developers, and expanding this list through increased toxicological testing of new excipients would provide more options for formulation design. finally, innovative approaches such as the use of novel carrier systems should be employed for the purpose of topical lung delivery, as carrier systems could greatly enhance the stability and pharmacokinetic profile of proteins. these approaches would greatly benefit the field of pulmonary drug delivery, and will ultimately allow more inhaled protein therapeutics to reach the clinic. funding support for this work is provided by the grant moe -t - - awarded to ruowen ge from singapore ministry of education, republic of singapore. capturing the benefits of competition for patients current approaches to the discovery of novel inhaled medicines inhaled protein/peptide-based therapies for respiratory disease nebulization as a delivery method for mabs in respiratory diseases carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies inhalation of immuno-therapeutics/ −prophylactics to fight respiratory tract infections: an appropriate drug at the right place! front immunol vegf neutralizing aerosol therapy in primary pulmonary adenocarcinoma with kras activating-mutations the airways, a novel route for delivering monoclonal antibodies to treat lung tumors inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes efficacy of aerosol therapy of lung cancer correlates with egfr paralysis induced by avidinox-anchored biotinylated cetuximab pegylation of antibody fragments greatly increases their local residence time following delivery to the respiratory tract repurposing of gamma interferon via inhalation delivery phase ii clinical trial results of alidornase alfa for the treatment of cystic fibrosis protalix biotherapeutics announces phase ii clinical trial results for alidornase alfa in cystic fibrosis presented at the th european cystic fibrosis society conference. protalix biotherapeutics designing inhaled protein therapeutics for topical lung delivery: what are the next steps? inhaled gm-csf in a pulmonary alveolar proteinosis patient refractory to plasmapheresis combined with multiple whole lung lavages synairgen doses first patient in covid- trial ansun biopharma enrolls first patient in proof of concept trial of das for the treatment of covid- direct administration in the respiratory tract improves efficacy of broadly neutralizing anti-influenza virus monoclonal antibodies in a murine model of acute lung infection, airway administration of a therapeutic antibody confers greater protection than parenteral administration challenges and future prospects for the delivery of biologics: oral mucosal, pulmonary, and transdermal routes non-invasive delivery strategies for biologics idealhalers versus realhalers: is it possible to bypass deposition in the upper respiratory tract? that's cool! -nebulization of thermolabile proteins with a cooled vibrating mesh nebulizer protein stability in pulmonary drug delivery via nebulization protein nebulization: i. stability of lactate dehydrogenase and recombinant granulocyte-colony stimulating factor to air-jet nebulization stability of urease during aerosolization protein nebulization some factors associated with the ultrasonic nebulization of proteins nebulizers for drug delivery to the lungs the function and performance of aqueous aerosol devices for inhalation therapy devices for improved delivery of nebulized pharmaceutical aerosols to the lungs vibrating mesh nebulisation of pro-antimicrobial peptides for use in cystic fibrosis effect of formulation on the stability and aerosol performance of a nebulized antibody a technical feasibility study of dornase alfa delivery with eflow® vibrating membrane nebulizers: aerosol characteristics and physicochemical stability insulin-like growth factor-i aerosol formulations for pulmonary delivery development of a drug delivery system for efficient alveolar delivery of a neutralizing monoclonal antibody to treat pulmonary intoxication to ricin effective nebulization of interferon-γ using a novel vibrating mesh factors to consider when selecting a nebulizer for a new inhaled drug product development program engineering of nebulized metal-phenolic capsules for controlled pulmonary deposition pulmonary monoclonal antibody delivery via a portable microfluidic nebulization platform in vivo deposition study of a new generation nebuliser utilising hybrid resonant acoustic (hydra) technology prospects of formulating proteins/peptides as aerosols for pulmonary drug delivery protein conformational stability in the hydrofluoroalkane propellants tetrafluoroethane and heptafluoropropane analysed by fourier transform raman spectroscopy computational modeling of lung deposition of inhaled particles in chronic obstructive pulmonary disease (copd) patients: identification of gaps in knowledge and data the impact of pulmonary diseases on the fate of inhaled medicines-a review drug delivery for traditional and emerging airway models. organs-on-a-chip nanodelivery in airway diseases: challenges and therapeutic applications addressing the peg mucoadhesivity paradox to engineer nanoparticles that "slip" through the human mucus barrier biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier nanoparticles coated with high molecular weight peg penetrate mucus and provide uniform vaginal and colorectal distribution in vivo surfactant displaces particles toward the epithelium in airways and alveoli pulmonary surfactant: surface properties and function of alveolar and airway surfactant transport of nanoparticles in cystic fibrosis sputum and bacterial biofilms by single-particle tracking microscopy protein nanocages that penetrate airway mucus and tumor tissue use of single-site-functionalized peg dendrons to prepare gene vectors that penetrate human mucus barriers rapid transport of large polymeric nanoparticles in fresh undiluted human mucus highly compacted biodegradable dna nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy pegylated enhanced cell penetrating peptide nanoparticles for lung gene therapy lung gene therapy with highly compacted dna nanoparticles that overcome the mucus barrier the penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles preclinical models for pulmonary drug delivery formulation technology to repurpose drugs for inhalation delivery will pulmonary drug delivery for systemic application ever fulfill its rich promise? inhaled insulin using the aerx insulin diabetes management system in healthy and asthmatic subjects characterizing systemic exposure of inhaled drugs: application to the long-acting β -agonist pf- inhaled proteins: challenges and perspectives d nmr analysis of the effect of asparagine deamidation versus methionine oxidation on the structure, stability, aggregation, and function of a therapeutic protein respiratory protease/antiprotease balance determines susceptibility to viral infection and can be modified by nutritional antioxidants role of proteases in lung disease: a brief overview role of proteases in chronic obstructive pulmonary disease proteases and antiproteases in chronic neutrophilic lung disease -relevance to drug discovery pegylation of lysine residues improves the proteolytic stability of fibronectin while retaining biological activity inhaled insulin forms toxic pulmonary amyloid aggregates technosphere®: an inhalation system for pulmonary delivery of biopharmaceuticals immunogenicity of different stressed igg monoclonal antibody formulations in immune tolerant transgenic mice the effects of substituted cyclodextrins on the colloidal and conformational stability of selected proteins formulation strategy and use of excipients in pulmonary drug delivery effects of ph and buffer concentration on the thermal stability of etanercept using dsc and dls practical, regulatory and clinical considerations for development of inhalation drug products particle engineering of materials for oral inhalation by dry powder inhalers. i-particles of sugar excipients (trehalose and raffinose) for protein delivery dry powders of stable protein formulations from aqueous solutions prepared using supercritical co -assisted aerosolization mechanisms of protein stabilization in the solid state stabilisation of proteins via mixtures of amino acids during spray drying amorphous powders for inhalation drug delivery pegylation, an approach for improving the pulmonary delivery of biopharmaceuticals what is the future of pegylated therapies? from synthesis to characterization of site-selective pegylated proteins pegylation prolongs the pulmonary retention of an anti-il- a fab' antibody fragment after pulmonary delivery in three different species delivery strategies for sustained drug release in the lungs multifunctional nanocarriers for lung drug delivery dry powder inhalation of macromolecules using novel peg-copolyester microparticle carriers inhalable dnase i microparticles engineered with biologically active excipients inhaled nano-and microparticles for drug delivery nanoparticles for drug delivery to the lungs advanced therapeutic strategies for chronic lung disease using nanoparticle-based drug delivery formulation of high-performance dry powder aerosols for pulmonary protein delivery microfabricated engineered particle systems for respiratory drug delivery and other pharmaceutical applications polymeric nanoparticles in development for treatment of pulmonary infectious diseases update on macrophage clearance of inhaled micro-and nanoparticles particle engineering to enhance or lessen particle uptake by alveolar macrophages and to influence the therapeutic outcome the inhibition of phagocytosis of respirable microspheres by alveolar and peritoneal macrophages distribution and cellular uptake of pegylated polymeric particles in the lung towards cell-specific targeted delivery drug delivery for tuberculosis: is inhaled therapy the key to success? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - mrdjc authors: hutchison, alastair a.; leclerc, francis; nève, véronique; pillow, j. jane; robinson, paul d. title: the respiratory system date: - - journal: pediatric and neonatal mechanical ventilation doi: . / - - - - _ sha: doc_id: cord_uid: mrdjc this chapter addresses upper airway physiology for the pediatric intensivist, focusing on functions that affect ventilation, with an emphasis on laryngeal physiology and control in breathing. effective control of breathing ensures that the airway is protected, maintains volume homeostasis, and provides ventilation. upper airway structures are effectors for all of these functions that affect the entire airway. nasal functions include air conditioning and protective reflexes that can be exaggerated and involve circulatory changes. oral cavity and pharyngeal patency enable airflow and feeding, but during sleep pharyngeal closure can result in apnea. coordination of breathing with sucking and nutritive swallowing alters during development, while nonnutritive swallowing at all ages limits aspiration. laryngeal functions in breathing include protection of the subglottic airway, active maintenance of its absolute volume, and control of tidal flow patterns. these are vital functions for normal lung growth in fetal life and during rapid adaptations to breathing challenges from birth through adulthood. active central control of breathing focuses on the coordination of laryngeal and diaphragmatic activities, which adapts according to the integration of central and peripheral inputs. for the intensivist, knowledge of upper airway physiology can be applied to improve respiratory support. in a second part the mechanical properties of the respiratory system as a critical component of the chain of events that result in translation of the output of the respiratory rhythm generator to ventilation are described. a comprehensive understanding of respiratory mechanics is essential to the delivery of optimized and individualized mechanical ventilation. the basic elements of respiratory mechanics will be described and developmental changes in the airways, lungs, and chest wall that impact on measurement of respiratory mechanics with advancing postnatal age are reviewed. this will be follwowed by two sections, the first on respiratory mechanics in various neonatal pathologies and the second in pediatric pathologies. the latter can be classified in three categories. first, restrictive diseases may be of pulmonary origin, such as chronic interstitial lung diseases or acute lung injury/acute respiratory distress syndrome, which are usually associated with reduced lung compliance. restrictive diseases may also be due to chest wall abnormalities such as obesity or scoliosis (idiopathic or secondary to neuromuscular diseases), which are associated with a reduction in chest wall compliance. second, obstructive diseases are represented by asthma and wheezing disorders, cystic fibrosis, long term sequelae of neonatal lung disease and bronchiolitis obliterans following hematopoietic stem cell transplantation. obstructive diseases are defined by a reduced fev /vc ratio. third, neuromuscular diseases, mainly represented by dmd and sma, are associated with a decrease in vital capacity linked to respiratory muscle weakness that is better detected by pimax, pemax and snip measurements. • describe the expanded concept of breathing in terms of multiple motor functions that ensure airway protection, volume homeostasis, and ventilation. • describe the upper airway structures and how their functions affect the entire airway. • describe the nasal functions involved in air conditioning, in protection, in the maintenance of airway patency, and in the consequences of nasal bypass and obstruction. • describe the oral cavity and pharyngeal regions and control of airway patency. • describe factors involved in obstructive sleep apnea and the effects of cpap therapy. • describe the coordination of sucking, nutritive swallowing, and breathing during development and the relationship to apnea and bradycardia. • describe the importance of nonnutritive swallowing in pharyngeal clearance and how this may be influenced by cpap. • describe the three major functions of the larynx involving breathing. • describe the triple mechanism of laryngeal closure in airway protection. • describe how flow and subglottic volume are controlled during eupnea. • describe the integrative nature of the central control of laryngeal functions. • describe the roles of laryngeal muscles and their coordination with pump muscles during development and in eupnea, sighs, grunting, incremental breathing, and gasping. • describe how this information has been/ can be applied in respiratory support. • describe afferent inputs that alter laryngeal muscle functions and alter breathing and cardiovascular function. • describe the impact of central behavioral state and induced central depression upon laryngeal function and the interactions with detected changes in the gaseous environment. it is impossible for anyone to find the correct function of a part unless he is perfectly acquainted with the action of the whole instrument. galen, ad - . breathing consists of multiple motor acts whose mechanical effects aim to ensure that the airway is protected, has optimal supra-and subglottic volumes, and provides vital ventilation. the upper airway extends from the nose or mouth to the larynx (seikel et al. ) , but its functions, in the context of ventilation, extend to the entire airway. maintenance of airway volume and ventilation is actively controlled by the centrally coordinated activities of nasal, oral, pharyngeal, and laryngeal upper airway muscles and those of the pump muscles. these act in concert with lower airway smooth muscle. effective breathing requires that the brain coordinates ventilatory functions with cardiovascular function and with other motor acts, e.g., swallowing, postural changes, and speech. adaptations in breathing must occur appropriately, rapidly, and constantly. protective and mechanical changes occur in milliseconds. changes in circulatory gas transport alter breathing within seconds. other adjustments optimize breathing in tune with changes in growth, aging, metabolism, and the environment. this chapter addresses how each upper airway structure plays critical roles in the dynamic processes of breathing. … we would do well to keep our mouths shut and reflect on the marvelous physiology of the nose. richard godfrey normal breathing occurs via the nose (fig. . ). inspired and expired air is conditioned by the nasal mucosa, whose surface area and blood supply are such that particles are filtered and temperature and humidity are modified. the nasal vascular system can achieve a °c gradient between the nasal ostia and the nasopharynx (godfrey ) , a property that enables air breathing at very different environmental temperatures while maintaining a remarkable constancy of temperature and humidity in the lower airway, thereby optimizing cellular function and ciliary action. given its vascularity, it is not surprising that the nose is a source of nitric oxide, that trauma to the nasal passages can be induced by nasal continuous positive airway pressure (ncpap) prongs and other cannulae, and that epistaxis can require hospital admission. the nose can sniff out noxious substances and protect the airway from particles by sneezing. it can increase its resistance rapidly, switching on a watery secretion "like a tap" (godfrey ) , and can trigger laryngeal closure and reduced ventilatory drive (editorial ) . the extreme protective reflex response to nasal irritation is the dive reflex that is typified by apnea with glottic closure, bradycardia, and redistribution of blood flow to the brain, heart, and adrenals (see also sect. . . ) (de burgh daly ; editorial ) . the dive reflex can be triggered by nasal water, tobacco smoke, or ice applied to the trigeminal area (angell james and de burgh daly ; de burgh daly ) . water entry into the nose is dramatic even for adults who "suffer a sense of impending suffocation and the almost impossibility of voluntarily making an inspiratory effort" (de burgh daly ) . exaggerated dive reflex responses can cause total upper airway closure and cardiac arrest and have been implicated in accidental and deliberately induced deaths (de burgh daly ). nasal breathing in the newborn and infant is the predominant but not obligatory form of breathing and is related to the high position of the epiglottis ( fig. . ) (seikel et al. ). there is a nasal cycle whereby resistance alternates from one nostril to the other every - h in % of humans (widdicombe ) . pressure in the axilla or on the lateral chest increases ipsilateral nasal resistance (widdicombe ) . resistance is highest in the regions adjacent to the external ostia, whose dimensions are altered by the alae nasi muscles that cause nasal flaring during exercise hyperpnea and respiratory distress, especially in newborns. newborn nasal resistance exceeds that of the adult in absolute terms but is less than that of their lower airways. nearly half of the adult's total airway resistance is nasal. thus, minor increases in nasal resistance can produce major overall effects on breathing (editorial ). in adult humans, nasal occlusion results in a switch to mouth breathing in < s (editorial ) . both this switch to oral breathing and the resumption of nasal breathing following release of the occlusion are delayed by nasal and pharyngeal anesthesia. occlusion of the nasal passages in infants results in mouth breathing in ~ s (range < - s) (editorial ; rodenstein ) . the response is quicker with advancing age but is decreased in rapid eye movement (rem) sleep, more so at weeks than in the newborn period (editorial ) . these observations led to a proposal that the response may be related to the sudden infant death syndrome (sids) (editorial ) . in premature infants, the change to oral breathing results in a sixfold increase in pulmonary resistance, which over time might result in fatigue with hypoventilation (miller et al. ) . oral breathing places an increased burden on the lower airway to modify the temperature and humidity of inspired gas, presumably via changes in lower airway vascularity. preventing nasal breathing can decrease gas exchange and functional residual capacity (frc) (editorial ) . postoperative nasal packing in adults can lead to arterial hypoxemia, apnea, and sleep disturbance, with the latter also occurring in normal volunteers after local anesthesia of the nasal passages (editorial ) . in newborn lambs, nasal obstruction also affects gas exchange, with hypoxemia, hypercapnia, and acidosis being observed. these effects are aggravated by carotid body denervation. the impact of nasal obstruction diminishes with advancing age (editorial ) . blockage of the nose (choanal stenosis being an extreme example) can cause obstructive sleep apnea (osa) (marcus ) . human neonates whose nasal resistance is increased by birth trauma or trauma secondary to repeated suctioning breathe orally. they can have cyanotic episodes, stridor, and hypercapnia; these problems disappear with resolution of the nasal injury (miller et al. ) . in summary, the nose provides air conditioning, and its sensory receptors initiate reflexes that alter upper airway patency and mediate extended ventilatory changes in response to a challenge. functions in breathing …after relaxing, many sword swallowers are able to relax and breathe while swallowing a sword. from swordswallow.com . the oral cavity extends from the lips to the plane of the faucial pillars, where it joins the pharynx ( fig. . ) . the three pharyngeal regions are the nasopharynx, from the posterior nares to the uvula; the oropharynx, from the uvula to the epiglottis; and the laryngopharynx, from the epiglottis to the esophagus. the pharynx is a conduit for air and/or food. the muscles of the tongue, especially the genioglossi, maintain patency of the oral cavity. pharyngeal patency is a function of the cavity dimensions (rodenstein ) and the balance between the opening forces exerted by pharyngeal muscle activities and the collapsing ones exerted by the tissue-intrapharyngeal pressure gradient and by pharyngeal mucosal adhesion (fig. . ) . patency is critically influenced by posture. narrowing occurs with neck flexion and hyperextension and can alter cavity pressures required to achieve flow. narrowing can also follow an inspiratory occlusion of the mouth/nose (a load) that augments diaphragmatic activity and thus negative pressure within the pharynx. upper and lower airway afferents induce reflex compensatory change in glossopharyngeal muscles to offset the load effect ( fig. . ) (bailey and fregosi ) . obstructive apnea occurs during sleep in ~ - % of children and adults (marcus ) . in children, a persistent partial form of upper airway obstruction, obstructive hypoventilation, is seen (marcus ) . in adults, a spectrum of decreased inspiratory airflow is seen in snoring, upper airway resistance syndrome, and osa. pharyngeal osa occurs when a critical tissue pressure (p crit ) exceeds the intrapharyngeal opening pressure (fig. . ) (marcus ; dempsey et al. ) and is influenced by factors that alter pharyngeal dimensions, namely, adenotonsillar hypertrophy, obesity (less common in children than adults), low subglottic airway volume, and craniofacial structural abnormalities. the major role played by the central motor output to the oral cavity and pharyngeal muscles that modify p crit is emphasized by the fact that osa occurs only in sleep, predominantly in rem sleep in children (marcus ) . the following factors also stress the importance of central control in osa. obstructive apnea occurring during mixed apnea in preterm newborns involves a direct central mechanism, as shown by the onset of pharyngeal and/or laryngeal closure before diaphragmatic activation (idiong et al. ) (see sect. . . ) . in adults pharyngeal closure can accompany central apnea (marcus ) . central arousal patterns during osa differ between children and adults (marcus ) . other factors affecting the incidence of osa are gender, a familial tendency, and racial/ethnic factors (marcus ) . anti-inflammatory medications can benefit osa, suggesting a role for inflammation in its etiology (praud and dorion ) . therapy with ncpap improves osa by increas-ing intrapharyngeal pressure and its transverse diameter (rodenstein ) , by augmenting lower airway volume and probably by stimulating breathing via pharyngeal pressure sensors (angell james and de burgh daly ) . in children and adults with osa, cpap therapy can improve their metabolism. the abilities to suck, swallow, and breathe are developed during fetal life (harding ). at all ages, swallowing is accompanied by laryngeal closure. term newborns and infants up to - months of age can lock the larynx into the nasopharynx (figs. . and . ) . this separation of the nasopharyngeal-laryngeal air passage from the oropharyngeal nutritive passage enables the term infant to breathe and feed simultaneously but with decreased ventilatory drive. this ability is not developed in the preterm neonate whose sucking pattern is also immature (lau ) . coordination of sucking-swallowing-breathing is defined by the ability to feed "by mouth with no overt signs of aspiration, oxygen desaturation, apnea, or bradycardia" and when "a ratio of : : or : : suck: swallow: breathe" is attained (lau ) . safe swallowing occurs at end-expiration and end-inspiration (lau ) . in term newborns, % of swallows occur at these points of the breathing cycle. in preterm infants, % of swallows occur during deglutition apnea (lau nonnutritive swallowing (nns) is "essential for survival," since > l of oral and nasal secretions are produced daily. without nns, "the lungs rapidly fill with these secretions, producing death within a few days" (thach ) . when pharyngeal secretions reach a critical volume, neural receptors, in the interarytenoid notch, stimulate the laryngochemoreflex which triggers nns (thach ) . the critical pharyngeal volume for nns may be increased by applied positive pharyngeal pressure, providing an explanation for the decrease in nns frequency with cpap (thach ) . in adult humans nns occurs mainly during expiration. in infants nns occurs at any time in the respiratory cycle (thach ) . volitional swallowing in adults clears the pharynx and reduces the protective laryngeal adductor reflex. during sleep, the protection provided by nns and glottic closure is imperfect, and some aspiration is common in normal individuals (thach ) . swallow breaths are short inspirations that precede a swallow, occurring when the upper pharyngeal sphincters are closed (thach ) . these breaths are thought to result in pharyngeal air being inhaled as opposed to being swallowed (thach ) . the increased gastric air found when positive pharyngeal pressure is applied suggests that cpap can alter normal pharyngeal clearance mechanisms and infers the need to titrate the applied pressure carefully (thach ) . finally, swallowing may be related to sleep apnea and be part of recovery from sleep apnea (see sect. . . ) (thach ) . in summary, patency of the oral cavity and the pharynx and the coordination with swallowing and sucking are critical for breathing. the term, but not preterm, newborn can suck and breathe simultaneously, although ventilatory drive is decreased. physiological control of breathing and swallowing involves important sensory input that limits aspiration and protects the lower airway. intensive care therapies can alter normal protective, breathing and swallowing functions. like a swiss watch, …our vocal tract depends on the precise functioning of many structures and muscles." jared diamond, (the third chimpanzee). the larynx has three major functions involving breathing. it serves as a protective structure guarding the subglottic airway; as a flow controller of subglottic absolute and tidal volumes during eupnea and complex coordinated movements; and as a vibratory modulator of flow that generates speech, song, and laughter ( fig. . ) . . . . . laryngeal closure and airway protection protection of the subglottic airway is a centrally controlled major task of "breathing." laryngeal stimulation can trigger a clearing response, e.g., an expiration reflex or a cough, or can result in airway closure. laryngeal closure occurs at the level of the epiglottis, at the vestibular folds, and at the vocal folds. this triple mechanism has been likened to closure of a nutcracker, an analogy whose accuracy is all too evident to intensivists faced with laryngospasm (fink ) . and flow/volume control in adult humans the glottis opens maximally during inspiration, closes gradually to a minimum about three quarters through expiration, and then opens again in late expiration (england et al. a ). glottic resistance is least at peak inspiration, increases as expiration progresses, and then decreases in late expiration to minimize inspiratory flow resistance with the onset of pump muscle activity (england et al. a ). there is no sensation of expiratory glottic closure in eupnea. accurate, rapid laryngeal opening and closure maintains an optimal subglottic airway volume, ensures tidal volume changes that enable gas exchange, and enhances airway patency and surfactant secretion. the smooth tidal flow pattern, produced by laryngeal and diaphragmatic activities interacting with the mechanics of the respiratory system, avoids tissue exposure to acceleration or deceleration injuries. the same laryngeal intrinsic muscles are involved in all laryngeal functions emphasizing that the central coordinations of the motor acts of breathing are truly integrative, a fact also stressed by the impacts that laryngeal sensory inputs and the resultant vagal outputs have on the cardiovascular system. laryngeal closure is important for other motor acts, e.g., effective lifting. central control of breathing is linked to emotions. it is of note that in laughter the order of abductor-adductor activities seen in breathing is reversed (luschei et al. the intrinsic laryngeal muscles and their innervation are shown. the left panel shows from bottom to top the posterior cricoarytenoids, the sole abductors of the larynx, and the abductors: the thyroarytenoids, the lateral cricoarytenoids, the transverse and oblique arytenoids, and the aryepiglottic muscles. all of these muscles are supplied by the recurrent laryngeal nerve (x). the internal branch of the sln is sensory, while the external sln branch is motor for the cricothyroid muscles (right panel) (from o'connor, d. reproduced with permission from myer et al. ( ) . redrawn by agreement with springer-verlag) breathing and vocalizations in practices aiming to augment metabolic and mental well-being. understanding the actions of the laryngeal intrinsic muscles is a necessary first step in gaining insights into the nature of the central control of breathing. the posterior cricoarytenoids (pca) are the sole abductors of the vocal cords. there are several adductors, with the thyroarytenoids (ta) being the major ones ( fig. . ) . some adductors, the cricothyroid and the vocalis part of ta, enhance abduction by tensing the vocal cords. this restricts vertical movement, improving flow control in the more horizontal plane. the magnitude of abductor activity exceeds that of the adductors when glottic size is increased and vice versa, consistent with relationships between glottic size and flow resistance (england et al. a; insalaco et al. ; kuna et al. ). animal studies indicate that, in general, glottic opening and closing are achieved by reciprocal laryngeal abductor and adductor activities ( fig. . ) (bartlett ; harding ; hutchison et al. ) . concurrent actions of laryngeal abductor and adductor muscles during inspiration and expiration may occur in adult humans, but their nature is unknown kuna et al. kuna et al. , . during eupnea the inspiratory outline of the pca emg resembles the flow pattern, while the ramp shape of the diaphragm emg relates to the inspired volume trace . in animals little expiratory ta activity is seen, and trans-upper airway pressure is minimal (fig. . ). in eupneic expiration in adult humans, pca activity diminishes, but some ta activity is present "rounding off" the early expiratory volume the thyroarytenoid (ta) muscles, and those of the diaphragm (d), together with flow, volume, and trans-upper airway pressure changes (reproduced with permission from hutchison et al. ( )) trace, but without the flow retardation or transupper airway resistance patterns typical of grunting (kuna et al. ) (fig. . ) . time delays exist between emg and mechanical flow changes . the timing delays differ in eupnea and grunting, reflecting different mechanoreceptor feedbacks and central outputs that affect function (fig. . ) . clinically, grunting is the expiratory noise produced when air flows through a partially closed glottis (harrison et al. ) . total glottic closure is silent but sensed. physiologically, grunting is a breathing pattern seen throughout life. it consists of a spectrum of degrees and timings of expiratory laryngeal closure, associated with volume retention and increased subglottic pressure, followed by laryngeal opening with a rapid return to baseline end-expiratory volume (eev) (figs. . and . ) (see sect. . . ) . in newborns with respiratory distress, harrison et al. showed that when grunting was prevented by endotracheal intubation, without positive end-expiratory pressure (peep), their oxygenation worsened (harrison et al. ). this finding established the role of airway peep and likely influenced the introduction of cpap therapy. harrison et al. also focused on venous return (harrison et al. ), stressing the importance of cardiac function in grunting. the outline of the volume-time trace in grunting (figs. . and . ) resembles that of a volume with a prolonged inspiratory time, as used in artificial ventilation to improve oxygenation. pre-surfactant, this strategy reduced the required peak inspiratory pressure and decreased the incidence of bronchopulmonary dysplasia. today, the maintenance of subglottic volume, the "open lung" approach, is a fundamental tenet of all ventilatory support. in keeping with the concept of alveolar interdependence, airway volume recruitment is achieved not by a maximal prolonged inflation but with an augmented breath (sigh) followed by an expiratory hold, mimicking the volume-time profile of grunting or of airway pressure release ventilation. spontaneous sighs can be biphasic, with inspiration being hutchison and bignall ( )) interrupted briefly by laryngeal closure. this mechanism may reset vagal afferent feedback, avoiding a hering-breuer inflation reflex and possible loss of the acquired volume (see sect. . . ) . in summary, human and animal data emphasize the importance of laryngeal control of expiratory subglottic airway volume. this central control strategy whereby airway pressure is dependent upon volume control has been shown by the study of bubble physics to produce a more stable mechanical system (hildebrandt ) . thus, coordinated central control of laryngeal and pump muscles is a major focus in the control of breathing. this knowledge can be applied in respiratory support (hutchison and bignall ) . behavioral state is a major controlling factor of breathing pattern. in fetal lambs, during the highvoltage electrocorticogram (ecog) state, apnea (no phasic laryngeal abductor or diaphragmatic activities) and tonic laryngeal adductor activity occur. laryngeal adductor activity can be enhanced by laryngeal contact with cooled lung liquid, by fetal movements, by "arousals," by swallowing, by uterine contractures, and by fetal hypoxemia. in the low-voltage ecog state, laryngeal and diaphragmatic activities are similar to those seen postnatally (harding ). hypercapnia mainly enhances fetal breathing in the low-voltage ecog state (harding ). in general, active laryngeal retardation of lung liquid egress is reported in the absence of fetal breathing movements and is related to lung growth (harding ). stimulation of the superior laryngeal nerve (sln) produces laryngeal closure (harding ) that will prevent aspiration of noxious material, e.g., meconium. the coordination of the acts of fetal swallowing (harding ) and "inspiratory" activities of the respiratory muscles stresses the developmental importance of the controller's ability to switch patterns rapidly between upper airway closure (laryngeal adduction) with lack of diaphragmatic activity (apnea) and laryngeal abductor and pump activities (see sect. . . ). airway volume is high in the fetus compared to the newborn. it has been speculated that during different fetal behavioral states, the brain is setting the homeostatic limits for high and low airway volume to prepare the fetus for the major needs of subglottic volume control at birth (hutchison ) (see also sect. . . ). life's greatest airway volume challenge, the establishment and maintenance of an air-filled airway at birth, is usually overcome without a hitch by breathing patterns whose complexities exceed those used during the majority of adult life. at birth, an incremental breathing pattern retains more inspired volume than is expired ( fig. . ) (hutchison et al. ) . incremental breathing shares features with grunting with the addition of timing changes in laryngeal and pump muscle activities at end-expiration when the onset of pump muscle activity occurs before laryngeal muscles open the glottis fully. the result is a decrease in expired volume and an increase in eev (hutchison et al. ). this incremental mechanical process is aided by the airway stability accrued from the increased end-expiratory positive subglottic pressure that limits the development of a negative airway pressure during inspiration. given their tendency to chest wall distortion, it is not surprising that incremental breathing can occur in preterm neonates (eichenwald et al. ) . incremental breathing is also seen in gasping during acute cerebral hypoxia-ischemia (hutchison et al. ) . gasping is typified by brief laryngeal abductor and pump muscle activities followed by long periods of laryngeal adductor activity with apnea (hutchison et al. ) . subglottic pressure is increased, maintaining airway volume and likely promoting autoresuscitation (hutchison et al. ) . laryngeal and pump muscle activities nasal and laryngeal afferent inputs alter laryngeal abductor and adductor activities and thus glottic size. the laryngochemoreflex (lcr), whose afferent pathway is the sln, results in protective responses, including swallowing, apnea, obstructed respiratory efforts, cough, hypertension, and arousal from sleep (thach ). an obstructive apnea with bradycardia results if the lcr stimulus is persistent, especially in the immature or depressed brain. this lcr response alters with age -coughing becomes the major response. however, acquisition of a viral infection in infancy can rekindle its potency (thach ) . it is augmented by hypoxemia and anemia and has been implicated in apnea of prematurity and sids (thach ) (see sect. . . ). other laryngeal sln afferents, including those from mechanoreceptors, drive receptors, and temperature receptors, affect laryngeal intrinsic muscle activities. although sln section does not alter the eupneic breathing pattern, these afferents are important. upper airway bypass can alter the inspiration-inhibition hering-breuer reflex. application of acid to the larynx in animals, mimicking chronic aspiration, alters the subsequent response to an applied airway load (see sect. . . ). during noninvasive ventilation, nonsynchronous delivery of airflow to the upper airway in neural expiration results in laryngeal closure (rodenstein ; scharf et al. ) . thus, noninvasive ventilation and pacing of a paralyzed diaphragm should be applied synchronously with neural inspiration (rodenstein ; scharf et al. ) . in intact animals, compensatory glottic abduction follows single-breath total occlusion of inspiration or expiration at the mouth/nose. during the unimpeded expiration following a single inspiratory occlusive load, unopposed ta activity can produce laryngeal closure. thus when no air enters the lung, a compensatory reflex mechanism can prevent expiratory volume loss, maintaining absolute subglottic volume. lower airway afferent inputs affect glottic size (bailey and fregosi ) . stretch receptor discharges, induced by peep, decrease expiratory ta activity (harding ) . by contrast increased expiratory glottic adduction follows rapidly adapting receptor stimulation, e.g., with deflation or irritant stimulation secondary to a pneumothorax (bartlett ) , or follows c-fiber stimulation, e.g., with experimental pulmonary edema (bartlett ). direct and indirect stimulation of chest wall muscle afferents can invoke several flow patterns involving glottic closure (bartlett ; stecenko and hutchison ) . while pseudoasthma can be fabricated by partial glottic closure (rodenstein ) , matching laryngeal control of flow pattern to maintain optimal subglottic airway volume may explain changes reported with true increased airway resistance. subglottic inspiratory flow limitation in croup is associated with expiratory flow resistance, probably glottic in origin (argent et al. ) . increased lower airway resistance in adult asthmatic patients induces a breathing pattern characterized by laryngeal expiratory flow retardation (collett et al. ; sekizawa et al. ) . in adults, resistive loads applied at the mouth also decrease expiratory glottic size (brancatisano et al. ) . this change may occur immediately, suggesting that resistive loading, unlike total occlusive (elastic) loading, produces sudden flow changes that stimulate airway receptors to cause laryngeal adduction (brancatisano et al. ) . therapy with cpap reverses the expiratory laryngeal adduction in some asthmatic subjects, suggesting that airway pressure changes may alter the dynamics between stretch receptor and irritant receptor stimulations, thus changing the breathing pattern (collett et al. ) . in normal adults a voluntary deep breath can decrease laryngeal resistance and lower airway resistance (sekizawa et al. ) . by contrast, bronchoconstrictive stimulation in normal adults can result in inspiratory and expiratory glottic narrowing (higenbottam ). an increased resistance to inspiratory flow may be advantageous in that more transpulmonary pressure is applied to opening a constricted peripheral airway. if lower airway volume and resistance changes affect laryngeal function, can absence of laryngeal control affect lower airway resistance? laryngeal bypass during invasive ventilation is associated with atelectasis and with the development of increased lower airway resistance (hutchison and bignall ) . the latter effect may stiffen the conducting airways and thus stabilize total airway volume but demand increased effort. in summary, the data reflect the importance of laryngeal subglottic volume control as a determinant of lower airway resistance and point to interactions between lower airway afferents and coordinated laryngeal and pump muscle activities in this dynamic process (see also sect. . . ). central control of coordinated laryngeal and diaphragmatic muscle activities is determined by developmental stage, behavioral states, metabolism (temperature), central inputs, and centrally acting chemicals. postnatally in lambs, increased expiratory ta activity with decreased pca activity occurs during the nrem state. by contrast, expiratory ta activity in rem is mainly absent, while pca activity is variable (harding ). in normal adult humans, expiratory ta activity is absent during stable nrem, while expiratory pca activity decreases in nrem and is variable in rem (kuna et al. . at all ages, expiratory ta activity occurs at arousal. thus behavioral state is a key factor in subglottic airway volume control that, in turn, is important in sleep apnea. increased central drive, with hyperventilation and/or hypercapnia, promotes laryngeal abduction in inspiration and expiration in adults and term newborns, in whom increased pca, diaphragmatic and intercostal muscle activities occur (bartlett ; insalaco et al. ; kuna et al. ; wozniak et al. ) . laryngeal adduction can occur during hypercapnic hyperventilation in preterm neonates, probably due to chest wall distortion (but see also sect. . . ) (eichenwald et al. ) . this adduction also occurs in adults at the mechanical limits of airway volume ). in general, however, increased central drive decreases laryngeal resistance unless mechanical limitations are present. decreased central drive with hypocapnia diminishes expiratory glottic size and is associated with periodic breathing in adults (kuna et al. ; rodenstein ) . laryngeal closure has been noted in human newborns and infants with apnea or suspected apparent life-threatening events milner , ) . during central apnea and periodic breathing in lambs, expiratory ta activity is noted (praud ) . in depressed human infants at birth, laryngeal closure can block intubation, and, in lambs, acute cerebral hypoxia-ischemia results in expiratory ta activity with laryngeal closure (hutchison et al. ) . centrally acting depressant drugs diminish central drive and, in lambs, produce laryngeal closure with apnea (praud ) . in former preterm infants, up to ~ - postmenstrual weeks, exposure to anesthesia and/or operative stress can result in apnea postoperatively (see sect. . . ) . thus, the intensivist should avoid hypocapnia during noninvasive ventilation and be aware that central depression can result in apnea with glottic closure. hypoxia stimulates expiratory laryngeal abduction and increases ventilation in human adults and newborn lambs (england et al. b; insalaco et al. ; praud et al. ) . in lambs, the increase in ventilation is dependent upon carotid body input -a sudden decrease in that input induces expiratory ta activity (praud et al. ). however, animal and human data indicate that the effects of carotid body input vary depending upon central state and the presence/absence of other inputs (de burgh daly et al. ). if animals are vagotomized and paralyzed, direct carotid body stimulation can induce expiratory ta activity, and exposure to hypoxia after airway vagal blockade or intrathoracic vagal section results in laryngeal adduction (bailey and fregosi ) . in adult humans, the degree of expiratory glottic adduction with hypoxia exceeds that during hypercapnia (england et al. b) . thus, it is argued that the "pure" carotid body reflex response is laryngeal expiratory adduction that will retain airway volume and promote oxygenation. this pure response can be countered by the presence of ventilation which increases airway stretch receptor feedback that results in an overall expiratory laryngeal abduction response. in the author's view, a unifying explanation for the diverse findings with hypoxia is that the effect of carotid body input is to augment the central coordinated output to laryngeal and pump muscles that is selected under different conditions (see sect. . . ). when central depression exists, protective inputs and/or absence of volume-related inputs produce an apneic response with glottic closure that is augmented by hypoxia. this can be seen in the "vagal" preterm infant who is sedated for a surgical procedure. at intubation laryngeal closure and apnea/bradycardia can be triggered. if hypoxemia ensues, the problems are aggravated. when tidal ventilation and airway volume feedback are restored, the impact of any ongoing hypoxemia is to augment breathing. hering and breuer found that their volumerelated reflexes were active even with hydrogen breathing. this fits the modern focus on ventilation for resuscitation from asphyxia. this chapter of upper airway physiology for the pediatric intensivist has focused on motor and specifically on laryngeal aspects relevant to the control of breathing patterns. the major message is that upper airway physiology is involved in all aspects of "breathing": protection, volume homeostasis, and ventilation; its functional impact covers the entire airway, from the nose to the alveolus. understanding upper airway physiology can guide and improve therapy, while therapy can aid a return to normal homeostasis or detract from it. current knowledge of upper airway physiology has had major implications for the application of invasive and noninvasive ventilatory support. much remains to be learned from the interactions between physics and biochemistry in the entire airway and how they affect breathing patterns. • the upper airway plays roles in all the extended functions of breathing, namely, in airway protection, in the control of supra-and subglottic volumes, and in tidal ventilation. • nasal functions include air conditioning and airway protection. stimulation can result in profuse secretions, altered patency, and the cardiorespiratory dive reflex. obstruction can affect gas exchange markedly; thus, a rapid switch to oral breathing is advantageous. • pharyngeal patency can be altered in sleep. nonnutritive swallowing is vital to minimize aspiration. therapy with cpap improves pharyngeal patency in osa but may alter pharyngeal clearing mechanisms and increase gastric air. • laryngeal closure can protect the airway rapidly. laryngospasm can be hard to treat. • controlled expiratory laryngeal closure modifies airflow and subglottic airway volume in normal breathing, at the establishment of airway volume at birth or when airway volume is threatened by mechanical, chemical, or central changes. • intrinsically or extrinsically induced changes in central state alter the laryngeal motor outputs in response to mechanical or chemical inputs. • understanding how laryngeal motor functions affect breathing patterns, airway pressures, and gas exchange is at the core of many technical and procedural advances in the provision of resuscitative measures and of invasive and noninvasive respiratory support. paul d. robinson and j. jane pillow the mechanical properties of the respiratory system are a critical component of the chain of events that result in translation of the output of the respiratory rhythm generator to ventilation. a comprehensive understanding of respiratory mechanics is therefore essential to the delivery of optimized and individualized mechanical ventilation. this chapter describes the basic elements of respiratory mechanics and reviews the developmental changes in the airways, lungs, and chest wall that impact on measurement of respiratory mechanics with advancing postnatal age. during spontaneous breathing, the forces driving inspiration are generated by the inspiratory muscles, whereas during mechanical ventilation, the forces are generated by the ventilator or by a combination of the ventilator with spontaneous inspiratory muscle contributions. the inspiratory muscle pressure needs to be sufficient to overcome three major mechanical properties of the respiratory system: elastance (e) (to overcome tissue forces required to change the lung volume (v)), resistance (r) (to overcome resistance to flow (v')), and inertance (i) (for acceleration (v'') of gas volumes). elastance is often considered in terms of its inverse, the compliance (c). the total pressure (p total ) generated is equal to the sum of the elastic (p el , proportional to volume and /compliance), resistive (p res , proportional to flow and resistance), and inertive (p in , proportional to acceleration and inertance) components: although pressure losses to inertia are considerable during high-frequency ventilation, the inertive component is normally a small portion of p total at normal breathing frequencies and can be effectively neglected. thus the equation driving flow during normal respiration can be simplified: nonetheless, the linearized relation of driving pressure to volume and flow does not fully characterize the pediatric respiratory system: resistance and compliance are both dependent on volume, volume history, and flow, particularly in the very small or premature neonate. further, the simplified equation does not fully incorporate the complexities of the respiratory system. almost all the tests used to measure respiratory mechanics in the infant and pediatric population have been developed in adults and then adapted for younger subjects. measurements of respiratory mechanics are most appropriately corrected to lung volume, such as functional residual capacity (frc). in the absence of a measure of frc, measurements of respiratory mechanics made in infancy are often related to body size (e.g., height/length or weight). measurements at the body surface are necessary to include the contributions of the chest wall. the chest wall contribution to respiratory mechanics can be isolated, by subtraction of the pleural measurements from those obtained at the body surface (e.g., airway opening). the respiratory system is in a passive state when there is no inspiratory muscle activity (p mus = ). a passive condition is present in the paralyzed patient but can also occur without paralysis following hyperventilation (mortola ) . under passive conditions, resting lung volume is determined by to describe the principal components of respiratory mechanics of the airways, lungs, and the chest wall and the developmental and environmental considerations that impact on these measurements in the neonatal and young child two opposing forces. the outward recoil of the chest wall results from the elastic characteristics of the diaphragm/abdomen and of the rib cage. the outward recoil of the chest wall directly opposes the inward recoil of the lung. inward recoil is determined by the viscoelastic properties of the lung, including the mechanical properties of the lung tissues, and the collapsing pressure generated at the alveolar air-liquid interface. during spontaneous breathing, the passive respiratory mechanics can be measured using occlusion techniques. occlusion of the airways at lung volumes above the resting lung volume relaxes the respiratory muscles by stimulating the slowly adapting stretch receptors and the vagally mediated hering-breuer inflation reflex. passive tests assess the mechanical properties of the entire respiratory system. simultaneous measurement of transpulmonary pressure allows measurement of respiratory system compliance (c rs ) to be partitioned into lung (c l ) and chest wall (c w ) components. transpulmonary pressure (p tp ) is derived from the difference in pressure at the airway opening (p ao ) and pleural pressure (or elastic recoil pressure, p el ), measured using an esophageal balloon, liquid-filled catheter, or miniature pressure transducer. other passive measurements of respiratory mechanics include forced expiratory maneuvers to provide measures of maximal flow at frc (v′ max,frc ) (lum et al. a ). partial forced expiratory flow-volume curves in infants are obtained by rapid compression of the chest through endinspiratory inflation of a jacket placed around the chest and abdomen. during tidal breathing, this rapid thoracoabdominal compression (rtc) technique provides a v′ max,frc that is similar to forced flows at low lung volumes (e.g., maximal expiratory flow mef %,frc ). modification of the rtc technique by raising lung volume of the infant towards total lung capacity (so-called raised volume rtc or rvrtc) allows assessment of forced expiratory flows over a more extended range of volumes. reported measures include forced vital capacity (fvc) and forced expiratory volumes after defined time periods (e.g., . , . , or s, termed fev . , fev . , and fev , respectively) and the ratio of these values e.g., (fev t /fvc, where t is the time period chosen). in contrast, dynamic tests of respiratory mechanics allow the relative contributions of the airways and lung tissues to be partitioned, in addition to separately identifying the chest wall contribution to airway and tissue mechanical properties. dynamic mechanics derive mechanical variables from analysis of dynamic waveforms obtained either during normal (tidal) breathing or via imposed oscillatory waveforms. during tidal breathing, multilinear regression is used to determine dynamic respiratory system compliance (c dyn,rs ) and resistance (r rs ). kano and colleagues showed that consideration of volume dependence is important when using this approach to assess dynamic mechanics during mechanical ventilation. consideration of volume dependence is important because ventilatory settings may "push" the pressure-volume curve onto the flattened upper portion of the curve (kano et al. ). in the overdistended lung, fits obtained by multilinear regression are improved by the inclusion of a volume-dependent elastance term in the regression model: where p ao is the airway opening pressure, v is the tidal volume, e + e v is the total elastance over the cycle (e and e v representing the volumeindependent and volume-dependent portions of elastance, respectively), and the final term p a,ee represents the alveolar pressure at end-expiration. an important consideration during the interpretation of dynamic respiratory mechanics is the concept of frequency dependence. kano showed that increasing the ventilation rate from to breaths/min in a group of near-term newborn infants increased e rs and r rs by a mean of . and . %, respectively (kano et al. ) . frequency dependence and the mechanical properties of the respiratory system under normal tidal breathing conditions are also determined using forced oscillatory techniques (fot). these techniques are essentially noninvasive and are especially useful in infants and children as no active subject cooperation is required. the technique involves application of a pressure waveform (forcing function) to the airway opening and measurement of the resultant flow. the measured impedance reflects the complex viscoelastic resistance of the respiratory system (z rs ). simultaneous measurement of the transpulmonary pressure and hence chest wall impedance (z w ) allows determination of the lung impedance (z l ) by subtraction. the impedance (z) can be separated into the resistance (r rs ), the impedance component in phase with flow, and reactance (x rs ), representing the impedance components in phase with volume (elastance) and acceleration (inertance). the low-frequency forced oscillation technique (lfot) measures impedance over a range of frequencies (usually ~ . - hz). lfot is obtained in infants by invoking the hering-breuer inflation reflex to inhibit temporarily any respiratory muscle activity, during which brief time ( - s) the lfot signal is applied. fitting the constant-phase model to the resultant pressure and flow data permits partitioning of respiratory mechanics into frequency-independent airway resistance (r aw ) and airway inertance (i aw ) and a constant-phase tissue component. this constant-phase tissue component is described by [(g − jh)/ωα, where g and h are coefficients for tissue damping and elastance, respectively, ω is angular frequency, and α determines the frequency dependence of the real (pressure change in phase with flow) and imaginary (pressure change in phase with volume) parts of the impedance] (hantos et al. a ). the interrupter technique provides a further option to assess partitioned mechanics. the interrupter technique involves measurement of changes in airway opening pressure after a midexpiratory occlusion, which is used to calculate airway resistance (r aw ). after airway occlusion at mid-expiration, there is a biphasic change in p ao : the immediate rapid rise in p ao represents the resistive pressure drop across the conducting airways and is followed by a secondary slower increase in p ao (often referred to as p dif ) generally attributed to stress recovery in the respiratory tissues (lung and chest wall) and gas redistribution associated with ventilation inhomogeneity (bates et al. ) . a major limitation of this technique is that it requires mechanical ventilation and paralysis to obtain reliable data. particular challenges for lung function testing in infants and children include the marked developmental changes occurring over the first months and years of life. additional considerations include position, sleep state and sedation, and feasibility of individual tests given minimal capacity of these age groups for active cooperation and preferential nasal breathing (stocks and hislop ) . thus, in contrast to the adult and older child, tests in infants are performed using a mask instead of a mouthpiece and nose clips. lung development represents a period of considerable change in both lung architecture and volume and is affected by several factors including genetic, in utero and postnatal environmental exposures, somatic growth, puberty, changes in muscularity, and ongoing alveolarization. our understanding of the interactions between these factors is based on a mix of pathological and physiological data, which are predominantly cross-sectional in nature. consensus between these studies is lacking. while some of the lack of agreement is attributable to technical approaches used by different authors, a comprehensive understanding of factors influencing respiratory mechanics over time can only be answered by strong longitudinal data, which are urgently required. these tests of lung mechanics provide us with essential insight into how tissue properties change with development, and a full understanding of the changes that occur during healthy development is an important step to detect the subsequent effects of disease and response of the individual to therapeutic interventions. measurements need to be accompanied by accurate records of height (length) and weight to facilitate interpretation of longitudinal data. over the course of development, there is considerable remodelling of all of the structural components of the respiratory system, although the exact patterns of change in airways, alveoli, and blood vessels may differ with respect to each other. the term "dysanaptic growth" was originally introduced by green et al. ( ) and describes the disproportionate but physiologically normal growth of the lung relative to the airways. in infancy, airway size relative to lung volume is larger than in older children and adults. there is considerable debate in the pediatric literature about the degree, extent, and stage of development to which biological variability of airway size to lung volume occurs. the data outlined in this chapter suggest that dysanapsis is a feature of all stages of postnatal lung development. whether disproportionate growth along the length of the airway tree occurs is less clear. increased growth of the larger central airways, in relation to peripheral generations, has been described through the first year of life, after which point adult relative proportions are achieved and maintained through further growth (horsfield et al. ) . disproportionate central and peripheral airway growth, however, is not a consistent finding in the literature (hislop et al. ) . the most rapid period of tracheal growth appears to occur during the first years of life (wailoo and emery ) . an elevated ratio of peripheral airway resistance to central airway resistance (and its contribution to total airway resistance) in young children compared to adults was originally proposed by hogg et al. ( ) , based on retrograde catheter measurements. the authors described relatively little change in the contribution of the central airways (those proximal to the th- th airway generations) to conductance with age but marked increase in peripheral airway conductance from the age of years of age. these changes were attributed to altered linear dimensions of the peripheral airways, based on morphometric data. the ratio of central to peripheral resistance can also be examined noninvasively by comparing measured forced expiratory flows (fef) breathing air to fef measured breathing a less-dense gas mixture of % helium/ % oxygen (heliox). fef measured breathing heliox is typically higher than during air breathing (e.g., . - . times at % fvc). in older subjects with peripheral airway disease, this pattern is lost with ratios approaching parity (cooper et al. ; dosman et al. ) . density dependence data during infancy, in comparison to values reported in later life, appear to challenge the findings of hogg et al. ( ) . davis et al. examined the changes in density dependence through the first years of life (davis et al. ) . fef - % higher were measured with heliox: although no relationship existed between density dependence and age, length, or fvc in the first years of life (in keeping with hogg et al. ( ) ), the values obtained were similar to those reported across other studies in older children ranging from school age to adulthood (summarized in table of the original manuscript (davis et al. ) ). these equivalent cross-sectional density dependence values suggest that there is no difference in the convective accelerative and turbulent pressure loss with age, supporting the notion that the ratio of resistance of the peripheral to the central airways is similar in infants, older children, and adults. sex-specific differences in respiratory mechanics are well recognized in infants and young children and are a particularly important consideration in forced expiratory maneuvers in infants. airways are larger in females before puberty, and this difference is detectable from infancy (tepper et al. a; hoo et al. a) : v′ max,frc is approximately % higher in girls over the first months of life (hoo et al. a ). similar sex-dependent increases in v′ max,frc are evident in preterm girls compared to preterm boys, suggesting such differences in lung function may be developmental rather than environmental in origin (stocks et al. ) . larger lungs have been reported in males between the ages of weeks and years (thurlbeck ) . presence and timing of the growth spurt is an important confounding factor, with lung growth occurring out of phase to somatic growth, especially in boys (degroodt et al. ; quanjer et al. ; schrader et al. ) . lung development in females is almost complete following menarche but continues throughout puberty in males (neve et al. ) . there is increasing evidence that the periconceptional and intrauterine exposures impact on development of the respiratory system and consequently impact on respiratory mechanics in infancy and childhood. factors known to influence lung mechanics after birth include maternal smoking, nutritional deprivation and intrauterine growth restriction, infection and/or inflammation, and maternal glucocorticoids. prenatal exposure to nicotine may cause abnormal airway branching and dimensions as well as increase airway smooth muscle and collagen deposition resulting in reduced lung function at birth that persists into early adulthood regardless of postnatal exposure (hayatbakhsh et al. ; svanes et al. ). lung function irregularities include airflow limitation, reduced fev , and airway hyperreactivity wongtrakool et al. ) . chronic restriction of nutrients and/or oxygen in late pregnancy impairs development of the fetal small airways and lungs, including reduced numbers of alveoli that are also enlarged with increased septal wall thickness and basement membranes compared to nonexposed infants (pike et al. ) . such differences in alveolar number can influence the subsequent rate of disease progression, including an accelerated rate of decline in fev with advancing age (stocks and sonnappa ). several cross-sectional studies have looked at the changes in airway resistance (reflecting airway size) during childhood. hall and colleagues using lfot described a quasilinear decrease in r aw with increasing length during infancy in infants, including some with repeat measurements (hall et al. ) . lanteri and sly examined changes across the pediatric age range and also reported linear decreases in both r rs and r aw with increasing height (when plotted on a loglog plot) in children (range weeks- years) with healthy lungs (fig. . ) (lanteri and sly ) . pooled data across the preschool age range reinforces the consistent relationship seen with increasing height (beydon et al. a decreasing resistance of the respiratory system (r rs ) and airway resistance (r aw ) with increasing height. cross-sectional data taken from subjects (aged weeks to years) (lanteri and sly ) . both resistance and height are plotted as natural log values but are labeled with absolute numbers for clarity examined (gerhardt et al. a ). this increase occurred at a slower rate than the increase in frc, which led to a rapid drop in specific conductance ( fig. . b ). this rapid decrease in specific airway resistance or conductance through early life has been described previously (doershuk et al. ; stocks and godfrey ) . tepper et al. measured maximal fef at frc, from partial expiratory flow-volume curves and corrected for changes in lung volume: they reported higher flows in the neonatal range which decreased to a steady value through the nd year of life, similar to those reported elsewhere in older children (tepper et al. a) . differential increases in anatomic dead space volume (twofold), compared to frc (threefold), have also been shown in the pediatric population (wood et al. ) . rapid postnatal increases in lung volume are reported widely. frc increases by a magnitude of times (from ml in infants to , ml in adults) (dunnill ) and over ten times in total lung weight (polgar and weng ) . the rapid growth of the distal lung, in comparison to relatively steady changes in airway dimensions, is a major feature of respiratory system development beyond birth. after the appearance of primitive saccules at approximately weeks gestation, mature alveoli with secondary septa appear from weeks gestation onwards. alveolar multiplication was initially thought to cease at around years of age (thurlbeck ) . more recent estimates indicate that increase in alveolar number continues until at least years (dunnill ) . recent advanced imaging studies using hyperpolarized helium magnetic resonance imaging (mri) provide evidence of ongoing alveolar multiplication in adolescence (narayanan et al. ) . increase in alveolar size (expansion) is also evident during infancy and childhood, with recent epidemiology studies suggesting lung size increases into early adulthood, when chest wall development is complete (quanjer et al. ; reid ). based on cross-sectional studies, specific lung compliance falls during early infancy before remaining relatively constant from the early preschool years. tepper et al., based on measurements of compliance from the linear portion of the static pressure-volume (pv) curve in almost infants, described an increase in lung compliance over the age range studied, but decreasing specific lung compliance with increasing body length in the first years of life (tepper et al. ). gerhardt et al. examined similar changes in infants and children over the first years of life. lung compliance increased markedly (by ~ - -fold) over the weight range examined (fig. . a) but in proportion to frc, resulting in a constant-specific compliance over the first years of life. the same pattern of findings was reported in children aged - years (greenough et al. ). this initial rapid period of alveolar growth is also supported by evidence from measurements using the interrupter technique and fot. lanteri and sly showed a biphasic change in p dif with age: p dif was highest in young infants, falling rapidly over the first months, before increasing again after approximately years of age (lanteri and sly ) . hall and colleagues, using lfot measures of tissue mechanics derived by fitting data to the constant-phase model, showed that both tissue parameters g and h decreased in a quasihyperbolic manner with increasing length between weeks and years of age (hall et al. ) . the difference in the pattern of change in g and h compared to the change in r aw with increasing length is further evidence of dysanapsis: tissue mechanical properties change more rapidly than airway mechanics over the first years of life ( fig. . ). the chest wall of the neonate and infant, and to a lesser extent the growing child, is especially compliant compared to the compliance of the chest wall in the adult subject. a highly compliant chest wall in infancy results in less opposition to the tendency of the lung to collapse, promoting a low residual lung volume and also distortion of the chest wall, resulting in a loss of volume during inspiration. the disproportionately high compliance of the chest wall compared to the compliances of the lung means that the compliance of the respiratory system (c rs ) is approximately equal to the compliance of the lung (c l ) during childhood, especially in neonates and infancy (davis et al. ; gerhardt et al. a) . several active (dynamic) mechanisms of respiratory mechanics serve to partially compensate for the instability in frc associated with a compliant chest wall and tendency for small airway closure during tidal breathing. infants acutely increase their end-expiratory lung volume (eelv) and maintain it above resting lung volume by modulating (abbreviating) their expiratory time (mortola and saetta ) ( fig. . a ). in addition, they reduce expiratory flow through post-inspiratory activity of the diaphragm and inspiratory chest wall muscles (kosch and stark ) (fig. . b) (lopes et al. ) , stiffening the chest wall and by increasing laryngeal resistance (± glottic closure) briefly (kosch et al. ) . such dynamic modifications of respiratory mechanics occur via neural (vagal) receptor-mediated reflexes. restriction of lung function measurement to periods of quiet sleep is necessary to reduce the variability in measurements resulting from such dynamic processes (henschen and stocks ) . the changes in chest wall, lung, and respiratory system mechanics over the first years of life were examined by papastamelos et al., in subjects (papastamelos et al. ) . the authors used a modified mead-whittenberger technique (cook et al. ) : manual ventilation overrode respiratory drive and relaxed the respiratory muscles, avoiding the need for intubation or induction of a hering-breuer reflex. in this cohort, the ratio of chest wall to lung compliance fell from a mean (sd) of . ( . ) to . ( . ) (p < . ). chest wall to lung compliance ratios are even higher in preterm infants (gerhardt and bancalari ) . the stiffening of the chest wall, due to rapid rib ossification, increasing musculature, and altered chest wall configuration (bryan and wohl ; mead ; openshaw et al. ; leiter et al. ), is such that near-adult values, where lung and chest wall compliance are equal (mittman et al. ) , are reached after the first year of life. stiffening of the chest wall over the first year of life allows the infant to shift its maintenance of frc from dynamic elevation of eelv to a more passive mechanism achieved by the balance of outward recoil of the chest wall and inward recoil of the lung (colin et al. ). stiffening of the chest wall likely also explains the increase in p dif in children after age of years observed by lanteri and sly (lanteri and sly ) . frc as a proportion of total lung capacity (tlc) increases with age through childhood, in the majority (engstrom et al. ; mansell et al. ; weng and levison ) , but not all (schrader et al. ), studies to date. residual volume (rv), as a proportion of tlc, also increases with age through childhood (merkus et al. ) , while closing capacity (measured using single-breath nitrogen washout) decreases significantly with age, as a proportion of tlc, converging towards rv (mansell et al. ) . this increased rv/ tlc ratio suggests that increased stiffness of the chest wall is not entirely compensated for by increase in expiratory muscle force over time (schrader et al. ). the study by merkus et al. also highlighted the need to use tlc as a measure of lung growth and not fvc, due to the fact that an increasing rv/tlc with age led to errors in maximal expired flows due to measurement at progressively higher lung volumes (merkus et al. ). the postnatal period is characterized by ongoing rapid lung development, with differing rates of growth seen in the airway, lung parenchyma, and chest wall. the dysanapsis that occurs between the components of the respiratory system has important consequences for measurements of lung mechanics performed during infancy and childhood. accounting for these developmental changes and dysanapsis is necessary to optimize disease detection and subsequent assessment of an individual's response to interventions. insights into these changes are largely derived from crosssectional studies, which have identified important sources of potential error in existing methodol- . this is compared to the passive expiratory time constant (slope of the dotted line) measured after an end-inspiratory occlusion. the difference between the two slopes is generated due to active use of the respiratory muscles during expiration ("braking"). the mag-nitude of difference between the active flow-volume curvederived eelv (frc) and the passive relaxation volume (v r ) reflects the degree of active (dynamic) mechanisms employed to elevate eelv. this active use of respiratory muscles is also illustrated in (b) from data collected in a separate infant study wherein diaphragm emg activity of breaths three and four extends into expiration (both figures reproduced with permission from the publishers (mortola and saetta ; kosch and stark ) ) • the postnatal period is characterized by ongoing rapid lung development in all parts of the respiratory system (airways, lung parenchyma, and chest wall). the physiologically normal rate of change of the lung relative to the airways is disproportionate. this dysanaptic growth pattern appears to be a feature of all stages of postnatal lung development. ogy. strong longitudinal data are now urgently required to confirm these apparent patterns and answer the important questions that remain. j. jane pillow the predominant neonatal acute respiratory diseases include transient tachypnea of the newborn (ttn), respiratory distress syndrome (rds) due to surfactant deficiency and/or structural immaturity, pulmonary interstitial emphysema (pie), meconium aspiration syndrome (mas), persistent pulmonary hypertension of the newborn, pneumonia, and congenital diaphragmatic hernia (cdh). as there are no reported measurements of lung mechanics or lung function for infants with pie and pneumonia, they are not discussed further. transient tachypnea of the newborn (ttn) is characterized by delayed resorption of fetal lung fluid within the distal airspaces. the mechanical consequences of ttn include reduced lung volume (functional residual capacity, frc) and consequently also decreased lung compliance (increased elastance), tidal volume, and respiratory rate (benito zaballos et al. ) . although increased interstitial fluid might be expected to increase lung tissue resistance, there are no reported studies of tissue resistance in infants with ttn. • passive measures of lung mechanics provide information about the mechanics of the entire respiratory system. • dynamic measures of lung mechanics allow partitioning of the lung and chest wall components to separately identify the chest wall contribution to airway and tissue mechanical properties. • standardization of the measurement technique is essential. results generated are corrected for either lung volume (e.g., frc) or, in the absence of this, a measure of growth (e.g., weight). • a number of periconceptional, intrauterine, and postnatal factors impact on the development and mechanics of the respiratory system. important postnatal factors include maternal smoking, nutritional deprivation and intrauterine growth restriction, infection and/or inflammation, and maternal glucocorticoids. • the rate of airway growth (detected by increases in conductance or decreases in resistance) is not as rapid as the rate of frc increase with age. this greater relative increase in lung volume leads to a rapid decrease in specific resistance during early childhood. • postnatal alveolarization appears to now extend into adolescence. rapid alveolar growth occurs during infancy leading to an initial fall in specific lung compliance, which reaches a plateau during ongoing lung growth. these changes are also evidenced by the changes seen in lfot tissue parameters and interrupter technique-derived p dif . • the highly compliant chest wall of the infant leads to employment of active (dynamic) measures to maintain eelv above frc. as the ratio of chest wall to lung compliance falls and reaches the adult values of parity beyond infancy, these gradually transition to more passive mechanisms as the chest wall stiffens through early childhood. • to describe flow (f), lung volumes (v), and respiratory pressure (p) measurements together with resistance (r) and compliance (c) measurements in neonatal respiratory diseases like ttn, rds is predominantly a disease of the distal lung parenchyma. surfactant deficiency promotes atelectasis, typically characterized by low lung volumes and reduced lung compliance. lung function is also reflective of the degree of structural maturation, as surfactant deficiency is predominantly a disease of the premature infant. in the intubated infant, lung resistance measures are highly variable and not reproducible ( - %, icc < . ), in contrast with less variable and more reproducible measurements of lung compliance (obtained from esophageal manometry). hence, the clinical relevance of dynamic mechanics measurements of resistance in intubated newborn infants with respiratory distress is questionable (gappa et al. a) . measurements of impedance, obtained using forced oscillatory mechanics (a quasistatic lung mechanics measurement), may provide a more reliable assessment of lung mechanics. dorkin measured respiratory impedance in six paralyzed and intubated infants, three of whom also had pulmonary interstitial emphysema (dorkin et al. ). the tracheal tube contributed to almost all the inertance and approximately % of the respiratory system resistance in the intubated infant. after subtraction of the impedance of the endotracheal tube, resistance ranged from to cm h o/l/s, compliance from . to . ml/ cm h o, and inertance from . to . cm h o/l/s (gappa et al. a; dorkin et al. ) . the low-frequency forced oscillation technique (lfot) evaluates impedance simultaneously across a range of frequencies (usually ~ . - hz). fitting of the resultant impedance data to the constant-phase model permits estimation of partitioned mechanical variables of the airways and the parenchymal tissues (hantos et al. b ). using the lfot, impedance measurements in naïve (surfactant-deficient) newborn preterm lambs showed that respiratory system resistance (r rs ) and reactance (x rs ) are markedly frequency dependent (pillow et al. a) . respiratory system resistance in the preterm infant is also dominated by the resistive properties of the tissues, contrasting sharply with the predominant airway contribution to respiratory system resistance in later life (pillow et al. ) . although compliance is also low (increased elastance), the tissue resistance is disproportionately greater, resulting in mechanical uncoupling of the parenchyma and increased hysteresivity (ratio of tissue resistance to tissue elastance) (pillow et al. a (pillow et al. , . increased surfactant pool size (pillow et al. a ) and lung volume recruitment (pillow et al. b ) both enhance mechanical coupling of the tissues, evident as a lowering of the hysteresivity ratio in the lung. increased contribution of the tissues to respiratory system mechanics, and the associated increased frequency dependence, results in elevation of the resonance frequency of the lung (pillow et al. a) . frequency dependence also becomes less marked with increasing postnatal age ( fig. . ) (pillow et al. ) . variability in measurements of lung mechanics in newborn infants in part reflects lung maturation associated with advancing gestation: lung compliance increases . ml/cm h o/week, to reach mean (sd) values of . ( . ) ml/cm h o at term equivalent (bhutani et al. ) . other factors include in utero fetal exposures such as placental nutrition, inflammation, antenatal steroids, and postnatal treatments including caffeine, glucocorticoids, surfactant, and ventilation modality. early treatment with caffeine in surfactant-treated immature baboons increased c rs over the first day of life and increased ventilatory efficiency index (yoder et al. ) . the initial benefit of antenatal steroids on improved lung compliance at birth fades beyond week after initial exposure (mcevoy et al. ). there is no evidence of that antenatal steroids have a persistent effect on lung mechanics: infants born at term after exposure to up to three courses of betamethasone at gestations between and weeks had no difference in gas mixing or lung volume/mechanics when compared to nonexposed term controls (hjalmarson and sandberg ) . like antenatal steroids, postnatal steroids also increase respiratory system compliance (durand et al. ) . low-dose and high-dose postnatal dexamethasone for cld achieve a similar increase in c rs suggesting equal effectiveness for improvement of lung volume (mcevoy et al. ) . early postnatal dexamethasone may be more effective than late dexamethasone in achieving lower r aw /r rs and higher specific conductance (sg aw ) (merz et al. ; vento et al. ) , which may indicate a degree of fixed change in the airway walls in infants receiving delayed glucocorticoid treatment. during administration, surfactant represents a fluid bolus in the airway that increases inspiratory and expiratory time constant, associated with an acute increase in respiratory system resistance. effective delivery of surfactant to the lung thus benefits from a transient increase in the inspiratory time and potentially brief increase in the delta p (peak inspiratory pressure-positive endexpiratory pressure) to overcome the increase resistance resulting from the fluid bolus. treatment with exogenous surfactant (da silva et al. ) or increases in positive end-expiratory pressure (peep) during recruitment from atelectasis increases lung volume: (dimitriou et al. ) lung volume increases by ± % within a median of min after surfactant administration, with altered distribution of lung volume towards the dorsal rather than ventral compartment. the increase in lung volume after surfactant or volume recruitment maneuvers increases maximal compliance of the respiratory system, with higher tidal volumes achieved at lower pressures than required prior to treatment (miedema et al. a; mcevoy et al. ) . importantly, the increase in compliance also impacts on the time constant (τ = r rs × c rs ) of the respiratory system. changes in the inspiratory and expiratory time constants need to be monitored as they necessitate adjustment of the inspiratory and expiratory times and influence the maximal frequency that can be used during ventilation with passive expiration. compared to treatment of rds with synchronized intermittent mandatory ventilation (simv), a small clinical trial showed that infants treated with high-frequency oscillatory ventilation (hfov) have early and sustained improvement in pulmonary mechanics and higher dynamic respiratory compliance (vento et al. ) . the improvement in pulmonary mechanics in patients treated with hfov is likely associated with enhanced lung volume recruitment. the neonatal lung with rds exhibits hysteresis (miedema et al. b) . hence lung recruitment maneuvers that aim to recruit the lung and subsequently ventilate it on the most compliant part of the deflation pressure volume curve can achieve effective ventilation with minimum pressure and volume cost of ventilation. importantly, recruitment of the lung by increasing mean distending pressure during hfov is also associated with changes in compliance and the time constant for volume delivery during hfov (pillow ) . consequently, volume delivery can vary substantially over the time course of an hfov volume recruitment maneuver (miedema et al. ) and potentially result in rapid fluxes of the partial pressure of arterial carbon dioxide. the effect of compliance on volume delivery during hfov is more evident at lower frequencies (pillow ; pillow et al. b ). the development of hfov ventilators that incorporate volume guarantee during hfov will provide protection from such rapid changes in ventilation during hfov. infants with rds often have their clinical course complicated by the persistence of a patent ductus arteriosus (pda), which presents as a leftright shunt. ligation of a pda (left-right shunt) increased dynamic compliance by % in newborn infants measured before and after ligation, but did not influence dynamic r rs or mean airway pressure (szymankiewicz et al. a ). although meconium aspiration syndrome (mas) is often considered as a high airway resistance disease due to the presence of meconium in the airways, studies in rabbits show that the acute aspiration of meconium also causes a significant reduction in the lung-thorax compliance (sun et al. ). impaired compliance after mas is responsive to standard surfactant instillation (sun et al. ) . larger volume ( ml/kg) surfactant lung lavage is an emerging treatment for mas: following surfactant lung lavage, dynamic compliance approximately doubled, and airway resistance nearly halved in a group of mas infants on mechanical ventilation (szymankiewicz et al. b ). these changes in dynamic respiratory mechanics were associated with a decrease in mean (sd) airway pressure from . ± . to . ± . cm h o within h after surfactant lung lavage. meconium appears to have a differential effect on hyperreactivity of the airways and the lung tissue. whereas tracheal smooth muscle reactivity increases with increasing meconium concentration in response to histamine and acetylcholine, a negative correlation was observed in the lung tissue (mokry et al. ). airway hyperresponsiveness weeks after birth (approximately days after cessation of ecmo) is responsive to bronchodilator treatment (koumbourlis et al. ) as evidenced by percent change in mef and the mef /fvc ratio. airway hyperreactivity after mas is also reduced by budesonide (mokry et al. ). limited information is available for the longterm lung function outcomes after mas. neonates treated with ecmo for meconium aspiration have better long-term lung function outcomes than infants with diaphragmatic hernia treated with ecmo in the neonatal period (spoel et al. a) , most likely reflecting differences in lung capacity and structure. at least % of children who had mas in the neonatal period have evidence of trapped air on lung function during mid-late childhood. there are no published reports evaluating responsiveness to bronchodilators beyond infancy after neonatal mas. persistent pulmonary hypertension of the newborn (pphn) presents with profound hypoxia either in the absence of significant lung disease (primary pphn) or hypoxia out of proportion with the degree of respiratory disease (secondary pphn -complicating rds, meconium aspiration, pneumonia, etc.). lung function in -yearold infants who had pphn and who were treated with inhaled nitric oxide (ino) but not extracorporeal membrane oxygenation (ecmo) was compared with lung function outcomes of infants who were randomized to receive either ecmo or conventional management as part of the uk ecmo trial. v′ max,frc was lower than predicted in all three groups (p < . ). there were no statistical differences between the three groups in the z-scores for v′ max,frc (hoskote et al. ) . nonetheless, only % of ino-treated infants had v′ max,frc z-scores below normal compared to and %, respectively, for ecmo and cm groups. a prospective evaluation of lung function in infants with pphn treated with/without ino was reported by dobyns and colleagues ( ) : compared to healthy control infants of the same age, there were no differences in lung volume or passive respiratory mechanics for infants with pphn, nor was there any effect of ino on later pulmonary function in the pphn group. together, these results suggest that ino treatment does not worsen outcome compared to ecmo or conventional management. infants with congenital diaphragmatic hernia have impaired airway function in the first year of life: maximal expiratory flows at frc were a mean z-score of − . lower than healthy term infants (i.e., . standard deviations below the mean frc for healthy term infants) with no evidence of significant change between and months of age (spoel et al. b) . conversely, and perhaps surprisingly, given the usual association of cdh with pulmonary hypoplasia in at least one lung, spoel noted that measured values of functional residual capacity were relatively high ( % fell above the normal range) (spoel et al. b ). as expected, mean z-score for fev and fvc was negatively influenced by the presence of chronic lung disease, the duration of ventilation, and ecmo support (spoel et al. a) . patients with cdh develop hyperinflation, with elevated plethysmographic frc at year (hofhuis et al. ) that is still evident at - years (spoel et al. a; hamutcu et al. ; majaesic et al. ). spoel showed that greater impairment was evident in infants with cdh who required extracorporeal membrane oxygenation (spoel et al. b ). however, poorer outcome in ecmotreated cdh may reflect the initial severity of disease rather than ecmo: beardsmore showed that ecmo per se did not worsen respiratory function at year of age compared to conventionally ventilated controls (beardsmore et al. ) . spoel and colleagues also noted deterioration in lung function over time ( - years) in patients with cdh who were treated with ecmo in the neonatal period (see table . ) (spoel et al. a ): mean (se) sds score for fev after bronchodilation was higher at years (− . ( . )) than at years (− . ( . )) and years (− . ( . )). deterioration over time may be related to maldevelopment of the alveoli and pulmonary vessels with disturbed lung growth. it is also possible that increased susceptibility to recurrent respiratory tract infections may contribute to deterioration in lung function over time. an active lifestyle and healthy eating pattern may be especially important for children with cdh to counteract the deterioration in lung function over time, given the known positive effect of participation in sports and the negative interaction of bpd is most commonly considered as the chronic respiratory condition complicating extreme prematurity and/or prolonged neonatal mechanical ventilation. factors that independently influence the tidal flow-volume-derived indices include variations in disease severity, degree of alteration to airway and lung mechanics, and also the requirement for oxygen supplementation ). there are, nonetheless, quantitative differences in tidal breathing function measured in bpd infants when compared with measurements obtained from healthy term and preterm controls. bpd infants are consistently more tachypneic than their healthy counterparts ), but differences in other lung function variables are less consistent. tidal volume (v t ) is either less than (paetow et al. ) or similar to (patzak et al. ; schmalisch et al. ) values obtained in healthy infants: v t relative to healthy infants may also decrease with advancing postnatal age (tepper et al. b) , likely reflecting the altered maturational progression in lung structure and function. bpd infants have increased minute ventilation (mv). increased mv is primarily due to increased respiratory rate rather than increases in v, in part reflecting increased dead space ventilation. infants with bpd have an increased work of breathing. within the tidal flow-volume loop, increased work of breathing is evident from linear or concave expiratory limb morphology. bpd infants also have a less variable shape to the tidal flow-volume waveform, indicating that they are functioning near their maximum respiratory capability with minimal reserve capacity to adapt to changes in intrinsic (e.g., airway obstruction, infection, or aspiration) or extrinsic (e.g., cold stress) environment . tidal flow indices are difficult to interpret in part due to opposing effects of neurorespiratory control and lung mechanics on the morphology of the tidal flow waveform. whereas bpd infants have higher respiratory drive (quantified from the mean inspiratory flow: v t /t i where t i is inspiratory time), the ratio of the time to peak expiratory flow relative to expiratory time (t ptef :t e ) after methacholine-induced airway obstruction can either increase or decrease (clarke et al. ) . normal fluctuations in v t , t i , and mv seen in healthy infants in response to alternate hypoxic-normoxic breath testing are not evident in bpd infants, indicating reduced chemoreceptor sensitivity to hypoxic stimulus (calder et al. ) . lung and chest wall mechanics of infants with bronchopulmonary dysplasia (bpd) were extensively reviewed by gappa and colleagues ( b) . changes are reflective of maldevelopment of the lungs and airways and remodelling of the lung parenchyma and airway walls associated with increased collagen content. in preterm infants, respiratory system compliance (c rs ) increases relative to body weight over the first years of life, while an initially high respiratory system resistance (r rs ) decreases over the same period (baraldi et al. a) . airway walls of preterm infants are more compliant than term infants as evidenced through measurements obtained using the high-speed interrupter technique (hit) (henschen et al. ) . following the nichd consensus conference in (jobe and bancalari ) , some investigators evaluated differences in lung function according to whether infants had mild, moderate, or severe chronic lung disease. using the single occlusion technique, hjalmarson and sandberg showed that infants with severe bronchopulmonary dysplasia (born at mean weeks ga) had increased specific conductance and decreased specific compliance (sc rs ) compared to healthy preterm infants (born at mean weeks gestation) (hjalmarson and sandberg ) . there were no differences in lung mechanics between the healthy preterm infants and those with mild or moderate bronchopulmonary dysplasia. the data published by tortorolo et al. indicate a similar trend towards lower c rs at day in infants who later went on to develop mild bpd and to a greater extent in severe bpd (tortorolo et al. ) . their results contrast with the findings by shao and colleagues in infants of similar gestations that infants with bpd had decreased c rs ( . vs . ml/kpa/kg), but no difference in specific sc rs ( . vs . ml/kpa/kg) or r rs ( . vs . cm h o/ml/s) compared to non-ventilated preterm infants. infants with bpd do not show an improvement in airway resistance (r aw , measured by plethysmography) over a -month period (shao et al. ) . several authors have attempted to use lung function as a predictor of bpd. the value of initial r rs for prediction of lung disease is unclear: some have found increased initial r rs is associated with respiratory outcome at year (choukroun et al. ; lui et al. ; snepvangers et al. ) , whereas others observed that r rs is not predictive of bpd (tortorolo et al. ) . both lui (lui et al. ) and merth (merth et al. ) showed that early rds is not an important determinant of later lung function. serial measurements of compliance, however, show that lower c rs values after day were evident in infants who later developed severe bpd. merth observed that bpd infants have reduced c rs at year of age irrespective of rds (merth et al. ) . v′ max,frc obtained using the tidal rapid thoracic compression technique is reported consistently as being lower than healthy controls throughout the first years of life, regardless of the bpd era or treatment strategies (lum et al. b ). reduced expiratory flows are indicative of abnormal structural and functional development of the airways (fig. . ) . serial lung function measurements in infants with both bpd and "healthy" unsedated preterm infants indicate a decline over the first year of life, suggesting that factors other than bpd may contribute to abnormal airway function in preterm infants (hoo et al. b) . raised volume rapid thoracic compression (rvrtc) measurements show similar mild-moderately severe airflow obstruction. however the predominance of airflow obstruction primarily at low lung volumes indicates the pathology is more likely to involve the small peripheral rather than larger central airways (lum et al. b ). concurrent increased residual volume (rv), frc, and rv/ tlc (total lung capacity) ratios were more marked in infants with recurrent wheeze, indicative of a degree of hyperinflation and gas trapping. intermediate values (between healthy controls and wheezy bpd infants) were observed for rv, frc, and rv/tlc in non-wheezy preterm infants (robin et al. ) , likely reflective of abnormal airway growth or the effects of preterm delivery. forced deflation from frc showed that preterm infants with developing bpd have severe lower airway obstruction as early as - weeks postnatal age. increased flows and fvc following bronchodilation indicate that reopening of obstructed airways is achieved with bronchodilators (motoyama et al. ) . a recent systematic review and meta-analysis assessed the effect of preterm birth on later fev : (kotecha et al. ) studies were included in the meta-analysis, including studies in children born preterm without bpd and studies in children with bpd diagnosed at either day of life (bpd ) or weeks postmenstrual age (bpd ). the meta-analysis showed that just being born preterm decreased fev compared to term-born controls, with further decrements in fev evident for the bpd and bpd week groups. the mean differences ( % ci) for % fev compared with term-born controls were − . % (− . %, − . %) for preterm group without bpd and − . % (− . to − . %) and − . % (− . to − . %) for the bpd and bpd groups, respectively. including data from preterm studies not including a control group resulted in a pooled % fev estimate of . % ( . - . %) for preterm infants without bpd, . % ( . - . %) for bpd , and . % ( . - . %) for bpd , respectively. of interest, the authors noted that %fev for bpd has improved over the years. bpd survivors also have lower forced expiratory flows: % of children with bpd had maximal flow at functional respiratory capacity (v max frc) below % of the predicted value (baraldi et al. a) . forced expiratory flow at % of forced vital capacity was reduced in young adolescents born prematurely, regardless of prior bpd or level of respiratory support (anand et al. ) . of concern, doyle and colleagues showed that airflow limitation worsened between and years ). together, these data suggest that the preterm infant population is at risk of developing chronic obstructive disease and should receive long-term respiratory follow-up (baraldi and filippone a; filippone et al. ; lum et al. ) . airway obstruction is accompanied by impaired diffusing capacity in children and adults born prematurely (hakulinen et al. ; vrijlandt et al. ) . similar findings in infants and toddlers with bpd in the face of normal alveolar volumes indicate parenchymal disease and impaired alveolarization (balinotti et al. ). several studies have evaluated the effect of bronchodilators on lung mechanics in infants with bpd. bronchodilators decrease r rs , without affecting c rs : ultrasonic nebulizers appear to be most effective (fok et al. ) . bronchial hyperresponsiveness at years of age was related to mean neonatal c rs and r rs over the first days in ventilated preterm neonates using breath occlusion test. c rs but not r rs was related to bronchial hyperresponsiveness at years' age (snepvangers et al. ). fifty-six percent of children in the epicure study born at weeks pma or less had abnormal baseline spirometry at years of age, with % showing a positive bronchodilator response: more marked responses were evident in the infants with prior bpd (fawke et al. ) . less than half of the epicure study children with abnormal lung function at years were receiving treatment, suggesting more targeted respiratory follow-up is warranted. the published literature on persistence of bronchial hyperreactivity into early adulthood in the population of young adults born prior to routine antenatal glucocorticoid and postnatal surfactant treatment is conflicting: both persistence (halvorsen et al. ) and resolution (narang et al. ) of bronchial hyperresponsiveness are reported, although both studies report persistently abnormal baseline spirometry. • measurements of dynamic mechanics are most often obtained in intubated infants, but measurements of dynamic resistance are highly variable and may persistence of bronchial hyperreactivity into adulthood is unknown for the current population of premature infants. véronique nève and francis leclerc a restrictive ventilatory defect is observed when expansion of the lung is restricted because of alterations in lung parenchyma or as a consequence of extraparenchymal diseases affecting pleura, chest wall, or neuromuscular apparatus. chronic ild are characterized by derangements of the alveolar walls and loss of functional alveolar-capillary units. pediatric ild comprises a heterogeneous group of rare disorders with considerable mortality (clement ; fan et al. ; fan and langston ) . chronic ild in immune-competent children has been defined as the presence of respiratory symptoms and/or diffuse infiltrates on chest radiographs, abnormal pulmonary function tests (pft) with evidence of restrictive ventilatory defect and/or impaired gas exchange, and persistence of any of these findings for > months (clement ) . pft, in children over years, show a reduced forced vc (fvc) and fev and a normal or elevated fev / fvc ratio (fan et al. ) (fig. . ) . the not be reliable. reasons for variability include the highly frequency-dependent nature of respiratory mechanics, rapidly changing nature of respiratory disease, maturation and the acute effects of antenatal exposures, and postnatal treatments and interventions. • rds is typically characterized by low lung volumes, reduced lung compliance, and elevated tissue resistance. • meconium aspiration is characterized by both increased resistance and decreased compliance. both resistance and compliance are improved by surfactant lavage. mas may be complicated by airway hyperreactivity and gas trapping beyond infancy. • infants with congenital diaphragmatic hernia have impaired airway function at year of age, with evidence of continuing deterioration throughout childhood. worse lung function is likely associated with initial severity of disease and intensity/duration of mechanical ventilation. • bpd infants are typically more tachypneic than their healthy counterparts and have increased work of breathing. airway walls are more compliant and may be prone to collapse. while lung function outcomes for infants with bpd have improved over the last one to two decades, airflow limitation remains an issue for long-term respiratory function after bronchopulmonary dysplasia and may worsen with time. diffusing capacity is also impaired in children and adults born prematurely and may reflect parenchymal disease and impaired alveolarization. • although patients receiving ecmo generally have worse lung function than those treated without ecmo, this is likely due to the initial severity of lung disease and duration of mechanical ventilation rather than an effect of ecmo on long-term lung function per se. to describe flow (f), lung volumes (v), and respiratory pressure (p) measurements together with resistance (r) and compliance (c) measurements in restrictive lung diseases, obstructive lung diseases, and neuromuscular disorders (nmd) decrease in tlc, in general, is relatively less than that of vc because of normal chest wall recoil and inspiratory muscle function in most patients (martinez and flaherty ) . functional residual capacity (frc) and residual volume (rv) are normal or elevated resulting in increased frc/tlc and rv/tlc (gaultier et al. ; steinkamp et al. ; zapletal et al. ) . the latter finding suggests air trapping (fan et al. ) . airflow limitation has been demonstrated in some studies (fan and langston ) . diffusing capacity of carbon monoxide (dl co ), that evaluates the capacity of the lung to exchange gas across the alveolar capillary interface, is low in absolute term but normal when corrected for alveolar v (gaultier et al. ; zapletal et al. ) . the lung p/v curve is shifted down, and elastic recoil p at maximum inspiration is increased (fan and langston ; steinkamp et al. ; zapletal et al. ) . reduced c l is observed, with lower specific c l in children with fibrotic changes on transbronchial lung biopsy specimen (steinkamp et al. ) . the decreased c l and increased elastic recoil can increase the retractive force exerted on the walls of lung airways and reduce the airway r (r aw ) or increase fev % and preserve the peak expiratory f (pef). however, once lung v becomes severely reduced, pef declines because it is then measured at a relatively small lung v (cotes et al. ) . pft can aid in establishing disease severity and prognosis. in nonspecific interstitial pneu- monia and idiopathic fibrosis, dl co < % corresponds to advanced disease and predicts impaired survival. similarly, exertional desaturation < % at baseline testing and a decrease in fvc > % over the course of the short-term follow-up identify patients at particular risk of mortality (martinez and flaherty ) . ali/ards are characterized by an acute onset of respiratory failure, diffuse bilateral pulmonary infiltrates on the chest radiograph, the absence of clinical evidence of left atrial hypertension, and a ratio of pao to fio (p/f) of less than mmhg (regardless of peep). acute lung injury (ali) is a subset of ards with less severe impairment in oxygenation (p/f < ) (bernard et al. ) . spo /fio (s/f) may be a good noninvasive surrogate marker for p/f in children: s/f ratios of and have been shown to correspond to p/f ratios of and , respectively, the ards cutoff of having % sensitivity and % specificity (bach and bianchi ) . decreased c l was associated to these items (ware and matthay ) . ali/ards are rare diseases in children and have mortality rates ranging from to % (flori et al. ; zimmerman et al. ). mechanical ventilation represents the main therapeutic support to maintain acceptable pulmonary gas exchange while treating the underlying disease. a "lung protective ventilation strategy" with limitation in airway p and tidal volume (vt) (the acute respiratory distress syndrome network ) led, in adult studies, to a reduction in mortality at day and a reduction in hospital mortality (petrucci and iacovelli ; the acute respiratory distress syndrome network ) . no published data exist for children, but practice in picu is derived from adult patients (khemani and newth the most characteristic alteration in acute ards lung is marked fall in c l caused by loss of surfactant function, atelectatic lung regions, accumulation of interstitial/alveolar plasma leakage (ware and matthay ) , and an associated fall in frc (hammer ) . in adults, the decrease in c l was shown to be more important in early ards from pulmonary origin (and associated with normal chest wall c (c cw )) than in extrapulmonary ards. the latter was associated with low c cw (gattinoni et al. ) . a decrease in respiratory system compliance (c rs ) and a proportional decrease in tlc, fvc, and frc were also observed in children during the acute phase of ards (hammer et al. ; newth et al. ) . ali/ards may resolve completely in some patients, while in others it progresses to fibrosing alveolitis with persistent hypoxemia and a further decrease in c l (ware and matthay ) . fibroproliferation occurs early in ards, and its extent may be predictive of outcome (marshall et al. ) . the recovery phase is characterized by the gradual resolution of hypoxemia and improved c l (ware and matthay ) . pharmacologic interventions, such as corticosteroids, starting in the late course of ards may reduce fibrosis and may have a beneficial impact on pulmonary outcome (tang et al. ). several studies have demonstrated persistent impairment in pulmonary function of unknown long-term significance for children who required mechanical ventilation in pediatric intensive care units for respiratory failure (khemani and newth ) . most survivors of ards have persistent mild reductions of dl co even as long as a year after their episode. the lung v and f return to normal in most instances, although a subset of patients will have persistent impairment. both obstructive and restrictive deficits may be seen (alberts et al. ; elliott et al. ; ghio et al. ; hert and albert ; peters et al. ) . timing of recovery occurring in the first year after ards was described in two prospective studies of adult survivors of ards (herridge et al. ; mchugh et al. ) . after discharge from the icu, a restrictive ventilatory defect and reduced dl co were observed in almost all patients and an obstructive defect in only %. improvement was observed until months after discharge. a relatively static period was observed after that. by months, abnormalities in fvc, tlc, and dl co were observed in , , and %, respectively, of patients. patients with more severe ards, as determined by their higher ali scores (corresponding to patients ventilated for > weeks), were more impaired for fvc throughout the follow-up and did not return to normal pulmonary function levels (mchugh et al. ) . patients of herridge's study were shown to have a mild restrictive defect with mild to moderate reduction in dl co at months. lung v and spirometric measurements were normal by months, but dl co remained low throughout the -month follow-up (herridge et al. ) . for the pediatric age group, a few small-sized observational cohort studies have reported sequelae in - %, in mostly asymptomatic subjects (ben-abraham et al. ; fanconi et al. ; golder et al. ; lyrene and truog ; weiss et al. ) . obstructive (reversible and nonreversible airflow obstruction) and restrictive abnormalities have been observed after discharge. like in adults, recovery during the following months reached plateau levels at months with no further improvement (golder et al. ) . decrease in c l was shown to persist in ≥ % of children and adults, evaluated - months (aggarwal et al. ) , or months after ards (klein et al. ) , and was associated with a restrictive defect in some patients. symptomatic upper airway obstruction as a result of laryngotracheal injury from long-term intubation has been described in minority ( %) of adults after ards with evidence of upper airway obstruction on inspiratory and expiratory f/v curves (elliott et al. ). the prevalence of childhood obesity is increasing in developed countries. obese children have more respiratory symptoms than their normal-weighted peers, and respiratory-related disorders increase with increasing weight. the prevalence of asthma has also increased in children. both obesity and asthma have their beginnings in early childhood (litonjua and gold ) . wheezing, asthma, and obesity seem to be associated (guerra et al. ; hancox et al. ; schachter et al. ). however, three large studies (bibi et al. ; schachter et al. ; wickens et al. ) showed a clear increase in symptoms of asthma in association with obesity but not more frequent airway hyperresponsiveness in obese children (deane and thomson ) . c cw is reduced in obesity, because of increased adiposity in the abdomen and around the thoracic cage that restricts rib expansion and because the decreased total thoracic and pulmonary v may pull the chest wall below its resting level to a flatten portion of its p/v curve. c cw decrease correlated with co retention, independent of body fat, and with shortness of breath (subramaian and strohl ) . c l may be decreased in some obese individuals because of a large pulmonary blood volume and intrinsic alterations of elastic characteristics of lung tissues (subramaian and strohl ) . as additional fat in the abdomen raises the diaphragm, the frc and expiratory reserve volume (erv) are reduced in the erected position and further reduced in the supine position (koenig ) . the lung bases are poorly ventilated which contributes to hypoxemia. tlc and vc may also be reduced, but rv is usually maintained (therefore rv/tlc ratio may be increased). in morbidly obese individuals, an increase in body mass correlates with reduced fev (carey et al. ) and fvc (fev / fvc ratio remains normal) (zerah et al. ) . data in children and adolescents confirm the reduced frc and static lung v (li et al. ) and the decrease in fvc and fev with increasing proportions of body fat as a percentage of body weight (lazarus et al. ). all these effects were shown to be reversible in morbidly obese patients (with body mass index (bmi) > ) following weight loss (camargo et al. ; carey et al. ; deane and thomson ) . in seated patients with simple morbid obesity, inspiratory and expiratory muscle strength is normal (yap et al. ) . when patients are supine, maximal inspiratory p (pimax) decreases by about half as a result of overstretching of the diaphragm, causing it to operate on the descending limb of its length-tension curve (laghi and tobin ) . morbidly obese patients without hypoventilation (simple obesity) compensate for the respiratory load by increasing respiratory drive and diaphragmatic pressure output (pankow et al. ) and increasing rib cage contribution to tidal breathing. scoliosis is the most common abnormality of the spine with direct effect on the thoracic cage. idiopathic scoliosis (including infantile, juvenile, and adolescent) accounts for - % of scoliosis. neuromuscular scoliosis (as in duchenne muscular dystrophy (dmd) or spinal muscular atrophy (sma)) and scoliosis associated with congenital vertebral abnormalities account each for % of scoliosis. infantile and congenital scoliosis, untreated, results in severe spinal deformities and is at risk of cardiopulmonary insufficiency before adulthood (canet and bureau ) . patients with scoliosis and a cobb angle < ° are usually asymptomatic, those with an angle between ° and ° often experience dyspnea on exertion, and those with the angle > ° are at risk for chronic respiratory failure (estenne et al. ) . scoliosis can produce severe reductions in lung v and restrictive ventilatory defect with decrease in fvc, fev , and tlc as well as a normal fev /fvc ratio (gagnon et al. ; muirhead and conner ; upadhyay et al. ; weber et al. ). among patients with moderate to severe scoliosis ( - °), the vc decrease is related to the cobb angle. when the cobb angle exceeds ° (severe scoliosis), vc falls to about % of predicted (laghi and tobin ) . impaired lung growth (davies and reid ) , significant decrease in c l and c cw (at about - % of predicted in children and adults with scoliosis) (laghi and tobin ) , and/or impaired muscle strength as a consequence of inefficient coupling between the respiratory muscles and the thoracic cage account for the effect of scoliosis on lung function. in adults with scoliosis and cobb angles of - °, pimax was about - % (estenne et al. ; laghi and tobin ) . decreased tlc is often associated with increased rv resulting in very high rv/tlc ratio (day et al. ) , probably reflecting the dysfunction of expiratory muscles, which do not allow full exhalation. significant gas trapping with elevated plethysmographic frc/helium frc ratio can occur with response to bronchodilators, indicating airway hyperresponsiveness that results from chronic airway inflammation secondary to the poor clearance of secretions (boyer et al. ) . the chest distortion causes airway distortion thereby contributing to a slight increase in airway r (r aw ) (canet and bureau ) . scoliosis, by inducing significant displacement/rotation of the intrathoracic trachea and/or main stem bronchi, can cause mechanical obstruction as shown on the f/v loop with flattening of the initial portion of the expiratory loop suggesting central airway obstruction (borowitz et al. ) . the decreased c rs may account for the increased work of breathing, with increased transdiaphragmatic pressure during tidal breathing; increased rib cage contribution to tidal breathing; transversus abdominis recruitment during exhalation, as observed in most patients with severe scoliosis (laghi and tobin ) ; and the associated increased risk of respiratory muscle fatigue and eventual respiratory failure. in contrast to idiopathic scoliosis which tends to stabilize (or progress at a lower rate) after the person reaches skeletal maturity, neuromuscular scoliosis (such as in dmd or sma) continues to worsen because of the progressive worsening of the muscle weakness. recurrent aspiration and pneumonias secondary to impaired clearance of airway secretions are potential complications. due to the severity of their primary muscle weakness, patients with neuromuscular scoliosis may not be able to maintain adequate ventilation and may develop severe atelectasis (koumbourlis ) . scoliosis is reported in - % of sma children and is due to the inability of the trunk muscles to support spine in the upright position. all children with type sma develop scoliosis starting from around years. the average curve is more than ° at years of age (mullender et al. ) . as the scoliosis progresses, respiratory function deteriorates, and the risk of life-threatening complications increases (rodillo et al. ) . spinal fusion is recommended when scoliosis progresses and reaches a cobb angle of between ° and ° in children ≥ years of age (tsirikos and baker ) . in dmd, scoliosis incidence ranges from to % (muntoni et al. ) . dmd develop scoliosis after losing independent ambulation (in the second decade of life). once scoliosis reaches °, it progresses with age and growth. corticosteroids may delay the development and progression of scoliosis in dmd (muntoni et al. ) . optimal timing for surgical intervention is while lung function is satisfactory and before cardiomyopathy becomes severe enough to risk arrhythmia under anesthesia (cobb angle between ° and °). best prognosis for recovery seems to be fvc > %, although others use the absolute vc of < . l as an indicator of rapid progression of scoliosis and poor prognosis (finder et al. ) . comparison between preand postoperative pulmonary function reveals no improvement due to correction of scoliosis. long-term studies show that decline of pulmonary function in dmd patients is unchanged in operated patients compared to patients who had no surgery (muntoni et al. ). asthma is the most frequent chronic disease observed in children (prevalence ranging from to % (isaac )). asthma is difficult to diagnose in children ≤ years. children presenting with wheeze at an early age belong to a heterogeneous group: early transient, late onset, and persistent wheezers (martinez and helms ) . half of the "early" wheezing children become asymptomatic by school age. they may have diminished lung function early on, but by years lung function is improved (martinez et al. ) . children who had wheezing that began in infancy and continued at years demonstrated normal pulmonary function initially with reduced lung function by years. those children with "persistent wheezing" have some ongoing chronic inflammatory process that results in airway alterations and some loss of lung function in early childhood, which extends to varying degrees in adulthood (oswald et al. ). respiratory syncytial virus (rsv) bronchiolitis in infancy is often associated with recurrent wheezing and asthma during subsequent years. however, wheezing tends to diminish by school age or adolescence. most follow-up studies of rsv bronchiolitis in infancy show that forced expiratory flow (fef) rates and fev are lower at school age compared with control groups (hall et al. ; pullan and hey ) . children who had been hospitalized for rsv bronchiolitis as infants later had lung function abnormalities similar to those found in children with asthma (kattan et al. ; wennergren and kristjansson ) . increased r to airflow is the basis of the clinical manifestations of asthma, including dyspnea and wheeze. usually, airflow limitation is reversible. fixed airway obstruction may be seen in later disease stage (strachan et al. ) or be a component of a specific asthma phenotype (bush ) . airway obstruction in childhood is associated with a reduced fev in adulthood (jenkins et al. ; roorda et al. ) . airflow obstruction (afo) can be assessed by body plethysmography, spirometry, forced oscillation technique (fot), and interrupter technique, but these are more difficult to perform in children < years. incentive spirometry can be performed in the majority of children ≥ years (beydon et al. b ) together with frc helium measurement and r measurement (using interrupter technique (r int )) (beydon et al. b) , fot, or plethysmography for measurement specific r aw (sr aw ) (dab and alexander ) . infant pfts are mainly research tools. the fev is the "gold standard" of measuring airway obstruction in children over years (miller et al. ; pellegrino et al. ) . preschoolers often do not exhale for more than s. therefore fev may not be an accurate index of bronchial obstruction in this age group, and the utility of fev . or fev . as outcome measure in this age group has been explored (aurora et al. ; beydon et al. b; neve et al. ; vilozni et al. ) . international guidelines (nhlbi ) recommend an initial evaluation and regular reeval-uation for the assessment of the severity and the control of asthma. asthma severity describes the underlying disease state as evaluated by fev and daytime and nighttime symptoms, all measured before treatment. patients with moderate and severe persistent asthma are said to have values of - % and < % of predicted, respectively. fev may not be the best measure of severity in childhood asthma because most asthmatic children have fev values in the normal range independent of disease severity when clinically stable (spahn et al. ) . diminished fev values in school-age children should identify children at risk of fixed airway obstruction at adulthood (rasmussen et al. ) . for children, fev /fvc appears to be a more sensitive measure of severity in the impairment domain (nhlbi ) a concave shape on the f/v curve may be observed as a result of small airway obstruction (pellegrino et al. ) . it may be observed in asthmatic children with a normal fev , together with a significant improvement following administration of a bronchodilator (basek et al. ; brand and roorda ) . a concave shape is associated with impairment in the fef between and % of fvc (fef - % ) that is believed to measure peripheral airway obstruction. fef - % is among the first parameters to be abnormal in pediatric asthma and often the most significantly impaired of all spirometric measures (paull et al. ; spahn and chipps ) . a fef - % ≤ % is well correlated with bronchodilator responsiveness in asthmatic children with normal fev and may suggest suboptimal asthma control (simon et al. ) . plethysmography may show lung distension/air trapping with larger rv and tlc in children than in adults (jenkins et al. ) . the rv is a sensitive parameter of airway obstruction in children, and a decrease in rv after bronchodilator administration appears to be specific for asthma diagnosis (walamies ) . air trapping may be observed when fvc and fev values are normal in mild or moderate asthma (cooper et al. ) or in controlled asthma (vilozni et al. ). indeed, the principal event taking place in the asthmatic lung is the closure of small airways with increase in rv that is associated to a protective increase in tlc to preserve the functional range of fvc. once the limit of the chest wall expansion has been reached, further increase in rv will result in falls in both fvc and fev (irvin and bates ) . frc may be elevated, due to airway closure and/or dynamically elevated with an increased expiratory time constant (stanescu ) . it is a compensatory mechanism that minimizes the increase in r aw and the expiratory flow limitation in obstructive airway disease. hence, at an early stage of the disease, an isolated increase in lung v may be the sole functional abnormality (landau et al. ; paton ) . in asthmatic children, frc increases with severity of asthma (greenough et al. ) and is more elevated in symptomatic children ). trapped air is associated with hypoxemia (wolf et al. ) but correlates poorly with f limitation and may be lacking in patients with severe asthma (basek et al. ; desmond et al. ). in preschool children with asthma, a -week inhaled corticosteroid therapy is associated with reduced hyperinflation as indicated by lower frc helium . bronchodilators were shown to decrease helium frc in % of children aged - years, and the decrease was correlated to baseline frc. some children exhibited an increase in frc after bronchodilation when baseline value was low (greenough et al. ) . children higher baseline r int measurement was shown in young preschool asthmatics (beydon et al. ; nielsen and bisgaard ) and children with a history of wheeze (mckenzie et al. ) compared with healthy children. children with persistent wheeze were shown to have higher r int value than those with transient or no previous wheeze, but there was an overlap in r int values between the three groups (brussee et al. ). using fot, increased r of the respiratory system at hz has been reported in asymptomatic asthmatic preschool children as compared with healthy subjects in some studies (nielsen and bisgaard ) . plethysmographic specific r aw (sr aw ), product of r aw , and plethysmographic thoracic gas volume (tgv) may be altered by both hyperinflation and decreased airway diameter. in preschool children, it was shown to be increased in children with a history of wheeze (lowe et al. ) ; it was able to identify responses to bronchodilators (nielsen and bisgaard ) and inhaled steroids (nielsen and bisgaard ) . sr aw was more strongly related to fef after % of fvc has been exhaled (fef % ) than to fev and could be used in preschool children to predict mild airflow limitation (mahut et al. ). however, there is no established cutoff for sr aw to separate healthy subjects from asthmatics (marchal and schweitzer ) . in cf, the combination of mucus retention, bacterial infections, and inflammation results in obstructive lung disease primarily involving the small airways (bedrossian et al. ; fox et al. ; ratjen and grasemann ) . restrictive alterations develop secondary to the damage of lung parenchyma by inflammatory changes and by neutrophil degradation products. chronic airway infection, progressing to bronchiectasis, gas trapping, and hypoxemia and hypercarbia, is the hallmark of cf lung disease. pulmonary insufficiency is responsible for at least % of cf-related death (cystic fibrosis foundation ). fev is the gold standard for lung function in cf. fev reflects the progression of pulmonary disease and correlates with mortality. an fev of less than % predicted in conjunction with other clinical indicators is used for selecting suitable candidates for lung transplantation (kerem et al. ) . in cf, obstruction primarily affects the small airways. an early change associated with airflow obstruction in small airways is a concave shape on the f/v curve and a reduction in the fef - % (pellegrino et al. ) such as reported in cf patients (corey et al. ; ). this fef often shows abnormalities in patients in whom fev is in the normal range. however, the large interindividual variability of this fef must be taken into account in its interpretation. diminished fevs and fefs have also been reported in sedated infants with cf (including infants considered to be asymptomatic by their physician) using the raised volume rapid thoracoabdominal compression technique (ranganathan et al. ; and in preschool children using incentive spirometry (kozlowska et al. ; marostica et al. ; vilozni et al. ). other techniques detecting small airway obstruction afo in small airways is associated with lung hyperinflation as indicated by increased rv, rv/ tlc, and tlc. a small airway obstruction syndrome with decreased vc and fev increased rv, but a normal fev /vc ratio and tlc has also been described (stanescu ) . the condition is attributed to premature closing of airway leading to air trapping as demonstrated by high-resolution computed tomography (hrct) scans (cotes et al. ) . studies using body plethysmography have provided evidence for trapped gases in the majority of patients with cf (beier et al. ) . the ratio of rv to tlc that indicates hyperinflation, a key feature of cf lung disease, has been found to correlate with disease severity in numerous studies (beier et al. ; landau et al. ; landau and phelan a) . percentage of children with hyperinflation and trapped gas increases with age, and children with severe hyperinflation at - years showed the most severe disease progression over time (kraemer et al. ) . in children < years, frc is the only lung volume that can be measured routinely. hyperinflation is one of the earliest features of cf (gappa et al. ) . elevated tgv has been found in cf infants (beardsmore et al. ) , and hyperinflation has been detected by the helium dilution technique in preschool children (beydon et al. ) . multiplebreath washout methods (mbw) may be particu-larly sensitive to changes in peripheral lung function and detect early functional abnormalities in infant and preschool children with cf (aurora et al. ; ranganathan et al. ) . frequency dependence of lung c as indicative afo in small airways has been observed in the majority of cf, but the invasive nature of this technique limits its clinical use (landau and phelan a) . alterations in lung elastic recoil were found with variable frequency (cook et al. ; landau and phelan a; mansell et al. ). as the airway disease becomes more advanced and/or more central airways become involved, fev will be reduced out of proportion to the reduction in vc and an obstructive ventilatory defect be observed. severity of lung disease in cf is classified by the degree of impairment in fev (with fev < % of predicted having severe disease) (pellegrino et al. ), (fig. . ) . the obstructive ventilatory defect is reversible if an improvement in fvc and/or fev of at least % of baseline after betaadrenergic agents is observed (pellegrino et al. ). significant reversibility can be observed in - % of cf patients, and - % show reduced lung function in response to short-acting inhaled bronchodilators (brand ; landau and phelan b; shapiro et al. ). studies in cf have shown decreased c and increased r (cook et al. ). due to the large surface area of small airways, their contribution to r aw is relatively small. r aw measurements are therefore normal in many patients with cf until they develop disease involving the larger airways (landau and phelan a) . as the disease progresses, bronchial obstruction leads to tissue destruction with bronchiectasis and the development of areas of pulmonary emphysema and fibrosis. in more advanced disease, the destruction of lung tissue leads to decreased c that parallels the decline in fev (hart et al. ) . this increases respiratory load and favors a rapid and shallow breathing pattern that further impairs gas exchange in cf patients. the loss of lung v that develops in patients due to tissue destruction as well as the hyperinflation decreases fvc: therefore fev /fvc ratio may be normal even in patients with severe disease (landau and phelan a) . a small proportion of cf patients also develop a restrictive lung disease with decreased plethysmo- (ries et al. ). pulmonary disease resulting from a neonatal respiratory disorder is called chronic lung disease of infancy (cld). bronchopulmonary dysplasia (bpd) (defined as the need for supplemental oxygen for at least days after birth) accounts for the vast majority of cases of cld. what is now considered the "old" bpd was originally described in slightly preterm newborns who had been exposed to aggressive mechanical ventilation and high concentrations of inspired oxygen. diffuse airway damage, smooth muscle hypertrophy, neutrophilic inflammation, and parenchymal fibrosis reflected extensive disruption of relatively immature lung structures. the "new" form of bpd is interpreted as a developmental disorder: despite being delivered several weeks before alveolarization begins, these infants often have only mild respiratory distress syndrome at birth, but lung development is affected with interruption of alveolarization at a very early stage with subsequent alveolar-capillary hypoplasia (baraldi and filippone b ). most of the information on long-term lung function in survivors of bpd refers to patients who had the condition before surfactant treatment was available ("old" form of bpd). in the first months of life, survivors of bpd are severely affected. infants with bpd at days of age have increased total and expiratory r and severe f limitation especially at low lung v (hazinski ). neonates and young infants with cld have increased levels of frc by plethysmography and decreased frc values by nitrogen washout, suggesting the presence of trapped air (wauer et al. ) . specific dynamic c (c dyn ) may be reduced by more than % (allen et al. ; gerhardt et al. b ) by small airway narrowing but also by interstitial fibrosis, edema, and atelectasis (hazinski ). lung mechanics measurement that reflects the severity of neonatal disease (i.e., c rs at - days) has been shown to correlate with subsequent reduction in lung function in -year-old bdp (baraldi et al. b; bhandari and panitch ) . childhood during infancy and early childhood, an improvement of airway physiology is observed, and c l improves over time (baraldi et al. b; bhandari and panitch ; gerhardt et al. b ). maximum flow rates at frc were reported to increase significantly within the first years along with a reduction in r aw (farstad et al. ; trachsel and coates ) . however analysis of fef shows that substantial afo persists in numerous survivors of bdp and in preterm infants without bpd during the first years of life (baraldi et al. b; tepper et al. b ). the degree of airflow limitation in the first years of life seems to predict later pulmonary function (at years) suggesting tracking of lung function with time, negligible "catch-up" growth of the lung, and irreversible early airway-remodelling process (baraldi and filippone b) . body plethysmography studies in school children and adolescents generally reveal normal tlc with hyperinflation as reflected by an increased rv and rv/tlc ratio. consistently children diagnosed with bpd are more prone to hyperinflation than prematurely born children without bpd. frc is normal or mildly increased. differences between frc determined by helium dilution technique and by plethysmography may indicate the presence of trapped air (trachsel and coates ) . at the age of years, c dyn was reported to be % of the control group, in bpd, and % in prematurely born children without cld (parat et al. ; trachsel and coates ) . school-age children with a history of bpd have lower fev than children born at term or those born prematurely without lung disease. they also have a lower fvc and fev /fvc ratio than children born at term (allen et al. ; bhandari and panitch ) . data from studies in children, adolescents, and young adults show that spirometric values are consistently lower in survivors of bpd, at any age between and years, than in controls born at term with fev ranging from normal to severely decreased values (baraldi and filippone b) . patients who were born prematurely but did not have bpd usually fare better, but they too may have airflow limitation at school age and later (baraldi and filippone b) . asthma-like symptoms are often associated to spirometric evidence of airflow limitation in children who had bpd as infants. but airflow limitation is only partially reversed by β -agonists in children suggesting a stabilized remodelling process. hrct studies have documented scattered parenchymal fibrosis and architectural distortion in many survivors of bpd, findings that are unusual in children with asthma (baraldi and filippone b) . there is no evidence that children with bpd born since the introduction of surfactant-replacement therapy (i.e., "new" bpd) have better spirometric results at school age than those born in the pre-surfactant era (i.e., "old" bpd) as shown in studies evaluating cohort of infants weighting less than , g at birth or who were born before a gestational age of weeks (doyle ; halvorsen et al. ) . these results suggest that prematurity itself has a very important independent influence on the long-term respiratory prognosis (baraldi and filippone b) . hematopoietic stem cell transplantation (hsct) is an established therapy for many chemosensitive or radiosensitive malignancies in children. bo is the most common late noninfectious pulmonary complication (i.e., that presents after the first days following transplantation) with % of cases occurring between and months. the reported incidence range is - % (soubani and uberti ) . bo seems to be less common in children than in adults (cerveri et al. ) . the most important association with bo is chronic graft versus host disease (gvhd), especially progressive chronic gvhd which evolves without hiatus from active acute gvhd. most cases of bo are thought to be secondary to bronchial mucosal damage from gvhd with inflammation of the small airways and subsequent obliteration. the main symptoms associated with bo are dry cough, dyspnea, and wheezing. twenty percent of patients are asymptomatic. spirometry is the main tool to diagnose and follow up patients with bo following hsct. based on the experience of lung transplantation, a "bo syndrome" has been defined by pft rather than histology (estenne et al. ) . it was suggested that the diagnosis of bo is made when there is evidence of ( ) new onset of afo with reduction in fev < % of predicted with a fev /fvc < . not responsive to bronchodilators; ( ) air trapping or small airway thickening or bronchiectasis on hrct of the chest with inspiratory and expiratory cuts with nonparenchymal involvement, rv on pft > % of predicted or pathological confirmation of constrictive bronchiolitis; and ( ) absence of infection in the respiratory tract documented by clinical symptoms, radiological studies, or microbiological cultures (soubani and uberti ) . there are some studies that suggested that a reduction in mean fef - % may precede the decline in fev and is a sensitive but not specific indicator of subsequent development of bo (estenne et al. ; ouwens et al. ; patterson et al. ; reynaud-gaubert et al. ) . a pediatric study defined afo as fev < % and fef - % < % of predicted (schultz et al. ) . since the evolution of the disease despite treatment is particularly negative with a progressive worsening of respiratory function and a high mortality, early diagnosis is important. this can be achieved by systematic regular monitoring of the respiratory function starting from the onset of acute gvhd (cerveri et al. ). decrease in vc is closely linked to weakness of respiratory muscles and disease progression. vc below % predicts nocturnal alveolar hypoventilation, and vc < % or < l, in duchenne patients, is strongly associated with respiratory failure. in mild respiratory muscle weakness, vc is less sensitive than maximum respiratory pressures. in patients with neuromuscular disorders, respiratory failure may present either acutely as a result of pneumonia or more slowly, as a result of progressive ventilatory decompensation. dmd and sma account for the majority of patients seen in pediatric practice. the most frequently noted abnormality of lung v in patients with respiratory muscle weakness is a reduction in vc. vc can be measured in cooperative children, usually older than years. vc reflects the strength of both inspiratory and expiratory muscles but is not specific, as it can be reduced by other factors than muscle weakness, such as reduction in both c l (gibson et al. ) and c cw in patients with chronic respiratory muscle weakness (de troyer et al. ) . the decreased c cw probably results from stiffening of tendons and ligaments of the rib cage and ankylosis of the costosternal and thoracovertebral joints (laghi and tobin ) . a decrease in c l could be related to diffuse microatelectasis in a few patients (estenne et al. ) . in children younger than years with nmd, higher c cw normalized to body weight than in controls has been reported (papastamelos et al. ) . such a high c cw results in chest wall deformation during tidal breathing and excessive work of breathing. it also predisposes to atelectasis and can result in fixed deformation of the chest wall (i.e., pectus excavatum). absence of lung stretch with sigh breaths and chest wall deformities can also result in reduced lung growth for children with nmd (bach and bianchi ; panitch ). in patients with nmd, a decrease in vc is an early sign of respiratory impairment. decrease in vc and tlc is closely linked to a weakness of respiratory muscles (braun et al. ; hahn et al. ; ragette et al. ) and disease progression (inkley et al. ; samaha et al. ). in patients with advanced nmd, a restrictive ventilatory defect is observed with tlc reduction. in dmd, a typical evolution of lung v is observed (hahn et al. ) . in ambulatory dmd the lung v increases with age (ascending phase), and predicted v is almost normal (tangsrud et al. ) . with loss of ambulation between and years (gozal ) , measured vc remains stable (plateau phase), but % predicted values begin to decline. in the following years, vc declines by about ml or - % per year (descending phase) phillips et al. ; rideau et al. ) . in sma, there is a characteristic pattern of involvement with intercostal muscle weakness and relative sparing of the diaphragm (kuzuhara and chou ; perez et al. ) . the rib cage is neither stabilized nor expanded during inspiration. over a period of time, the retraction of the rib cage has a detrimental effect on alveolar development. in type sma, with disease beginning before birth, pulmonary hypoplasia has been described (cunningham and stocks ) . the best parameter to monitor respiratory muscle strength in children with sma over years is fvc (% predicted) (manzur et al. ) . in sma, lung v (% predicted) decreases with age, with a greater vc decrease in type than in type sma. a decline in vc from to % was shown to occur in type sma from to years (souchon et al. ) . the fvc may therefore be normal or near normal in stronger ambulant type sma (samaha et al. ) . in type sma, fvc is more severely impaired and was shown to decline from % predicted to %, from to years, with a yearly average decline by - % between and years of age (barois et al. ; herridge et al. ; souchon et al. ) . a restrictive pattern was observed in a majority ( %) of type sma children followed longitudinally . in intermediate type sma, severe impairment in fvc has also been described (barois et al. ) with progressive decrease in fvc from % predicted (at years) to % (at years) in children without tracheotomy and from % predicted (at years) to % (at years) in children with tracheotomy (ioos et al. ). progression of scoliosis seems to contribute to vc decline in children with nmd (miller et al. ), but treatment of scoliosis with spinal stabilization did not prevent further vc decline in patients with dmd (kennedy et al. ; miller et al. ). in type sma, beneficial effects of spinal surgery on pulmonary function remain controversial (mullender et al. ; wang et al. ), but the rate of pulmonary function decline may be slowed (wang et al. ). static lung v may also be affected in some nmd patients by coexistent lung or airway disease (american thoracic society, european respiratory society ). measurement of postural change in vc gives a simple index of weakness of the diaphragm relative to the other inspiratory muscles. a fall of % or more in the supine compared with the erect posture is generally associated with severe diaphragmatic weakness (american thoracic society, european respiratory society ). studies in adults with generalized nmd suggest that supine vc is a simple, sensitive, and specific test for diaphragm weakness and can replace invasive diagnostic tests (fromageot et al. ; lechtzin et al. ) . thresholds of vc have been identified to predict treatable complications and outcome in patients with nmd. a vc below % is a sensitive and specific predictor of the onset of sleep-disordered breathing; vc below % predicts nocturnal alveolar hypoventilation, and vc < % or < l, in dmd, is strongly associated with respiratory failure and poor survival unless patients are treated with mechanical ventilation (baydur et al. ; canny et al. ; hukins and hillman ; mellies et al. ; phillips et al. phillips et al. , ragette et al. ; simonds et al. ; wallgren-pettersson et al. ) . rv is usually normal or increased, the latter, particularly with marked expiratory weakness (kreitzer et al. ) . consequently, tlc is less markedly reduced than vc, and the rv/tlc and frc/tlc ratios are often increased without necessarily implying airway obstruction (american thoracic society, european respiratory society ). a hypodynamic type of ventilatory defect with increased rv, low vc, and normal tlc can be observed early in the course of nmd. such a presentation has recently been described in patients with dmd (tangsrud et al. ) . these children may later exhibit chest wall deformities leading to a true restrictive syndrome. r aw is normal in uncomplicated respiratory muscle weakness. the maximum expiratory and maximum inspiratory f/v curves characteristically show a reduction in those f that are most effort dependent, that is, maximum expiratory f at large lung v (including pef) and maximum inspiratory f at all lung v. with severe expiratory weakness, an abrupt fall in maximum expiratory f is seen immediately before rv is reached (vincken et al. ) . oscillations of maximum expiratory and/or inspiratory f, the so-called sawtooth appearance, are seen particularly when the upper airway muscles are weak and in patients with extrapyramidal disorders (american thoracic society, european respiratory society ; vincken and cosio ) . in mild respiratory muscle weakness, vc is less sensitive than maximum respiratory p measurement. vc is normal, or only minimally reduced, if respiratory muscle strength is more than % of predicted (laghi and tobin ) . this finding results from the sigmoid shape of the p/v relationship of the respiratory system. several invasive and noninvasive tests to assess respiratory muscle strength have been reported to be of value in testing respiratory muscle strength in patients with nmd. in children, normative data are only available for pimax, pemax, and sniff nasal inspiratory pressure (snip). pimax and pemax are tests of global inspiratory and expiratory muscle strength. they were found to be reduced in nmd patients (baydur ; black and hyatt ) . the pimax decline was related to the decline of inspiratory reserve volume and tlc, and the pemax decline was related to the decline of erv and the increase of rv in children and adults with dmd (hahn et al. ) . in dmd, earlier in the course of the disease, inspiratory muscle strength evaluated by pimax remained relatively well preserved (as compared with pemax) implying relative sparing of the diaphragm (hahn et al. ; mcdonald et al. ) . in patients with diaphragm weakness, a vc decline of % or more following supine positioning is associated with a mean pimax decline of ± % (ragette et al. ) . sleepdisordered breathing usually develops when pimax is less than cm h o. diurnal hypercapnia is likely when respiratory muscle strength falls to cm h o (ragette et al. ) . the sniff is a natural maneuver which many children find much easier to perform than pimax. inspiratory muscle strength can easily be assessed by snip in children with nmd (stefanutti et al. ) . a recent report comparing snip and pimax in patients with nmd found that the values of pimax were at least the same or even greater than the snip, particularly in patients with severe ventilatory restriction. this can be explained by the fact that patients with severe neuromuscular disorders may not be able to perform a rapid sniff maneuver owing to significant muscle atrophy (hart et al. ) . the reduction of pemax is the first sign of respiratory muscle dysfunction in dmd children (hahn et al. ; mcdonald et al. ) . expiratory muscles that contribute to pemax are primarily the abdominal muscles, and their strength normally exceeds that of inspiratory muscles (american thoracic society, european respiratory society ). therefore pemax < pimax indicates prevailing expiratory muscle weakness, a characteristic for children with type and sma . recurrent chest infections may therefore occur early in sma children due to a predominance of expiratory muscle weakness with insufficient cough and retention of airway secretions. in patients with muscular dystrophies, pemax > cm h o has been found to be necessary for an effective cough (mellies and dohna-schwake ; mellies et al. ; szeinberg et al. ) . assessment tools to measure the different components of cough include also inspiratory vc (ivc) and the peak expiratory flow or peak cough flow (pcf). expiratory muscle weakness is often associated with a decrease in pcf and erv. the effect of coughing can be visualized on the maximum expiratory f/v curve in healthy subjects as a transient f exceeding the maximum achieved during forced expiration. the absence of such supramaximal f transients during coughing presumably results in impaired clearance of airway secretions and is associated with more severe expiratory muscle weakness (american thoracic society, european respiratory society ; polkey et al. ) . patients who could not generate peak f transients had significantly reduced pef, fvc, and pemax values ≤ cm h o (szeinberg et al. ) . impaired coughing leads to mucus retention, atelectasis, and recurrent pneumonia. in adults with nmd, pcf below - l/min is associated with insufficient clearance of airway secretions (bach and saporito ) . pcf (below l/) and ivc < . l seem also to be able to identify children with nmd at high risk for severe chest infections (dohna-schwake et al. ) . baseline pcf measurements above l/ min, however, do not guarantee adequate airway clearance, because respiratory muscle function can deteriorate during respiratory infections (labanowski et al. ) . for this reason a peak cough expiratory flow rate of l/min has been used to identify patients who would benefit from assisted cough techniques (finder et al. ; laroche et al. ) . in dmd, the likelihood of having a pcf value < l/min has been shown to rise significantly when fvc is < . l (gauld and boynton ) . the illustrations presented in this paper were captured with the jaeger program . . . (viasys healthcare, höchberg, germany). • a restrictive ventilatory defect of pulmonary origin is usually associated with a decrease in lung c (c l ) that can be due to an increase in the quantity of interstitial tissue in the lung, like in interstitial lung disease (ild), pulmonary fibrosis, infiltration, or edema. acute lung injury (ali) and acute respiratory distress syndrome (ards) result from pulmonary edema and inflammation. • restrictive defect that arises in the chest wall as a consequence of severe obesity or disease process affecting the ribs or the vertebral column, such as kyphoscoliosis, is associated with reduction in c cw . • in restrictive diseases, expansion of the lung is restricted because of alterations in lung parenchyma or as a consequence of extraparenchymal diseases affecting pleura, chest wall, or neuromuscular apparatus. a restrictive ventilatory defect is observed in these diseases with reduction in total lung capacity (tlc) and normal forced expiratory volume in s (fev )/ vital capacity (vc) ratio. • obstructive diseases of the lung are extremely common. airflow limitation is a functional consequence of asthma and chronic obstructive pulmonary disease (chronic bronchitis, emphysema), cystic fibrosis (cf), bronchiectasis, and bronchiolitis. airflow limitation is also observed in bronchiolitis obliterans (bo). an obstructive defect is defined by a reduced fev / vc ratio. severity of lung function impairment is based on fev % of predicted (fev < % corresponding to severe impairment). airflow obstruction (afo) is often reversible in asthma with improvement in fev and/or fvc ≥ % of baseline ( fig. . ) . afo in small airways is suspected from a concave shape on the fig. . in cystic fibrosis, as the airway disease becomes more advanced and/or more central airways become involved, fev will be reduced out of proportion to the reduction in vital capacity (vc) and an obstructive ventilatory defect be observed with a reduced fev /vc ratio. a fev 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(ii) consensus statement for standard of care in spinal muscular atrophy the acute respiratory distress syndrome assessment of functional residual capacity using nitrogen washout and plethysmographic techniques in infants with and without bronchopulmonary dysplasia pulmonary function in asymptomatic adolescents with idiopathic scoliosis respiratory and cardiac function in children after acute hypoxemic respiratory failure standards of pulmonary function in children relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases obesity and asthma in - year old new zealand children in the physiology of the nose hypoxemia in attack free asthmatic children: relationship with lung volumes and lung mechanics prenatal nicotine exposure alters lung function and airway geometry through alpha nicotinic receptors relationship between anatomic dead space and body size in health, asthma, and cystic fibrosis laryngeal and pump muscle activities during co breathing in neonates effects of posture on respiratory mechanics in obesity lung function in immature baboons with respiratory distress syndrome receiving early caffeine therapy: a pilot study lung function in children and adolescents with idiopathic interstitial pulmonary fibrosis effects of obesity on respiratory resistance incidence and outcomes of pediatric acute lung injury key: cord- - okbdw a authors: sin, david; mclennan, gordon; rengier, fabian; haddadin, ihab; heresi, gustavo a.; bartholomew, john r.; fink, matthias a.; thompson, dustin; partovi, sasan title: acute pulmonary embolism multimodality imaging prior to endovascular therapy date: - - journal: int j cardiovasc imaging doi: . /s - - - sha: doc_id: cord_uid: okbdw a the manuscript discusses the application of ct pulmonary angiography, ventilation–perfusion scan, and magnetic resonance angiography to detect acute pulmonary embolism and to plan endovascular therapy. ct pulmonary angiography offers high accuracy, speed of acquisition, and widespread availability when applied to acute pulmonary embolism detection. this imaging modality also aids the planning of endovascular therapy by visualizing the number and distribution of emboli, determining ideal intra-procedural catheter position for treatment, and signs of right heart strain. ventilation–perfusion scan and magnetic resonance angiography with and without contrast enhancement can also aid in the detection and pre-procedural planning of endovascular therapy in patients who are not candidates for ct pulmonary angiography. acute pulmonary embolism (pe) is a frequently encountered disease associated with high morbidity and mortality [ ] . most cases of acute pe originate from lower extremity deep vein thrombosis [ ] . the thirty-day mortality rate is estimated to be %, and the one-year mortality rate is estimated to be % [ ] . the incidence of acute pe is higher in males ( per , people) compared to females ( per , people) [ ] [ ] [ ] . advanced age is correlated with increased incidence of acute pe [ , ] . acute pe presents with variable severity [ ] [ ] [ ] [ ] . this can be explained by the varying degrees of pulmonary vasculature obstruction secondary to venous thromboembolism. gradual increases in pulmonary artery pressure can be seen when greater than - % of an arterial bed's cross-sectional area is occluded as a result of stressed endothelial cells releasing thromboxane and other vasoactive mediators [ ] . increased pulmonary artery pressure resulting from acute pe obstruction increases right heart strain secondary to elevated right ventricular afterload [ ] . right ventricular dysfunction can be observed acutely as a result of the increased afterload as well as myocardial ischemia [ ] . continued stress on the ventricles can cause protracted contractions, ischemia, and desynchronization of the left and right ventricles [ ] . prolonged elevation of pulmonary vascular pressures can also cause pulmonary hypertension that lasts beyond the original event [ ] . dyspnea, pleuritic chest pain, and cough are the most common presenting symptoms of acute pe, while other signs of acute pe include unilateral leg edema, sinus tachycardia, and tachypnea [ , ] . initial testing for patients with suspected acute pe should include brain natriuretic peptide, troponin, and ecg (table ) . these investigations can be helpful in narrowing down the differential diagnosis. these tests also provide prognostic data when acute pe is present [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the wells score is used to determine the pre-test probability of acute pe in hemodynamically stable patients. a patient's wells score categorizes them as having a low, intermediate, or high pre-test probability of acute pe [ , , , ] . the low, intermediate, and high risk categories correspond to . %, . %, and . % pre-test probability of acute pe, respectively based on a meta-analysis [ ] . a wells score of zero essentially excludes the possibility of acute pe with a low false-negative rate and a high sensitivity. the modified geneva score may also be used to determine the pre-test probability of acute pe. this scoring system utilizes clinical variables to categorize a patient into low, intermediate, or high risk groups that corresponded to %, %, and % prevalence of acute pe in one study [ ] . a simplified version of the modified geneva score has been found to maintain diagnostic accuracy and has been externally validated [ , ] . patients who are categorized as having a low or intermediate pre-test probability of acute pe can be assessed with a laboratory d-dimer test. a negative d-dimer test result in these patients essentially excludes the possibility of acute pe. a meta-analysis found that patients with a negative d-dimer and without a high pre-test probability of acute pe had a . % -month incidence of venous thromboembolism [ ] . it is important to consider that the d-dimer can also be nonspecifically elevated in certain conditions, such as pregnancy, recent hospitalization, active neoplastic disease, and other chronic inflammatory states. a prospective longitudinal study of patients with systemic lupus erythematosus with recurrent activity found that unexplained, persistent elevation of d-dimer levels, especially above . µg/ ml, were associated with elevated risk of thrombosis [ ] . another study found that d-dimer levels in patients with estimated glomerular filtration rate of - ml/min were % sensitive in ruling out acute pe although they were not specific enough to diagnose acute pe in this population [ ] . increased age has been associated with elevations in d-dimer concentrations, and a greater age-adjusted d-dimer threshold was found to be more specific ( % versus %) although less sensitive ( % versus %) in detecting acute pe in patients greater than years old [ ] . patients with a high pre-test probability and occasionally those with intermediate pre-test probability require imaging to assess for acute pe. computed tomography pulmonary angiography (ctpa) is usually the non-invasive imaging modality of choice. ctpa offers % sensitivity, % specificity, and % positive predictive value when diagnosing acute pe in patients considered to have a high pre-test probability [ ] . a positive d-dimer test result also requires ctpa imaging to confirm or exclude acute pe [ , , ] . the simplified pulmonary embolism severity index (spesi) is a sensitive clinical prediction score used to risk stratify diagnosed acute pe patients [ , , ] . this tool considers the variables of age > years old, history of cancer, chronic cardiopulmonary disease, heart rate ≥ beats per minute, systolic blood pressure < mmhg, and arterial oxyhemoglobin saturation < %. a patient is scored by receiving one point per variable present [ ] . a score of is considered low-risk with an associated . - . % -day mortality rate while a score of ≥ is considered high-risk with a . - . % -day mortality rate [ , ] . stratifying diagnosed acute pe patients by prognostic risk can be helpful in identifying low-risk patients who may benefit from outpatient therapy and revealing higher risk patients who should receive inpatient treatment [ ] . the european society of cardiology pe guidelines utilize the spesi in addition to right ventricular strain on echocardiogram or ct, elevated troponin levels, and hemodynamic instability to classify patients with pe as low-, intermediate-low, intermediate-high, and high-risk pe [ ] . other prognostic scoring systems including the bova and fast scores utilize clinical, imaging, and laboratory data to estimate risk of early pe-associated mortality although their implications for clinical decision-making have not yet been elucidated [ ] [ ] [ ] [ ] [ ] [ ] . the performance of endovascular therapy for acute pe treatment is evolving and gaining increasing interest. endovascular treatment enables the removal of thromboembolic material from the pulmonary arterial system through catheter-directed lysis or aspiration thrombectomy. endovascular treatment can be especially beneficial in patients with persistent hypotension or shock secondary to acute pe [ ] . this treatment has the potential to improve right ventricular function by relieving elevated pulmonary vascular pressures and stabilizing hemodynamics [ ] . a pulmonary embolism response team can help decide on the best therapy for a patient with acute pe [ ] [ ] [ ] . endovascular therapy can be considered in patients with contraindications to systemic thrombolysis who have submassive acute pe, evidenced by elevated troponin and brain natriuretic peptide, and right heart strain [ , , ] . endovascular therapy of acute pe usually involves placing a side hole infusion catheter through the thromboembolism and infusing tissue plasminogen activator (tpa). one mg of recombinant tpa per hour per catheter for a maximum total of mg is a typical dosage per the seattle protocol [ ] . the ultima trial found that - mg of recombinant tpa over h in addition to unfractionated heparin reversed right ventricular dilatation at h greater than unfractionated heparin alone [ ] . these doses are lower than that used in systemic thrombolysis and are therefore thought to be associated with a lower risk of intracranial or other hemorrhage [ ] . aspiration thrombectomy with immediate removal of the offending thromboembolic material from the pulmonary arterial system is another endovascular treatment approach [ ] . aspiration thrombectomy is specifically beneficial for patients with contraindication to systemic or catheter directed thrombolysis secondary to elevated bleeding risk [ , ] . the perfect registry prospectively enrolled patients receiving catheter-directed therapy for acute pe in a multicenter registry. the study showed that catheterdirected therapy for acute pe decreased right-sided heart strain and pulmonary artery pressures without causing major bleeding events [ ] . the optalyse pe trial was a prospective, multicenter, parallel-group trial that included patients with acute pe treated with ultrasound-assisted catheter-directed thrombolysis. the patients were randomized to groups that varied by tpa dose (range of to mg) and infusion duration (range of to h). the endpoints of rv/ lv diameter ratio and thromboembolic burden were significantly decreased in the treatment groups. major bleeding occurred in only % of patients, and one intracranial hemorrhage event was attributed to ultrasound-assisted catheter-directed thrombolysis [ ] . studies have confirmed that endovascular treatment of acute pe is safe and effective with regard to short term hemodynamic stabilization. additional studies should be done to assess the effect of catheter-directed therapy on long-term sequela of pe namely cted and cteph with right ventricular failure. computed tomography pulmonary angiography (ctpa) is the current non-invasive imaging modality of choice to assess acute pe. its strengths include its accuracy, speed of acquiring images, and widespread availability. ctpa may reveal alternative diagnoses contributing to a patient's presentation if acute pe is not visualized [ ] . a prospective randomized trial assessing acute pe detection with ctpa compared to pulmonary angiography as gold standard found ctpa to have % accuracy [ ] . ctpa also offers superior spatial resolution and multi-planar reconstruction [ ] . wide-array ct scanners can cover substantial length per rotation and are associated with reduced motion artifacts. dual-energy ct can help to rule out acute segmental and sub-segmental pe by color-coding perfusion based on the iodine concentration (iodine or z-effective mapping) [ ] . dual-energy ctpa involves using two distinct energy levels to capture the image [ ] . this technique enables differentiation between tissues with similar attenuation values using various processing techniques such as iodine maps, virtual non-contrast (vnc) and virtual monochromatic images (vmi). iodine maps accentuate iodine-containing tissue and improve the sensitivity of perfusion defects. vnc images imitate non-contrast images by virtually removing iodine and can be used for calcium scoring or as a substitute for true non-contrast images. vmi imitate an x-ray beam with one energy level and are created by a linear combination of basis pair images in different proportions. vmi can decrease artifacts and thereby improve specificity [ , ] . lung perfusion maps can be derived from iodine maps (figs. and ) [ ] . a pulmonary perfused blood volume (pbv) map color codes parenchymal tissue by iodine concentration [ , ] . perfusion defects are normalized to the vascular iodine concentration, and areas that do not fall within this attenuation range are excluded. hence, lung abnormalities appear dark on pbv maps. pbv maps can also be merged with conventional ct images to better analyze the lungs' form and function [ , ] . dual-energy ct can salvage suboptimal studies and reduce the contrast exposure to patients. this is accomplished by using low-energy vmi less than kev, which exhibits greater photoelectron attenuation and thus greater contrast [ ] . as many as % of regularly acquired ctpa studies are non-diagnostic, and % of those are caused by poor contrast enhancement [ ] . while poorly enhanced studies often require repeat contrast doses and repeat scanning with associated radiation exposure, low energy vmi avoids this by virtually increasing vessel attenuation and contrast-to-noise ratio (cnr). the subjective image quality was found to be best at kev vmi when compared to polyenergetic images in one study [ ] . another study found that kev produced the greatest cnr and sound-to-noise ratio (snr) while maintaining image quality and using % of the typical iodine concentration [ ] . dual-energy ct has also been found to produce high snr, and cnr while requiring only % of the typical iodine based contrast agent dose [ ] . high-energy vmi has the ability to reduce artifacts, with kev producing the least artifacts [ ] . beam hardening artifacts originating from dense contrast in the superior vena cava is especially reduced with high-energy vmi [ ] . the high-pitch helical mode of dual-source scanners also results in diagnostic image quality by requiring decreased breath hold duration and thus leading to reduced motion artifacts. this mode is also associated with decreased radiation and contrast exposure to the patient [ ] . a retrospective study of ultra-high-pitch dual-source ctpa in patients with suspected pe found that a reduced voltage ( kv) compared to a standard voltage ( kv) resulted in significantly reduced radiation dose, greater subjective image quality, and improved snr and cnr. diagnostic agreement between readers for the reduced voltage was very high (κ = . ) [ ] . iterative reconstructive algorithms can further reduce patients' radiation exposure [ ] . a retrospective study of patients divided into three groups differentiated by ct optimization technique found that iterative reconstruction resulted in a significant radiation dose reduction of - % when combined with automated tube current modulation. the same study found that iterative reconstruction improved levels of objective noise [ ] . another study found that iterative model reconstruction could reduce radiation doses up to % while preserving image quality [ ] . ctpa can be helpful in the planning stages of endovascular therapy for acute pe. in the coronal orientation, it can reveal both the number and distribution of emboli. during fig. -year-old female with known anca-negative, mediumsize-vessel vasculitis presenting with progressive dyspnea over a period of weeks. a dual-energy ctpa demonstrates filling defects of several subsegmental arteries, one of them illustrated in this axial plane (arrow). b z-effective map of the dual-energy ctpa demonstrating iodine distribution with blue colors representing high iodine concentration and yellow and red colors representing low iodine concentration. this axial plane at the same level shows a wedge-shaped area of low iodine concentration (arrows) corresponding to an area of reduced perfusion caused by the embolus seen in a. further perfusion defects can be appreciated on the same plane (arrowheads) corresponding to more emboli not detected with regular ctpa imaging the procedure coronal reconstruction can be correlated to ctpa images to ensure proper catheter position within the acute thromboembolic material. right heart strain is a common pathology associated with acute pe, and ctpa reveals signs of right heart strain including increased rv/ lv diameter ratio of . or greater, interventricular septal bowing towards the left ventricle, contrast reflux into the hepatic vein as well as inferior vena cava (ivc), and increased ivc diameter compared to baseline [ ] . capturing the pulmonary artery size allows its comparison to prior cts and may show an acute enlargement secondary to pe. ctpa also enables characterization of the venous anatomy including proximal ivc and the patency of the central veins. this information is important for access planning purposes (figs. and ) . dual-energy ct perfusion images simulate true perfusion by allowing the comparison of a tissue's innate physical density with its enhancement during acquisition [ ] . these perfusion images do not require changing the cta protocol, which confers the benefits of not requiring additional radiation or contrast and thereby minimizing motion misregistration from repeated acquisitions [ ] . the resulting images correlate well with those of scintigraphic perfusion images. pbv images have shown modest correlation with lung scintigraphy in cteph patients [ ] . one study of dual-energy ct perfusion images compared to scintigraphy showed % sensitivity and % specificity [ ] . another c-e signs of right heart strain and acute pe on axial ctpa imaging including reflux of contrast into hepatic veins and ivc (c), acute dilatation of main pulmonary artery (d) as well as rv to la ratio of more than with straightening of the interventricular septum. f and g are representative coronal and axial ctpa slices showing patent svc and patent bilateral internal jugular veins. this information can be gained from the ctpa and is helpful for procedure planning purposes, particularly if the endovascular treatment approach will be pursued via internal jugular vein access study comparing dual-energy ct perfusion images to scintigraphy at the segmental level showed % sensitivity and % specificity [ ] . acute and chronic pe present differently on ctpa. acute pes are typically located at vessel bifurcations and may completely or partially obstruct pulmonary vasculature [ , ] . a complete obstruction is characterized on ctpa as a hypoattenuating contrast defect occupying a vessel's entire lumen and can be seen in acute pe. the vessel diameter at the obstruction level is usually maintained or increased slightly. partial obstructions may be located centrally (indicative of acute pe) or eccentrically (indicative of chronic pe). complete obstruction in the setting of acute pe can cause distal infarcts that appear on ctpa as a triangular subpleural consolidation or ground-glass opacity with fine reticular changes. chronic pe appearance varies based on the extent of obstruction and degree of chronicity. complete obstruction presents as a lack of contrast distal to the obstruction and an immediate narrowing of the vessel diameter. partial obstruction is characterized by a narrow diameter and partially attenuated vessel or dilation distal to the obstruction. chronic nonobstructive pe manifests as a narrow vessel, irregular intima, and intraluminal bands and webs [ ] . the abrupt narrowing of vessels is caused by recanalization of the thrombus. thrombi along a vessel wall can become endothelialized or "laminated" and will appear as an irregular intimal surface contour that forms obtuse angles with the contrast column. laminated thrombi often present with calcifications. bands are linear structures that run along the long axis of a vessel and may appear in the setting of chronic pe. webs are networks of bands that are often found at vessel bifurcations in chronic pe and are associated with distal neovasculature [ , , ] . chronic pe raises vascular resistance and is characterized by dilation of the central pulmonary arteries secondary to pulmonary hypertension. the main pulmonary artery (mpa) diameter at the level of its bifurcation lateral to the ascending aorta is used to assess for the presence of pulmonary hypertension. mpa diameters greater than mm in men and mm in women are typical predictive cut-offs for pulmonary hypertension [ ] . a greater cut-off of . mm has also been suggested [ ] . a mpa-to-ascending aorta diameter ratio greater than is also a reliable method of assessing for pulmonary hypertension. this measurement offers % sensitivity, % specificity, % positive predictive value, and % negative predictive value [ ] . in cteph pulmonary arteries can appear tortuous with calcified walls [ ] . chronic pe can present with right ventricular hypertrophy evidenced by ventricular wall thickness greater than mm [ ] . development of right ventricular dysfunction causes right ventricular enlargement [ ] . right ventricular enlargement can dilate the tricuspid valve annulus leading to tricuspid regurgitation. the lung parenchyma distal to the occlusion or stenosis of chronic pe presents with a mosaic perfusion pattern that appears as well-demarcated hypoattenuated tissue with narrow vasculature contrasted with the hyperattenuated tissue being in possession of larger vasculature of well-perfused lung parenchyma. areas of infarction can resolve in the long-term to form peripheral nodules, cavities, subpleural scars, or irregular peripheral lines [ ] . right heart strain is important to recognize on ctpa and has characteristic signs on imaging as previously described (fig. ) . a rv/lv diameter ratio ≥ . is predictive for poor clinical outcomes after acute pe [ , , ] . a study of fig. -year-old female presenting with severe shortness of breath and chest pain. the patient has a history of metastatic breast cancer. a-c coronal ctpa slices showing pulmonary embolus in right and left pulmonary arteries extending into multiple segmental branches. d rv to lv of . suggestive of right heart strain. e in this case there is no significant contrast reflux into suprahepatic inferior vena cava and / or hepatic veins patients found that rv/lv diameter ratio ≥ . was an accurate predictor of in-hospital death or clinical deterioration [ ] . a meta-analysis found that right ventricular dilation is associated with elevated -day mortality, increased risk of death from pe, and increased -month mortality rate (or . ) [ ] . ten to fifteen percent of acute pes cause infarction of the lung. this appears as a wedge-shaped peripheral lung opacity, often referred to as a "hampton hump," on ctpa. these opacities can have a central ground glass appearance [ ] . ctpa has its inherent limitations secondary to artifacts. patient breathing causes motion artifacts that particularly affects the lower lung zones. cardiac motion may also disrupt the pericardial zone image quality. attenuation along a vessel may be disturbed by beam hardening artifacts from contrast originating from abutting vasculature, wires, or medical devices [ ] . studies have found . % to . % of ctpa studies to be non-diagnostic [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ventilation/perfusion (v/q) scanning was the mainstay diagnostic method for acute pe before the development of newer ct techniques [ ] . this imaging modality can be valuable when estimating the probability of an acute pe [ , ] . patients who are pregnant, have renal failure or contrast allergies, or cannot fit into a ct scanner also particularly benefit from v/q scans. v/q scans expose patients' breasts to times less radiation compared to ct, which helps to reduce breast cancer risk in young women [ ] [ ] [ ] . the fetal radiation dose associated with v/q scans has been estimated to be . - times higher than the fetal radiation dose associated with low-dose ctpa. while v/q scans are associated with a greater fetal risk for childhood cancer compared to ctpa, their aggregated radiation risk for a pregnant patient and her fetus is lower compared to ctpa. this difference in aggregated radiation risk increases with greater maternal body mass index and increased gestational age and suggests that v/q scans are more dose-efficient than ctpa for pregnant patients [ , ] . v/q scan is the indicated diagnostic test for acute pe in pregnant patients with a normal chest radiograph. a retrospective study of pregnant or postpartum women suspected to have an acute pe found that the patients with a normal chest radiograph were more likely to have a diagnostic image from v/q scanning compared to ctpa. various retrospective studies have found that - % of v/q scans of pregnant patients suspected to have acute pe resulted in diagnostic studies [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ctpa has also been associated with a significantly higher incidence of sub-optimal studies for assessing acute pe in pregnant patients compared to age-matched non-pregnant controls [ ] . this further contributes to the evidence supporting v/q scan as the diagnostic test of choice in pregnant patients with a normal chest radiograph who are suspected to have acute pe. v/q scans make use of ventilation agents labeled with technetium- m (tc- m) or radioactive noble gases such as xenon- or krypton- m. technetium- m-labeled diethylenetriaminepentaacetic acid (dtpa) is the most commonly used agent [ ] . tc- m-labeled macro-aggregated albumin (maa) is injected intravenously to image perfusion for v/q scans. the patient is positioned upright for the scan, which acquires multiple planar images. single-photon emission computed tomography (spect)/ct using a low-dose ct technique may also be performed to better localize abnormalities [ ] . the perfusion scan may be acquired before or after the ventilation scan. imaging perfusion first guides the projection used for ventilation scans using xenon- . a normal perfusion scan can preclude the need for a ventilation scan, which is particularly valuable for patients requiring minimization of radiation exposure such as the pregnant patient population. some authors have proposed primarily using perfusion-only scintigraphy in the diagnostic assessment of acute pulmonary embolism to reduce potential viral transmission by aerosolization in the setting of the current global covid- pandemic [ ] . -year-old male patient with acute dyspnea. a ctpa shows emboli in the left pulmonary artery bifurcation and the lower lobe segmental artery on the right side (arrows) b significant enlargement of the right ventricle with a nearly inversed configuration of the inter-ventricular septum, consistent with right heart strain. c a less specific, but also typical sign of right heart strain is the reflux of contrast material into the inferior vena cava and hepatic veins v/q scans are interpreted with a corresponding chest radiograph taken within - h of the scan. acute pe is often visualized as peripheral wedge-shaped perfusion defects in a lobar, segmental, or sub-segmental distribution in the absence of an associated ventilation abnormality. this mismatched defect can also be found with other conditions including malignancy, vascular abnormalities, vasculitis, veno-occlusive disease, and mediastinal lymphadenopathy and therefore a chest radiograph is valuable for comparison purposes [ ] . the most commonly used criteria for interpretation of v/q scans for acute pe are the modified prospective investigation of pulmonary embolism diagnosis (pioped) ii and prospective investigative study of acute pulmonary embolism diagnosis (pisaped) criteria [ , ] . patients can be categorized as high probability, intermediate probability, very low probability, normal, and non-diagnostic using the modified pioped ii criteria. a normal scan is characterized by diffusely homogenous radiotracer activity in the lungs on ventilation and perfusion scans while a high probability scan is characterized by two or more large segmental mismatch defects or segmental defect equivalents. a very low probability scan will appear as a non-segmental defect [ ] . the pioped ii criteria have found v/q scans to have % sensitivity and % specificity for acute pe, and the pisaped criteria found to have % sensitivity and % specificity for diagnosing pe [ , ] . utilizing spect can improve v/q scan sensitivity and specificity by enabling three-dimensional visualization of the lung. the addition of spect has been found to offer a % sensitivity and % specificity for diagnosing acute pe [ ] . magnetic resonance angiography (mra) is an evolving imaging modality that can be used for evaluating the possibility of acute pe in certain patient populations. pregnant or young patients may benefit from mra instead of ctpa if acute pe is suspected due to the lack of ionizing radiation exposure. patients with history of anaphylactoid reactions to iodine contrast media and those with chronic kidney disease may benefit from mra as well [ ] . mra assessment for acute pe includes axial and coronal static steady-state free precession (ssfp) sequences, contrast-enhanced d mra using t -weighted gre sequences, and an optional time-resolved contrast-enhanced d mra for dynamic perfusion imaging [ ] . the static ssfp sequences are acquired during free breathing or inspiratory breath-hold. these sequences can detect acute pe without the use of iv contrast due to the bright blood signal (fig. ) . a non-contrast mra is especially valuable for pregnant patients who ideally should not receive gadolinium contrast [ , ] . the d-balanced ssfp sequence is commonly used. it creates t /t weighting with radiofrequency pulse phase alteration and gradient echo refocusing that results in a steady state. a long t with high signal contrast causes blood to appear bright which facilitates thrombus detection [ ] . this sequence offers high sensitivity for field heterogeneity and requires only a short repetition time to minimize artifacts [ ] . balanced ssfp has also been shown to provide fast, accurate measurement of pulmonary artery diameters [ ] . arterial spin labelling makes use of slice selective acquisition with repeat imaging after an initial inversion pulse. it can be particularly valuable when combined with faster sequences. this technique acquires an image with upstream blood tagged by an inversion radiofrequency pulse and another image without such tagging [ ] . a subtraction between these images depict signal solely from the tagged blood and helps with visualizing vessels and tissue perfusion [ ] . the fresh blood imaging technique makes use of the ekg-gated d partial fourier fast spin echo technique. this sequence makes arterial blood in systole appear dark because of flow void and in diastole appear bright because of slows flow. veins produce some intensity in systole and diastole due to slow flow [ ] . an image with high signal intensity in the arteries and low signal intensity in the veins can be created by subtracting the systolic and diastolic images [ ] . however this sequence is not commonly used to diagnose pe due to its susceptibility to misregistration [ ] . contrast-enhanced d mra offers high spatial resolution of the pulmonary vasculature (fig. ) . this technique utilizes intravenous gadolinium contrast that causes t shortening in adjacent tissues leading to a high signal intensity in mra images [ ] . coronal images are typically acquired during inspiratory breath-holds. usually pre-contrast images for subtraction purposes are obtained, followed by arterial phase images, and late arterial phase images [ ] . timing the acquisition accurately achieves high snr and allows separation of the arterial and venous phase [ ] . the time at which the pulmonary arteries show maximum contrast enhancement is assessed utilizing a bolus-tracking technique (fig. ) [ ] . bolus-tracking techniques include utilization of dynamic low resolution magnetic resonance fluoroscopy and starting the acquisition just before contrast enters the pulmonary arterial tree. one could also utilize a test bolus injection of to ml of contrast to assess the time required for the contrast to reach the target vasculature [ ] . d t -weighted spoiled gradient echo sequence acquisition uses values of tr = . - ms, te = . - . ms, flip angle = - °, matrix = × × , fov = mm, and parallel imaging factor (r) = [ ] . acquiring data in an oval area of k-space and zero-filling corners enables isotropic spatial resolution. fractional echo read-out can reduce te and tr. this sequence can achieve mm spatial resolution in phase encoded direction and . mm spatial resolution in frequency encoded direction [ ] . timeresolved contrast-enhanced d mra is performed with repeated rapid volumetric sequences that sample the center of the k-space more frequently than the periphery [ , ] . data that are missing at each time point are shared between k-spaces by applying a variety of techniques [ ] [ ] [ ] [ ] . the images are captured during shallow breathing after the first contrast-enhanced d mra acquired in coronal orientation demonstrates filling defects, among others a long filling defect in the left lower lobe artery with a "railway sign" (a, white arrows) and the filling defect is shown as a "polo mint sign" on the axial reconstruction of the same data set (b, white arrow). c time-resolved, contrast-enhanced d mra reveals extensive wedge-shaped perfusion defects in the left upper and lower lobes (black arrows) pass of a gadolinium contrast bolus. there is some evidence that time-resolved contrast-enhanced mra during patient free-breathing may achieve accurate diagnoses and vessel measurements, which could make this sequence especially beneficial in the pediatric population and in patients with severe dyspnea [ ] . when using power injectors this technique is particularly helpful for visualizing perfusion defects when pursuing subtraction images (fig. d and c) [ , ] . imaging plays a crucial role in the assessment of acute pulmonary embolism (pe) prior to endovascular intervention. ctpa is the modality of choice for the diagnosis of acute pe given its availability as well as excellent sensitivity and specificity. this imaging modality facilitates detection and characterization of the extent of the pulmonary embolus (particularly helpful in coronal view to correlate with angiography in the case of endovascular treatment) and enables assessment of right heart strain. further, ctpa allows evaluation of the access route for endovascular interventions to ensure patency of the central venous system. mri offers a limited role in the diagnosis of acute pe in certain patient populations, specifically in pregnant patients. in current clinical practice d mra largely relies on gadolinium based contrast administration for diagnosis of acute pe. however, non-contrast mra sequences such as ssfp are evolving for the assessment of the pulmonary arterial vasculature. funding not applicable. for the clinical guidelines committee of the american college of physicians ( ) evaluation of patients with suspected acute pulmonary embolism: best practice advice from the clinical guidelines committee of the american college of physicians task force for the diagnosis, and management of acute pulmonary embolism of the european society of cardiology (esc) ( ) esc guidelines on the diagnosis and management of acute pulmonary embolism secular trends in incidence and mortality of acute venous thromboembolism: the ab-vte population-based study pulmonary embolism mortality in the united states, - : an analysis using multiple-cause mortality data trends in the incidence of deep vein thrombosis and pulmonary embolism: a -year population-based study incidence and mortality of venous thrombosis: a population-based study incidence of and mortality from venous thromboembolism in a real-world population: the q-vte study cohort clinical characteristics of patients with acute pulmonary embolism: data from pioped ii clinical characteristics of patients with acute pulmonary embolism clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease value of the ventilation/perfusion scan in acute pulmonary embolism. results of the prospective investigation of pulmonary embolism diagnosis (pioped) blood flow redistribution and ventilation-perfusion mismatch during embolic pulmonary arterial occlusion imaging of acute and chronic thromboembolic disease: state of the art interventricular mechanical asynchrony in pulmonary arterial hypertension: leftto-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling acute pulmonary embolism: a concise review of diagnosis and management clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department state-of-the-art pulmonary arterial imaging-part acute pulmonary embolism: imaging techniques, findings, endovascular treatment and differential diagnoses clinical prediction rules for pulmonary embolism: a systematic review and metaanalysis prediction of pulmonary embolism in the emergency department: the revised geneva score simplification of the revised geneva score for assessing clinical probability of pulmonary embolism prometheus study group ( ) performance of clinical decision rules in the diagnostic management of acute pulmonary embolism: a prospective cohort study d-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. a systematic review of management outcome studies d-dimer level and the risk for thrombosis in systemic lupus erythematosus d-dimer to rule out pulmonary embolism in renal insufficiency an age-adjusted d-dimer threshold for emergency department patients with suspected pulmonary embolus: accuracy and clinical implications multidetector computed tomography for acute pulmonary embolism imaging of acute pulmonary embolism: an update prognostic clinical prediction rules to identify a lowrisk pulmonary embolism: a systematic review and meta-analysis prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism prognostic models in acute pulmonary embolism: a systematic review and meta-analysis risk stratification and management of acute pulmonary embolism esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the identification of intermediate-risk patients with acute symptomatic pulmonary embolism validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism comparison of risk assessment strategies for not-high-risk pulmonary embolism effectiveness of prognosticating pulmonary embolism using the esc algorithm and the bova score a novel h-fabp assay and a fast prognostic score for risk assessment of normotensive pulmonary embolism a simple score for rapid risk assessment of non-high-risk pulmonary embolism antithrombotic therapy for vte disease: antithrombotic therapy and prevention of thrombosis a pulmonary embolism response team (pert) approach: initial experience from the cleveland clinic pulmonary embolism response teams impact of multidisciplinary pulmonary embolism response team availability on management and outcomes endovascular therapy for acute pulmonary embolism endovascular therapy for acute severe pulmonary embolism a prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the seattle ii study randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism catheter-tip embolectomy in the management of acute massive pulmonary embolism catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques pulmonary embolism response to fragmentation, embolectomy, and catheter thrombolysis (per-fect): initial results from a prospective multicenter registry a randomized trial of the optimum duration of acoustic pulse thrombolysis procedure in acute intermediate-risk pulmonary embolism: the optalyse pe trial management of suspected acute pulmonary embolism in the era of ct angiography: a statement from the fleischner society suspected acute pulmonary embolism: evaluation with multi-detector row ct versus digital subtraction pulmonary arteriography dual-energy ct of the heart for diagnosing coronary artery stenosis and myocardial ischemia-initial experience update on cardiovascular applications of multienergy ct state of the art: utility of multi-energy ct in the evaluation of pulmonary vasculature dual-energy ct: spectrum of thoracic abnormalities dualenergy ct: clinical applications in various pulmonary diseases chronic thromboembolic pulmonary hypertension dual-energy ct (dect) lung perfusion in pulmonary hypertension: concordance rate with v/q scintigraphy in diagnosing chronic thromboembolic pulmonary hypertension (cteph) dual-energy mdct: comparison of pulmonary artery enhancement on dedicated ct pulmonary angiography, routine and low contrast volume studies the indeterminate ct pulmonary angiogram: imaging characteristics and patient clinical outcome prognostic value of perfusion defect volume at dual energy cta in patients with pulmonary embolism: correlation with cta obstruction scores, ct parameters of right ventricular dysfunction and adverse clinical outcome spectral optimization of chest ct angiography with reduced iodine load: experience in patients evaluated with dual-source, dual-energy ct low-contrast agent dose dual-energy ct monochromatic imaging in pulmonary angiography versus routine ct high-pitch computed tomography pulmonary angiography with iterative reconstruction at kvp and ml contrast agent volume high pitch, low voltage dual source ct pulmonary angiography: assessment of image quality and diagnostic acceptability with hybrid iterative reconstruction state-of-the-art pulmonary ct angiography for acute pulmonary embolism iterative reconstruction and automatic tube voltage selection reduce clinical ct radiation doses and image noise ct pulmonary angiography: dose reduction via a next generation iterative reconstruction algorithm multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test dual-energy ct for imaging of pulmonary hypertension: challenges and opportunities comparative assessment of qualitative and quantitative perfusion with dual-energy ct and planar and spect-ct v/q scanning in patients with chronic thromboembolic pulmonary hypertension lung perfused blood volume images with dual-energy computed tomography for chronic thromboembolic pulmonary hypertension: correlation to scintigraphy with singlephoton emission computed tomography severity assessment of pulmonary embolism using dual energy ct-correlation of a pulmonary perfusion defect score with clinical and morphological parameters of blood oxygenation and right ventricular failure advanced imaging in pulmonary hypertension: emerging techniques and applications imaging in chronic thromboembolic pulmonary hypertension reference values for normal pulmonary artery dimensions by noncontrast cardiac computed tomography: the framingham heart study prediction of pulmonary hypertension in patients with or without interstitial lung disease: reliability of ct findings a ct sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter signs of right ventricular dysfunction: prognostic role in acute pulmonary embolism predictive value of computed tomography in acute pulmonary embolism: systematic review and meta-analysis computed tomography to assess risk of death in acute pulmonary embolism: a meta-analysis indeterminate ct pulmonary angiogram: why and does it matter yield of ct pulmonary angiography in the diagnosis of acute pulmonary embolism: short report suboptimal ct pulmonary angiography in the emergency department: a retrospective analysis of outcomes in a large academic medical center comparison of interpretations of ct angiograms in the evaluation of suspected pulmonary embolism by on-call radiology fellows and subsequently by radiology faculty diagnosis of acute pulmonary embolism in outpatients: comparison of thin-collimation multi-detector row spiral ct and planar ventilation-perfusion scintigraphy prospective comparison of helical ct with angiography in pulmonary embolism: global and selective vascular territory analysis. interobserver agreement clinical value of thin collimation in the diagnostic workup of pulmonary embolism the negative predictive value of spiral computed tomography for the diagnosis of pulmonary embolism in patients with nondiagnostic ventilation-perfusion scans combined ct venography of the lower limbs and spiral ct angiography of pulmonary arteries in acute pulmonary embolism: preliminary results of a prospective study the effect of imaging modality on patient management in the evaluation of pulmonary thromboembolism contrastenhanced helical ct for pulmonary embolism detection: interand intraobserver agreement among radiologists with variable experience helical ct and perfusion scintigraphy: diagnosis of pulmonary embolus in the clinical practice high-pitch versus standard mode ct pulmonary angiography: a comparison of indeterminate studies computerized tomographic pulmonary angiography versus ventilation perfusion lung scanning for the diagnosis of pulmonary embolism multiple applications besides pulmonary embolism snm practice guideline for lung scintigraphy . radiation dose to patients from radiopharmaceuticals: a compendium of current information related to frequently used substances estimating risk of cancer associated with radiation exposure from -slice computed tomography coronary angiography detection of pulmonary embolism during pregnancy: comparing radiation doses of ctpa and pulmonary scintigraphy perfusion scintigraphy versus -slice ct angiography in pregnant patients suspected of pulmonary embolism: comparison of radiation risks pulmonary embolism in pregnant patients: assessing organ dose to pregnant phantom and its fetus during lung imaging suspected pulmonary embolism in pregnancy: clinical presentation, results of lung scanning, and subsequent maternal and pediatric outcomes diagnosing pulmonary embolism in pregnancy using computed-tomographic angiography or ventilation-perfusion of thoracic radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy pulmonary embolism during pregnancy: diagnosis with lung scintigraphy or ct angiography? pulmonary embolism in pregnancy: ct pulmonary angiography versus perfusion scanning the value of ventilation-perfusion imaging in pregnancy perfusion scintigraphy: diagnostic utility in pregnant women with suspected pulmonary embolic disease quality of ct pulmonary angiography for suspected pulmonary embolus in pregnancy diagnostic evaluation of pulmonary embolism during the covid- pandemic sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in pioped ii tomographic imaging in the diagnosis of pulmonary embolism: a comparison between v/q lung scintigraphy in spect technique and multislice spiral ct contrast-enhanced pulmonary mra for the primary diagnosis of pulmonary embolism: current state of the art and future directions magnetic resonance imaging for the evaluation of pulmonary embolism update on mr imaging of the pulmonary vasculature mr pulse sequences: what every radiologist wants to know but is afraid to ask intraindividual comparison of contrast-enhanced mri and unenhanced ssfp sequences of stenotic and non-stenotic pulmonary artery diameters contrast enhanced pulmonary magnetic resonance angiography for pulmonary embolism: building a successful program high temporal and high spatial resolution mr angiography ( d-mra) timeresolved contrast-enhanced d mr angiography undersampled projection-reconstruction imaging for time-resolved contrast-enhanced imaging reduction of partial-volume artifacts with zero-filled interpolation in three-dimensional mr angiography high-resolution time-resolved contrastenhanced mr abdominal and pulmonary angiography using a spiral-tricks sequence time-resolved contrast-enhanced three-dimensional magnetic resonance angiography of the chest: combination of parallel imaging with view sharing (treat) free breathing contrast-enhanced time-resolved magnetic resonance angiography in pediatric and adult congenital heart disease detection of pulmonary embolism with freebreathing dynamic contrast-enhanced mri the impact of injector-based contrast agent administration in time-resolved mra publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -sdz d r authors: karnik, ankur a.; karnik, ashok m. title: pneumothorax and barotrauma date: - - journal: critical care medicine doi: . /b - - . - sha: doc_id: cord_uid: sdz d r nan weissberg and refaely reported on patients with pneumothorax. of male and female patients, . % of the pneumothoraces were spontaneous, . % were traumatic, and . % were iatrogenic. chen and col-leagues, in their university-based teaching hospital icu, found that of patients who developed pneumothorax while in the icu, % were related to procedures, most commonly thoracentesis. the reported recurrence rates of pneumothorax vary widely, depending on the type of pneumothorax and the duration of follow-up. a compilation of studies showed that the recurrence rate in "primary" spontaneous pneumothorax (psp) ranged from % to % with a mean recurrence rate of % in those without defi nitive preventive treatment. table - categorizes episodes of pneumothorax seen at nassau university medical center, a -bed hospital and trauma center in the suburbs of new york city. conventionally, psp has been defi ned as a pneumothorax that occurs spontaneously in a patient who has no underlying lung disease. however, a condition is unlikely to remain "primary" or "idiopathic" as we gain understanding about this disease process. diagnoses labeled as "primary" then shift into the category of "secondary." understanding the development of ptx in a patient who has known blebs and bullae is easy. however, computed tomography (ct) can detect abnormalities predisposing to psp in patients with normal chest radiograph. ct has demonstrated emphysema-like changes (elcs) in patients with psp. bense and others reported on nonsmoking cases of spontaneous pneumothorax (sp) who were not defi cient in alpha- antitrypsin. in cases ( %), ct showed elcs. these changes were found mainly in the upper and peripheral regions. no elcs were detected in the control group. other investigators , have also reported similar fi ndings on ct in their cases of psp. described a patient with recurrent psp in whom inhalation of aerosolized fl uorescein followed by autofl uorescence thoracoscopy allowed in vivo localization of various areas of extensive subpleural fl uorescein accumulation, which were not visible with normal white thoracoscopy. this has led to the concept of "porous" pleura. in a study on swedish patients, bense and colleagues found that smoking increased the risk of developing psp -fold in women and -fold in men. although cessation of smoking appears to reduce the risk of recurrence, continued smoking increases the risk of recurrence. cottin and colleagues found that in smokers who underwent surgery for recurrence or persistence of psp, ( . %) had evidence of respiratory bronchiolitis. smit and colleagues performed spirometrically controlled high-resolution ct density measurements in patients with sp and found that the mean lung density was lower in patients with pneumothorax. they hypothesized that peripheral airway infl ammation leads to airway obstruction with a check valve phenomenon, causing air trapping and development of pneumothorax. no correlation was found between air trapping and smoking habit or elcs. although rare, familial inheritance of pneumothorax has been reported. , the analyses suggest two possible models of inheritance: an autosomal dominant gene with incomplete penetrance and an x-linked recessive gene. the occurrence of recurrent sp in a finnish brother and his sisters also raises the possibility of autosomal recessive inheritance. as in sp, patients with marfan syndrome are tall, and pneumothorax is a common pulmonary complication. marfan syndrome is caused by the mutation in the fbn gene on chromosome . this gene is responsible for the formation of -to -nm microfi brils in the extracellular matrix of connective tissue. cardy and colleagues hypothesized that familial sp is caused by a connective tissue disorder that exhibits mendelian inheritance and postulated fbn as the causative gene. another interesting syndrome in which patients develop sp has been described. brit-hogg-dube (bhd) is an autosomal dominant cancer syndrome characterized by benign skin and renal tumors, pleuropulmonary blebs and cysts, and sp. the gene has been mapped to chromosome p . and recently identifi ed, expressing a novel protein called folliculin. , as a result of a breach in the visceral or parietal pleura, air enters the pleural space. when the amount of air is large and the increase in intrapleural pressure great, the mediastinum shifts to the opposite side and the diaphragm is depressed (fig. - ) . a decrease in vital capacity, functional residual capacity, total lung capacity, and oxygen transfer occurs. in a large pneumothorax, the arterial oxygen pressure (pao ) falls and the alveolar-arterial oxygen pressure difference [p(a-a)o ] increases. the factors that lead to hypoxemia during a large pneumothorax are anatomic shunt, hypoventilation, and relative overperfusion of partially collapsed, underventilated lungs. anthonisen reported that in patients with pneumothorax, airway closure occurs at low lung volumes and suggested that this was the main cause of ventilation maldistribution in such patients. animal studies suggest that the progressive hypoxemia with increasing pneumothorax is primarily the result of increasing degrees of pulmonary vascular shunting associated with increasing parenchymal collapse. the classifi cation given in box - combines the circumstances of occurrence of pneumothorax, the etiologic factors, and the state of the underlying lung. when pneumothorax occurs without trauma and is not iatrogenically induced, it is called sp. sp occurring in an otherwise healthy person is called psp, as mentioned earlier. secondary sp (ssp) occurs in patients with a variety of underlying lung diseases. other interesting categories of sp are catamenial pneumothorax, pneumothorax in drug addicts and acquired immunodefi ciency syndrome (aids) patients, and familial sp. investigators have found subpleural blebs or bullae at apices on chest radiographs and at thoracotomy in patients with sp. the pathogenesis of these blebs and the factors that lead to their rupture remain controversial. psp is classically seen in previously healthy young men with an asthenic body habitus. melton and colleagues found that the incidence of psp rose with increasing height among adults of both sexes, more so in males. it reached a fi gure of more than per , personyears for those inches or taller. it has been suggested that the greater prevalence of sp in tall, thin males is the result of a combination of circumstances. in an extremely long and narrow chest, the apical alveoli are underperfused; such alveoli are more readily torn by gravitational stress. inherited weakness of connective tissue might also contribute to the pathogenesis, as suggested by the numerous reports of sp in families and concurrent occurrence of sp in twins. morrison and colleagues have reported a family exhibiting spontaneous pneumothorax in a father and three offspring and suggested that isolated autosomal dominant pneumothorax may be a distinct entity. most patients with sp are heavy smokers. in one series, % of all patients were smokers. an increase in cigarette consumption during a particular year was followed within to years by an increased incidence of sp; the reverse occurred with decreased cigarette consumption. smoking increases the relative risk of developing sp about -fold in women and -fold among men, and there is a statistically signifi cant dose-response relationship between smoking and sp. pneumothorax secondary to underlying lung disease in adults, sp has been reported to occur as a result of a large variety of diseases including asthma, staphylococcal septicemia, pulmonary infarction, sarcoidosis, idiopathic pulmonary hemorrhage, pulmonary alveolar proteinosis, familial fi brocystic pulmonary dysplasia, tuberous sclerosis, cryptogenic fi brosing alveolitis, eosinophilic granuloma, coccidioidomycosis, echinococcal disease, chronic obstructive pulmonary disease (copd), shaver's disease (bauxite pneumoconiosis), lymphangioleiomyomatosis, von recklinghausen's disease, gastropleural and colopleural fi stulas through the diaphragm into the left pleural cavity, radiation therapy to the thorax, wegener's granulomatosis, cystic fi brosis, acute bacterial pneumonia, and as a complication of the chemotherapy used in the treatment of malignancy and pulmonary metastases from a variety of malignancies. the most common cause of secondary sp, however, is copd. sp in copd patients is a serious complication with excessive morbidity and mortality. , the clinical presentation of pneumothorax in copd patients is often atypical-pain may be absent, anxiety and breathlessness may predominate and be out of proportion to the collapsed lung, and the classic sign of hyperresonance may not be helpful because of the underlying emphysema. the air leak in these patients is usually large, and the tissues slow to heal, so it is weeks before the tubes can be taken out. when the peripheral veins of chronic abusers of drugs become obliterated because of a sclerotic or infectious process, the individual may attempt to use larger veins in the groin or neck. attempted subclavicular or supraclavicular injection ("pocket shoot") of drugs in the street setting has led to unilateral or bilateral pneumothoraces. [ ] [ ] [ ] [ ] [ ] douglas and levison found that the incidence of pneumothoraces is equal in both sexes and that it is less of a problem in teenagers (because they are unwilling to invade the clearly dangerous territory of neck veins or because they have not yet exhausted the peripheral veins) and in addicts older than years of age (probably because either conservation alters their behavior or they do not survive to their fi fth decade). it was also noted that although most drug users describe using small ( -or -gauge) needles, a large, complete, or tension pneumothorax usually develops. quite often the pneumothorax is bilateral. , pneumothorax in acquired immune defi ciency syndrome patients since the fi rst report of spontaneous pneumothorax in patients with aids in by wollschlager and colleagues, numerous other authors [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] have reported on the occurrence of pneumothorax in these patients. sp is an uncommon event ( . %) in the general population and occurs rarely in association with infectious pneumonia. spontaneous pneumothorax in patients with aids has become the leading cause of nontraumatic pneumothorax in this population. with the diagnosis of aids, a patient's risk of sustaining a nontraumatic pneumothorax increases to times that of general population. a high incidence ( % to %) has been reported in patients with aids and pneumocystis carinii pneumonia (pcp). , , pneumocystis carinii, which was thought to be a protozoan, has been renamed as pneumocystis jerovici and is now classifi ed as an archiascomycetous fungus. mechanical ventilation and bronchoscopy are quite often required in aids patients, and these two factors further increase the chance of pneumothorax occurring in these patients. , in patients with aids, the pneumothorax is frequently bilateral, recurrent, and not responsive to conservative therapy. , most often it is related to the infection with p. jerovici, but other infections like mycobacterium tuberculosis, m. avium intracellulare, pulmonary cytomegalovirus, pneumococcus organisms, or pulmonary toxoplasmosis may be associated. in a study of patients of aids with pcp, the overall mortality was reported to be . %; pneumothorax was found to be one of the seven factors that predicted -day mortality. the exact pathogenesis of the pneumothorax in these patients is not clear. in aids patients who have or have had active pcp, large confl uent areas of thin-walled blebs, distributed randomly on the surface of each lobe, have been reported. it has been postulated that the cystic changes may result from a check-valve mechanism caused by airway infl ammation and resultant partial airway obstruction or may be the result of disordered parenchymal architecture secondary to chronic infection and infl ammation. , various investigators , , have pointed out that the incidence of spontaneous pneumothorax is especially high in those patients who receive aerosolized pentamidine for pcp prophylaxis. this has been attributed to poor distribution of the aerosolized pentamidine at the periphery of the lung, which allows the development of a peripheral necrotizing pneumonitis, producing a bronchopleural fi stula with resultant pneumothorax. alternately, an ongoing acute infection in inadequately treated areas may eventually result in cystic dilation of distal airway. martinez and colleagues have suggested that the sulfi te in the isethionate component of the aerosol may cause an irritant cough, resulting in a rupture of the cysts. it has been found that low diffusing capacity of lung for carbon monoxide before pentamidine therapy for secondary prophylaxis is associated with an increased risk of bilateral pneumothoraces and increased mortality in these patients. a "catamenial pneumothorax" is defi ned as a spontaneous or recurrent pneumothorax occurring within hours from the onset of menstruation. alifano and colleagues described women with spontaneous pneumothorax who had been referred for surgical treatment. in eight cases ( %), the catamenial character of the pneumothorax was recognized by clinical history. in all eight cases, the pneumothorax was recurrent (one to four previous episodes) and right sided. a diaphragmatic abnormality was found in all eight cases. two mechanisms have been described for pneumothorax related to endometriosis. the most common is the movement of endometrial implants to the diaphragm, preferentially to the right side because of the recognized peritoneal circulation up from the pelvis to the right side. these implants then create channels or "holes" through the diaphragm that allow the implants or air to move into the chest. the second and much less frequent cause of endometrial implants in the chest is through the venous implants that lodge in the lung itself. clinical manifestations of thoracic endometriosis include chest pain, dyspnea, and hemoptysis. bilateral pneumothoraces and concurrent hemothorax, hemoptysis, chest pain, and pneumothorax have been described. traumatic pneumothorax most often occurs as a result of penetrating injury but may also occur with closed chest trauma consequent to alveolar rupture from thoracic compression, fracture of a bronchus, esophageal rupture, or rib fractures that lacerate the pleura. , traumatic pneu-mothorax can be subclassifi ed into open, closed, tension, or hemopneumothorax. a tension pneumothorax needs to be managed immediately by letting the air out with a large-bore needle. open pneumothorax should have a moist sterile gauze pack placed over the open wound, followed by a chest tube. hemopneumothorax requires insertion of a chest tube. increasing use of computed tomography (ct) scan to evaluate blunt abdominal trauma has revealed a new diagnostic entity that has been called occult pneumothorax. [ ] [ ] [ ] [ ] [ ] [ ] in the series of trauma patients reported by hill and colleagues, there were patients ( pneumothoraces) who were seen to have a pneumothorax on ct that was not seen on admission chest radiograph. the management of these pneumothoraces is controversial. wolfman and colleagues, reporting on occult pneumothoraces, suggested that most small (minuscule) occult pneumothoraces can be managed by close observation. moderatesized pneumothoraces can also be managed by observation if the patient is not on a ventilator, but most of the anterolateral pneumothoraces need chest tube placement. the leading causes of iatrogenic pneumothorax are transthoracic needle aspiration ( % to %), subclavian venipuncture ( % to %), and thoracentesis ( % to %). positive pressure ventilation has been reported to be the causative factor in only % of all iatrogenic pneumothoraces. most patients require treatment for to days, and hospitalization is prolonged in only a small number of patients because of this complication. , an important complication of mechanical ventilation is barotrauma. in one of the series, of patients receiving ventilatory support for longer than hours developed pneumothorax. more recently, lassence and colleagues reported that iatrogenic pneumothorax occurred in % of intensive care unit patients. risk factors were aids, acute respiratory distress syndrome (ards), or cardiogenic pulmonary edema at admission, body weight less than kg, central vein or pulmonary artery catheter insertion, and use of inotropic agents during the fi rst hours. when the lungs are exposed to high volumes, tissue disruption may occur. air passes along bronchovascular bundles to the lung hilum and then to other interstitial spaces and may enter pleural or pericardial cavities. in a ventilated patient, a rise in peak and plateau pressures should alert the clinician to the possible complication of pneumothorax. petersen and baier reported a % incidence of barotrauma in patients who required a peak airway pressure above cm h o. an early radiologic feature and a harbinger of life-threatening barotrauma is the presence of pulmonary interstitial emphysema. pulmonary interstitial emphysema manifests radiologically as small parenchymal cysts, circular cuffs around larger pulmonary vessels projected end-on (perivascular halos), small dots representing small peripheral vessels surrounded by areas of radiolucency, linear streaks of air radiating toward the hilum, and large cystic collections of air and subpleural air. , the air, having entered the interstitium, then dissects proximally along bronchovascular sheaths toward the lung hilum and mediastinum. once in the mediastinum, the accumulated air takes the path of least resistance and may produce subcutaneous emphysema, pneumopericardium, pneumoperitoneum, or retroperitoneum ( fig. - ). if the mediastinal pressure rises abruptly or if decompression via these routes is not suffi cient, the mediastinal parietal pleura may rupture, resulting in pneumothorax. entry of gas into the pulmonary circulation may produce systemic air embolism. even pneumoscrotum has been described as an unusual complication of barotrauma. pneumomediastinum can produce several interesting radiographic signs such as pneumopericardium, continuous diaphragm sign, continuous left hemidiaphragm sign, naclerio's sign, v sign at confl uence of brachiocephalic veins, thymic spinnaker-sail sign, ring-round-the-artery sign, and extrapleural sign. previous studies had shown that the factors that predispose to barotrauma are high peak and mean airway pressures, positive end-expiratory pressure (peep), use of volume-cycled ventilators, intubation of the right bronchus, chronic airways obstruction, and aspiration pneumonia. [ ] [ ] [ ] [ ] however, some studies , have shown that the incidence of barotrauma is independent of airway pressure. experts now accept that pulmonary edema and lung injury during mechanical ventilation are the consequence of "volutrauma" rather than "barotrauma." the best treatment for barotrauma is early recognition, and prevention-delayed treatment has a mortality of %. the recommended preventive measures are to decrease peak airway pressure by decreasing tidal volume, peak fl ow, and ventilatory rate; to use the best peep; and to employ assist-control mode, independent lung ventilation, and high-frequency positive pressure ventilation. in a study published by the acute respiratory distress syndrome network, it was found that treatment with a ventilator strategy designed to protect the lungs from excessive stretch resulted in decreased mortality and increased the number of days without ventilator use in patients with acute lung injury and acute respiratory distress syndrome. after a literature review of more than procedures of fi beroptic bronchoscopy (fob) with transbronchial biopsy, milam and colleagues found that the rate of pneumothorax was . %. after analyzing their series of patients who had undergone fob with transbronchial biopsy, milam and colleagues, frazier and colleagues, and blasco and colleagues concluded that an immediate postbronchoscopic chest radiograph rarely provides clinically useful information and that in fob without transbronchial biopsy, an immediate postbronchoscopy radiograph is not necessary. in a study published in june , izbicki and colleagues also concluded that in asymptomatic patients, routine radiograph after transbronchial biopsy is not necessary. when biopsies are performed, the following groups of patients should be considered for postbronchoscopy radiograph: comatose or mentally retarded patients, patients receiving positivepressure ventilation, patients with severe respiratory compromise as a result of disease or surgery, patients with bullous disease, patients who complain of chest pain, and outpatients. pneumothorax after bronchoalveolar lavage without biopsy is extremely rare. similarly, the complication of pneumothorax after transbronchial needle aspiration is also low ( of patients). the incidence of pneumothorax after percutaneous needle biopsy [ ] [ ] [ ] [ ] is much higher and ranges from % to %. although some authors have found that a more central location of the lesion, copd, and lung hyperinfl ation increase the risk of pneumothorax, [ ] [ ] others found no correlation between development of pneumothorax and spirometric parameters or the presence of obstructive airways disease. , however, kazerooni and others found that in patients with emphysema, there is a high incidence of pneumothorax after transthoracic needle aspiration; there is rapid development of pneumothorax in these cases, requiring chest tube placement. delayed pneumothorax after percutaneous fi ne needle aspiration, although extremely unusual, has been reported in two cases and patients should be warned of this possible complication. more recently, choi and colleagues reported on their series of patients who had undergone transthoracic needle biopsy (ttnb). a follow-up chest radiograph was obtained immediately and hours, hours, and hours after the biopsy procedure. a pneumothorax that developed after hours was defi ned as delayed pneumothorax. pneumothorax developed in of the patients ( . %), and delayed pneumothorax developed in patients ( . %). female gender and absence of emphysematous changes correlated with an increased rate of delayed pneumothorax. the reported incidence of pneumothorax after thoracentesis ranges from . % to . %. [ ] [ ] [ ] [ ] [ ] various mechanisms may explain the pneumothoraces that occur after thoracentesis: the lung may be punctured at the time of needle entry or after the fl uid has been withdrawn or a small amount of air may be drawn into the chest during aspiration or along the needle track if high negative intrapleural pressures develop. raptopoulos and colleagues found that ultrasonographically guided thoracentesis, use of the smallest possible needle, and aspiration of the smallest possible amount of fl uid are complicated by pneumothorax signifi cantly less often than thoracentesis done with conventional techniques. age, sex, underlying lung condition, overall clinical condition, size of the effusion, and type of tap (diagnostic or therapeutic) had no signifi cant effect on the occurrence of pneumothorax after thoracentesis. in a recent review article, feller-kopman concluded that the use of ultrasound for thoracentesis has been associated with improved yield and reduced complication rate and is quickly becoming the standard of care for procedural guidance. colt and colleagues, reporting on thoracenteses performed in adult patients, found that hospitalization status, critical illness, effusion size or type, presence of loculations, operator, needle type, amount of fl uid withdrawn, occurrence of dry tap, and type of thoracentesis were not associated with increased frequency of pneumothorax. the only predictor showing signifi cant correlation was repeated thoracentesis. after an analysis of thoracenteses in patients, aleman and colleagues concluded that, in asymptomatic patients, the risk of developing pneumothorax was so low that the practice of obtaining a routine chest radiograph may not be justifi ed. chakrabarti and colleagues reported the use of blind percutaneous pleural biopsy by abrams needle in patients; pneumothorax was seen in eight patients ( %), with only two patients requiring specifi c intervention. in james fi rst reported pneumothorax as a complication of passing a narrow-bore nasogastric tube. since that time numerous authors [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] have reported this complication. narrow-bore feeding tubes are particularly likely to give rise to pneumothorax because of the tube's small diameter ( . mm), self-lubricating properties, and wire stylet-all of which permit their undetected entry into the tracheobronchial tree, perforation of pulmonary tissue, and lodging in the pleural cavity. other factors associated with increased risk of a misplaced feeding tube include the presence of an endotracheal or tracheostomy tube (these may increase pulmonary passage of the tube by preventing glottis closure and perhaps by inhibiting swallowing), altered mental status, denervation of airways, esophageal stricture, enlargement of the heart, and neuromuscular weakness. the clinical signs commonly used to ascertain correct placement of the feeding tube may be misleading. normally, to confi rm the correct placement of a feeding tube in the stomach, a small amount of air is injected. this produces a characteristic gurgle in the left upper quadrant of the abdomen, but a "pseudoconfi rmatory gurgle" with a feeding tube in the chest has been reported. aspiration of large amounts of fl uid through the tube is also taken to be a test of correct placement into the stomach, but delayed aspiration of a large quantity of undigested enteral feeding solution from the pleural space, mistaken for gastric contents, has been reported. percutaneous tracheostomy was fi rst described in . in , ciaglia and colleagues described percutaneous dilational tracheostomy (pdt). fikkers and colleagues described cases of subcutaneous emphysema and pneumothorax after percutaneous tracheostomy in a series of cases. they described of their own cases which had developed complications to include subcutaneous emphysema, mediastinal emphysema, and pneumothorax. their review of literature showed that the incidence of subcutaneous emphysema was . % and that of pneumothorax . %. findings associated with ptx included diffi cult pdt and the use of a fenestrated cannula. development of air in the pleural space after partial resolution of total bronchial obstruction, as a complication of lobar collapse, and after therapeutic thoracentesis for malignant effusions has been described. acute lobar collapse results in a sudden increase in negative pleural pressure surrounding the collapsed lobe. although the parietal and visceral pleural surfaces remain intact, the gas originating from the ambient tissues and blood is drawn into the pleural space, producing a pneumothorax called pneumothorax ex vacuo. recognition of this type of pneumothorax is crucial because managing it requires relieving the bronchial obstruction rather than inserting a chest tube. the diagnosis of trapped lung requires documentation of chronicity and absence of pleural infl ammation, pleural malignancy, or endobronchial lesion. the pathognomonic radiographic sign of a trapped lung is the pneumothorax ex vacuo, characterized as a small to moderate-sized air collection after evacuation of effusion. experts have recognized that sports-related air leaks and pneumothorax occur more frequently than the literature suggests. levy and colleagues and patridge and colleagues each described three cases of pneumothorax or pneumomediastinum caused by blunt trauma sustained during a contact sport. kizer and colleagues identifi ed patients who had sustained a spontaneous or traumatic air leak while engaged in an outdoor sport. although traditionally the term barotrauma has been used to describe development of extra alveolar air in a patient on mechanical ventilation, there are other situations in which, because of increased intraalveolar pressure, air leaks out of alveoli. pulmonary barotrauma (pbt) of ascent is a well-known complication of compressed air diving. tetzlaff and colleagues found that preexisting small lung cysts or end-expiratory fl ow limitation may increase the risk of pbt, although neuman and colleagues contested these conclusions. some experts have suggested that even minor forms of pbt should be considered a contraindication to further diving because the divers are prone to recurrences that can occur even at shallow depths. clinically signifi cant pbt has been reported from self-infl ating bag-valve devices, after infl ation of party balloons, as a result of blast injury, , during submarine escape training, after automobile air bag deployment, and in a normal healthy volunteer after repeated measurements of maximal respiratory pressure. the clinical features of pneumothorax depend on its size, the underlying lung condition, and whether the pneumothorax is tension in type. psp usually develops in tall, thin males while the patients are at rest. most often the onset of symptoms is not related to physical exertion. surprisingly, many patients do not seek medical attention immediately after developing symptoms. in one series, % of patients waited for more than week after developing symptoms. chest pain and dyspnea are the two main symptoms associated with the development of pneumothorax. in one series of patients, all patients had one of the two symptoms and of patients ( %) had both. the chest pain is sudden in onset; pleuritic in nature initially; and then becomes a persistent dull ache, localized to the affected site. the degree of dyspnea depends on the size of the pneumothorax and the condition of the underlying lung. cough, malaise, orthopnea, or hemoptysis may be the presenting symptoms. small pneumothoraces (< %) may not be detectable clinically, especially in a patient with emphysema. larger pneumothorax may produce tachycardia and tachypnea. decreased motion, vocal resonance, and breath sounds on the side of pneumothorax; hyperinfl ation; and hyperresonance usually exist. pleural friction rub may be present. in a large pneumothorax, the trachea and apex beat may be shifted to the opposite side and liver dullness may be masked. the presentation in tension pneumothorax is more dramatic. because of a ball-valve mechanism, air enters the pleural cavity but cannot escape, thereby building up positive pressure. as the tension continues to increase, the diaphragm is fl attened, the mediastinum is shifted to the opposite side, and ultimately cardiopulmonary collapse results. in left-sided pneumothorax and in pneumomediastinum, systolic clicks, crunching, and whooping sounds have been described. [ ] [ ] [ ] various unusual presentations and physical signs of pneumothorax have been described. horner's syndrome may occur and is attributed to traction on sympathetic ganglion, secondary to mediastinal shift in tension pneumothorax. , unilateral periorbital emphysema resembling ptosis was reported by widder in two obtunded, cachectic patients. the presence of undue resonance obtained by digital percussion on the medial zone of the clavicle with the patient in the orthostatic position has been described as an early and sole sign of pneumothorax. the clinical features of pneumothorax in certain situations may not be typical, and the diagnosis is made by having a high index of suspicion. during a transbronchial biopsy a patient may complain of pleuritic pain, followed by progressive dyspnea. after subclavian vein catheterization, progressive dyspnea or alteration in the vital signs should alert the clinician to this complication. in a mechanically ventilated patient, development of pneumothorax can be suspected by new-onset respiratory distress, hypotension, agitation, unilateral decrease in breath sounds, worsening oxygenation, and a decrease in static and dynamic compliance. , , in sports-related pneumothorax, the presentation may be atypical, and pneumothorax may be diffi cult to recognize because an athlete's physical fi tness may mask the serious injury and athletes may be more inclined to downplay their symptoms. simultaneous bilateral pneumothoraces is a rare and interesting condition. in humans, the right and left pleural spaces are completely separated. theoretically, any patient who has undergone a median sternotomy, mediastinal surgery, heart or heart-lung transplant surgery is at risk for having a persistent pleuro-pleural channel. most pleural rents probably heal but rarely a pleuro-pleural channel persists. schorlemmer and colleagues have referred to this condition as "iatrogenic buffalo chest" because the north american buffalo is one of few mammals that have communicating pleural spaces. a unilateral thoracic procedure in this situation has been described to cause bilateral pneumothoraces , and "shifting pneumothorax." johri and colleagues reported a patient who had undergone a thymoma resection in the remote past and developed bilateral pneumothoraces after undergoing transthoracic needle biopsy of a right lung nodule. sayar and colleagues described patients who presented with simultaneous bilateral spontaneous pneumothorax (sbsp). they represented % of all patients with pneumothorax. of the patients, ( %) had no underlying lung disease. in seven patients, sbsp was secondary to pulmonary metastases, histiocytosis, undefi ned interstitial pulmonary disease, tuberculosis, pneumonia, and chronic obstructive pulmonary disease. the presence of pneumothorax may produce electrocardiographic changes suggesting myocardial ischemia or infarction. poor r wave progression in the anterior precordial leads with a decrease in r-wave from v to v , rightward shift of frontal axis, diminution of precordial r voltage, decrease in qrs amplitude, and precordial twave inversion have all been described. [ ] [ ] [ ] the absence of st-segment elevation and a signifi cant q-wave and reversal of electrocardiographic changes in the sitting position suggest pneumothorax. most of these changes have been described in left-sided pneumothorax. alikhan and biddison have described a new ecg sign of right-sided pneumothorax: loss of s-wave in lead v and prominent r-wave voltage, which may mimic posterior wall myocardial infarction. strizik and forman found pr-segment elevation in inferior leads and reciprocal prsegment depression in an avr lead in a case of left tension pneumothorax and attributed these to atrial ischemia or injury. the chest radiograph confi rms the presence of pneumothorax in most cases. the air in the pleural space rises to the apex of the hemithorax and causes relaxation atelectasis of the upper portion of the lung. classically, the clinician fi nds a visceral pleural line with absence of lung markings peripheral to this line. when the fi lm cartridge used for the portable chest fi lm is placed under the patient, the skin on the back can fold over on itself to produce a line that runs down the hemithorax, which can easily be mistaken for pneumothorax ( fig. - ). this line, pro- duced by the redundant skinfold, can be differentiated from the line of pneumothorax by the following three features: ( ) the lung markings are present peripheral to the skinfold; ( ) the skinfold has a wavy appearance; and ( ) in the skinfold, there is a gradual increase in radiodensity as the line is approached from the hilum. however, in the presence of a consolidated lung, a pneumothorax presents as an edge instead of a line. when pneumothorax is strongly suspected clinically but a pleural line is not clearly seen, possibly because of an overlying rib, gas in the pleural space can be detected by either of two procedures: ( ) radiography in the erect posture (potentially more diagnostic with full expiration) or ( ) radiography in the lateral decubitus position with a horizontal x-ray beam. some authors, - however, have suggested that the expiratory fi lm does not increase diagnostic capability. the diagnosis of pneumothorax in the critically ill patient is more diffi cult to establish. the following four variables occur statistically more often in patients with initial failure to diagnose pneumothorax: mechanical ventilation, atypical radiographic location of pneumothorax, altered mental status, and development of pneumothorax after peak physician staffi ng hours. in the icu setting, radiographs are typically obtained in the supine position, making pneumothorax diagnosis more diffi cult. in the supine position the gas within the pleural space rises to the highest point in the hemithorax, which, in this position, is the anterior costophrenic sulcus. various authors have described the depression and clear visualization of the diaphragm anteriorly, creating a "double" appearance to the diaphragm, a deep lateral costophrenic angle on the involved side ("the deep sulcus sign") ( fig. - ) , an unusually distinct cardiac apex and pericardial fat tags, and increased hyperlucency of the upper abdominal quadrants. [ ] [ ] [ ] [ ] [ ] a sharp line outlining the descending aorta may be produced by air trapped behind the inferior pulmonary ligament. any of these fi ndings should lead to a prompt cross-table lateral or decubitus study or a ct scan to establish the diagnosis of pneumothorax. although not done commonly for the diagnosis of pneumothorax, ct of the chest may detect an unsuspected pneumothorax in a critically ill patient (fig. - ) . in view of the diffi culty of clinically diagnosing pneumothorax in critically ill patients, hall and colleagues have recommended daily chest radiographs for this group of patients. in those patients who are treated with peep, interstitial gas may be seen as an early sign of barotrauma: more than % of these go on to develop features of barotrauma. the interstitial gas is manifested radiographically by cystic changes, linear streaks along the bronchi and vessels, halos of gas around vessels, and subpleural gas. ct scan may also be useful to detect pneumothorax in complex cystic lung diseases. ultrasound examination is not used in the routine diagnosis of pneumothorax but may be of diagnostic utility. during the ultrasound examination, a kind of back-andforth movement of lung ("lung sliding"), synchronized with respiration, is normally seen. lichtenstein and menu found that absence of lung sliding was suggestive of pneumothorax. in a normal subject, in vertical orientation, the ultrasound screen shows artifacts rising from the pleural line and spreading to the edge of the screen ("comet-tail" artifacts). lichtenstein and colleagues, in a more recent report, concluded that ultrasound detection of "comet-tail" artifact at the anterior wall allows complete pneumothorax to be excluded. the goals of management of pneumothorax are ( ) to rid the pleural space of air and allow re-expansion of the lung with the least possible morbidity and ( ) to decrease the likelihood of recurrence. approaches for the management of the initial episode include observation, supplemental oxygen, simple aspiration of the pneumothorax, or tube thoracostomy. the choice of therapy in a given patient depends on various factors such as the size of pneumothorax, whether the pneumothorax is primary or secondary, the condition of the lungs, the clinical stability of the patient, the occupation of the patient, and whether the pneumothorax has occurred in a special setting. for prevention of recurrence, chest tube placement with pleurodesis or various surgical interventions including thoracotomy or video-assisted thoracic surgery (vats) may be necessary. however, as a postal survey of american college of chest physicians (accp) members showed, there exists marked practice variation in the clinicians' approaches to the management of spontaneous pneumothorax and bronchopleural fi stula. this was partially explained by differences between pulmonologists and thoracic surgeons. many new recommendations that suggest a shift from the previous practices have been made and are discussed later. a number of methods have been described to measure the size of pneumothorax. [ ] [ ] [ ] engdahl and colleagues found that the size of pneumothorax measured from a chest radiograph did not correlate with ct, whereas the size of pneumothorax as estimated by ct correlated well with the amount of air aspirated in of patients treated with drainage. they suggested that the decision to treat should be based on clinical status and, if it is considered important to determine the size, ct should be used. various approaches to the management of pneumothorax are discussed in subsequent sections. an estimated . % of the volume of pneumothorax is absorbed each hours. therefore if a patient has a % pneumothorax, it will take days for the air to be absorbed spontaneously. different authors have used different sizes of pneumothorax in recommending expectant management: less than %, less than %, , or an apical collapse of less than cm and lateral collapse of less than cm. the absorption of gas from the pleural space depends, besides other factors, on the gradient between the partial pressure in the capillaries and in the pleural space. on room air, the net gradient is only mm hg, whereas it exceeds mm hg when the patient is on % oxygen. studies , have shown that administering % oxygen increases absorption of air fourfold to sixfold. hospitalized patients with any type of pneumothorax, who are not subjected to aspiration of air or tube thoracostomy, should be treated with supplemental oxygen at high concentrations. in those patients whose pneumothorax is large (more than % to %), progressive, or tension type; who are symptomatic; have an underlying chronic lung disease; are on a ventilator; or who have a recurrent pneumothorax, the pleural space air needs to be removed by various therapeutic means rather than be allowed to be absorbed spontaneously. the following methods have been used for the removal of air. inserting an intercostal tube is a traumatic, painful procedure associated with a risk of hemorrhage. if connected to an underwater seal, the tube confi nes the patient to bed, thereby increasing the risk of thromboembolism and prolonging the duration of hospitalization. in view of these disadvantages, some investigators have treated pneumothorax by simple aspiration. [ ] [ ] [ ] [ ] simple aspiration is usually performed in the second intercostal space in the midclavicular line. the catheter is connected to a three-way tap with the exit tube placed under water to ensure correct direction of airfl ow. resistance is felt as the reexpanded lung impinges on the cannula. a confi rmatory chest radiograph is performed. a large tension pneumothorax needs to be evacuated immediately. thoracocentesis using a catheter (e.g., seldinger technique) that is advanced into the pleural cavity by means of a metal needle, a butterfl y needle, or a regular disposable needle is fraught with danger because the lung may be punctured. wung and colleagues have described the use of a spring-loaded veress needle (american cystoscope makers, inc., stamford, conn.) for emergency thoracentesis. this needle consists of a slender spring-loaded inner tube, which is blunt tipped and has a side aperture, enclosed in a -gauge sharp needle. the spring action allows the inner needle to retract while the outer needle is puncturing the chest wall but lets it spring out as soon as the pleural cavity is punctured. simple aspiration is a technique with low morbidity that is well tolerated and allows the patient to be mobile and return to work rapidly. it may be used as the initial procedure in the absence of signs of tension. unfortunately, simple aspiration leaves the patient with a % to % chance of recurrence. , [ ] [ ] [ ] however, in a recent randomized, prospective, multicenter pilot study involving patients with the fi rst episode of psp, noppen and colleagues reported that manual aspiration seemed equally effective as chest tube drainage and was safe, well tolerated, and feasible as an outpatient procedure in the majority of patients. devanand and colleagues, after a meta-analysis of three randomized controlled trials (rcts) with a combined total of patients, concluded that simple aspiration is advantageous in the initial management of psp because of shorter hospitalization. no significant difference in recurrence was reported at year using either modality, but the effi cacy data were inconclusive. modern chest tubes are made of clear plastic with varying internal diameters, multiple holes and distance markers, and radiopaque stripes that outline the proximal drainage hole. they are pliable but not supple enough to kink. the second intercostal space in the midclavicular line is generally chosen for insertion of the tube because the area is wide and avascular. the tube is inserted using the trocar or blunt dissection method. most institutions now prefer the latter. after insertion the tube is directed anteroapically and secured to prevent accidental removal. the tube is then connected to a water-seal drainage or a drainage system. to avoid the risk of reexpansion pulmonary edema, it is recommended that negative suction not be applied in the absence of a bronchopleural fi stula. bell and colleagues, in chest tube removals in trauma patients, found that the post-chest tube removal pneumothoraces rates did not differ whether the chest tube was removed at end-expiration or end-inspiration. in the absence of trauma and with good aseptic technique, prophylactic antibiotics are not recommended. the complications associated with thoracostomy that have been reported in the literature include laceration of the lung, spleen, liver, and stomach; intercostal artery bleeding; infarction of a peripheral segment of the lung aspirated into the drainage part of the chest tube; and delayed pulmonary perforation and subcutaneous emphysema. , a blocked tube may result in a residual pleural space with the development of empyema. a number of authors , have described the use of small lumen catheters for treating a simple pneumothorax. in view of the ease of insertion, good response, and low incidence of complications, it has been suggested that a small lumen catheter may be a useful alternative to tube thoracotomy. although catheter failure included kinking, malposition, inadvertent removal by the patient, occlusion of the tube or valve by pleural fl uid, and large air leak, no complication attributable to tube placement occurred. liu and colleagues reported their experience with the use of pigtail catheters in patients versus traditional chest tube in patients and found that the pigtail drainage was no less effective than the traditional chest tube. the questions pertaining to chest tubes such as smallbore tube versus large-bore tube, whether to apply suction or not, and whether the tube should be taken out at the end of inspiration or expiration have been discussed nicely by baumann should be in a review article in . these points are summarized in the management algorithms given later. samelson and colleagues and martin and colleagues have described their experiences with the thoracic vent (one-way valve feature) in managing simple pneumothorax. the thoracic vent is inserted in the second intercostal space in the midclavicular line. the authors point out that this device has the advantage of a urethane tube that does not kink, a self-contained one-way valve, and a unique signal diaphragm that refl ects pleural pressure; however, the device is not suitable for use in patients who are expected to have large-volume or protracted air leaks. as mentioned earlier, the initial episode of spontaneous pneumothorax may be managed by simple observation or drainage. once the initial episode of pneumothorax has resolved, the decision as to the need for measures to prevent recurrence must be made. in the following groups of patients, further management needs to be planned after the resolution of pneumothorax: recurrent pneumothorax, patients with chronic air leak, patients with demonstrable large bullae, and patients who live in remote areas or pursue an occupation in which a recurrence could be a hazard (e.g., airline personnel or divers). different recurrence rates have been reported by various authors and range from % to %. , , , the following are established risk factors for recurrence: more than one previous episode, copd, air leak for more than hours during the fi rst episode, and large cysts seen on radiograph. the following are possible risk factors for recurrence: nonoperative management of fi rst episode (versus tube drainage) and tube drainage for only hours during fi rst episode (versus to days). further management in these high-risk groups is aimed at preventing recurrence. the following approaches have been used. chemical pleurodesis via chest tube, at thoracotomy, or vats can be used to institute preventive measures. pleurodesis (adhesion of visceral and parietal pleura) can be done by introducing the sclerotic agent via a chest tube, or it can be done in the operating room with open thoracotomy or thorascopy. however, there is no consensus about the timing or method of pleurodesis. a practical approach is outlined later in the management algorithm. because sterile tetracycline is no longer available, intrapleural instillation of doxycycline has been used as an alternative for pleurodesis. talc, fi nely powdered magnesium silicate, is another effective pleural irritant, producing fi brosis and adhesions. numerous complications and side effects such as fever, pain, infection, and respiratory failure have been reported with its use, but lange and colleagues found that although talc may result in mild restrictive respiratory impairment in long-term follow-up, it was not clinically signifi cant and there were no recorded cases of mesothelioma. in the past, patients with failed pleurodesis underwent surgical intervention. thoracic surgery in such patients is complicated by partial pleural symphysis. also, previous chemical pleurodesis makes lung transplantation more diffi cult technically. in view of these concerns, kirby and ginsberg recommend that chemical pleurodesis be used only in selected patients who are too ill for surgery. the objectives of surgical treatment are to obtain full reexpansion of the affected lung, control complications, tackle the underlying lung problem, and prevent recurrence through pleural sclerosis by mechanical abrasion or pleurectomy. surgical management during the fi rst episode of sp is indicated under the following circumstances: % to % of patients have a persistent leak resulting from a large fi stula that needs to be closed surgically; about % of patients have frank hemothorax, and surgical intervention is required in these patients to control the bleeding; a trapped lung may fail to reexpand, and decortication is required in such cases. if the patient is a diver, airline pilot, or lives in a remote area, surgery should be considered after the fi rst episode to prevent a recurrence. apical bullous disease can be surgically approached by a transaxillary approach , or through the auscultation triangle. in a young female, a cosmetically acceptable scar is produced by a submammary anterolateral incision. in an older individual with diffi cult pneumothorax complicated by other problems, a formal posterolateral thoracotomy is recommended. , , if bilateral pleurectomy is required, a midline sternotomy is preferred. this permits access to both pleural cavities with minimum interference with respiratory function and causes minimal postoperative pain. sites of air leaks and obvious bullae are oversewn. with modern stapling instruments, blebs and bullae can be excised easily with an airtight seal, without sacrifi cing a great amount of normal underlying lung tissue. if one large cyst is fed by a major bronchial branch, then control of the feeding bronchus and marsupialization or plication of the bulla is performed. segmentectomy and lobectomy to deal with underlying pathology are rarely necessary. obliteration of pleural space can be achieved by abrasion of the pleura with a dry gauze sponge, apical pleurectomy, or an extensive pleurectomy. when bilateral pleurectomy is advisable, it should be done in stages, to days apart. in most of the cases, blebectomy and pleural abrasion are suffi cient. in their study, murray and colleagues suggested an entirely different approach to the problem of recurrent pneumothorax. they used a limited axillary thoracotomy as primary treatment for recurrent pneumothorax, without a preoperative chest tube. modern thoracoscopy allows minimally invasive access to the chest cavity. it allows full visualization of the lung and pleura and, when combined with resection of blebs and pleurodesis or pleurectomy, results in a low recurrence rate, minimal patient discomfort, and rapid recovery. identifi ed bullae can be treated with a variety of modalities. [ ] [ ] [ ] chemical or mechanical pleurodesis can be performed during vats. [ ] [ ] [ ] thoracoscopic identifi cation and treatment of bronchopleural fi stulas are also possible in patients with prolonged air leaks despite chest tube drainage. bilateral vats has been found to be a safe and effi cacious procedure for patients with bilateral bullous disease and patients presenting with simultaneous or nonsimultaneous bilateral sp. , pneumocystis jerovici pneumonia-related pneumothorax is complicated by a virulent form of necrotizing subpleural lesions, which result in diffuse air leaks that are refractory to the standard treatment. , asymptomatic patients can be observed. an aggressive stepped-care management with large-bore intercostal tube drainage, chemical pleurodesis, and early video-assisted thoracic talc poudrage has been recommended for symptomatic patients. in patients with an air leak persisting for more than days, thoracotomy with stapling of blebs and mechanical pleurodesis has been recommended. when chemical pleurodesis is unsuccessful and open surgical pleurectomy is not desirable because of the patient's underlying disease, morbidity, and poor prognosis, thoracoscopic pleural ablation offers a therapeutic alternative. pleurodesis as an initial step in the management of pneumothorax in cystic fi brosis is considered contraindicated because it results in extensive pleural adhesions that jeopardize subsequent lung transplantation. therefore noyes and orenstein have recommended a stepwise management of pneumothorax in cystic fi brosis. if initial tube thoracostomy does not bring resolution of air leak within days, blebectomy should be performed. if blebectomy proves unsuccessful, with either continuing air leak or recurrence, a defi nitive pleural ablative procedure should be undertaken. the initial episode of catamenial pneumothorax is managed in the usual manner. recurrences, which occur hours before or after menstrual fl ow, are managed by pleurodesis or hormonal treatment. therapeutic options include oral contraceptive pills, danazol, progestational agents, and gonadotropin-releasing hormone (gnrh) analogues. thoracotomy should be considered if the patient is unable to take ovulation-suppressing drugs, has a recurrent pneumothorax while on drugs, or wants to become pregnant. at thoracotomy, any diaphragmatic defects should be closed, any subpleural blebs should be oversewn, and pleural abrasion should be performed to effect a pleurodesis. , a patient who has a previous or current catamenial pneumothorax is at increased risk for barotrauma with positive pressure ventilation and represents a unique challenge to the anesthetist. postoperative hormonal therapy is often required to prevent recurrences. hysterectomy or tubal ligation may benefi t selected patients. pneumothorax complicating pregnancy is managed in the usual way, but in view of the high rate of recurrence of pneumothorax during parturition, thoracotomy with resection of apical blebs (if present) should be considered. air or gas trapped in body cavities expands in direct proportion to the decrease in atmospheric pressure. at an altitude of , feet, a pneumothorax will increase . times in size. if a patient with pneumothorax, especially secondary to copd, has to be transported, the following precautions should be taken: (a) the ability of the patient to take supplemental oxygen without causing alveolar hypoventilation must be established before the fl ight and supplemental oxygen administered during the fl ight; (b) a chest tube with a heimlich fl utter valve should be in place; and (c) the patient should travel with a medically knowledgeable companion. the epidemic of the severe acute respiratory syndrome (sars) brought several ethical issues associated with new, severe epidemic diseases into sharp focus. of the six cases described by sihoe, pneumothoraces were bilateral in three patients, mechanical ventilation was indicated in three patients, and two patients died. air leaks or recurrences occurred in all four patients who accepted chest tubes. these air leaks took to days to resolve. peripheral leukocytes and serum lactate dehydrogenase were higher in sars patients with pneumothorax. these complications refl ected severe pathologic changes in lung tissues and the strong pulmonary and systemic infl ammatory responses that accompany sars. during the sars epidemic, health care providers were at risk, with substantial risk for those who performed bronchoscopy. by the end of the epidemic, approximately % of reported cases were in health care workers and some died. felice concluded that if multiple management options are available and they can be expected to result in equivalent, optimal patient outcomes, options that pose lesser risks to health care providers should be selected. lymphangioleiomyomatosis (lam) is a rare and frequently fatal disease that exclusively affects women of childbearing age. thin-walled cyst formation occurs in the pulmonary parenchyma, and lung function declines progressively. the lam pleural disease consensus group reviewed the responses to a questionnaire by patients. of these, patients (incidence, %) reported at least one spontaneous pneumothorax during their lifetime and out of ( %) indicated that they had subsequent pneumothoraces. because of the morbidity and cost associated with multiple recurrences, the authors recommended early, defi nitive intervention, preferably at the time of the initial pneumothorax. although pleurodesis may be associated with an increased risk of perioperative bleeding with lung transplantation, their data suggested that the complications are manageable and do not preclude successful transplantation. a persistent pulmonary air leak, which may occur as a result of pneumothorax or after pulmonary resection, is a diffi cult and frustrating problem to manage. convention-ally, the air leak persisting for more than days is called bronchopleural fi stula and it is not an uncommon problem. in the series reported by chee and colleagues, the overall incidence of bronchopleural fi stula was . %. in pulmonary resection cases, cerfolio and colleagues, on univariate analysis, found that the increased age and the following fi ndings on pulmonary function testing predicted air leak on postoperative day one: low forced expiratory volume in second/forced vital capacity ratio (fev /fvc), increased residual volume/total lung capacity ratio (rv/tlc), increased rv, and increased functional residual capacity (frc). in the patients with air leaks who are managed by tube thoracostomy, cerfolio and colleagues found that conversion from suction to a water seal is an effective way of sealing an expiratory air leak. if the leak persists beyond days, tube thoracostomy is deemed to have failed and a more defi nitive treatment is planned. such cases are usually managed surgically, but patients who are unfi t or unwilling for surgery pose a management dilemma. chemical pleurodesis may be tried but does not succeed if the lung has failed to expand. in such a situation, autologous "blood patch" pleurodesis has been found useful. , kinoshita and colleagues have described a technique for such cases. they used a large amount of diluted fi brin glue for pleurodesis in patients with intractable pneumothorax or intrapleural dead space and found it useful. if pleurodesis also fails, the leak is localized during fi ber-optic bronchoscopy and the fi stula is sealed by using a sealant. pectoral myoplasty, in which the right pectoralis major muscle was transferred into the thorax and draped over the area of lung with multiple leaks, has been used when other interventions fail. murata and colleagues have described a closure with intravenous administration of a coagulation factor xiii concentrate. ferguson and colleagues reported closure of a persistent distal bronchopleural fi stula using a one-way endobronchial valve designed for the treatment of emphysema. ziskind and colleagues, in , described a case of pneumothorax in which accidental application of high, negative intrapleural pressure led to acute pulmonary edema. since that time, unilateral expansion pulmonary edema has been recognized as a complication that can occur during the management of pneumothorax (fig. - ). re-expansion pulmonary edema tends to occur with greater frequency in patients to years of age, when there is complete collapse of the lung, when the pneumothorax has remained untreated for more than hours, and when rapid re-expansion occurs secondary to the application of negative pressure; age-related changes in the older patients seem to afford some protection. , the exact pathogenesis of re-expansion pulmonary edema is not known, but various factors such as bronchial obstruction, decrease in surfactant, and increased capillary permeability , have been implicated. the development of bilateral re-expansion pulmonary edema after unilateral pleurodesis in a young male without heart disease might suggest that forces leading to ipsilateral reexpansion pulmonary edema also affect the contralateral lung. pavlin and colleagues have described three cases of re-expansion hypotension that followed rapid evacuation of persistent unilateral pneumothorax. besides the presence of pulmonary collapse for more than days, the other risk factors were signifi cant arterial hypoxemia during pneumothorax, an elevated or rising hemoglobin and hematocrit level, and development of respiratory distress after insertion of a pleural drain. the mechanism of hypotension and shock after pulmonary re-expansion is not clear, but volume depletion and myocardial depression possibly play a role. slow expansion by intermittent clamping of the chest tube, especially in high-risk patients, may prevent both reexpansion edema and reexpansion hypotension. , paradoxically, vigorous fl uid therapy may be advantageous in preserving circulation dynamics despite coexisting pulmonary edema. myocardial stimulants may be useful if myocardial depression is suspected. diuretics have been used to manage re-expansion pulmonary edema but may prove dangerous in the presence of hypovolemia and shock. it has been recommended that a more logical approach in patients with shock and hypoxemia may be to use mechanical ventilation with peep, which would reduce further fl uid shift into the re-expanded lung. plasma expanders, fl uid replacement, and vasopressor therapy can be used as needed. , development of tension pneumothorax has been reported after inadvertent, improper attachment of a heimlich valve. , a more aggressive approach to managing pneumothorax has been advocated recently. guidelines for managing pneumothorax have been published. , pneumothorax size: american college of chest physician (accp) guidelines defi ne a small pneumothorax as less than cm in apex-to-cupola distance; british thoracic society (bts) guidelines defi ne a small pneumothorax as a visible rim of less than cm between the lung margin and chest wall. stable patient: the accp defi nes a stable patient as one who has all of the following: respiratory rate less than breaths per minute; heart rate greater than beats per minute or less than beats per minute; normal blood pressure; room air saturation of greater than %; and ability to speak in whole sentences. may need to be replaced by a larger tube if leaking persists and creates management diffi culty. the clinician fi nds it most practical to use a "roadmap" in different clinical scenarios. the difference between didactic medicine and bedside medicine is that the former is taught in a classroom and begins with a "diagnosis"; the latter starts at the bedside with a clinical scenario as the starting point. figure - represents an algorithmic approach to management that is based on the accp and bts guidelines and practical experience. it can be applied to most patients with pneumothoraces. ■ psp occurs primarily in tall, thin, previously healthy young men, most of whom are smokers. chest radiograph often shows apical subpleural blebs or bullae. rupture of these bullae is not related to physical activity but may be related to changes in atmospheric pressure. copd is the most common cause of secondary pneumothorax. presentation of pneumothorax in copd is often atypical and causes excessive morbidity and mortality. ■ a high incidence of pneumothorax occurs in aids patients, related to pcp and the mechanical ventilation and bronchoscopy that are commonly required in these patients. in this group of patients, pneumothorax is frequently bilateral, recurrent, and unresponsive to conservative therapy. ■ traumatic pneumothorax, which occurs as a result of a penetrating injury, may occur with closed chest trauma. ■ ptx is a common complication of mechanical ventilation. interstitial emphysema is a harbinger of this complication. high peak and mean airway pressures, peep, use of volume-cycled ventilators, intubation of right mainstem bronchus, chronic airways obstruction, and aspiration pneumonia increase the incidence. ■ pneumothorax ex vacuo, sports-related pneumothorax, and barotrauma unrelated to mechanical ventilation are interesting conditions that are not common, but they are important to be aware of. ■ simultaneous bilateral pneumothoraces and "shifting pneumothoraces" are rare but interesting conditions and may develop because of persistent pleuro-pleural communication called iatrogenic buffalo chest. ■ an immediate postbronchoscopy chest radiograph is rarely useful but should be done in certain groups of patients (e.g., comatose, mentally retarded, ventilated, or with respiratory compromise). ■ ptx induced by a misplaced small-bore feeding tube is not uncommon. clinical signs may be misleading. ■ a visceral pleural line with absence of lung markings peripherally is the classic radiographic sign of ptx. when the chest radiograph is obtained in the supine position, the signs are very different. ■ the approach to management of a ptx is dictated by the clinical condition rather than merely the size of the ptx, which is best estimated by ct scan of the chest. expectant therapy is recommended for a small psp in a stable patient. reabsorption of air is hastened by % oxygen. ■ air can be removed by simple aspiration, a small lumen catheter, or tube thoracostomy. unstable patients with large secondary ptxs must be managed with tube thoracostomy. ■ a staged approach is recommended for chest tube removal. in psp cases, the tube can be removed to hours after evidence of air leak was last seen; this waiting period is to hours in secondary ptx. ■ defi nitive management of recurrent pneumothorax or persistent leak can be done by open thoracotomy or video-assisted thoracoscopy associated with pleurodesis, pleural abrasion, parietal pleurectomy, or bullectomy. in patients unsuitable or unwilling for surgery, chemical pleurodesis via a chest tube may be done. ■ ptx tends to recur in patients with cystic fi brosis. blebectomy, without stripping the pleura, is recommended in these patients so that they may remain transplant candidates. pleurodesis should not be done in these cases because adhesion development jeopardizes subsequent lung transplantation. ■ ptx in pregnancy is managed in the usual manner initially. in view of the high recurrence rates during parturition, thoracotomy with resection of blebs should be considered. ■ re-expansion pulmonary edema is an important complication and can be prevented by slow expansion in high-risk patients. spontaneous pneumothorax cited by ransdell ht, mcpherson: management of spontaneous pneumothorax spontaneous pneumothorax ) : . cited by kirby tj, ginsberg rj: management of the pneumothorax and barotrauma thoracentesis: the plan of continuous aspiration experience with , patients pneumothorax in the icu. patient outcomes and prognostic factors current aspects of spontaneous pneumothorax nonsmoking, non-alpha -antitrypsin defi ciency-induced emphysema in nonsmokers with healed spontaneous 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with true autosomal dominant inheritance primary spontaneous pneumothorax in two siblings suggests autosomal recessive inheritance familial spontaneous pneumothorax and fbn mutations clinical and genetic studies of brit-hogg-dube syndrome pleuropulmonary pathology of birt-hogg-dube syndrome fishman's pulmonary diseases and disorders respiratory gas exchange in patients with spontaneous pneumothorax spontaneous pneumothorax in emphysema regional pulmonary function during experimental unilateral pneumothorax in the awake state regional lung function in spontaneous pneumothorax the pathophysiology of progressive tension pneumothorax pathogenesis of spontaneous pneumothorax with special reference to the ultrastructure of emphysematous bullae infl uence of height on the risk of spontaneous pneumothorax familial spontaneous pneumothorax familial primary spontaneous pneumothorax consistent with true autosomal dominant inheritance spontaneous pneumothorax in norfolk time relation between sale of cigarettes and the incidence of spontaneous pneumothorax smoking and the increased risk of contracting spontaneous pneumothorax fraser and paré's diagnosis of diseases of the chest spontaneous pneumothorax in chronic obstructive pulmonary disease: complications, treatment and recurrences diseases of the pleural space complications of attempted central venous injection performed by drug abusers man's worst enemy-himself spontaneous bilateral pneumothorax in drug addicts alternate therapy for traumatic pneumothorax in "pocketshooters pneumothorax in drug abusers: an urban epidemic? pulmonary manifestations of acquired immunodefi ciency syndrome (aids) pneumocystis carinii pneumonia with spontaneous pneumothorax: a report of three cases spontaneous pneumothorax with pneumocystis carinii infection: occurrence in patients with acquired immuno-defi ciency syndrome spontaneous pneumothoraces in aids patients receiving aerosolized pentamidine (letter) pneumocystis carinii pneumonia complicated by lymphadenopathy and pneumothorax pneumothorax in patients with immunodefi ciency syndrome cystic parenchymal changes associated with spontaneous pneumothorax in an hiv-positive patient spontaneous pneumothorax in patients with acquired immunodefi ciency syndrome treated with prophylactic aerosolized pentamidine pneumothorax with pneumocystis carinii pneumonia in aids: incidence and clinical characteristics spontaneous pneumothorax in aids patients with recurrent pneumocystis carinii pneumonia despite aerosolized pentamidine prophylaxis pneumothorax in aids safi rstein bh: spontaneous pneumothorax in pneumocystis carinii pneumonia: common or uncommon? bilateral pneumothoraces hasten mortality in aids patients receiving secondary prophylaxis with aerosolized pentamidine: association with a lower dco prior to receiving aerosolized pentamidine spontaneous pneumothorax complicating pneumonia spontaneous pneumothorax in the aids population treatment of pneumothorax in the patients with aids surgical management of spontaneous pneumothorax in patients with acquired immunodefi ciency syndrome pneumocystis carinii: an update value of bronchoalveolar lavage in the diagnosis of pulmonary infection in acquired immunedefi ciency syndrome pneumothorax in aids: case reviews and proposed clinical management simultaneous bilateral pneumothorax in an hiv-infected patient pneumothorax during pulmonary toxoplasmosis in an aids patient (letter) aids-related pneumocystis carinii pneumonia in the era of adjunctive steroids catamenial pneumothorax. a prospective study secondary spontaneous pneumothorax. catamenial pneumothorax catamenial pneumothorax and other thoracic manifestations of endometriosis major airway injury in closed chest trauma injuries to the tracheobronchial tree in closed trauma management of the pneumothorax and barotrauma an objective method to measure and manage occult pneumothorax occult traumatic pneumothorax: immediate tube thoracostomy versus expectant management occult pneumothorax in patients with abnormal trauma: ct studies ct detection of occult pneumothorax in multiple trauma patients tube thoracostomy for occult pneumothorax: a prospective randomized study of its use failure of chest x-rays to diagnose pneumothoraces after blunt trauma the occult pneumothorax: an increasing diagnostic entity in trauma validity of ct classifi cation on management of occult pneumothorax: a prospective study iatrogenic pneumothorax: etiology and morbidity. results of a department of veterans affairs cooperative study signifi cance of iatrogenic pneumothoraces management of subcutaneous emphysema, pneumomediastinum, and pneumothorax during respirator therapy pneumothorax in the intensive care unit: incidence, risk factors and outcome barotrauma in human research (editorial) the icu book incidence of pulmonary barotrauma in a medical icu pulmonary interstitial gas: first sign of barotrauma due to peep therapy pulmonary interstitial emphysema in the adult respiratory distress syndrome pneumothorax and barotrauma another complication of barotrauma (letter) pneumomediastinum: old signs and new signs pneumothorax complicating continuous ventilatory support pulmonary barotrauma complicating positive end expiratory pressure (abstract) incidence of pneumothorax and pneumomediastinum in patients with aspiration pneumonia requiring ventilatory support barotrauma: pathophysiology, risk factors and prevention the relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome evaluation of a ventilator strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome the acute respiratory distress syndrome network: ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome immediate chest roentgenography following fi beroptic bronchoscopy pneumothorax following transbronchial biopsy: low diagnostic yield with routine chest roentgenograms safety of the transbronchial biopsy in outpatients is routine chest radiography after transbronchial biopsy necessary? a prospective study of cases the value of transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions predicting risk of pneumothorax in needle biopsy of the lung pneumothorax with fi ne-needle aspiration of thoracic lesions. is spirometry a predictor? transthoracic needle aspiration in the study of pulmonary infections in patients with hiv percutaneous transthoracic needle aspiration biopsy: a comprehensive review of its current role in the diagnosis and treatment of lung tumors prediction of pneumothorax rate in percutaneous aspiration of the lung postbiopsy pneumothorax: estimating the risk by chest radiography and pulmonary function tests risk of pneumothorax not increased by obstructive lung disease in percutaneous needle biopsy traill zc, gleeson fv: delayed pneumothorax after ct-guided percutaneous fi ne needle aspiration lung biopsy incidence and risk factors of delayed pneumothorax after transthoracic needle biopsy of the lung thoracentesis: a safer needle thoracentesis: complications, patient experience and diagnostic value value of chest ultrasonography versus decubitus roentgenography for thoracentesis complications associated with thoracentesis complications associated with thoracentesis: a prospective, randomized study comparing three different methods pneumothorax after thoracentesis (letter) factors affecting the development of pneumothorax associated with thoracentesis ultrasound-guided thoracentesis evaluation of patient-related and procedure-related factors contributing to pneumothorax following thoracentesis the value of chest roentgenography in the diagnosis of pneumothorax after thoracentesis the role of abrams percutaneous pleural biopsy in the investigation of exudative pleural effusion an unusual complication of passing a narrow bore nasogastric tube pneumothorax attributable to nasogastric tube fatal hydrothorax and empyema complicating a malpositioned nasogastric tube inadvertent transbronchial insertion of narrow-bore feeding tubes into the pleural space pneumothorax from nasogastric feeding tube insertion: a report of fi ve cases pneumothorax complicating smallbore feeding tube placement incorrect positioning of nasogastric feeding tubes and the development of pneumothorax entrifl ex feeding tube: need for care in using it patient safety: effect of institutional protocols on adverse events related to feeding tube placement in the critically ill elective percutaneous dilational tracheostomy: a new simple bedside procedure; preliminary report emphysema and pneumothorax after percutaneous tracheostomy. case reports and an anatomic study spontaneous pneumothorax following partial resolution of total bronchial obstruction pneumothorax ex vacuo asymptomatic hydropneumothorax after therapeutic thoracentesis for malignant pleural effusion pleural fi brosis pulmonary barotrauma: diagnosis in american football players. three cases in three years sports-related pneumothorax pulmonary air leaks resulting from outdoor sports. a clinical series and literature review risk factors for pulmonary barotrauma in divers recommend caution in defi ning risk factors for barotrauma in divers (letter) pulmonary barotrauma and related events in divers sudden severe barotrauma from self-infl ating bag-valve devices clinically signifi cant pulmonary barotrauma after infl ation of party balloons tension pneumoperitoneum after blast injury: dramatic improvement in ventilatory and hemodynamic parameters after surgical decompression blast lung injury from an explosion on a civilian bus pulmonary barotrauma in submarine escape training bilateral pneumothorax following airbag deployment pneumomediastinum, pneumothorax and subcutaneous emphysema following the measurement of maximal expiratory pressure in a normal subject the management of spontaneous pneumothorax spontaneous pneumothorax systolic clicks due to left sided pneumothorax clicks and sounds (whoops) in left sided pneumothorax: clinical and phonocardiographic study clicks secondary to pneumothorax confounding the diagnosis of mitral valve prolapse horner's syndrome occurring with spontaneous pneumothorax horner's syndrome occurring with spontaneous pneumothorax ptosis associated with iatrogenic pneumothorax: a false lateralizing sign orriols r: a new physical sign in pneumothorax cardiovascular-pulmonary monitoring in the intensive care unit worsening oxygenation in the mechanically ventilated patient: causes, mechanisms, and early detection bilateral pneumothoraces secondary to iatrogenic buffalo chest; an unusual complication of median sternotomy and subclavian catheterization frequency and management of pneumothoraces in heart-lung transplant recipients communication between the two pleural cavities after major cardiothoracic surgery: relevance to percutaneous intervention shifting pneumothorax after heartlung transplantation bilateral pneumothoraces after unilateral transthoracic needle biopsy of a lung nodule simultaneous bilateral spontaneous pneumothorax report of cases and review of literature electrocardiogram changes suggestive of coronary artery disease in pneumothorax: their reversibility with upright posture the electrocardiographic manifestations of spontaneous left pneumothorax left tension pneumothorax mimicking myocardial ischemia after percutaneous central venous cannulation electrocardiographic changes with right-sided pneumothorax new ecg changes associated with a tension pneumothorax the radiology of abnormal intrathoracic air the value of routine expiratory chest fi lms in the diagnosis of pneumothorax comparison of upright inspiratory and expiratory chest radiographs for detecting pneumothoraces expiratory chest radiographs do not improve visibility of small apical pneumothoraces by enhanced contrast risk factors for the misdiagnosis of pneumothorax in the intensive care unit basilar pneumothorax in the supine adult the deep sulcus sign supine subpulmonary pneumothorax radiographic recognition of pneumothorax in the intensive care unit radiology in the intensive care unit thoracic computed tomography in the critically ill patient effi cacy of daily routine chest radiographs in intubated, mechanically ventilated patients role of ct in management of pneumothorax in patients with complex cystic lung disease a bedside ultrasound sign ruling out pneumothorax in the critically ill a comet-tail artefact: an ultrasound sign ruling out pneumothorax the clinician's perspective on pneumothorax management spontaneous pneumothorax management guidelines previewed determining the size of pneumothorax in the upright patient textbook of respiratory medicine pneumothorax size: correlation of supine anteroposterior with erect posteroanterior chest radiographs chest radiograph-a poor method for determining the size of a pneumothorax pneumothorax: a therapeutic update spontaneous alveolar rupture at birth northfi eld tc: oxygen therapy for spontaneous pneumothorax treatment of pneumothorax by simple aspiration a place for aspiration in the treatment of spontaneous pneumothorax results of simple aspiration of pneumothoraces spontaneous pneumothorax (sp): comparison of simple aspiration and tube thoracostomy a spring-loaded needle for emergency evacuation of pneumothorax the diffi cult pneumothorax manual aspiration versus chest tube drainage in fi rst episodes of primary spontaneous pneumothorax. a multicenter, prospective, randomized pilot study simple aspiration versus chest-tube insertion in the management of primary spontaneous pneumothorax: a systematic review chest tubes: indications, techniques, management and complications recurrent re-expansion pulmonary edema chest tube removal: end-inspiration or end-expiration? delayed pulmonary perforation: a rare complication of the tube thoracostomy complications of percutaneous dart therapy in management of pneumothorax treatment of pneumothoraces utilizing small caliber chest tubes role of small caliber chest tube drainage for iatrogenic pneumothorax pigtail tube drainage in the treatment of spontaneous pneumothorax the thoracic vent: clinical experience with a new device for treating simple pneumothorax use of a pleural catheter for the management of simple pneumothorax spontaneous pneumothorax spontaneous pneumothorax in norfolk management of secondary spontaneous pneumothorax. there is confusion in the air tetracycline pleurodesis: adios, farewell, adieu talc pleurodesis for the treatment of pneumothorax and pleural effusion lung function - years after treatment of idiopathic spontaneous pneumothorax with talc poudrage or simple drainage surgical experience in the management of spontaneous pneumothorax pleurectomy through the triangle of auscultation pleurectomy for recurrent pneumothorax (letter) a limited axillary thoracotomy as primary treatment for recurrent spontaneous pneumothorax thoracoscopic ablation of blebs in the treatment of recurrent or persistent spontaneous pneumothorax nd:yag laser pleurodesis through thoracoscopy: new curative therapy in spontaneous pneumothorax videothoracoscopic ligation of bulla and pleurectomy for spontaneous pneumothorax talc pleurodesis during videothoracoscopy for pneumocystis carinii pneumonia-related pneumothorax. a new technique treatment of complicated spontaneous pneumothorax by simple talc pleurodesis under thoracoscopy and local anesthesia pleural abrasion: a new method of pleurodesis colt hg: thoracoscopy: new frontiers bilateral video-assisted thoracoscopic surgery for bilateral spontaneous pneumothorax bilateral videoassisted thoracoscopic surgery in the supine position for primary spontaneous pneumothorax treatment of aids-related spontaneous pneumothorax. a decade of experience heart-lung transplantation: lessons learned and future hopes treatment of pneumothorax in cystic fi brosis in the era of lung transplantation (editorial) recurring catamenial pneumothorax treated with a gn-rh analogue catamenial pneumothorax catamenial pneumothorax spontaneous pneumothorax complicating pregnancy-case report and review of the literature ama commission on emergency medical services: medical aspects of transportation board commercial aircraft commercial air transportation of a patient recovering from pneumothorax severe acute respiratory distress syndrome complicated by spontaneous pneumothorax sars, pneumothorax and our response to epidemics lymphangioleiomyomatosis. management of pneumothorax in lymphangioleiomyomatosis. effects on recurrence and lung transplantation complications persistent air leak in spontaneous pneumothorax-clinical course and outcome a prospective algorithm for the management of air leaks after pulmonary resection autologous "blood patch" pleurodesis for persistent pulmonary air leak autologous blood patch pleurodesis for secondary spontaneous pneumothorax with persistent air leak intrapleural administration of a large amount of diluted fi brin glue for intractable pneumothorax medical management and therapy of bronchopleural fi stulas in the mechanically ventilated patient pectoral myoplasty for recurrent pneumothorax: an extrathoracic solution to an intrathoracic problem the treatment of refractory pneumothorax in diffuse panbronchiolitis by intravenous administration of coagulation factor xiii concentrate closure of a bronchopleural fi stula using bronchoscopic placement of an endobronchial valve designed for the treatment of emphysema acute pulmonary edema following treatment of spontaneous pneumothorax with excessive negative intrapleural pressure clinical analysis of reexpansion pulmonary edema unilateral pulmonary edema resulting from treatment of spontaneous pneumothorax experimental pulmonary edema following re-expansion of pneumothorax evidence for increased permeability in reexpansion pulmonary edema changes in pulmonary microvascular permeability accompanying re-expansion oedema: evidence from dual isotope scintigraphy bilateral reexpansion pulmonary edema following unilateral pleurocentesis reexpansion hypotension: a complication of rapid evacuation of prolonged pneumothorax re-expansion pulmonary edema: a potentially serious complication of delayed diagnosis of pneumothorax peep ventilation-the treatment for life-threatening re-expansion pulmonary edema tension pneumothorax complicating smallcaliber chest tube insertion baumann mh, strange c: treatment of spontaneous pneumothorax. a more aggressive approach? management of spontaneous pneumothorax on behalf of the bts pleural disease group, a subgroup of the bts standards of care committee: bts guidelines for the management of spontaneous pneumothorax the authors thank faroque khan, mb, macp, for valuable advice and for contributing most of the radiographs; dvorah balsam, md, for fig. - ; and leonard octavius barrett, md, facs, chief of thoracic surgery at numc, for his comments regarding the surgical therapy. key: cord- -e fvj l authors: hamm, h.; fabel, h.; bartsch, w. title: the surfactant system of the adult lung: physiology and clinical perspectives date: journal: clin investig doi: . /bf sha: doc_id: cord_uid: e fvj l pulmonary surfactant is synthesized and secreted by alveolar type ii cells and constitutes an important component of the alveolar lining fluid. it comprises a unique mixture of phospholipids and surfactant-specific proteins. more than years after its first biochemical characterization, knowledge of the composition and functions of the surfactant complex has grown considerably. its classically known role is to decrease surface tension in alveolar air spaces to a degree that facilitates adequate ventilation of the peripheral lung. more recently, other important surfactant functions have come into view. probably most notable among these, surfactant has been demonstrated to enhance local pulmonary defense mechanisms and to modulate immune responses in the alveolar milieu. these findings have prompted interest in the role and the possible alterations of the surfactant system in a variety of lung diseases and in environmental impacts on the lung. however, only a limited number of studies investigating surfactant changes in human lung disease have hitherto been published. preliminary results suggest that surfactant analyses, e.g., from bronchoalveolar lavage fluids, may reveal quantitative and qualitative abnormalities of the surfactant system in human lung disorders. it is hypothesized that in the future, surfactant studies may become one of our clinical tools to evaluate the activity and severity of peripheral lung diseases. in certain disorders they may also gain diagnostic significance. further clinical studies will be necessary to investigate the potential therapeutic benefits of surfactant substitution and the usefulness of pharmacologic manipulation of the secretory activity of alveolar type ii cells in pulmonary medicine. summary. pulmonary surfactant is synthesized and secreted by alveolar type ii cells and constitutes an important component of the alveolar lining fluid. it comprises a unique mixture of phospholipids and surfactant-specific proteins. more than years after its first biochemical characterization, knowledge of the composition and functions of the surfactant complex has grown considerably. its classically known role is to decrease surface tension in alveolar air spaces to a degree that facilitates adequate ventilation of the peripheral lung. more recently, other important surfactant functions have come into view. probably most notable among these, surfactant has been demonstrated to enhance local pulmonary defense mechanisms and to modulate immune responses in the alveolar milieu. these findings have prompted interest in the role and the possible alterations of the surfactant system in a variety of lung diseases and in environmental impacts on the lung. however, only a limited number of studies investigating surfactant changes in human lung disease have hitherto been published. preliminary results suggest that surfactant analyses, e.g., from bronchoalveolar lavage fluids, may reveal quantitative and qualitative abnormalities of the surfactant system in human lung disorders. it is hypothesized that in the future, surfactant studies may become one of our clinical tools to evaluate the activity and severity of peripheral lung diseases. in certain disorders they may also gain diagnostic significance. further clinical studies will be necessary to investigate the potential therapeutic benefits of surfactant substitution and the usefulness of pharmacologic manipulation of surfactant (=surface active agent) is a material capable of lowering surface tension. the existence of a pulmonary surface active substance was first postulated by van neergard in [ ] . he found the calculated surface tension of the alveolar air-liquid interface to be too high to prevent endexpiratory alveolar collapse and atelectasis. therefore, he predicted the presence of an agent able to exert and maintain a low alveolar surface tension as a prerequisite for the adequate ventilation of the peripheral airways and for normal lung function. it was almost another years until pattle [ ] and clements [ ] found a substance in lung edema fluid and in lung extracts that indeed lowered the surface tension dramatically. the material was found to be composed of a phospholipid and a protein fraction. in , avery and mead [ ] drew attention to the role of a surfactant deficit in hyaline membrane disease (irds) of premature infants. thus, clinical relevance and a first therapeutic perspective became apparent in surfactant research. more than another years later, the understanding of the pulmonary surfactant system has grown tremendously. the precise composition of the surfactant is known down to the genetic codes of surfactent-specific proteins, making the industrial production of different surfactants a realistic prospect. much has been learnt about surfactant synthesis in the alveolar type ii cell and its regulation and metabolism. intratracheal surfactant re-placement is on the verge of becoming a routine life-saving therapy in irds. accumulating evidence suggests that in adult respiratory distress syndrome (ards) a similar disturbance of the surfactant system is involved which may possibly be ameliorated by substitution therapy. in recent years, surfactant functions other than the maintenance of normal lung function have come into view. perhaps most important among these findings is that surfactant plays a major role in pulmonary defense mechanisms and local immunomodulation. therefore, the role of surfactant in different lung diseases and in the defense against various environmental impacts on the respiratory tract is attracting growing attention. the purpose of this article is to present a review of the current knowledge on the pulmonary surfactant system with emphasis on possible clinical implications and future perspectives for adult pulmonary medicine. surfactant is a complex mixture of lipids and proteins ( fig. ) . additionally, carbohydrate components are found in both the lipid [ ] and the protein fractions [ ] , but their precise functions remain to be established. most of the present data on surfactant composition is based on analyses of lung lavages [ , ] , which are thought to reflect adequately the situation in the alveolar lining fluid. however, it has to be kept in mind that lavage specimens may to some degree be contaminated with lipids of nonsurfactant origin, e.g., lipids stemming from cell membranes or lipids secreted by airway epithelial cells [ ] . fewer data exist on the intracellular surfactant composition, e.g., in the lamellar bodies of alveolar type ii cells. however, the surfactant composition of the intra-and extracellular compartments seems to be similar [ , ] . the pool size of extracellular surfactant has been investigated in animals and ranges from about - mg/kg body weight in adults. mature newborns have -to -fold higher values [ ] . assuming similar values in man, a kg person would thus have an estimated alveolar surfactant pool of approximately . - . g. however, there are no available data on the normal surfactant pool size in man, and there may possibly be considerable interindividual variations. lipids are the major surfactant component by weight (fig. ) . they make up about %- % of whole isolated surfactant [ ] . approximately % of this lipid fraction consists of a mixture of phospholipids. the remaining % are composed of other lipids, mainly cholesterol, which seems to be blood-derived and is of uncertain functional significance [ ] . phospholipids combine hydrophobic and hydrophilic properties and are therefore involved in the coating of boundary areas and surfaces. they possess the ability to achieve low surface tensions at air-liquid interfaces and support, for example, the formation of micelles and lamellae. however, phospholipids not only have structural functions but may in many ways be involved in different dynamic biological processes [ ] . the phospholipid composition of human lung surfactant is shown in fig. . in other mammals, this distribution is very much the same. none of these phospholipids is unique to surfactant, but in contrast to the phospholipid profile in other organs, the relative concentrations of phospatidylcholine and phosphatidylglycerol are higher. surfactants of amphibians and birds lack phosphatidylglycerol, suggesting that this phospholipid was introduced late in evolution [ ] . in human fetal lung development, phosphatidylglycerol becomes detectable only late in pregnancy and may serve as an indicator of fetal pulmonary maturity [ ] , although it does not seem to contribute to the reduction of alveolar surface tension [ ] . phosphatidylcholine accounts for approximately % of total surfactant phospholipids and for about two-thirds of whole surfactant (fig. ). approximately % of its fatty acids are saturated under normal conditions [ ] , the most common saturated acid being palmitic acid. dipalmitoylphosphatidylcholine (dppc) is the surfactant component which is predominantly responsible for the reduction of alveolar surface tension [ ] . its hydrophilic (choline) residue associates with the alveolar liquid phase while the hydrophobic (palmitic acid) residue reaches into the air phase [ ] . pattle [ ] first noted that a protein component in surfactant material seemed necessary for proper surfactant function. in , king et al. [ ] could, for the first time, demonstrate the existence of specific surfactant proteins. by weight, protein accounts for approximately % of whole isolated surfactant. about % of this protein portion consists of contaminating serum proteins while only % are made up by the surfactant-specific proteins (fig. ) . four surfactant specific proteins (sp) have so far been identified (table ) . a simplified nomenclature of these proteins has recently been proposed [ ] and is increasingly being accepted, despite certain difficulties and disadvantages [ ] . the first three proteins are simply termed surfactant protein a, b, and c in descending rank of their molecular masses. more recently, a fourth protein called sp-d has been described. the primary structures of surfactant proteins a, b, and c have been identified, and their commercial production by modern techniques of molecular biology is possible [ , ] . sp-a is the major surfactant protein in regard to relative abundance as well as size. in vivo, sp-a is found as a group of isoforms with a molecular weight ranging from approximately to kda, depending on the extent of posttranslational modifications [ ] . it has structural homologies with clq, a protein of the classical complement path-way [ , ] , and contains a collagen-like domain [ ] which is the probable association site of sp-a monomeres. after alveolar secretion, sp-a is predominantly :found as a multimeric molecule resembling a flower bouquet [ ] . recent evidence suggests that in man, there are at least two different sp-a subtypes encoded on two separate genes [ , ] . this may have structural implications for the arrangement of the naturally occurring sp-a multimeres [ ] , but the functional significance of these findings awaits further clarification. sp-a seems to play an important role in the formation of a preliminary alveolar surfactant layer called tubular myelin which is found immediately after alveolar secretion [ , , ] . in concert with sp-b and sp-c, sp-a probably enhances the surface activity of the surfactant monolayer [ ] . however, the importance of the presence of sp-a regarding this aspect of surfactant function is still debated [ ] . sp-a seems to be unique among the surfactant specific proteins as it apparently has additional functions in the surfactant complex apart from influencing surface activity. the structural homologies to the complement protein clq stimulated investigations of possible common biological functions of these two proteins. indeed, it was found that the presence of sp-a enhances the phagocytosis of opsonized sheep erythrocytes by macrophages and monocytes in a concentration-dependent manner [ ] . furthermore, sp-a is able to increase the phagocytosis of staphyloccocus aureus [ ] , herpes simplex virus type [ ] , and colloidal gold particles [ ] . thus, sp-a seems to play an important role in the local host defense mechanisms of the lung. another probable function of sp-a is its ability to regulate the alveolar surfactant concentration. in vitro, sp-a inhibits the secretion of phosphatidylcholine from cultured alveolar type ii cells [ ] and enhances the uptake of surfactant lipids [ ] . possibly, these sp-a effects are mediated by an alveolar type ii cell receptor [ ] . sp-b is a small protein of a molecular weight of approximately kda under reducing conditions [ ] . although it is very hydrophobic, it remains soluble in aqueous solutions to some extent. sp-b forms thiol-dependent oligomers of different sizes with the dimer probably being the most common form in vivo [ , ] . it has no known immunomodulatory or regulatory function but seems to be a key protein in the formation of a functionally optimal and stable surfactant monolayer on the alveolar surface [ , , ] . also, sp-b seems to play a role in the formation of tubular myelin in cooperation with sp-a [ ] . its amino acid sequence contains high amounts of cysteine, suggesting that disulfide bridges may be important to the role of this protein in the surfactant complex [ ] . indeed, intramolecular disulfide bridges seem to contribute to the structural properties of the sp-b polypeptide chain, and an intermolecular disulfide link may explain the frequent natural occurrence of sp-b dimers [ ] . furthermore, sp-b has a strong positive net charge (at physiological ph) which seems to be important to the interaction between sp-b and the anionic phospholipids [ , ] . however, the structural interaction between sp-b and other surfactant components still has to be more clearly defined. sp-c is a very small protein with a molecular weight of approximately kda. it is extremely hydrophobic, which is in part due to a high content of the hydrophobic amino acid valine [ ] . it is therefore only soluble in organic solvents. small size, hydrophobicity, and low immunogenicity make the investigation of this protein a difficult task. as far as its functional role in the surfactant complex is presently understood, it contributes to the formation and stabilization of the alveolar surfactant monolayer in cooperation with sp-b [ ] . probably, sp-c has no role in tubular myelin formation [ ] . the molecular structure and most of the properties of sp-c are substantially different from sp-b, suggesting that both proteins have separate roles in the surfactant complex. indeed, in vitro studies indicate that sp-c may be more important to the adsorption of phospholipids, while sp-b supports the reduction of surface tension more effectively [ ] . there seem to be no similarities of sp-c to other proteins of known functions that would suggest an additional role of sp-c [ ] . sp-d is a collagenous glycoprotein synthesized by alveolar type ii cells which has only recently been described [ , ] . the question still remains whether this protein is a true surfactant protein or a protein that is synthesized independently of the surfactent pathway and is only functionally associated with the surfactant complex. in rat bronchoalveolar lavage (bal) fluids, the total sp-d content was found to be approximately % of that of sp-a [ ] . it has a molecular size of approximately kda (reduced) and appears to build polymeric complexes comprised of the -kda subunits. sp-d has certain structural similarities with sp-a and probably is readily soluble in the alveolar milieu. like sp-a, sp-d does not contribute to the surface activity of the surfactant complex [ ] . its function is still hypothetical. structural analogies with proteins like mannosebinding protein, conglutinin, and sp-a suggest that it may have a role in local host defense [ ] , perhaps by functioning like an opsonin. a recent study indicates that sp-d may also have regulatory functions by counteracting the inhibitory effects of sp-a on phospholipid secretion by alveolar type ii cells [ ] . the site of alveolar surfactant synthesis and secretion is the cuboidal alveolar type ii cell which covers less than % of the alveolar surface. there is evidence to suggest that surfactant synthesis and secretion in the lung are not exclusively restricted to the alveolar type ii cell but that they may also take place in higher parts of the airways, for instance in clara cells [ , ] and possibly even in the tracheal epithelium [ ] . this may contribute to normal mucociliary function [ ] . however, the significance of these findings awaits further investigation. the alveolar surfactant components are synthesized and assembled in the endoplasmic reticulum of alveolar type ii cells and then transferred to the golgi apparatus prior to forming socalled lamellar bodies in the cytoplasm (fig. ) . this process has been followed by autoradiography and by immunocytochemistry for phospholipids and sp-a [ ] . as shown by transmission electron microscopy [ ], lamellar bodies undergo a process of maturation while travelling through the cytoplasm and are eventually transported into the alveolar space by merocrine secretion after fusion with the cell membrane. here, the lamellar bodies rapidly transform into tubular myelin, an intermediate surfactant material that is composed of a lattice of highly ordered tubules. sp-a is thought to play a role in the formation of tubular myelin and has recently been located at the corners of the tubular framework by immune electron microscopic techniques [ ] . another recent in vitro study [ ] suggests that in tubular myelin formation the presence of sp-b but not of sp-c is necessary in addition to sp-a. finally, this material is spread to reach its definitive form, the surfactant monolayer (figs. , ) . pulmonary surfactant is not a static accessory of the alveolus but undergoes a constant dynamic process of turnover and metabolism. this review will present only a short summary of the present knowledge on these processes. for more detailed information, the interested reader is referred to a number of recently published reviews which emphasize these aspects [ , , , , - , , , ] . basically, all phospholipid components of surfactant seem to be synthesized and incorporated into the lamellar bodies within the alveolar type ii cell. this is supported by findings that the phospholipid composition of isolated lamellar bodies is virtually identical to that of bal [ ] . dppc is the best studied phospholipid regarding intracellular synthesis pathways. it is de novo synthesized from blood-derived phospholipid precursors and can probably also be remodelled from unsaturated or recycled phosphatidylcholine. less evidence exists on the synthesis and precise pathways of secretion of the surfactant-specific proteins. alveolar sp-a gene expression is restricted to the alveolar type ii cell as shown by in situ hybridization [ ] . it is synthesized as a preprotein of approximately kda and a second variant of approximately kda. different posttranslational modifications of this protein like sialylation, acetylation, and sulfation have been described [ ] . single sp-a monomeres are oligomerized to hexameric bundles resembling flower bouquets [ ] . probably, surfactant proteins and the phospholipids are all assembled and introduced into the lamellar bodies within the type ii cell before secretion [ ] . however, many details of this process remain to be investigated. for instance, it is not yet quite certain whether all of the individual proteins are introduced into the lamellar bodies or if some of them join the surfactant complex after secretion into the alveolar space [ ] . fur-thermore, no evidence exists on the possible association of sp-d with intracellular lamellar bodies and their secretion. surfactant synthesis has been found to be influenced by a number of different stimuli [ ] (table ). glucocorticoids, camp, oestrogens, and thyroid hormones, among others, have been described as enhancing surfactant synthesis. however, the in vivo role and importance of these factors is not clearly determined. some of these stimuli, e.g., glucocorticoids, may vary in their effects depending on dose and time [ ] , and there may be different pathways for the regulation of surfactant phospholipid and protein synthesis [ ] . a recent in vivo study [ ] has investigated the influence of exogenously administered glucocorticoids and of adrenalectomy on the regulation of surfactant proteinsl glucocorticoid administration resulted in the accumulation of mrnas of surfactant proteins sp-a, b, and c, with the highest response being sp-b mrna. however, adrenalectomy did not change the mrna levels but decreased the total pulmonary sp-a levels. this study demonstrates that exogenous glucocorticoids enhance surfactant protein synthesis and suggests that adrenal hormones may have a role in the pulmonary response to stress. on the other hand, endogenous steroids under normal conditions do not seem to be important to baseline surfactant protein synthesis at the mrna level but may to a minor degree contribute to translational or posttranslational processing. the inhibition of surfactant production is possibly controlled by a feedback mechanism involving a surfactant protein [ ] . surfactant secretion into the alveolar space is accomplished by exocytosis of the lamellar bodies. experimental data suggest that various stimuli like high volume lung inflation and increased ventilation rate, adrenergic agents, estrogens, and thyroid hormones may enhance surfactant secretion, while beta-blockade and an sp-a-dependent feedback mechanism have inhibitory effects [ , , ] (table ). sp-d seems to counteract the inhibitory effect of sp-a [ ] . again, the in vivo significance of these experimental data remains under discussion. turnover studies with different labeled surfacrant phospholipids after secretion have demonstrated half-lives of between and h [ , ] . the fate of secreted surfactant material seems to be determined by five mechanisms: -intraalveolar catabolism -phagocytosis and degradation by alveolar macrophages [ , ] -removal by the mucociliary escalator -recycling into the alveolar type ii cell -redistribution into other surrounding tissue clearance studies in rabbits [ ] have shown that approximately % of radiolabeled phosphatidylcholine is removed via the upper airways in h, suggesting that this pathway is only of minor importance. further work by the same group [ ] supports evidence that most surfactant material is probably redistributed into the surrounding tissue or is recycled into alveolar type ii cells. many aspects of the regulation of these processes remain to be clarified. sp-a has been shown to enhance the uptake of liposomes into the alveolar type ii cell [ ] . this process is probably mediated by an sp-a receptor on the epithelial surface of type ii cells, which also controls the reuptake of sp-a [ ] . s u r f a c t a n t a n d l u n g f u n c t i o n this review will only give a short introduction into the role of surfactant in alveolar stability and in the work of breathing. the interested reader is referred to a number of articles [ , , , , ] which discuss these aspects in detail. the lowering of surface tension is the best known function of surfactant material and led to its discovery. however, this classical surfactant function probably was not the initial reason for the development of this material in evolution since animals with less complex lung architectures and thus without a need for surface-tension lowering agents already possess a pulmonary surfactant system [ ] . surfactant material has been shown to reduce the surface tension at the alveolar air-liquid interface down to levels that are required for normal ventilation of the peripheral lung. it reduces the respiratory work load throughout the respiratory cycle and improves lung compliance. the most important surfactant component in this regard is saturated phosphatidylcholine. other surfactant components like sp-a and more importantly, sp-b and sp-c, have been described to enhance the surface activity of this phospholipid. the hydrophobic saturated fatty acids of saturated phosphatidylcholine are aligned in parallel and rise out of the liquid phase into the alveolar air. the hydrophilic choline residues are packed in the aqueous phase of the alveolus. this arrangement remains stable through ventilatory compression and extension of the alveolus and reduces the strong alveolar cohesive forces close to zero. thus, alveolar surfactant material successfully prevents alveolar collapse and atelectasis as observed in surfactant-deficient lungs, e.g., in irds. surfactant material may contribute to pulmonary defense mechanisms and local immunomodulation in four different ways: -support of nonspecific defense mechanisms -direct bactericidal properties of surfactant components -immunomodulatory action on lymphocytes -augmentation of macrophage activities in the alveolar milieu surfactant is part of the alveolar and bronchial epithelial lining fluid which is thought to act as a nonspecific barrier against adhesion and invasion of microorganisms. also, surfactant has antioxidant activities [ ] which may contribute to the protection of the alveolar epithelium by scavenging toxic (reduced) oxygen species. several reports have addressed the possible antibacterial properties of surfactant material. studies of rat alveolar lining material identified long-chain free fatty acids as bactericidal surfactant components and demonstrated their antibiotic action against pneumococci in vitro [ ] . however, studies of human alveolar lining material obtained by bal could not demonstrate antibacterial effects against pneumococci or haemophilus influenzae [ ] . the in vivo significance of these findings is still uncertain, and the antibiotic effect of surfacrant remains controversial. lung surfactant has been shown to influence the activities of lymphocytes and macrophages. these influences are probably of significant in vivo importance for the maintenance of a balance between excessive immune responses and favorable cellular defense mechanisms. surfactant suppresses the activation and the proliferative response of lymphocytes to various stimuli in a dose-dependent manner [ , , ] . this suppressor activity is contained in the lipid fraction of surfactant [ ] . the major surfactant phospholipids phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol were shown to be responsible for this immunoregulatory effect. the mechanism of this effect has not yet been clarified but may be related to changes in cell membrane dynamics [ ] . surfactant exerts its effects only on the resting lymphocyte or on the early stage of lymphocyte activation. activated lymphocytes are not affected. the suppression seems to be largely irreversible, even after the removal of surfactant material from the medium. the inhibitory effects of surfactant have been shown for a variety of lymphocyte activities such as proliferation, differentiation, immunoglobulin production, and natural killer cell activity [ , , , , ] . nearly all studies on the influence of surfactant on alveolar macrophage activity report an enhancement of macrophage functions. in detail, it has been shown that surfactant material supports phagocytosis [ , ] and intracellular killing [ , ] of staphylococcus aureus and the phagocytosis of herpes simplex virus type [ ] . it may also enhance the migration of alveolar macrophages [ ] and their cytotoxicity against tumor cells [ ] . it has to be stressed that these studies report the results of in vitro investigations mostly with animal material. thus, the significance of these findings for normal human lung defense mechanisms is not yet definitely established. in general, alveolar macrophages are thought to be less active than blood monocytes or macrophages residing in other tissues [ , ] . recent studies [ , , ] have shown that sp-a is probably responsible for the enhancement of alveolar macrophage functions as isolated sp-a had the same stimulant effect on macrophages as whole surfactant, while surfactant lipids had no effect [ ] . probably, this macrophage stimulation is mediated by a macrophage receptor which binds sp-a. the specific binding and uptake of sp-a by macrophages has been demonstrated by electron microscopy [ ] . a recent report [ ] suggests that the sp-a receptor may be identical with the leukocyte clq receptor, which is a tempting hypothesis since sp-a has structural homologies with the complement protein clq. surfactant material, as part of the alveolar epithelial lining fluid, is thought to represent a first defense line against inhaled particles and gases reaching the alveolar space. apart from building a "mechanical" barrier, it probably plays an active role in the elimination of foreign particles, e.g., by enhancing macrophage activities and by exerting antioxidant effects [ ] against a variety of oxidant gases. on the other hand, the surfactant system itself may be damaged by inhaled particles and gases. a number of studies have been published addressing the impact of air pollutants and other toxicants on the pulmonary surfactant system. varying study designs such as the use of different animal or in vitro models and different doses and exposure times have led to divergent and sometimes conflicting results. furthermore, some of the studies focussing only on phospholipid alterations leave some doubt as to whether these changes are truly related to surfactant abnormalities or rather reflect other mechanisms like unspecific cell membrane damage. it certainly has to be kept in mind that the surfactant system is only one of the potential targets of pollutants and toxicants reaching the lung periphery, and hazardous effects on the surfactant system may be of a direct or indirect or as yet unknown nature. this review will only give a short overview of the known or proposed effects of some pollutants and toxicants on the surfactant system. for further information, the reader is referred to a number of reviews and articles focussing on this subject [ , , , , ozone is a major component of photochemical smog. it acts as a highly aggressive oxidant and leads to the transudation of blood proteins and to edema in the alveolar space even at comparatively low concentrations. furthermore, chronic low-dose ozone exposure is known to increase the susceptibility to pulmonary infections. it is believed that the pulmonary toxicity of ozone is at least in part due to impairment of the surfactant system [ ] . several reports support this hypothesis. in rats exposed to . ppm of ozone for days, giant lamellar bodies were observed in the alveolar type ii cells after day . this could suggest that ozone may impair surfactant secretion [ ] . short-term exposure ( . h) of isolated rat alveolar type ii cells to variable amounts of ozone resulted in impaired intracellular synthesis of phospholipids [ ] . exposure of bonnet monkeys to variable low-dose concentrations of ozone for - days led to changes of fatty acid compositions and a marked increase in phosphatidylcholine levels in lung lavage fluids [ ] . short-term ( - h), high dose ( ppm) ozone exposure of rats resulted in ultrastructural alterations of intracellular lamellar bodies and inhibited proper unfolding of secreted lamellar body membranes in the alveolar space [ ] . in vitro ozone exposure of sp-a led to impairments of important physiologic sp-a functions like self-association and sp-a-mediated lipid aggregation [ ] . these studies sugest that ozone even at low levels leads to changes in surfactant metabolism and secretion and to alterations of composition and properties of the secreted surfactant material. thus, it seems likely that the pulmonary toxicity of ozone is in part due to impairment of the surfacrant system. one of the many remaining questions is whether ozone-induced surfactant abnormalities are also involved in the increased susceptibility to pulmonary infections of chronically exposed individuals. the majority of atmospheric nitrogen oxides is derived from natural sources. however, in urban areas, nitrogen oxides from energy utilization largely determine air pollution levels with these gases [ ] . the pulmonary toxicity of nitrogen dioxide is similar to that of ozone, inducing free radical reactions and lipid autoxidation [ ] . probably, both these air pollutants have synergistic toxic effects on the lung. short-term exposure ( h) of rats to high levels ( ppm) of nitrogen dioxide resulted in phosphatidylcholine and phosphatidylglycerol accumulation in lung tissue with a peak at h postexposure. incorporation studies suggested that this increase was due to enhanced phospholipid synthesis [ ] . long-term exposure ( months) to low levels ( . ppm), by contrast, led to a significant decrease in the lung lipid content and changes in the phospholipid fatty acid composition [ ] . these studies may indicate that the acute effect of nitrogen dioxide on alveolar type ii cells is enhanced surfactant lipid synthesis, while chronic low-dose exposure leads to a decrease in surfactant synthesis capacity. however, the evidence is still scarce and not all observed phospholipid changes are necessarily related to the surfactant system. further studies are necessary to define more precisely the possible impact of nitrogen dioxide on alveolar type ii cells and surfactant material. also, in view of a more realistic approach to urban air pollution, it seems important to learn more about the co-toxicity of ozone and nitrogen dioxide. the toxicity of hyperbaric oxygen or oxygen at high concentrations is well-known and represents one of the problems of mechanical high oxygen ventilation, e.g., in intensive care units. the toxic effect is due to aggressive oxygen-derived free radicals which attack various cell constituents and probably also the surfactant system. in detail, it has been found that rabbits exposed to % oxygen for h exhibited a marked decrease in phosphatidylcholine synthesis and cell lipid content followed by a recovery to normal patterns and subsequently supranormal levels beginning days postexposure [ ] . the same group [ ] showed that intratracheal surfactant substitution significantly diminished the progression of hyperoxic injury. in rats exposed to % oxygen for h, increased levels of phosphatidylcholine and sp-a were found in lung lavages [ . it was concluded that hyperoxic lung injury is not due to intraalveolar decreases of these two major surfactant components. however, in another animal study dppc was decreased and the pg:pi ratio was markedly lower than baseline values after - days exposure to % oxygen. longer periods of exposure resulted in a further drop of dppc values [ ] . pulmonary oxygen toxicity does not seem to be consistently related to changes of surface tension measured in lung lavage fluids of exposed animals [ ] . in conclusion, hyperoxic lung injury may be associated with alveolar type ii cell changes in surfactant biosynthesis. however, different studies have found partly conflicting results, and the way in which hyperoxic lung injury contributes to quantitative and functional changes of alveolar surfactant is still poorly understood. it should also be remembered that the oxidant attack of oxygen is not limited to type ii cells or surfactant, and thus, some of the described phospholipid changes may not exclusively reflect surfactant abnormalities. cigarette smoke is a complex mixture of particles and gases. a reduced yield of phospholipids from bal fluids of smokers compared with nonsmokers has been described [ ] . this difference was interpreted to be partly due to lower lavage fluid recovery from smokers related to their known tendency to bronchoconstriction. additionally, it was thought to reflect the enhanced phagocytosis activity of alveolar macrophages [ ] . another group found no such quantitative differences between smokers and nonsmokers but described a decreased phospholipid/protein ratio in smokers [ ] . in rats exposed to cigarette smoke, a decrease of surfactant material in lung lavages was found. additionally, a progressive injury of alveolar type ii cells was observed over time as determined by electron microscopy, indicating that type ii cells and therefore possibly the surfactant system may be one of the targets of cigarette smoke in the peripheral lung [ ] . in vitro studies showed that smoke particles but not the gas phase of cigarette smoke interacted with a surface film of surfactant and altered its surface active properties in such a way that the maximum surface area was reduced, but the minimum surface tension was increased [ ] . this may possibly contribute to altered mechanical properties of the lungs of smokers. in conclusion, only a few studies have so far investigated the possible impacts of cigarette smoke on the surfactant system. thus, our knowledge about the effects of this important pulmonary toxicant is still very fragmentary and awaits further investigations. smoke generated from the burning of polyurethane foam has been shown to increase significantly the total phospholipid content of lung lavages from rats after short-term exposure [ ] . diesel exhausts were shown to induce pulmonary phospholipidosis in rats [ ] . in another study, short-term exposure of rats to mg/m diesel exhaust resulted in an increased labeling index in type ii cells and enhancement of whole lung d n a synthesis [ ] . additionally, lavage phospholipid values were increased, and there was evidence of reversible alterations of fatty acid and phospholipid metabolism. hydrogen sulfide is an irritant gas with toxic effects on the respiratory tract. an animal study suggests that higher doses impair the ability of sur-factant to lower surface tension. however, this does not seem to be due to a direct effect of hydrogen sulfide on surfactant material but due to surfactant inhibitors in the pulmonary edema fluid induced by hydrogen sulfide [ ] . dusts, especially those with a high fibrogenic potential, seem to stimulate the production of surfactant [ ] . silica (usually quartz dust) inhalation leads to a striking increase in the alveolar surfactant phospholipid and sp-a content [ , ] . recently, the accumulation of sp-d has also been reported [ ] . morphologically, these observations are accompanied by type ii cell hypertrophy and hyperplasia [ , ] . the lungs of silica-exposed animals share common features with alveolar proteinosis in man so that they may be used as animal models of this disease. asbestos inhalation provokes a very similar accumulation of surfactant material in the alveolar space [ , ] . the heavy metal cadmium is a known pulmonary toxicant. the main sources of human exposure are cigarette smoke, automobile emissions, and metal-processing plants. in rats, the inhalation of cadmium chloride led to an early decrease of phospholipids in lung lavage, accompanied by an increase in tissue phospholipids. after days, levels of lavage phospholipids then markedly increased above normal values [ ] . in vitro studies with alveolar type ii cell cultures exposed to cadmium chloride demonstrated inhibition of surfactant secretion, while cadmium alone had no such effect [ ] . paraquat, a commercially important herbicide, has marked toxic effects on the lung, particularly on the alveolar type ii cell. in vivo and in vitro studies have shown that the synthesis of surfactant phospholipids decreases after exposure. however, it is not yet clear whether this effect on surfactant production is the primary cause for paraquat-associated respiratory failure. a major problem in the clinical treatment of paraquat poisoning is the synergistic toxicity of high oxygen mechanical ventilation [ ] . the number of available studies on surfactant changes in human lung diseases is still limited. however, with further improvement of investigative tools and increasing interest in possible clinical implications, it should be expected that such studies will prosper in the near future. the main material for surfactant studies in man is bal because it is available at a low risk to the patient and gives access to all alveolar surfactant components. nev- ertheless, this method has its limitations. bal does not give direct insight into cellular changes of alveolar type ii cells and methods of quantification of the obtained epithelial lining fluid are limited by the complex nature of fluid dynamics during the procedure [ , ] . also, not all phospholipids in bal fluid must necessarily be surfactant phospholipids. they may in part stem from airway epithelial cell secretions [ ] or from cell membranes (alveolar cells, but also leucocytes, macrophages, etc.), which seems particularly important to consider in inflammatory lung diseases (e.g., [ ] ). nonetheless, the first clinical studies have shown that quantitative changes of surfactant components in different lung diseases can be found in comparison with healthy controls. normal values for sp-a in human bal are found in the range of about . - ~tg/ml lavage fluid ( [ , , ] and own unpublished data). normal total phospholipid levels seem to vary considerably among individuals and also among laboratories [ , , , , , , ] . additionally, chromatographic determination of the distribution of individual bal phospholipids (fig. ) is often used to describe surfactant abnormalities. recently, simpler enzymatic methods were recommended for phospholipid analysis in bal fluids [ ] . however, at present, only phosphatidylcholine and phosphatidylglycerol may be quantified by this method. another frequent approach is to investigate the biophysical properties (ability to lower surface tension) of the obtained surfactant material. various conditions such as severe trauma, major surgical procedures, burns, sepsis, acute pancreatitis, and aspiration pneumonia are capable of inducing this form of acute lung injury. it may rapidly progress to respiratory failure and continues to have a high mortality of around %- % [ , ] with hardly a change over the years in spite of many improvements in modern intensive care medicine. ards may be triggered or aggravated by high oxygen mechanical ventilation which is necessary in many of these patients. surfactant changes are thought to play an important role in the pathogenesis of this condition. however, it should be emphasized that ards is a severe, multifactorial disease in which surfactant is only one piece of the puzzle. serious disturbances of surfactant phospholipid composition and surfactant function as well as a reduced sp-a content in the bal have been described in animal models [ , ] and in man [ , , , ] , while the total phospholipids have not consistently been found to be reduced. the pathogenesis of these changes seems complex and is still only partly understood. again, some of the reported phospholipid changes may not be directly related to surfactant abnormalities but may be caused by other mechanisms like breakdown of cell membranes. one of the major mechanisms leading to surfactant disturbances in ards is probably connected to a massive fluid and protein accumulation in the alveolar compartment. especially in the early stages of ards, the increased permeability of the alveolocapillary barrier leads to noncardiogenic pulmonary edema with high concentrations of plasma-derived proteins. edema fluid and coagulated proteins block the alveolar air spaces and impair normal gas exchange [ , ] . several lines of evidence suggest that many of these plasmaderived proteins also have a strong potential for inactivation of surfactant material [ , , ] . in detail, this has been experimentally demonstrated for fibrinogen [ ] , fibrin monomers [ ] albumin [ ] , and even hemoglobin [ ] . these results suggest that in ards a major problem is probably not only the postulated deficit of alveolar type ii cell function but also a relative deficit of functionally intact surfactant material due to massive protein inactivation. it remains to be investigated whether or not the protein inactivation of alveolar surfactant is, to a minor degree, also relevant to other pulmonary diseases. another possible mechanism of surfactant inactivation in ards is that surfactant phospholipids may be degraded by phospholipase a , an enzyme which is probably involved in ards caused by pancreatitis or sepsis [ , ] . furthermore, it has been shown that e. coli endotoxin reduces surfactant synthesis in vitro [ ] and in vivo [ ] . many authors have called for clinical studies to investigate the benefit of surfactant substitution therapy in ards [ , , , ] , but there are still numerous problems to be solved like dosage, timing, and delivery method [ ] which dampen the enthusiasm for patient trials. much of the optimism is certainly due to the fact that ards shares common features with irds in which surfactant replacement is on the verge of becoming a standard therapy. additionally, animal studies (e.g., [ ] ) and human case reports [ , , , ] support the hope for a beneficial effect of surfactant replacement therapy in ards. the first controlled clinical trials are presently under way. even if beneficial effects on survival can be demon-strated, a significant mortality will probably remain, since the cause of death in ards is not invariably related to respiratory failure [ ] . idiopathic pulmonary fibrosis (ipf) is a progressive fibrosing lung disease of unknown origin which involves alveolar epithelial injury and alveolar type ii cell proliferation [ ] . total phospholipids in bal were found to be reduced, with decreases of pg and dppc and an increase in pi [ ] . another study [ ] reported similar findings in untreated patients. total phospholipids in bal were less than half that of controls, with raised percentages of pi and lowered pg. the severity of these changes correlated with more advanced histopathologic fibrosis. in patients (including the patients of the former study), the sp-a content of bal was reported to be significantly lower than in normal controls [ ] . in patients with untreated ipf, the pg level was lowered, and its increase after the commencement of steroid therapy seemed to indicate clinical improvement [ ] . these studies suggest that surfactant studies may be of clinical value to assess the prognosis and proper management in ipf [ ] . sarcoidosis is a generalized granulomatous disease of unknown origin which frequently involves the lung. in patients, total phospholipids in bal were not significantly decreased, and changes in phospholipid composition were not found [ ] . in partial agreement with these observations, no significant changes in total bal phospholipids were found in untreated patients with sarcoidosis [ ] , but there was an increase in the pg:pi ratio. if confirmed, these findings could be of interest as a clinical tool to separate sarcoidosis from ipf in the differential diagnosis of fibrosing lung diseases. another study of untreated patients described a decrease of dppc in bal [ ] . in untreated patients with active sarcoidosis, our group found raised sp-a levels in bal in comparison with healthy controls [ ] . further studies are necessary to confirm surfactant changes in pulmonary sarcoidosis and to evaluate their role in this disease and their potential in the differential diagnosis of fibrosing lung disorders. the known immunoregulatory role of surfactant makes this pulmonary disease an interesting object of surfactant studies. however, only a few reports have so far addressed the role of surfactant in hypersensitivity pneumonitis (hp). in a recent study, untreated patients with hp are mentioned whose sp-a values in bal were lower than in normal subjects [ ] . by contrast, our own preliminary data from bal fluids of patients with untreated, active hp show higher sp-a values than controls [ ] . also, the sp-a content of alveolar macrophages (obtained by bal) as assessed by immunocytochemistry was elevated in untreated hp patients in comparison with healthy controls [ ] . another recent study demonstrated that acute immune lung injury in guinea pigs is augmented in animals with partial surfactant depletion while surfactant replacement ameliorated the parameters of lung injury [ ] . this prompted a somewhat optimistic comment that surfactant replacement might be useful in the therapy of cell-mediated immune diseases of the lung [ ] . it is an attractive hypothesis that surfactant abnormalities may play a role in the pathogenesis of pneumonia and/or that surfactant changes occur as a consequence of alveolar infection. as an example, viral infection could damage alveolar surfacrant, facilitating the secondary invasion of bacteria. as yet, only a few studies have investigated these questions, so that our knowledge of the role of surfactant in pneumonia is still rather incomplete. in patients with bacterial pneumonia, changes in the fatty acid composition of bal phospholipids have been described [ ] . in an animal model of pneumocystis carinii pneumonia, increased amounts of total phospholipids and decreases in the percentage of pc were observed [ ] . it was hypothesized that these findings contribute to the altered lung mechanics and respiratory distress in this disease. however, it should be stressed once more that phospholipid changes may not necessarily reflect true surfactant abnormalities. in patients with acquired immunodeficiency syndrome (aids)-related pneumonia (mostly p. carinii pneumonia), a marked increase of sp-a in bal was reported in comparison with healthy controls [ ] . phospholipid analysis was not done, and it remained unclear whether the observed changes were primarily related to human immunodeficiency virus (hiv) infection or to pneumonia. further studies of the reactions and the potential role of the surfactant system in bacterial or viral invasion of the alveolar space are certainly necessary and may be awaited with interest. this is a rare disease in which for unknown reasons the alveolar type ii cell synthesizes and secretes excessive amounts of abnormal surfactant material. lungs of silica-exposed animals share common features with human alveolar proteinosis (see above), but there is no evidence that dust exposure has a role in the pathogenesis of this disease in man. a typical finding is the accumulation of tubular myelin-like multilamellated structures in the alveoli [ ] . the bal fluid is characterized by increased content of total phospholipids with a relative decrease in pg and an increase in pi [ ] . diagnosis is usually made histologically but may also be made by the demonstration of excessively high sp-a levels in bal or simply in sputum [ ] . further studies of surfactant material and alveolar type ii cells of these patients may possibly help to identify the cause of this condition, which is presumably related to a disturbance of the normal type ii cell regulation. radiation pneumonitis and subsequent fibrosis are known problems after radiotherapy of thoracic organs. animal studies have shown that the number of lamellar bodies in type ii cells drops dramatically immediately after radiation and that this is accompanied by an increase in lavage surfactant content [ ] . in vitro studies by the same group demonstrated that this is a direct effect of radiation on type ii cells and that these cells exhibit changes which may indicate a switch of phospholipid synthesis to cell membrane repair after radiation damage. these experimental findings indicate that radiation may lead to massive surfactant secretion from type ii cells early after exposure followed by a sharp drop in further surfactant synthesis. in patients with pleural mesothelioma, hemithorax irradiation caused protracted accumulation of proteins in the alveolar epithelial lining fluid which may inhibit the surface activity of surfactant. no significant changes in total phospholipid content were found, but pg, pi, pc, and sp-a levels were decrased, while the sphingomyelin concentrations were markedly increased [ ] . however, the raised sphingomyelin levels in this study probably originate from other sources than alveolar surfactant. the changes were most evident months after the completion of radiotherapy. unfortunately, immediate or early effects of radiation were not investigated. further work will be necessary to determine the role of surfactant abnormalities in the pathogenesis of radiation pneumonitis. drug-induced pulmonary disease (dipd) is often accompanied by histological changes of alveolar type ii cells like dysplasia and proliferation [ , ] . therefore, it is reasonable to expect changes of the type ii cell surfactant production in druginduced lung injury. however, only a few drugs which are potentially able to induce dipd have so far been investigated in this respect. polychemotherapy has in one report been described as inducing decreased phosphatidylcholine levels and increased phosphatidylglycerol levels in bal of patients with bronchial carcinoma [ ] . bleomycin is an antineoplastic drug which has a known capability to induce fibrosing lung disease. in animal studies, bleomycin lung injury is frequently used as a model of pulmonary fibrosis [ ] . bleomycin induces proliferation of type ii cells and giant intracellular lamellar bodies in mice. in rats with bleomycin lung disease, the bal after days and revealed increased amounts of total phospholipids, with increased percentages of pc and pi, while that of pg was decreased. these changes coincided with an altered lung compliance [ ] . another study described an initial decrease of total phospholipids after days and a subsequent . -fold increase over control animals on days and [ ] . the percentage of pg was reduced, and that of pi was increased. sp-a levels did not change throughout the experiment. from these results, a rather general conclusion was drawn that sp-a is insensitive to lung injury and repair. decreased bal phospholipids were also found in the early phase of fibrosis in hamsters. the surface-active properties of surfactant were inhibited and lung pressure-volume curves deteriorated [ ] . in conclusion, bleomycin apparently leads to a decrease of total phospholipid values within the first days of lung injury, followed by an increase above normal values with a decreased pg: p! ratio. it remains to be confirmed that these observations adequately and specifically reflect the injury of alveolar type ii cells. it seems surprising that sp-a, a more specific secretory product of alveolar type ii cells than phospholipids, did not change in the one study cited above. the conclusion that sp-a is insensitive to lung injury is not convincing, since changes in sp-a levels have been reported in idio-pathic pulmonary fibrosis and other lung disorders. it has been hypothesized that an increase of alveolar surfactant material may contribute to the pathogenesis of pulmonary fibrosis by activating alveolar macrophages which in turn stimulate fibroblasts [ ] . however, there is no experimental support to this idea, and from a clinical point of view, this hypothesis appears doubtful since most patients with alveolar proteinosis do not tend to develop pulmonary fibrosis. amphiphilic drugs like amiodarone, propranolol, chloramphenicol, and chlorpromazine may interact with pulmonary phospholipids and thus surfactant phospholipids, causing pulmonary phospholipidosis. a proposed mechanism is that normal phospholipid degradation is impaired by binding to the drugs. inhibition of phospholipases may also be involved [ ] . it seems reasonable to suspect surfactant abnormalities in many other drug-induced lung disorders because dipd is often associated with morphological alterations of type ii cells. as an example, we recently observed morphological changes of alveolar type ii cells in a case of acute mesalazine alveolitis [ ] . subsequent analysis of the bal fluid of this patient revealed an increase of sp-a content approximately -fold above healthy controls. byssinosis is a lung disease observed in cotton workers. clinically, patients present with fever, flulike symptoms, and bronchoconstriction. lipopolysaccharides from gram-negative bacteria found in respirable cotton dusts are thought to be responsible for this disease. a recently published in vitro study suggests that cotton extracts cause biophysical alterations of the lung surfactant [ ] . it is hypothesized that these effects play a part in the pathogenesis of byssinosis. bal from lung transplants of dogs were recently investigated with the principle aim of finding surfactant phospholipid changes specific to infection or rejection [ ] . this differential diagnosis represents one of the major problems in the treatment of lung recipients. however, the data obtained in this study were essentially inconclusive. the optimism that surfactant abnormalities specific to rejection or infection will be found in the future seems somewhat questionable because both are inflammatory processes with presumably similar responses of alveolar type ii cells. another recent study [ ] determined dppc levels in bal of excised dog lungs during hypothermic storage ( ° c for h) and after left lung transplantation ( dogs, -h postoperative observation period). a decrease of dppc levels was found in both situations. however, in a second group of transplanted dogs receiving l-carnitine infusions preand postoperatively, dppc levels and oxygen tension were higher postoperatively than in the group not treated with carnitine. it was concluded that the drop in dppc levels reflected ischemic damage to alveolar type ii cells and that carnitine (a cofactor for fatty acid transport into mitochondria) improved surfactant synthesis and therefore pulmonary gas exchange in the transplants. however, analysis of other bal phospholipids and surfactant-specific proteins is lacking in this study, and it remains to be confirmed that carnitine infusions really have such in vivo effects. a current review of this subject [ ] outlines some of the possible perspectives of surfactant analysis and treatment in lung transplantation in more detail. certainly, much more work has to be done to assess the usefulness of surfactant studies or even surfactant replacement therapies in lung recipients. as outlined before, surfactant therapy may prove to have beneficial effects on the course of ards and is now being investigated in clinical trials. presently, there is no convincing evidence to suggest that such a treatment may also be of use in other adult lung diseases. a number of surfactant preparations are now in use, and some of them are already marketed for the treatment of irds. their composition and therefore their properties vary considerably, and it is not yet clear which preparation will be the best considering efficacy, safety, availability, and price. it seems possible that different surfactants will in the future prove optimal for different indications, thus perhaps leading to a variety of specifically designed preparations. bovine surfactant preparations (e.g., survanta, surfactant-ta, alveofact) are organic solvent extracts of minced cow lungs and contain phospholipids in a natural composition plus sp-b and sp-c but no sp-a. in a randomized controlled trial of a bovine surfactant preparation (single dose) for the prevention of irds [ ] , it could be demon- strated that the survival rate without bronchopulmonary dysplasia was significantly improved. furthermore, there was a tendency to a better overall survival rate and a reduction in total time of mechanical ventilation. a single-dose regimen of survanta reduced the severity of respiratory distress and the frequency of pneumothorax but not the mortality in another randomized controlled study of irds [ ] . survanta has also been reported to improve lung recoil but not arterial blood gases in a rabbit lung model of ards [ ] . surfactant-ta in a randomized controlled trial has been shown to diminish the amount of respiratory support necessary in premature infants with irds [ ] . another similar study demonstrated the reduction of intracranial hemorrhage and bronchopulmonary dysplasia in infants surviving irds [ ] . in an anecdotal report of cases of ards, surfactant-ta was also reported to have beneficial effects, although the dose was unusually low [ ] . porcine surfactants (e.g., curosurf) are organic solvent extracts from minced porcine lungs with a composition comparable to bovine surfactants. beneficial effects of curosurf have been described in patients with ards [ ] and in a series of children with severe irds [ ] . also, natural surfactants from amnion fluid or bal have been used. a serious drawback of all natural surfactants is their limited availability and their high prices. alec is a simple preparation of only two phospholipids, dppc and pg (in a weight proportion of : ). exosurf (or exosurf neonatal) is a mixture of dppc, hexadecanol, and tyloxapol and also does not contain surfactant-specific proteins. in a recently published, large, multicenter trial in infants with irds [ ] , exosurf in a two-dose regimen was shown to reduce mortality and perinatal morbidity. however, in a sheep model of ards, aerosolized exosurf failed to demonstrate a beneficial effect [ ] . presently, great efforts are being made to produce synthetic surfactants which resemble natural surfactants more closely. the genes of sp-a, b, and c have been cloned so that these proteins can be produced by methods of recombinant dna technology [ ] . surfactant phospholipids can easily be produced by chemical synthesis. thus, different surfactant preparations can now be designed and studied in vitro and in vivo. these syn-thetic surfactants will have the advantage of high quality and nearly unlimited availability, which is an important prerequisite for pharmacological trials and subsequent clinical use on a larger scale. however, several remaining issues will have to be solved, e.g., the optimal composition of such "designer surfactants." probably, only the phospholipids dppc and pg will be necessary in conjunction with surfactant proteins to guarantee full surfactant efficacy [ ] . another issue which is presently debated is whether or not sp-a is a necessary component of synthetic surfactant preparations. bovine and porcine surfactant preparations without sp-a have already been shown to be effective, and it is feared that the addition of sp-a may increase the immunogenicity and impair the stability of the preparation. however, the addition of sp-a enhances the biophysical activity and increases the resistance of surfactants against inhibitory proteins in vitro, which seems an important aspect, especially when treating ards [ ] . most data on surfactant dosage in adults are derived from animal studies or clinical trials of irds treatment (e.g., [ , , , , ] ). usually, a single dose or a two-dose regimen is preferred over repeated surfactant instillations. an adequate single dose for the treatment of ards is thought to be in the range of - mg phospholipids/kg body weight [ , , , , ] . alternatively, for example, a cumulative total dose of g has been used [ ] . surfactant preparations containing proteins should be expected to have a potential for sensitization of a patient to foreign proteins. data from children with irds treated with exogenous surfactant indicate that circulating surfactant-anti-surfactant immune complexes frequently occur [ ] . however, many irds patients without substitution therapy also seem to have such circulating immune complexes [ ] , and negative effects have not yet been observed. a recently published study [ ] demonstrated igm antibodies to surfactant specific proteins in patients with severe irds and showed that the antibody occurrence decreased after surfactant treatment. it was concluded that irds can lead to a leak of surfactant-specific proteins into the circulation and that surfactant treat- ment may reduce this leak by reducing the lung damage. another issue is that exogenous surfactant could interfere with endogenous surfactant synthesis and secretion. indeed, in vitro evidence on surfactant regulation (see above) would suggest that surfactant substitution could have such unwanted effects, e.g., by feedback inhibition of type ii cells. however, a recent in vivo study in rabbits [ ] has shown that this was not the case. on the contrary, administration of different surfactant preparations tended to stimulate endogenous surfactant synthesis and secretion. in conclusion, several studies and existing clinical experience suggest that surfactant substitution therapy is not associated with serious risks. however, possible long-term effects are not yet known, and further studies should continue to monitor patients for potential side effects of surfactant treatment. pharmacologic improvement of surfactant abnormalities or deficits in human lung diseases, especially in ards, would be of considerable clinical value. despite some encouraging in vitro and animal studies, no clinical studies have yet convincingly demonstrated the usefulness of theoretically promising pharmacologic agents. one of the problems in ards is probably that successful pharmacological substances would require very strong stimulatory effects on alveolar type ii cells to overcome not only the alveolar surfactant deficit but also the inhibitory effects of exudated proteins in the alveoli. steroids are known to interfere with many of the mechanisms thought to be involved in ards. their actions include beneficial effects on surfactant synthesis. however, a number of large clinical trials have not been able to prove a clinical benefit of steroid therapy in ards (for review see [ ] ). this is not necessarily due to a failure of steroids to enhance surfactant synthesis but may simply reflect the multiple disturbances associated with ards. steroids are frequently and with some success used in mothers at risk of premature delivery to prevent irds (for review see [ ] ). beta-agonists are able to enhance surfactant synthesis and secretion from alveolar type ii cells in vitro. these agents are also used to suppress premature labor in mothers and possibly accelerate fetal lung maturation as a beneficial side effect [ , ] . however, no clear evidence has so far been presented to support such in vivo effects of beta-agonists. ambroxol, a drug which is primarily marketed as a mucolytic agent, seems to enhance surfactant production and secretion [ , ] and has been reported to be useful for the prevention and treatment of irds (for review see [ ]). we were not able to find studies investigating a potential use of ambroxol in ards. this review has attempted to summarize briefly the present knowledge on the pulmonary surfactant system and has tried to outline some of the available information which may in the future become relevant to clinical pulmonary medicine. after more than years of research, the surfactant system of the human lung has not yet become part of routine diagnostic or therapeutic considerations in adult pulmonary medicine. however, with growing knowledge from basic research, surfactant studies are beginning to give us some new insights into the mechanisms involved in various lung diseases and in the degree of involvement of alveolar type ii cells. thus, a variety of possible perspectives have now arisen, ranging from diagnostic to therapeutic implications and preventional aspects. it does not seem likely that surfactant analyses will in the future be used primarily to arrive at a specific diagnosis of a disease since there are probably not many conditions which feature characteristic surfactant abnormalities. however, present evidence fosters speculations that surfactant studies may prove useful in giving some information about the activity, intensity, and perhaps the duration of some pulmonary diseases or pollutant exposure, and they may be found helpful in the differential diagnosis of fibrosing lung disease. furthermore, it can be speculated that surfactant studies may help to monitor the effects of therapies and to assess the prognosis of various lung diseases. however, much more work has to be done to investigate these hypotheses, and possible useful results will have to be weighed against the established clinical tools. therapeutic perspectives are at present mainly focussed on ards. here, the first results of clinical trials will soon be available and are awaited with interest. other indications of surfactant therapy are not yet clearly visible and remain highly speculative. however, the known role of the surfactant system in pulmonary host defense mechanisms and local immunomodulation will continue to stimulate clinical interest in its role in inflammatory and immunologic disorders of the lung. surfactant in pulmonary oxygen toxicity long-term nitrogen dioxide exposure surfactant apoprotein a (sp-a) is synthesized in airway cells surface properties in relation to atelectasis and hyaline membrane disease surfactant protein sp-b induces ordering at the surface of model membrane bilayers ozone stress initiates acute perturbations of secreted surfactant membranes hormonal regulation of pulmonary surfactant chemical structure of phospholipids in the lungs and airways of sheep surface tension induced by dipalmitoyl lecithin in vitro under physiological conditions lung derived surface active material (sam) inhibits natural killer cell tumor cytotoxicity changes in fatty acids in phospholipids of the bronchoalveolar fluid in bacterial pneumonia and in adult respiratory distress syndrome decreased phosphatidylcholine in the lung fluid of patients with sarcoidosis enhancement of macrophage and monocyte cytotoxicity by the surface active material of lung lining fluid sequential changes in phospholipid composition and synthesis in lungs exposed to nitrogen dioxide structure and function of phosphatidylglycerol-deficient lung surfactant toxicity of inhaled cadmium chloride: early responses of the antioxidant and surfactant systems in rat lungs immunomodulation by pulmonary surfactant regulation of lung surfactant secretion surfacrant proteins and anti-surfactant antibodies in sera from infants with respiratory distress syndrome with and without snrfactant treatment surface tension of lung extracts smoking and pulmonary surfactant pulmonary surface tension and alveolar stability pulmonary surfactant protein b (sp-b): structure-function relationships role of surfactant free fatty acids in antimicrobial defenses drug-induced pulmonary disease. part : cytotoxic drugs drug-induced pulmonary disease. part : noncytotoxic drugs decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial lung surfactant associated proteins and type iv collagen share common epitopes surfactant protein d. increased accumulation in silica-induced pulmonary lipoproteinosis biophysical alteration of lung surfactant by extracts of cotton dust effects of silica on the composition of the pulmonary extracellular lining the pharmacology of ambroxol review and new results pulmonary surfactant pulraonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type ii cells acute tung injury induced by phospholipase a surfactant replacement in adult respiratory distress syndrome pulmonary phospholipidosis in rats respiring air containing diesel particulates pathogenesis of pulmonary fibrosis induced by chrysotile asbestos. virchows arch experimental bleomycin lung in mice physiologic and toxicologic responses of alveolar type ii cells low yield of pulmonary surfactant in cigarette smokers in vivo regulation of surfactant proteins by glucocorticoids sixty years of surfactant research isolation and characterization of cdna clones for the -kda pulmonary surfactant-associated protein adult respiratory distress syndrome -prognosis after onset artificial pulmonary surfactant inhibited by proteins surfactant replacement therapy with a single postventilatory dose of a reconstituted bovine surfactant in preterm neonates with respiratory distress syndrome: final analysis of a multicenter, doubleblind, randomized trial and comparison with similar trials lipid content of alveolar lining material collected by bronchoalveolar lavage randomized controlled trial of exogenous surfactant for the treatment of hyaline membrane disease pharmacological treatment of the adult respiratory distress syndrome a multicenter randomized controlled clinical trial of bovine surfactant for prevention of respiratory distress syndrome pulmonary defense mechanisms in boa constrictor effects of hydrogen sulfide exposure on surface properties of lung surfactant increased surfactant protein a (sp-a) content in human alveolar macrophages in hypersensitivity pneumonitis lung surfactant and pulmonary toxicology synthesis and assembly of lung surfactant effects of ozone on phospholipid synthesis by alveolar type ii cells isolated from adult rat lung clinical experience with exogenous natural surfactant absence of phosphatidylglycerol (pg) in respiratory distress syndrome in the newborn analysis of labeling and clearance of lung surfactant phospholipids in rabbit evidence of lung surfactant abnormality in respiratory failure changes in surfactant in bronchoalveolar lavage fluid after hemithorax irradiation in patients with mesothelioma surfactant protein a in bronchoalveolar lavage of sarcoidosis and hypersensitivity pneumonitis phospholipids as dynamic participants in biological processes lung surfactant surfactant cholesterol metabolism of the isolated perfused rat lung pulmonary surfactant apoproteins: a review of protein and genomic structure lung lipids and disease. respiration pulmonary surface film stability and composition the role of lung surfactant role of pulmonary surfactant in the development and treatment of adult respiratory distress syndrome effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity surface property changes from interactions of albumin with natural surfactant and extracted lung lipids type ii pneumocyte changes during hyperoxic lung injury and recovery down-regulation of immune responses in the lower respiratory tract: the role of alveolar macrophages changes in phospholipids in bronchoalveolar lavage fluid of patients with interstitial lung diseases alterations of acidic phospholipids in bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis dissolution and reassembly of tubular myelin-like multilamellated structures from the lungs of patients with pulmonary alveolar proteinosis a multicenter, randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome surface and tissue forces, surfactant protein a, and the phospholipid components of pulmonary surfactant in bleomycin-induced pulmonary fibrosis in the rat changes in phosphatidylglycerol in bronchoalveolar lavage fluids from patients with cryptogenic fibrosing alveolitis changes of alveolar stability and phospholipids in pulmonary surfactant in acute pancreatitis surfactant for the treatment of respiratory distress syndrome surfactant protein b : disulfide bridges, structural properties, and kringle similarities human alveolar lining material and antibacterial defenses types of interaction of amphiphilic drugs with phospholipid vesicles enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material analysis of bronchoalveolar lavage and pulmonary alveolar surfactant for diagnosis of rejection and infection in heart-lung transplantation alveolar type ii cells, surfactant protein a (sp-a), and the phospholipid components of surfactant in acute silicosis in the rat structure of alveolar epithelial cells in patients with fibrotic lung disorders fluid dynamics during bronchoalveolar lavage secretions from primary hamster tracheal surface epithelial cells in culture: mucin-like glycoproteins, proteoglycans, and lipids isolation of apoproteins from canine surface active material -and pneumonia-induced lung injury. ii. properties of pulmonary surfactant pulmonary surfactant in bronchoalveolar lavage after canine lung transplantation inactivation of exogenous surfactant by pulmonary edema fluid surfactant protein d (sp-d) counteracts the inhibitory effect of surfactant protein a (sp-a) on phospholipid secretion by alveolar type ii cells characterization of pulmonary surfactant protein d: its copurification with lipids animal models and clinical pilot studies of surfactant replacement in adult respiratory distress syndrome surfactant replacement improves lung recoil in rabbit lungs after acid aspiration injury to type ii pneumocytes in rats exposed to cigarette smoke endotoxin suppresses surfactant synthesis in cultured rat lung cells functional abnormalities of lung surfactant in experimental acute alveolar injury in the dog glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein a in fetal human lung a controlled clinical trial of synthetic surfactant in infants weighing g or more with respiratory distress syndrome bronchoalveolar lavage lipids in idiopathic pulmonary fibrosis biochemical analyses of bronchoalveolar lavage fluids of healthy human volunteer smokers and nonsmokers human leucocyte clq receptor binds other soluble proteins with collagen domains specific interaction of lung surfactant protein a (sp-a) with rat alveolar macrophages limitations of using urea to quantify epithelial lining fluid recovered by bronchalveolar lavage surfactant in adult respiratory distress syndrome surfactant apoprotein.-a concentration in sputum for diagnosis of pulmonary alveolar proteinosis sublethal hyperoxic injury to the alveolar epithelium and the pulmonary surfactant system characterization of antioxidant activities of pulmonary surfactant mixtures idiopathic pulmonary fibrosis. abnormalities in the bronchoalveotar lavage content of surfacrant protein a immunologic consequences of exogenous surfactint administration degradation of pulmonary surfactant disaturated phosphatidylcholines by alveolar macrophages hypertrophy and hyperplasia of alveolar type ii cells in response to silica and other pulmonary toxicants adverse effects of toxins and drugs on the surfactant systems causes of mortality in patients with the adult respiratory distress syndrome toxicological data on nox: an overview pulmonary surfactant: physiology, pharmacology and clinical uses exogenous surfactant treatment for the adult respiratory distress syndrome? a historical perspective effects of pulmonary oxygen injury on airway content of surfactant-associated protein a surfactant for adults with respiratory failure surfactant analysis and replacement therapy: a future tool of the lung transplant surgeon surfactant treatments alter endogenous surfactant metabolism in rabbit lungs bacteremia-induced suppression of alveolar surfactant production rat lung lavage surfactant enhances bacterial phagocytosis and intracellular killing by alveolar macrophages structural and functional changes of surfactant protein a induced by ozone changes of lung surfactant and pressure-volume curve in bleomycin-induced pulmonary fibrosis effects of smoke inhalation on surfactant phospholipids and phospholipase a activity in the mouse lung properties, function and origin of the alveolar lining layer the relation between surface tension and area in the alveolar lining film purification and biochemical characterization of cp (sp-d), a collagenous surfactant-associated protein surfactant protein d is a divalent cation-dependent carbohydrate-binding protein clearance of surfactant phosphatidylcholine from adult rabbit lungs clearance of surfactant phosphatidylcholine via the upper airways in rabbits localization of surfactant protein synthesis in human lung by in situ hybridization increased recovery of surfactant protein a in aids-related pneumonia surfactant abnormalities in patients with respiratory failure after multiple trauma altered pulmonary surfactant in uncomplicated and septicemia-complicated courses of acute respiratory failure a proposed nomenclature for pulmonary surfactant-associated proteins the role of surfactant-associated proteins biochemical modification of pulmonary surfactant after bromhexine derivatc injection rheological and transport properties of airway secretions in cystic fibrosis -relationships with the degree of infection and severity of the disease changes in lipids of lung lavage in monkeys after chronic exposure to ambient levels of ozone immunologic system in the respiratory tract pulmonary surfactant as a physiologic immunosuppressive agent curstedt t ( ) the adult respiratory distress syndrome: first trials with surfactant replacement pulmonary surfactant suppresses the immune lung injury response to inhaled antigen in guinea pigs idiopathic pulmonary fibrosis -abnormalities in bronchoalveolar lavage fluid the surfactant system of the lung changes in pulmonary surfactant composition following macc chemotherapy for lung carcinoma binding and uptake of pulmonary surfactant protein (sp-a) by pulmonary type ii epithelial cells lung surfactant: a biotechnological challenge alveolar macrophage migration -influence of lung lining material alteration of surfactant function due to protein leakage: special interaction with fibrin monomer surfactant abnormalities and adult respiratory failure surfactant phospholipids and lavage phospholipase a in experimental pneumocystis carinii pneumonia giant lamellar bodies in alveolar type ii cells of rats exposed to a low concentration of ozone the effect of pulmonary surface-active material on the generation and expression of murine b-and t-lymphocyte effector functions in vitro isolation and characterization of a sulfated glyceroglucolipid from alveolar lavage of rabbit early versus late surfactant replacement therapy in severe respiratory distress syndrome surfactant replacement: immunological considerations surfactant abnormality after endotoxin-induced lung injury in guinea pigs structure-function relationships of bovine pulmonary surfactant proteins sp-b and sp-c the proximal border of the human respiratory unit, as shown by scanning and transmission electron microscopy and light microscopical cytochemistry human pulmonary surfactant protein (sp-a), a protein structurally homologous to clq, can enhance fcr-and crl-mediated phagocytosis altered lipid synthesis in type ii pneumocytes exposed to lung surfactant correlation of changes in pulmonary surfactant phospholipids with compliance in bleomycin-induced pulmonary fibrosis in the rat synthesis of surfactant lipids in the adult and fetal lung: pathways and regulatory aspects metabolism of phospholipids in the lung aspects of metabolism and storage of pulmonary surfactant: experiments with isolated type ii pneumocytes and lamellar bodies pulmonary surfactant protein a enhances the host-defence mechanism of rat alveolar macrophages surfactant protein a is opsonin in phagocytosis of herpes simplex virus type by rat alveolar macrophages enhancement of biophysical activity of lung surfactant extracts and phospholipid-apoprotein mixtures by surfactant protein a neue auffassungen fiber einen grundbegriff der atemmechanik surfactant protein a is localized at the corners of the pulmonary tubular myelin lattice macromolecular organization of natural and recombinant lung surfactant protein sp - structural comparison of recombinant pulmonary surfactant protein sp-a derived from two human coding sequences: implications for the chain composition of natural human sp-a surfactant proteins and sp-d function and regulation of expression of pulmonary surfactant-associated proteins identification of surfactant proteolipid sp-b in human surfactant and fetal lung mesalazine alveolitis isolation and characterization of the human pulmonary surfactant apoprotein gene glycosylation and secretion of surfactant-associated glycoprotein a endobronchial surface active phospholipids: clinical conclusions changes in lipid structure produced by surfactant proteins sp-a, sp-b, and sp-c immunoregulatory properties of pulmonary surfactant: effect of lung lining fluid on proliferation of human blood lymphocytes immunosuppression by pulmonary surfactant: mechanisms of action relations among recoil pressure, surface area, and surface tension in the lung effects of short-term exposure to diesel exhaust on lung cell proliferation and phospholipid metabolism clearance and recycling of pulmonary surfactant metabolism and turnover of lung surfactant surfactant apoprotein mr= . - . enhances uptake of liposomes by type ii ceils role of bovine pulmonaryassociated proteins in the surface active property of phospholipid mixtures effects of aerosolized artificial surfactant on repeated oleic acid injury in sheep acknowledgements. we would like to thank prof. k. morgenroth, ruhr-universitfit bochum, for the excellent electron mi-croscopic photographs (figs. - ) and prof. schfifer (byk-gulden co., konstanz, germany), prof. akino and prof. kuroki (sapporo medical college, japan) for aiding our laboratory with sp-a antigen and antibodies. key: cord- -fk um nw authors: farver, carol f.; zander, dani s. title: molecular basis of pulmonary disease date: - - journal: molecular pathology doi: . /b - - - - . - sha: doc_id: cord_uid: fk um nw pulmonary pathology includes a large spectrum of both neoplastic and non-neoplastic diseases that affect the lung. many of these are a result of the unusual relationship of the lung with the outside world. every breath that a human takes brings the outside world into the body in the form of infectious agents, organic and inorganic particles, and noxious agents of all types. although the lung has many defense mechanisms to protect itself from these insults, these are not infallible; therefore, lung pathology arises. damage to the lung is particularly important given the role of the lung in the survival of the organism. any impairment of lung function has widespread effects throughout the body, since all organs depend on the lungs for the oxygen they need. pulmonary pathology catalogs the changes in the lung tissues and the mechanisms through which these occur. this chapter presents a review of lung pathology and the current state of knowledge about the pathogenesis of each disease. it suggests that a clear understanding of both morphology and mechanism is required for the development of new therapies and preventive measures. pulmonary pathology includes a large spectrum of both neoplastic and non-neoplastic diseases that affect the lung. many of these are a result of the unusual relationship of the lung with the outside world. every breath that a human takes brings the outside world into the body in the form of infectious agents, organic and inorganic particles, and noxious agents of all types. although the lung has many defense mechanisms to protect itself from these insults, these are not infallible and so lung pathology arises. damage to the lung is particularly important given the role of the lung in the survival of the organism. any impairment of lung function has widespread effects throughout the body, since all organs depend on the lungs for the oxygen they need. pulmonary pathology catalogs the changes in the lung tissues and the mechanisms through which these occur. what follows is a review of lung pathology and the current state of knowledge about the pathogenesis of each disease. we believe that a clear understanding of both morphology and mechanism is required for the development of new therapies and preventive measures. lung cancer is a major cause of morbidity and mortality throughout the world. the most recent estimates available from the surveillance, epidemiology, and end results (seer) program of the national cancer institute are that in over , people in the united states were diagnosed with cancer of the lung and bronchus, and over , will have died due to this disease [ ] . however, in the past decade incidence and mortality rates have begun to move in a more positive direction, particularly in men. overall, men show a decline in lung cancer incidence, while in women, although lung cancer rates grew from through , they stabilized from through [ ] . similarly, cancer death rates due to lung cancer have declined for men and have slowed for women. although, for women, lung cancer death rates have increased since , the rate of increase has slowed to . % annually from to [ ] . these trends parallel changes in the prevalence of tobacco smoking, the most important risk factor for development of lung cancer. given the tremendous societal and individual impacts of this disease, it is not surprising that the molecular biology of lung cancer is a major focus of investigation. elucidation of the molecular pathogenesis of these neoplasms has progressed significantly, offering insights into new, targeted therapies, and predictors of prognosis and therapeutic responsiveness. recognition of precursor lesions for some types of lung cancers has been facilitated by our expanded understanding of early molecular changes involved in carcinogenesis. the world health organization (who) classification scheme is the most widely used system for classification of these neoplasms (table . ) [ ] . although there are numerous histologic types and subtypes of lung cancers, most of the common malignant epithelial tumors can be grouped into the categories of nonsmall cell lung cancers (nsclcs) and small cell carcinomas (sclcs). nsclcs include adenocarcinomas (acs), squamous cell carcinomas (sqccs), large cell carcinomas, adenosquamous carcinomas, and sarcomatoid carcinomas. sclcs include cases of pure and combined small cell carcinoma. common pulmonary symptoms associated with these tumors include cough, shortness of breath, chest pain or tightness, and hemoptysis (coughing up blood). since some tumors cause airway obstruction, they predispose to pneumonia, which can be an important clue to the existence of a tumor in some patients. constitutional symptoms can include fever, weight loss, and malaise. some neoplasms will declare themselves with symptoms related to local invasion of adjacent structures such as chest wall, nerves, superior vena cava, esophagus, or heart. sclcs are known for early and widespread metastasis and are therefore particularly prone to being discovered through presentations as metastases in distant sites. some tumors are discovered due to pathophysiologic changes triggered by the release of soluble substances from tumor cells. endocrine syndromes due to elaboration of hormones are well recognized, and include cushing syndrome, syndrome of inappropriate antidiuretic hormone, hypercalcemia, carcinoid syndrome, gynecomastia, and others. hypercoagulability commonly occurs with lung cancers, leading to manifestations of venous thrombosis, nonbacterial thrombotic endocarditis, and disseminated intravascular coagulation. hematologic changes can include anemia, granulocytosis, eosinophilia, and other abnormalities. other paraneoplastic syndromes such as clubbing of the fingers, myasthenic syndromes, dermatomyositis/polymyositis, and transverse myelitis are noted in subsets of patients. when lung cancer is suspected, evaluation of the patient includes a thorough clinical, radiologic, and laboratory assessment, with collection of tissue or cytology samples to establish a pathologic diagnosis of malignancy and to classify the tumor type. fiberoptic bronchoscopy is often performed to collect samples for diagnosis. sample types can include transbronchial and endobronchial biopsies, bronchial brushings, bronchial washings, bronchoalveolar lavage samples, and transbronchial needle aspirates. submission of sputum samples for cytologic malignant epithelial tumors examination can provide a diagnosis in some cases, particularly for centrally located tumors such as sqcc and sclc. tumors arising in a peripheral location can also be sampled, in many cases, by fine needle aspiration or core needle biopsy performed under radiologic guidance. if a pleural effusion is present in combination with a lung parenchymal tumor, analysis of the pleural fluid cytology often allows one to establish a diagnosis. pleural biopsy, mediastinoscopy with biopsy, and wedge biopsy can also be performed, depending on the clinical and radiologic findings. for tumors with apparent distant metastasis, biopsy of the metastasis focus can both establish a pathologic diagnosis and determine the stage of the tumor. the prognosis of lung cancers is closely related to tumor stage. for nsclcs, the american joint commission on cancer tnm staging system is widely used (table . ) [ ] , and for sclcs, disease is classified as limited (restricted to one hemithorax) or extensive. overall, for lung cancers, the -year survival is . % for men and . % for women [ ] . an important factor leading to this relatively poor survival is the late stage at which many lung cancers are diagnosed. information from the seer database, from - , indicates that %, %, %, and % of patients were diagnosed with localized, regional, distant, or unstaged disease, respectively [ ] . the corresponding -year survival rates are . %, . %, . %, and . %, and year survival rates are . %, . %, . %, and . % [ ] . for patients with nsclcs, treatment depends on stage and comorbid conditions [ ] . surgical resection is the preferred approach to treatment of localized nsclcs, provided there is no medical contraindication to operative intervention. lobectomy or more extensive resection (depending on tumor extent) is usually recommended rather than lesser surgeries, unless other comorbid conditions preclude these procedures. tumor cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus t tumor with any of the following features of size or extent: > cm in greatest dimension, involves main bronchus ! cm distal to the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung t tumor of any size that directly invades the chest wall, diaphragm, mediastinal pleura, parietal pericardium; or lies < cm distal to the carina but without involvement of the carina; or is associated with atelectasis or obstructive pneumonitis of the entire lung t tumor of any size that invades the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or has separate tumor nodule(s) in same lobe; or is associated with a malignant pleural effusion. regional lymph nodes (n) nx regional lymph nodes cannot be assessed n no regional lymph node metastasis n metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, including intrapulmonary nodes involved by direct extension of the primary tumor n metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) n metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s). mx distant metastasis cannot be assessed m no distant metastasis m distant metastasis; includes separate tumor nodule(s) in a different lobe. occult t n m stage tis n m stage ia t n m stage ib t n m stage iia t n m stage iib t n m t n m stage iiia t n m t n m t n m t n m stage iiib any t n m t any intraoperative mediastinal lymph node sampling or dissection is also recommended for accurate pathologic staging and determination of therapy. subsets of patients also benefit from chemotherapy and radiotherapy. for more advanced nsclc and for sclc, chemotherapy and radiotherapy are the primary treatment modalities [ ] . rare patients with limited-stage sclcs can be considered for surgical resection with curative intent. development of lung cancer occurs with multiple, complex, stepwise genetic and epigenetic changes involving allelic losses, chromosomal instability and imbalance, mutations in tumor suppressor genes (tsgs) and dominant oncogenes, epigenetic gene silencing through promoter hypermethylation, and aberrant expression of genes participating in control of cell proliferation and apoptosis [ ] . there are similarities as well as type-specific differences in the molecular alterations between nsclcs and sclcs, and between sqccs and acs [ ] [ ] [ ] . oncogenes that play a part in the pathogenesis of lung cancer include myc, k-ras (predominantly acs), cyclin d , bcl , and erbb family genes such as egfr (epidermal growth factor receptor) (predominantly acs) and her /neu (predominantly acs) [ , ] . also, lung cancers often display abnormalities involving tsgs including tp , rb, p ink a , and new candidate tsgs on the short arm of chromosome (dutt , fhit, rasff a, fus- , bap- ) [ , ] . as research advances, these lists continue to grow, and as knowledge has expanded about the roles of these genes in carcinogenesis and tumor behavior, new targeted therapeutic agents have been designed to treat this disease ( figure . and table . ) [ ] . many other agents are under investigation. in cancers, chromosomal regions harboring tsgs and oncogenes are often deleted or amplified. allele loss involving loci in p - is a consistent feature of lung cancer pathogenesis [ , ] . wistuba et al. reported allelic losses of p, often multiple and discontinuous, in % of the lung cancers studied and in % of the precursor lesions [ ] . larger segments of allelic loss were noted in most sclcs ( %) and sqccs ( %) than in acs ( %) and preneoplastic/preinvasive lesions [ ] . there was allelic loss in the -kb p . deletion region in % of the lung cancers; % of the normal or reneoplastic/preinvasive lesions associated with lung cancers; and % of the normal, mildly abnormal, or preneoplastic/ preinvasive lesions found in smokers without lung cancer, but no loss was seen in the samples from people who had never smoked [ ] . p - deletions are also frequent and early events in the pathogenesis of lung carcinomas [ ] , and other common alterations include loh at q, q, q, and p [ ] . allelic losses that are more frequent in sqccs than acs include deletions at p (tp ), q (rb), p (p ink a ), p - , and several regions of p [ , , , ] . a recent study utilizing a bacterial artificial chromosome array to perform high-resolution whole genome profiling of sqcc and ac cell lines showed that regions of frequent amplification shared by both types of tumors included p; chromosome , q, q , q, and q; and common regions of deletion included p, q, p, p, q; chromosome ; and chromosome [ ] . however, acs appeared to have higher frequencies of deletion of chromosome ; p, q, q; and chromosome than sqccs, and possess small regions of amplification on chromosomes and not seen in sqccs. chromosome arms q and q were frequently deleted in ac but amplified in sqcc cell lines. both types of tumors showed deletion of chromosome arm p, but it was more frequent in the sqcc cell lines, while amplification of chromosome p was more frequent in acs. amplification of chromosome q was common to both types of tumors but showed frequent alteration at q - q in the sqcc lines and at q in the ac lines. inactivation of recessive oncogenes is believed to occur through a two-stage process. it has been suggested that the first allelic inactivation occurs, often via a point mutation, and the second allele is later inactivated by a chromosomal deletion, translocation or other alteration such as methylation of the gene promoter region [ ] . inactivating mutations in the tsg tp , which encodes the p protein, are the most frequent mutations in lung cancers. these mutations are found in up to % of nsclcs and over % of sclcs, and are largely attributable to direct dna damage from cigarette smoke carcinogens [ ] . tp mutational patterns show a prevalence of g to t transversions in % of smokers' lung cancers versus only % of lung cancers in nonsmokers [ ] . p protein is a transcription factor and a key regulator of cell cycle progression; cellular signals induced by dna damage, oncogene expression, or other stimuli trigger p dependent responses including initiating cell cycle arrest, apoptosis, differentiation, and dna repair [ ] . loss of p function in tumor cells can result in inappropriate progression through the dysregulated cell cycle checkpoints and permits the inappropriate survival of genetically damaged cells [ ] . the p ink a -cyclin d -cdk -rb pathway, which plays a central role in controlling the g to s phase transition of the cell cycle, is another important tumor suppressor pathway that is often disrupted in lung cancers. it interfaces with the p pathway through p arf and p waf/cip . thirty percent to % of nsclcs contain mutations of p ink a , including homozygous deletion or point mutations and epigenetic alterations, leading to p ink a inactivation [ ] . almost % of sclcs and smaller numbers of nsclcs, on the other hand, display loss of rb expression [ ] , and mutational mechanisms usually responsible include deletion, nonsense mutations, and splicing abnormalities that lead to truncated rb protein [ ] . p ink a leads to hypophosphorylation of the rb protein, which causes arrest of cells in the g phase. the active, hypophosphorylated form of rb regulates other cellular proteins including the transcription factors e f , e f , and e f , which are essential for progression through the g /s phase transition. loss of p ink a protein or increased complexes of cyclin d-cdk - or cyclin e-cdk lead to hyperphosphorylation of rb with resultant evasion of cell cycle arrest and progression into s phase [ , ] . cell cycle progression is inhibited by p waf/cip through its inhibition of the cyclin complexes. the %- % of nsclcs lacking detectable alterations in p ink a and rb may have abnormalities of cyclin d and cdk , which cause inactivation of the rb pathway [ ] . figure . provides an overview of the p and retinoblastoma (rb) pathways, showing the complex interactions between the components [ ] . epigenetic alterations (hypermethylation of the cpg island) of tsgs are also frequent occurrences during pulmonary carcinogenesis, and methylation profiles of nsclcs show relationships to smoke exposure, histologic type, and geography. methylation rates of p ink a and apc and the mean methylation index (mi) (a reflection of the overall methylation status) in current or former smokers were significantly higher than in never smokers; the mean mi of tumors was highest in current smokers; methylation rates of apc, cdh , and rarbeta were significantly higher in acs than in sqccs; methylation rates of mgmt and gstp in cases from the united states and australia significantly exceeded those from japanese and taiwanese cases; and no significant gender-related differences in methylation patterns were found [ ] . proto-oncogene activation and growth factor signaling are important in pulmonary carcinogenesis. the tyrosine kinase epidermal growth factor receptor (egfr) is frequently mutated in nsclcs, particularly in acs, and the mutational status is important in determining response to tyrosine kinase inhibitors. a related pathway, the phosphoinositide -kinase (pi k)/akt/mammalian target of rapamycin (mtor) pathway, is frequently deregulated in pulmonary carcinogenesis. as reviewed by marinov et al., this pathway has been reported to mediate the effects of several tyrosine kinase receptors, including egfr, c-met, c-kit, and igf-ir, on proliferation and survival in nsclc and sclc [ ] . clinical trials are ongoing, investigating the efficacy of the mtor inhibitor rapamycin and its analogues on lung cancer [ ] . her /neu is another related receptor tyrosine kinase that is upregulated in approximately %- % of nsclcs [ , ] , but unlike the situation with her /neu-positive breast cancers, treatment with anti-her /neu antibody (trastuzumab) does not seem to yield comparable benefits for nsclc when used alone or in combination with chemotherapy [ , ] . point mutations of ras family proto-oncogenes (most often at k-ras codons , , or ) are detected in %- % of lung acs and %- % of all nsclcs [ ] . although farnesyl transferase inhibitors prevent ras signaling, these agents have not shown significant activity as single-agent therapy in untreated nsclc or relapsed sclc [ ] . myc family genes (myc, mycn, and mycl), which play roles in cell cycle regulation, proliferation, and dna synthesis, are more frequently activated in sclcs than in nsclcs, either by gene amplification or by transcriptional dysregulation [ ] . vascular endothelial growth factor (vegf) is a homodimeric glycoprotein that is overexpressed in many lung cancers and directly stimulates endothelial cell proliferation, promotes endothelial cell survival in newly formed vessels, and induces proteases involved in the degradation of the extracellular matrix needed for endothelial cell migration [ ] . its angiogenic effects are mediated by three receptors: vegfr- , vegfr- , and vegfr- ; ligand binding leads to tyrosine kinase activation and activation of the signaling pathways required for angiogenesis [ ] . monoclonal antibodies to vegf (bevacizumab) and tyrosine kinase inhibitors to vegfrs have been developed and show promise for treatment of nsclc. a phase iii trial of bevacizumab showed significantly improved overall and progression-free survival when this agent was used in combination with standard first-line chemotherapy in patients with advanced nsclc, and several smallmolecule vegfr tyrosine kinase inhibitors have yielded favorable results in phase i and ii trials in nsclc [ ] . micrornas are a recently discovered class of nonprotein-coding, endogenous, small rnas which regulate gene expression by translational repression, mrna cleavage, and mrna decay initiated by mirna-guided rapid deadenylation [ ] . some micrornas such as let- have been suggested to play roles in carcinogenesis by functioning as oncogenes or tumor suppressors, negatively regulating tsgs and/or genes that control cell differentiation or apoptosis [ ] . investigations of the therapeutic potential of micrornas are also under way. in the version of the who classification scheme, ac is defined as "a malignant epithelial tumour with glandular differentiation or mucin production, showing acinar, papillary, bronchioloalveolar or solid with mucin growth patterns or a mixture of these patterns" [ ] . ac has become the most frequent histologic type of lung cancer in parts of the world. it occurs primarily in smokers, but represents the most common type of lung cancer in people who have never smoked and in women. a small subset of these tumors arise in patients with localized scars or diffuse fibrosing lung diseases such as asbestosis and interstitial pneumonia associated with scleroderma [ ] . these neoplasms usually arise in the periphery of the lung, and are more likely to invade the pleura and chest wall than other histologic types of lung cancers. radiologic studies can show one or more nodules, ground-glass opacities, or mixed solid and ground-glass lesions. on gross examination, the neoplasms are often solitary gray-white nodules or masses, sometimes with necrosis or cavitation, which pucker the overlying pleura. mucin-producing tumors can have a glistening, gelatinous appearance. other presentations include a pattern of consolidation resembling pneumonia (usually bronchioloalveolar carcinoma) ( figure . ), multiple nodules, diffuse interstitial widening due to lymphangitic spread, endobronchial lesions with submucosal infiltration, and diffuse visceral pleural infiltration and thickening resembling mesothelioma. common histologic patterns displayed by acs include acinar ( figure chapter molecular basis of pulmonary disease mixtures of these patterns are very frequent. less common histologic subtypes include fetal ac, mucinous (colloid) ac, mucinous cystadenocarcinoma, signet ring ac, and clear cell ac [ ] . acs usually exhibit differentiation toward clara cells or type ii pneumocytes or, less often, goblet cells. they manifest a range of differentiation extending from very well-differentiated tumors with extensive gland formation and little cytoatypia, to poorly differentiated, solid tumors that cannot be categorized as acs unless one orders a mucin stain (figure . ) . however, most examples include readily identifiable glands. invasiveness is reflected by the presence of neoplastic glands that infiltrate through stroma or pleura, stimulating a fibroblastic (desmoplastic) response ( figure . ) , or by cells in the lumens of blood vessels or lymphatics. in recent years, atypical adenomatous hyperplasia (aah) has been recognized as a precursor lesion for peripheral pulmonary acs. this lesion is defined as "a localized proliferation of mild to moderately atypical cells lining involved alveoli and, sometimes, respiratory bronchioles, resulting in focal lesions in peripheral part iv molecular pathology of human disease alveolated lung, usually less than mm in diameter and generally in the absence of underlying interstitial inflammation and fibrosis" (figure . ) [ ] . aah exists on a histologic continuum with bronchioloalveolar carcinoma (bac), which is defined as an in situ (noninvasive) form of ac, in which the neoplastic cells grow along alveolar septa (lepidic growth) without invasion of stroma or vasculature ( figure . , figure . ) [ ] . most bacs exceed cm in diameter and consist of cells with greater degrees of cytoatypia than aah. although aah is found in approximately % of patients without lung cancer at autopsy [ ] , it has been reported in %- % of lung resection specimens with all types of primary lung cancer and %- % of lung resection specimens with ac [ ] . the progenitor cell for bac and aah is believed to be an epithelial cell located at the junction between the terminal bronchiole and alveolus, termed the bronchioalveolar stem cell [ ] . a recently published large-scale study of primary lung acs, using dense single nucleotide polymorphism arrays, described significantly recurrent copy-number alterations in these tumors (table . ) [ ] . twenty-six of autosomal chromosome arms showed consistent large-scale copy-number gain or loss, and recurrent focal events, including amplifications and homozygous deletions, were found. although some of the alterations involved regions known to harbor a proto-oncogene or tsg, these genes remain to be identified in some of the other regions affected. amplification of chromosome q . was the most common event noted, found in % of samples. this region includes nkx - , which encodes a lineage-specific transcription factor (thyroid transcription factor- [ttf- ]) that activates transcription of target genes including the surfactant proteins, and may be an important proto-oncogene involved in a significant fraction of lung acs. immunohistochemical staining for ttf- can be performed to detect expression of this factor in most lung adenocarcinomas, aiding in the determination of the lung as the site of origin of the tumor (figure . ). additional work using small interfering rna (sirna)mediated knockdown of this gene in lung cancer cell lines with amplification led to reductions in tumor cell proliferation, through both decreased cell cycle progression and increased apoptosis, suggesting that gene amplification and overexpression contribute to lung cancer cell proliferation rates and survival [ ] . egfr and k-ras mutations are mutually exclusive mutational events in ac of the lung, which suggests the existence of two independent oncogenic pathways [ , ] . egfr is a receptor tyrosine kinase whose activation by ligand binding leads to activation of cell signaling pathways such as ras/mitogen-activated protein kinase (mapk) and phosphatidylinositol- -kinase, which in turn propagates signals for proliferation, blocking of apoptosis, differentiation, motility, invasion, and adhesion [ ] . tumor-acquired mutations in the tyrosine kinase domain of egfr, often associated with gene amplification, have been found in approximately %- % of nsclcs in the united states, and are associated with ac histology, never-smoker status, east asian ethnicity, and female gender [ , , ] . egfr mutations are frequently in-frame deletions in exon , single missense mutations in exon , or in-frame duplications/insertions in exon , and occasional missense mutations and double mutations can also be detected [ , ] . egfr mutation has an inverse correlation with methylation of the p ink a gene and sparc (secreted protein acidic and rich in cysteine), an extracellular ca þ-binding glycoprotein associated with the regulation of cell adhesion and growth [ ] . egfr status is an important predictor of response to egfr kinase inhibitors: patients with egfr mutations are most likely to have a significant response to egfr tyrosine kinase inhibitor therapy, and egfr amplification and protein overexpression have been reported to correlate with survival after egfr tyrosine kinase inhibitor therapy [ , ] . k-ras is a member of the ras family of proteins, which function as signal transducers between cell membrane-based growth factor signaling and the mapk pathways [ ] . k-ras mutations are associated with smoking, male gender, and poorly differentiated tumors [ ] . her (also known as egfr or erbb ), a member of the egfr family of receptor tyrosine kinases, is mutated in less than % of nsclc, and does not occur in tumors with egfr or k-ras mutation [ ] . the her mutations are in-frame insertions in exon and are significantly more frequent in acs ( . %), never smokers ( . %), asian ethnicity ( . %), and women ( . %), similar to egfr mutations [ ] . alterations in dna methylation appear to be important epigenetic changes in cancer, contributing to chromosomal instability through global hypomethylation, and aberrant gene expression through alterations in the methylation levels at promoter cpg islands [ ] . this lesion, which has been defined as a precursor lesion for peripheral pulmonary adenocarcinomas, consists of a wellcircumscribed nodule measuring several millimeters in diameter, in which alveolar septa are lined by mildly moderate atypical cells. epigenetic differences exist between egfr-mediated and k-ras-mediated tumorigenesis, and may interact with the genetic changes. a recent study showed that the probability of having egfr mutation was significantly lower among those with p ink a and cdh methylation than in those without, and the methylation index was significantly lower in egfr mutant cases than in wild-type. in contrast, k-ras mutation was significantly higher in p ink a methylated cases than in unmethylated cases, and the methylation index was higher in k-ras mutant cases than in wild-type [ ] . sqcc is defined as "a malignant epithelial tumour showing keratinization and/or intercellular bridges that arises from bronchial epithelium," in the who classification scheme [ ] . it is a common histologic type of nsclc that is closely linked to cigarette smoking. in most patients, this tumor arises in a mainstem, lobar, or segmental bronchus, producing a central mass on imaging known tumor suppressor genes and proto-oncogenes defined as found in either cosmic , cgp census , or other evidence; if there is more than one known proto-oncogene in the region, only one is listed (priority for listing is, in order: known lung adenocarcinoma mutation; known lung cancer mutation; other known mutation (by cosmic frequency); listing in cgp census). @myc is near, but not within, the peak region. ksingle gene deletions previously seen, this study provides new mutations as well. part iv molecular pathology of human disease studies. many of these tumors have an endobronchial component that can cause airway obstruction, leading to postobstructive pneumonia, atelectasis, or bronchiectasis. not infrequently, it is the pneumonia that prompts evaluation of the patient and leads to discovery of the tumor. less often, sqccs develop in the periphery of the lung. gross examination reveals a tan or gray mass that usually arises in a large bronchus and often includes an endobronchial component (figure . , figure . ). partial or complete airway obstruction can be associated with changes of pneumonia, bronchitis, abscess, bronchiectasis, or atelectasis. necrosis and cavitation are very common in these tumors. involvement of hilar lymph nodes by tan-gray tumor can be visible in some resected specimens. microscopically, the key features of this tumor are its keratinization, sometimes with formation of keratin pearls, and intercellular bridges ( figure . ). as is true of acs, the degree of differentiation of this tumor varies from very well differentiated cases, in which there are abundant keratinization and intercellular bridges and little cytoatypia, to very poorly differentiated cases, in which keratinization and intercellular bridges can be quite inconspicuous and the tumor consists of sheets of large atypical cells with marked cytoatypia and frequent mitoses. however, most cases fall more toward the middle of the spectrum. invasiveness is reflected by the presence of irregular nests and sheets of cells that infiltrate through tissues, stimulating a fibroblastic response, or by cells inside vascular or lymphatic spaces. invasive sqccs are often accompanied by sqcc in situ and dysplasia, their precursor lesions. these lesions arise in the bronchi and may be contiguous with the invasive tumor or exist as one or more separate foci. these precursor lesions can also be observed without coexisting invasive carcinoma. like sqcc, tobacco smoking is the main predisposing factor for sqcc in situ and dysplasia. unlike invasive sqcc, however, these lesions are not invasive-they do not extend through the basement membrane of the bronchial epithelium. grossly, they may be invisible or appear as flat, tan or red discolorations of the bronchial mucosa, or tan wart-like excrescences. microscopically, these lesions encompass a chapter molecular basis of pulmonary disease range of squamous changes that include alterations in the thickness of the bronchial epithelium, the maturational progress of squamous differentiation, cell size, and nuclear characteristics ( figure . , figure . ) [ , ] . as dysplasia increases from mild to moderate to severe, the epithelium thickens, and maturation is increasingly impaired. the basilar zone expands with epithelial cell crowding, the intermediate zone shrinks, and there is reduced flattening of the superficial squamous cells. cell size, pleomorphism, and anisocytosis usually increase, and there is coarsening of the chromatin and appearance of nucleoli, nuclear angulations, and folding. in carcinoma in situ, although the epithelium may or may not be thickened and the cell size may be small, medium, or large, there is minimal or no maturation from the base to the superficial aspect, and the atypical nuclear features are present throughout the entire thickness of the epithelium. mitoses appear in the lower third (mild or moderate dysplasia), lower two-thirds (severe dysplasia), or throughout the full thickness of the epithelium (carcinoma in situ). basal cells in the bronchial epithelium are believed to represent the progenitor cells for invasive sqcc, and the sequence of events leading to sqcc is believed to include basal cell hyperplasia, squamous metaplasia, squamous dysplasia, carcinoma in situ, and invasive sqcc (figure . ) [ , [ ] [ ] [ ] . regression of lesions preceding invasive sqcc can occur, particularly the earlier lesions [ ] . however, severe dysplasia and carcinoma in situ are associated with a significantly increased probability of developing invasive sqcc in patients followed over time with surveillance bronchoscopy [ ] . wistuba and colleagues evaluated sqccs and precursor lesions for loss of heterozygosity (loh) at chromosomal regions ( p , p . , p . - . , p , p - , p , q , p , q rb, and p tp ) part iv molecular pathology of human disease frequently deleted in lung cancer and found multiple, sequentially occurring allele-specific molecular changes in separate, apparently clonally independent foci, early in the pathogenesis of sqccs of the lung, suggesting a field cancerization effect [ , ] . they observed clones of cells with allelic loss at one or more regions in % percent of histologically normal epithelium and % of specimens with hyperplasia or metaplasia; increasing frequency of loh within clones with increasing histopathologic lesional severity; the most frequent and earliest regions of allelic loss at p , p - , p , and p ; increasing size of the p deletions with progressive histologic changes; and tp allelic loss in many histologically advanced lesions (dysplasia and cis) [ ] . an overview of the sequential molecular events leading to invasive sqcc is shown in figure . [ ] . large cell carcinoma is an undifferentiated nsclc without light microscopic evidence of squamous or glandular differentiation, although squamous or glandular features may be detectable by ultrastructural examination (figure . ) [ ] . histologic subtypes of large cell carcinoma include large cell neuroendocrine carcinoma (lcnec), combined lcnec, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype [ ] . clinical signs and symptoms resemble those of other types of nsclc. most tumors develop as peripheral lung masses, except for basaloid carcinomas, which usually form centrally located masses. histologically, large cell carcinomas consist of sheets and nests of large cells with vesicular nuclei, prominent nucleoli, and moderate or abundant amounts of cytoplasm. lcnecs demonstrate neuroendocrine architectural features and immunohistochemical or ultrastructural evidence of neuroendocrine differentiation. basaloid carcinomas display nests of small, monomorphic, rounded or fusiform tumor cells with little cytoplasm, numerous mitoses, comedo-type necrosis, and hyaline or mucoid stromal degeneration. clear cell carcinoma consists of large tumor cells with clear cytoplasm. precursor lesions are not currently recognized for any of the subtypes of large cell carcinoma. however, basaloid carcinoma is associated with squamous dysplasia in about one-third of cases [ ] . large cell carcinomas are poorly differentiated carcinomas that can demonstrate features of ac (most frequent), sqcc, or neuroendocrine differentiation when examined by immunohistochemistry, electron microscopy, or molecular methods [ ] . these tumors often demonstrate losses of p, q, p, q, q, and p, and gains of q and p, more closely resembling acs than other histologic types of lung cancer [ ] . common molecular abnormalities include tp mutation, c-myc amplification, and p promoter hypermethylation, while k-ras mutation is less common [ ] . egfr tyrosine kinase domain mutation is not characteristic of large cell carcinomas, and egfrviii (deletion mutations in the extracellular domain of egfr) is uncommon [ , ] . the major categories of pulmonary neuroendocrine (ne) neoplasms include small cell carcinoma (sclc), large cell neuroendocrine carcinoma (lcnec), typical carcinoid, and atypical carcinoid. sclc and lcnec are high-grade carcinomas, typical carcinoid is a low-grade malignant neoplasm, and atypical carcinoid occupies an intermediate position in the spectrum of biologic aggressiveness. in one large series, the -year and -year survival rates for typical carcinoid were % and %, % and % for atypical carcinoid, % and % for lcnec, and % and % for sclc, respectively [ ] . by light microscopy, these tumors display ne architectural features including organoid nesting, a trabecular arrangement, rosette formation, and palisading. these patterns are more prominent in carcinoids than in lcnecs and may or may not be visible in individual sclcs. typical carcinoids contain fewer than mitoses per mm ( hpf) and lack necrosis ( figure . ), while atypical carcinoids show - mitoses per mm ( hpf) or necrosis, which is often punctate [ ] . sclc consists of small, undifferentiated tumor cells with scant cytoplasm and finely granular chromatin and absent or inconspicuous nucleoli ( figure . ). nuclear molding is characteristic, necrosis is common, and the mitotic rate is typically high, with a mean of over mitoses per mm [ ] . combined differences also exist in the characteristics of patients with carcinoids, as compared to patients with sclc and lcnec. patients with carcinoids are typically younger and less likely to smoke than those with sclcs and lcnecs, the vast majority of whom have a current or previous history of tobacco smoking [ , ] . rare patients with carcinoids have the multiple endocrine neoplasia (men ) syndrome, an association that is not seen with sclcs and lcnecs. in addition, an association with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (dipnech) has been noted for carcinoids but not for sclcs and lcnecs, leading to classification of dipnech as a preinvasive lesion in the most recent version of the who classification scheme [ ] . dipnech is a diffuse proliferation of single cells, small nodules (ne bodies), and linear proliferations of pulmonary ne cells that may reside in the bronchial and/or bronchiolar epithelia ( figure . ) , and may be accompanied by extraluminal proliferations part iv molecular pathology of human disease (tumorlets and carcinoids) [ ] . however, morphologically identifiable precursor lesions for sclc and lcnec have not been established. molecular markers of pulmonary ne tumors include chromogranin a, synaptophysin (figure . ) , and n-cam (cd ). these markers are expressed by all categories of ne tumors, with higher frequencies observed in the carcinoids and atypical carcinoids than in small cell and large cell neuroendocrine carcinomas. gastrin-releasing peptide, calcitonin, other peptide hormones, the insulinoma-associated (insm ) promotor and the human achaete-scute homolog- (hash ) gene have also been reported as overexpressed by these tumors [ , ] . thyroid transcription factor- (ttf- ) is expressed by %- % of sclcs, %- % of lcnecs, and %- % of carcinoids [ ] [ ] [ ] [ ] . sclcs [ ] [ ] [ ] [ ] [ ] [ ] . more than % of sclcs and sqccs demonstrate large, often discontinuous segments of allelic loss on chromosome p, in areas encompassing multiple candidate tumor suppressor genes, including some of those listed previously [ , ] . atypical carcinoids show a higher frequency of loh at p, q, p , and p than typical carcinoids, but not as high as the high-grade ne tumors [ ] . some typical and atypical carcinoids possess mutations of the multiple endocrine neoplasia (men ) gene on chromosome q or loh at this locus [ ] , while these abnormalities occur with lower frequencies in sclcs and lcnecs, supporting separate pathways of tumorigenesis [ ] . men encodes for the nuclear protein menin, which is believed to play several roles in tumorigenesis by linking transcription factor function to histone-modification pathways, in part through interacting with the activator-protein- family transcription factor jund, modifying it from an oncoprotein into a tumor suppressor protein [ ] . oncogenes frequently amplified in sclcs include myc ( q ), mycn ( p ), and mycl ( p ), and additional amplified genes that represent candidate oncogenes include the antiapoptotic genes tnfrsf ( p ), dad ( q ), bcl l ( q ), and bcl l ( q ) [ ] . the myc proteins are transcription factors that are important in cell cycle regulation, proliferation, and dna synthesis, and can induce p arf , leading to apoptosis through p if cellular conditions do not favor proliferation [ ] . tsgs are inactivated in the majority of sclcs. eighty percent to % of sclcs demonstrate tp mutations, as compared to more than % of nsclcs, fewer atypical carcinoids, and virtually no typically carcinoids [ , ] . most of the tp mutations in sclcs are missense point mutations that result in a stabilized p mutant protein which can be easily detected by immunohistochemistry [ ] . p protein overexpression occurs frequently in high-grade ne carcinomas, but is unusual in typical carcinoids and intermediate in atypical carcinoids [ , ] . dysregulation of p produces downstream effects on bcl- and bax. antiapoptotic bcl- predominates over proapoptotic bax in the high-grade ne carcinomas, while the reverse is true for carcinoids [ ] . lcnecs resemble sclcs in their high rates of tp mutation and predominance of bcl- expression over bax expression [ ] . alterations compromising the p ink a /cyclin d /rb pathway of g arrest are consistent in high-grade pulmonary ne carcinomas ( %), primarily through loss of rb protein, but are less frequent in atypical carcinoids ( %) and are uncommon in typical carcinoids [ ] . mutations in the rb gene exist in many sclcs, with associated loss of function of the gene product [ , , ] . in another study, % of the ne carcinomas (excluding carcinoids) versus % of the non-ne carcinomas exhibited loh and loss of rb-protein expression [ ] . the hypophosphorylated form of rb protein functions as a cell cycle regulator for g arrest; cyclin d overexpression and p ink a loss produce persistent hyperphosphorylation of rb with consequent evasion of cell cycle arrest [ ] . recent data also suggest that in sclcs, overexpression of mdm (a transcriptional target of p ) or p arf loss leads to evasion of cell cycle arrest through the p and rb pathway ( figure . ) [ ] . the transcription factor e f- appears to play a role in cellular proliferation by activating genes required for s phase entry. e f- product is overexpressed in % of sclcs and % of lcnecs, and is significantly associated with a high ki index and bcl- :bax ratio > [ ] . a mediator of the proteasomal degradation of e f- , the s phase kinase-associated protein (skp ) f-box protein accumulates in high-grade ne carcinomas ( %), and its overexpression has been associated with advanced stage and nodal metastasis in pulmonary ne tumors [ ] . in the high-grade ne tumors, skp appears to interact with e f- and stimulate its transcriptional activity toward the cyclin e promoter [ , ] . telomeres play an important role in the protection of chromosomes against degradation. telomerases, the enzymes that synthesize telomeric dna strands, serve to counterbalance losses of dna during cell divisions. high telomerase activity has been noted in over % of sclcs and lcnecs [ ] [ ] [ ] versus % or fewer typical carcinoids [ , ] . expression of human telomerase mrna component (hterc) and human telomerase reverse transcriptase (htert) mrna were reported, respectively, in % and % of typical carcinoids; and in % and % of atypical carcinoids, lcnecs and sclcs, and telomere length alterations in lcnecs and sclcs were greater than in typical carcinoids [ ] . aberrant methylation of cytosine-guanine (cpg) islands in promoter regions of malignant cells is an important mechanism for silencing of tsgs (epigenetic inactivation). methylation of dna involves the transfer of a methyl group, by a dna methyltransferase, to the cytosine of a cpg dinucleotide [ ] . rassf a is a potential tsg that undergoes epigenetic inactivation in virtually all sclcs and a majority of nsclcs through hypermethylation of its promoter region [ , ] . ne tumors have lower frequencies of methylation of p , apc, and cdh (h-cadherin) than nsclcs [ ] . sclcs have higher frequencies of methylation of rassf a, cdh (e-cadherin), and rarb than carcinoids [ ] . promoter methylation of casp , which encodes the apoptosis-inducing cysteine protease caspase , was also found in % of sclcs, % of carcinoids, and no nsclcs, suggesting that casp may function as a tsg in ne lung tumors [ ] . although histologically defined precursors for sclc are lacking, a higher incidence of genetic abnormalities is found in the normal or hyperplasic airway epithelium of patients with sclc than nsclc [ ] . by extension, it has been suggested that sclc may arise directly from histologically normal or mildly abnormal epithelium, rather than evolving through a sequence of recognizable histologic intermediary changes [ ] . relatively little is known about molecular abnormalities in precursors of carcinoids. although carcinoids have been viewed as arising from tumorlets, q (int- ) allelic imbalance is significantly more common in carcinoids ( %) than in tumorlets ( %), and may represent an early event in carcinoid tumor formation [ ] . the int- gene lies in close proximity to men , a tumor suppressor gene frequently mutated in ne tumors [ ] . the molecular pathology of dipnech remains to be elucidated. mesenchymal neoplasms included in the who classification scheme (table . ) encompass a spectrum of malignant and benign proliferations that show differentiation along multiple lineages. overall, these tumors are much less common in the lung than are epithelial neoplasms. information about molecular pathogenesis has emerged for some of the mesenchymal neoplasms. pulmonary inflammatory myofibroblastic tumor (imt) is a lesion composed of myofibroblastic cells, collagen, and inflammatory cells that primarily occurs in individuals less than years of age, and is the most common endobronchial mesenchymal lesion in childhood ( figure . ) [ ] . synovial sarcoma is usually a soft tissue malignancy, but uncommonly arises in the pleura or the lung and often takes an aggressive course [ ] . pulmonary hamartomas are benign neoplasms consisting of mixtures of cartilage, fat, connective tissue, and smooth muscle, which present as coin lesions on chest radiographs and are excised in order to rule out a malignancy ( figure . ). many imts demonstrate clonal abnormalities with rearrangements of chromosome p and the anaplastic lymphoma kinase (alk) gene [ ] . the rearrangements involve fusion of tropomyosin (tpm) n-terminal coiled-coil domains to the alk c-terminal kinase domain, producing two alk fusion genes, tpm -alk and tpm -alk, which encode oncoproteins with constitutive kinase activity [ ] . like their soft tissue counterparts, more than % of pulmonary and pleural synovial sarcomas demonstrate a chromosomal translocation t(x; ) (syt-ssx) [ , ] . detection of this translocation can be very helpful for confirming the diagnosis of synovial sarcoma in this unusual location. most pulmonary hamartomas show abnormalities of chromosomal bands p , q - , or other regions [ ] , corresponding to mutations of high-mobility group (hmg) proteins, a family of nonhistone chromatin-associated proteins that serve an important role in regulating chromatin architecture and gene expression [ ] . malignant mesothelioma (mm) is an uncommon, aggressive tumor arising from mesothelial cells on serosal surfaces, primarily the pleura and peritoneum, and less often the pericardium or tunica vaginalis. the most important risk factor for mm is exposure to the subset of asbestos fibers known as amphiboles (crocidolite and amosite) [ ] . the incidence of this tumor in the united states peaked in the early to mid- s, and appears to be declining, likely related to decreases in the use of amphiboles since their peak period of importation in the s [ ] . these tumors are characterized by long latency periods between asbestos exposure and clinical presentation of the tumor, with a mean of - years [ ] . radiation, a nonasbestos fiber known as erionite, and potentially other processes associated with pleural scarring have also been implicated in the causation of smaller numbers of cases of malignant mesothelioma [ ] , and a role for simian virus (sv ) in the genesis of this tumor has been suggested by some, but remains controversial [ , ] . pleural mm most commonly arises in males over the age of . presenting features typically include a hemorrhagic pleural effusion associated with shortness of breath and chest wall pain. weight loss and malaise are common. by the time the tumor is discovered, patients usually have extensive involvement of the pleural surfaces. with progression, the tumor typically invades the lung, chest wall, and diaphragm. lymph node metastasis can cause superior vena caval obstruction, and cardiac tamponade, subcutaneous nodules, and contralateral lung involvement can also occur. from the time of diagnosis, the median survival is months [ ] . treatment may include surgery, chemotherapy, radiotherapy, immunotherapy, or other treatments, often in combination [ ] . the intent of surgery is usually palliative. whether extrapleural pneumonectomy with chemotherapy and radiotherapy can lead to cure is unclear [ ] . new agents are currently under investigation for their potential to improve the life expectancy and quality of life in patients with this aggressive malignancy. gross pathologic features of mm include pleural nodules which grow and coalesce to fill the pleural cavity and form a thick rind around the lung. a firm tan appearance is common, and occasionally the tumor can have a gelatinous consistency (figure . ). extension along the interlobar fissures and invasion into the adjacent lung, diaphragm, and chest wall are characteristic. further spread can occur into the pericardial cavity and around other mediastinal structures, and distant metastases can also develop. histologically, mm manifests a wide variety of histologic patterns. the major histologic categories include epithelioid mesothelioma, sarcomatoid mesothelioma, desmoplastic mesothelioma, and biphasic mesothelioma [ ] . epithelioid mesothelioma consists of round, ovoid, or polygonal cells with eosinophilic cytoplasm and nuclei that are usually round with little cytoatypia (figure . ). these cells most often form sheets, tubulopapillary structures, or gland-like arrangements, and some tumors can have a myxoid appearance due to production of large amounts of hyaluronate. sarcomatoid mesothelioma is composed of malignant-appearing spindle cells occasionally accompanied by mature sarcomatous components (osteosarcoma, chondrosarcoma, others). desmoplastic mesothelioma can be a diagnostic challenge due to its frequently bland appearance and resemblance to organizing pleuritis. it consists of variably atypical spindle cells in a dense collagenous matrix ( figure . ). helpful features for separating figure . malignant mesothelioma. the tan/white tumor involves the entire pleura surrounding and compressing the underlying parenchyma, which appears congested but relatively unremarkable. chapter molecular basis of pulmonary disease this tumor from organizing pleuritis include invasion of chest wall muscle or adipose tissue and necrosis. biphasic mesotheliomas include both epithelioid and sarcomatoid elements, each comprising at least % of the tumor [ ] . pathologic diagnosis of mm has been greatly assisted by the expanded availability of antibodies for use in immunohistochemistry [ ] . mesothelial differentiation can be supported by immunoreactivity with cytokeratin / , calretinin ( figure . ), hbme- , d - , and other antibodies. histologic distinction of epithelioid mesotheliomas from metastatic acs is a common need in practice, and a panel approach using calretinin and cytokeratin / , with other antibodies reactive with acs (cea, moc- , ber-ep , leu m , b . , and others) will usually be successful. electron microscopy can also be helpful in difficult cases by demonstrating long thin microvilli in many mms with an epithelioid component. pan-cytokeratin staining is helpful for supporting a diagnosis of sarcomatoid or desmoplastic mm as opposed to sarcoma, since most (but not all) sarcomas will not stain for pan-cytokeratin. other mesothelial and mesenchymal markers can also be useful for assisting in the differentiation of mm from histologically similar sarcomas. precursor lesions for mm have not been clearly defined from a histologic standpoint, although it is likely that an in situ stage exists [ ] . the term atypical mesothelial hyperplasia has been recommended for surface (noninvasive) proliferations of mesothelial cells of uncertain malignant potential [ ] . exposure to asbestos fibers is believed to trigger the pathobiological changes leading to the majority of mms. currently, it is believed that asbestos may act as an initiator (genetically) and promoter (epigenetically) in the development of mms [ ] . the degree to which tumorigenesis results from direct interactions of the fibers with the mesothelial cells, or through other mechanisms involving oxidative stress (or both), is unresolved [ , ] . multiple chromosomal alterations are often noted in mms, and inactivation of tsgs plays an important part in the pathogenesis of mm [ ] . a variety of genetic abnormalities have been reported including deletions of p - , p , p, q, q, p , q - , q, and proximal q, monosomy , and gains of q, p, p, q - , and q - part iv molecular pathology of human disease [ , ] . the most common genetic abnormality in mm is a deletion in p encompassing the cdkn a locus encoding the tumor suppressors p ink a and p arf , which participate in the p and rb pathways and inhibit cell cycle progression ( figure . ) [ , ] . recent studies have shown that sv large t antigen (present in some mms) inactivates the tsg products rb and p , raising the possibility that asbestos and sv could act as co-carcinogens in mm and suggesting that perturbations of rb-and p -dependent growth-regulatory pathways may be involved in the pathogenesis of mm [ ] . other common findings include inactivating mutations with allelic loss in the tsg neurofibromin (nf ), found at chromosome q [ ] , and inactivation of cdkn a/p arf and gpc (another tsg) by promoter methylation [ ] . loss of cdkn a/ p arf also results in mdm -mediated inactivation of p [ ] . however, in mms, unlike many other epithelial tumors, mutations in the tp , rb, and ras genes are rare [ ] . the wnt signal transduction pathway is also abnormally activated in mms and appears to play a role in pathogenesis [ ] . activation of the pathway leads to accumulation of b-catenin in the cytoplasm and its translocation to the nucleus. interactions with tcf/ lef transcription factors promote expression of multiple genes including c-myc and cyclin d. the mechanism of activation does not appear to involve mutations in the b-catenin gene, but may instead involve more upstream components of the pathway, such as the disheveled proteins [ ] . recent evidence also suggests that the phosphatidylinositol -kinase (pi -k/akt) pathway is frequently activated in mms, and that inhibition of this pathway can increase sensitivity to a chemotherapeutic agent [ ] . the wilms' tumor gene (wt ) is also expressed in most mms, but its role in the pathogenesis of mm is unclear [ ] . finally, egfr signaling in mms has recently become a focus of greater attention, and there are some data showing that the egfr is an early cell membrane target of asbestos fibers and is linked to activation of the mapk cascade [ ] . unfortunately, a phase ii clinical trial of gefitinib treatment in patients with mms did not show effectiveness, despite egfr overexpression in over % of cases [ ] . another study found that common egfr mutations conferring sensitivity to gefitinib are not prevalent in human malignant mesothelioma [ ] . further investigation continues into new, potentially efficacious agents for the treatment of mm. non-neoplastic pulmonary pathology comprises inflammatory and fibrosing diseases of the conducting airways, alveoli, vessels, and lymphoid tissue. this pathology may be localized or diffuse, may either have an obvious etiology or be idiopathic, and may cause injury that is reparable or irreparable. most importantly, an understanding of non-neoplastic lung pathology plays a vital role in the clinical management of these diseases. this section covers the major types of obstructive and interstitial diseases, the vascular lesions, the pneumonias, the occupational diseases, the major histiocytic conditions, and the most common developmental anomalies. this list does not include all of the non-neoplastic diseases that can affect the lung, but it represents those that are responsible for the majority of illness. also, the conditions highlighted within each of these categories are those about which we best understand the molecular biology of the disease mechanisms. obstructive lung diseases are characterized by a reduction in airflow due to airway narrowing. this airflow reduction occurs, in general, by two basic mechanisms: (i) inflammation and injury of the airway, resulting in obstruction by mucous and cellular debris within and around the airway lumen; and (ii) destruction of the elastin fibers of the alveolar walls, causing loss of elastic recoil and subsequent premature collapse of the airway during the expiratory phase of respiration. there are four major obstructive lung diseases: asthma, emphysema, chronic bronchitis, and bronchiectasis. asthma is a chronic inflammatory disease of the airways that affects more than million people worldwide. the prevalence of disabling asthma has increased over % since , ranging from as low as % in rural ethiopia to over % among children in parts of central and south america [ ] . in the united states, asthma affects approximately %- % of the population and is the leading cause of hospitalization among children less than years of age [ ] . clinically, the disease is defined as a generalized obstruction of airflow with a reversibility that can occur spontaneously or with therapy. it is characterized by recurrent wheezing, cough, or shortness of breath resulting from airway hyperactivity and mucus hypersecretion. the hyperresponsiveness is a result of acute bronchospasm and can be elicited for diagnostic purposes using histamine or methacholine challenges. the key feature of these symptoms is that they are variable-worse at night or in the early morning, and in some people worse after exercise. it has previously been assumed that these symptoms are separated by intervals of normal physiology. however, evidence is now accumulating that asthma can cause progressive lung impairment due to chronic morphologic changes in the airways. the treatment strategies for this complex disease are myriad. in atopic individuals, allergen avoidance should be the primary therapy. for example, in children, reducing exposure to house dust mites early in life decreases sensitization and the incidence of disease. for those who do develop the disease, avoidance of allergens later in life improves symptom control. established treatments for asthma flairs include inhaled corticosteroids, and short-acting and long-acting b -adrenoceptor agonists. phosphodiesterase (pde) inhibitors such as theophylline have been used for decades to treat asthmatic bronchoconstriction, but both cardiac and central nervous systems side effects have limited their use. newer pde inhibitors without side effects include non-xanthine drugs such as rofumilast. the pathologic changes to the airways in asthma are very similar to those seen in chronic bronchitis. they consist of a thickened basement membrane with epithelial desquamation, goblet cell hyperplasia, and subepithelial elastin deposition. in the wall of the airway, smooth muscle hypertrophy and submucosal gland hyperplasia are also present ( figure . ). in acute asthma exacerbations, a transmural chronic inflammatory infiltrate with variable amounts of eosinophilia may be present, resulting in epithelial injury and desquamation that can become quite pronounced. one sees clumps of degenerating epithelial cells mixed with mucin in the lumen airway. these aggregates of degenerating cells are referred to as creola bodies and can be seen in expectorated mucin from these patients. also present in these sputum samples are charcot-leyden crystals, rhomboid-shaped structures that represent breakdown products from eosinophil cytoplasmic granules ( figure . ). the changes seen in the walls of these airways represent long-term airway remodeling caused by prolonged inflammation. this remodeling may play a role in the pathophysiology of asthma. the amount of airway remodeling is highly variable from patient to patient, but remodeling has been found even in patients with mild asthma. currently, the effect of the treatment on this chronic pathology is unclear [ ] . the pathogenesis of asthma is complex, and most likely involves both genetic and environmental components. most experts now see it as a disease in which an insult initiates a series of events in a genetically susceptible host. no single gene accounts for the familial component of this disease. genetic analysis of these patients reveals a prevalence of specific hla alleles, polymorphisms of fc erib, il- , and cd [ , ] . asthma can be classified using a number of different schema. most commonly, asthma is divided into two categories: atopic (allergic) and nonatopic (nonallergic). atopic asthma results from an allergic sensitization usually early in life and has its onset in early childhood. nonatopic asthma is late-onset and, though the immunopathology has not been as well studied, probably has similar mechanisms to atopic asthma. although this nosology is convenient for purposes of understanding the mechanisms of the disease, most patients manifest a combination of these two categories with overlapping symptoms. th pathogenetic mechanisms of both types encompass a variety of cells and their products. these include airway epithelium, smooth muscle cells, fibroblasts, mast cells, eosinophils, and t-cells. the asthma response includes two phases: an early response comprising an acute bronchospastic event within - minutes after exposure, and a late response that peaks approximately - hours and that can have prolonged effects. if one wants to understand this complex response, it is best to divide it into three components: (i) a type hypersensitivity response, (ii) acute and chronic inflammation, and (iii) bronchial hyperactivity. type hypersensitivity in general, human asthma is associated with a predominance of type helper cells with a cd þ phenotype. these th -type cells result from the uptake and processing of viral, allergen, and environmental triggers that initiate the episode. the processing includes the presentation of these triggers by the airway dendritic cells to naive t-cells (th ), resulting in their differentiation into populations of th and th . the th differentiation is a result of il- release by the dendritic cells, and the th cells then part iv molecular pathology of human disease further propagate the inflammatory reaction in two ways. first, they release a variety of cytokines such as il- , il- , and il- that mediate a wide variety of responses. il- and il- stimulate b-cells and plasma cells to produce ige, which, in turn, stimulates mast cell maturation and the release of multiple mediators, including histamine and leukotrienes. second, these th cells secrete il- that, together with il- , also stimulates mast cells to secrete histamine, tryptase, chymase, and the cysteinyl leukotrienes causing the bronchoconstrictor response that occurs rapidly after the exposure to the allergen. il- from these lymphocytes also recruits eosinophils to the airways and stimulates the release of the contents of their granules, including eosinophil cationic protein (ecp), major basic protein (mbp), eosinophil peroxidase, and eosinophil-derived neurotoxin. these compounds not only induce the bronchial wall hyperactivity but are also responsible for the increased vascular permeability that produces the transmural edema in the airways. the cells can differentiate into th cells as a result of il- produced by dendritic cells. these th cells produce interferon-gamma (ifn-g), il- , and lymphotoxin, which play a role in macrophage activation in delayedtype hypersensitivity reactions as seen in diseases such as rheumatoid arthritis and tuberculosis [ ] . these th cells are predominantly responsible for defense against intracellular organisms and are more prominent in normal airways and in airways of patients with emphysema than in asthmatics. however, in severe forms of asthma, th cells are recruited and have the capacity to secrete tumor necrosis factor (tnf)-a and ifn-g, which may lead to the tissue-damaging immune response one sees in these airways (figure . ) [ , ] . acute and chronic inflammation the role of acute and chronic inflammatory cells, including eosinophils, mast cells, macrophages, and lymphocytes, in asthma is evident in the abundance of these cells in airways, sputum, and bronchoalveolar samples from patients with this disease. the number of eosinophils in the airways correlates with the severity of asthma and the amount of bronchial hyperresponsiveness. proteins released by these cells including ecp, mcp, and eosinophil-derived neurotoxin cause at least some of the epithelial damage seen in the active form of asthma. neutrophils are prominent in the more acute exacerbations of asthma and are probably recruited to these airways by il- , a potent neutrophil chemoattractant released by airway epithelial cells [ ] . these cells also release proteases, reactive oxygen species (ros), and other proinflammatory mediators that, in addition to the epithelial damage, also contribute to the airway destruction and remodeling that occurs in the more chronic forms of this disease. the susceptibility of the epithelium in asthma to this oxidant injury may be increased due to decreased antioxidants such as superoxide dismutase in these lungs [ ] . finally, mast cells are activated to release an abundance of mediators through the binding of ige to fceri, high-affinity receptors on their surface. allergens bind to ige molecules and induce a cross-linking of these molecules, leading to activation of the mast cell and release of a number of mediators, most notably histamine, tryptase, and various leukotrienes, including leukotriene d (ltd ), and interact with the smooth muscle to induce contraction and the acute bronchospastic response [ ] . allergen bronchial hyperactivity the cornerstone of asthma is the hyperactive response of the airway smooth muscle. the mechanism by which this occurs combines neural pathways and inflammatory pathways. as stated, the inflammatory component of this response comes predominantly from the mast cells. the major neural pathway involved is the nonadrenergic noncholinergic (nanc) system. although cholinergic pathways are responsible for maintaining the airway smooth muscle tone, it is the nanc system that releases bronchoactive tachykinins (substance p and neurokinin a) that bind to nk receptors on the smooth muscle and cause the constriction that characterizes the acute asthmatic response [ ] . in addition to these acute mechanisms, the airway also undergoes structural alterations to its formed elements. in the mucosa, these changes include goblet cell hyperplasia and basement membrane thickening. within the submucosa and airway wall, increased deposition of collagen and elastic fibers results in fibrosis and elastosis, and both the smooth muscle cells and the submucosal glands undergo hypertrophy and hyperplasia. these irreversible changes are a consequence of chronic inflammatory insults on the airways through mechanisms that include release of fibrosing mediators such tgfb and mitogenic mediators such as epidermal and fibroblast growth factors (egf, fgf). the exact mechanisms by which this occurs are not clearly defined, but the similarity of these factors with those involved in branching morphogenesis of the developing lung has led to a focus on the effect of inflammation on the interaction of the epithelium with the underlying mesenchymal cells [ ] . the term chronic obstructive pulmonary disease (copd) applies to emphysema, chronic bronchitis, and bronchiectasis, those diseases in which airflow limitation is usually progressive, but, unlike asthma, not fully reversible [ ] . the prevalence of copd worldwide is estimated at %- % in adults over the age of [ ] . though there are different forms of copd with different etiologies, the clinical manifestations of the most common forms of the disease are the same. these include a progressive decline in lung function, usually measured as decreased forced expiratory flow in second (fev ), a chronic cough, and dyspnea. emphysema and chronic bronchitis are the most common diseases of copd and are the result of cigarette smoking. as such, they usually exist together in most smokers. chronic bronchitis is defined clinically as a persistent cough with sputum production for at least months in at least consecutive years without any other identifiable cause. patients with chronic bronchitis typically have copious sputum with a prominent cough, more commonly get infections, and typically experience hypercapnia and severe hypoxemia, giving rise to the clinical moniker blue bloater. emphysema is the destruction and permanent enlargement of the air spaces distal to the terminal bronchioles without obvious fibrosis [ ] . these patients have only a slight cough, while the overinflation of the lungs is severe, inspiring the term pink puffers. the pathologic features of copd are best understood if one considers the whole of copd as a spectrum of pathology that consists of emphysematous tissue destruction, airway inflammation, remodeling, and obstruction [ ] . the lungs of patients with copd usually contain all of these features, but in varying proportions. the pathologic features of chronic bronchitis include mucosal pathology that consists of epithelial inflammation, injury, and regenerative epithelial changes of squamous and goblet cell metaplasia. in addition, the submucosa shows changes of remodeling with smooth muscle hypertrophy and submucosal gland hyperplasia. these changes are responsible for the copious secretions characteristic of this clinical disease, although studies have reported no consistent relationship between these pathologic features of the large airways and the airflow obstruction [ ] . the pathology definition of emphysema is an abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of the alveolar walls without fibrosis [ ] . the four major pathologic patterns of emphysema are defined by the location of this destruction. these include centriacinar, panacinar, paraseptal, and irregular emphysema. the first two of these are responsible for the overwhelming majority of the clinical disease. centriacinar emphysema (sometimes referred to as centrilobular) represents % of the cases and is a result of destruction of alveoli at the proximal and central areas of the pulmonary acinus, including the respiratory bronchioles ( figure . ). it predominantly affects the upper lobes the remaining two types of emphysema, paraseptal and irregular, are rarely associated with clinical disease. in paraseptal emphysema, the damage is to the distal acinus, the area that abuts the pleura at the margins of the lobules. damage in this area may cause spontaneous pneumothoraces, typically in young, thin men [ ] . irregular emphysema is tissue destruction and alveolar enlargement that occurs adjacent to scarring, secondary to the enhanced inflammation in the area. though this is a common finding in a scarred lung, it is of little if any clinical significance to the patient. though the emphysema in these lungs plays the dominant role in causing the obstruction, small airway pathology is also present. respiratory bronchiolitis refers to the inflammatory changes found in the distal airways of smokers. these consist of pigmented macrophages filling the lumen and the peribronchiolar airspaces and mild chronic inflammation and fibrosis around the bronchioles (figure . ). the pigment in these macrophages represents the inhaled particulate matter of the cigarette smoke that has been phagocytized by these cells. the macrophages in turn release proteases, which destroy the elastic fibers in the surrounding area, resulting in the loss of elastic recoil and the obstructive symptoms. in general, copd is a result of inflammation of the large airways that produces the airway remodeling characteristic of chronic bronchitis as well as inflammation of the smaller airways that results in the destruction of the adjacent tissue and consequent emphysema. the predominant inflammatory cells involved in this process are the alveolar macrophages, neutrophils, and lymphocytes. the main theories of the pathogenesis of copd support the interaction of airway inflammation with two main systems in the lung: the protease-antiprotease system and the oxidant-antioxidant system. these systems help to protect the lung from the many irritants that enter the lung via the large pulmonary surface area that interfaces with the environment. in the protease-antiprotease system, proteases are produced by a number of cells, including epithelial cells and inflammatory cells that degrade the underlying lung matrix. the most important proteases in the lung are the neutrophil elastases, part of the serine protease family, and the metalloproteinases (mmps) produced predominantly by macrophages. these proteases can be secreted in response to invasion by environmental irritants, most notably infectious agents such as bacteria. in this setting, their role is to enzymatically degrade the organism. however, proteases can also be secreted by both inflammatory and epithelial cells in a normal lung to repair and maintain the underlying lung matrix proteins [ ] . to protect the lung from unwanted destruction by these enzymes, the liver secretes antiproteases that circulate in the bloodstream to the lung and inhibit the action of the proteases. in addition, macrophages that secrete mmps also secrete tissue inhibitors of metalloproteinases (timps). a delicate balance of proteases and antiproteases is needed to maintain the integrity of the lung structure. an imbalance that results in a relative excess of proteases (either by overproduction of proteases or underproduction of their inhibitors) leads to tissue destruction and the formation of emphysema. this imbalance occurs in different ways in the two major types of emphysema: centriacinar and panacinar. in centriacinar emphysema, caused primarily by cigarette smoking, there is an overproduction of proteases primarily due to the stimulatory effect of chemicals within the smoke on the neutrophils and macrophages. though the exact mechanism is not completely understood, most studies support that nicotine from the cigarette smoke acts as a chemoattractant, and ros also contained in the smoke, stimulate an increased release of neutrophil elastases and mmps from activated macrophages, leading to the destruction of the elastin in the alveolar spaces [ ] . this inflammatory cell activation may come about through the activation of the transcription factor nfkb that leads to tnfa production [ ] . in addition, the elastin peptides themselves may attract additional inflammatory cells to further increase the protease secretion and exacerbate the matrix destruction [ ] . unlike centriacinar emphysema, panacinar emphysema is most commonly caused by a genetic deficiency of antiproteases, usually due to alpha- anti-trypsin (aat) deficiency, a condition that affects approximately , people in the united states [ ] . aat deficiency is due to a defect in the gene that encodes the protein aat, a glycoprotein produced by hepatocytes and the main inhibitor of neutrophil elastase. the affected gene is the serpina gene (formerly known as p ), located on the long arm of chromosome ( q - . ). the genetic mutations that occur have been categorized into four groups: base substitution, in-frame deletions, frame-shift mutations, and exon deletions. these mutations usually result in misfolding, polymerization, and retention of the aberrant protein within the hepatocytes, leading to decreased circulating levels. aat deficiency is an autosomal codominant disease with over allelic variants, of which the m alleles (m -m ) are the most common; these alleles produce normal serum levels of a lessactive protein [ ] . individuals who manifest the lung disease are usually homozygous for the alleles z or s (zz and ss phenotype) or heterozygous for the m alleles (mz, or sz phenotype) [ ] . an aat concentration in plasma of less than % of normal confers a risk for emphysema [ ] . in individuals with the zz genotype, the activity of aat is approximately one-fifth of normal [ ] . the second system in the lung involved in the pathogenesis of emphysema is the oxidant-antioxidant system. as in the protease system, the lung is protected from oxidative stress in the form of ros by antioxidants produced by cells in the lung. ros in the lung include oxygen ions, free radicals, and peroxides. the major antioxidants in the airways are enzymes including catalase, superoxide dismutase (sod), glutathione peroxidase, glutathione s-transferase, xanthine oxidase, and thioredoxin, as well as nonenzymatic antioxidants including glutathione, ascorbate, urate, and bilirubin [ ] . the balance of oxidants and antioxidants in the lung prevents damage by ros. however, cigarette smoke increases the production of ros by neutrophils, eosinophils, macrophages, and epithelial cells [ ] . evidence that damage to the lung epithelium and matrix is a direct result of ros includes the presence of exhaled h o and -isoprostane, decreased plasma antioxidants, and increased plasma and tissue levels of oxidized proteins, including various lipid peroxidation products. in addition to this direct effect, ros may also induce a proinflammatory response that recruits more inflammatory cells to the lung. in animal models, cigarette smoke induces the expression of proinflammatory cytokines such as il- , il- , tnfa, and il- from macrophages, epithelial cells, and fibroblasts, perhaps through activation of the transcription factor nfkb [ , ] (figure . ) . finally, there is some evidence that cigarette smoke further disturbs the oxidant-antioxidant balance in the lung by depleting antioxidants such as ascorbate and glutathione [ ] . bronchiectasis represents the permanent remodeling and dilatation of the large airways of the lung most commonly due to chronic inflammation and recurrent pneumonia. these infections usually occur because airway secretions and entrapped organisms cannot be effectively cleared. this pathology dictates the clinical features of the disease, which include chronic cough with copious secretions and a history of recurrent pneumonia. the five major causes of bronchiectasis are infection, obstruction, impaired mucociliary defenses, impaired systemic immune defenses, and congenital. these may produce either a localized or diffuse form of the disease. localized bronchiectasis is usually due to obstruction of airways by mass lesions or scars from previous injury or infection. diffuse bronchiectasis can result from defects in systemic immune defenses in which either innate or adaptive immunity may be impaired. diseases due to the former include chronic granulomatous disease (cgd), and diseases due to the latter include agammaglobulinemia/hypogammaglobulinemia and severe combined immune deficiencies. defects in the mucociliary defense mechanism that is responsible for physically clearing organisms from the lung may also cause diffuse bronchiectasis. these include ciliary dyskinesias that result in cilia with aberrant ultrastructure and cystic fibrosis (cf). congenital forms of bronchiectasis are rare but do exist. the most common include mounier-kuhn's syndrome and williams-campbell syndrome, the former causing enlargement of the trachea and major bronchi due to loss of bronchial cartilage, and the latter causing diffuse bronchiectasis of the major airways probably due to a genetic defect in the connective tissue [ , ] . the pathology of bronchiectasis is most dramatically seen at the gross level. one can see dilated airways containing copious amounts of infected secretions and mucous plugs localized either to a segment of the lung or diffusely involving the entire lung as in cystic fibrosis (figure . ) . microscopic features include chronic inflammatory changes similar to those of chronic bronchitis but with ulceration of the mucosa and submucosa leading to destruction of the smooth muscle, and elastic in the airway wall and the characteristic dilatation and fibrosis. these enlarged airways contain mucous plugs comprising mucin and abundant degenerating inflammatory cells, a result of infections that establish themselves in these airways following the loss of the mucociliary defense mechanism. bacteria may be found in these plugs, most notably p. aeruginosa. the pathogenetic mechanism of bronchiectasis is complex and depends on the underlying etiology. in general, the initial damage to the bronchial epithelium is due to aberrant mucin (cystic fibrosis), dysfunctional cilia (ciliary dyskinesias), and ineffective immune surveillance (defects in innate and antibody-mediated immunity), leading to a cycle of tissue injury, repair, and remodeling that ultimately destroys the normal airway. the initial event in this cycle usually involves dysfunction of the mucociliary mechanism that inhibits the expulsion from the lungs of organisms and other foreign substances that invade the airways. this may be due to defects in the cilia or the mucin. ciliary defects are found in primary ciliary dyskinesia, a genetically heterogeneous disorder, usually inherited as an autosomal recessive trait that produces immotile cilia with clinical manifestations in the lungs, sinuses, middle ear, male fertility, and organ lateralization [ ] . over proteins make up the axoneme of the cilia, but mutations in genes, dnai and dnah , which encode for proteins in the outer dynein arms, most frequently cause this disorder [ ] . in cf the main defect affects the mucin. in patients with this autosomal recessive condition, there is a low volume of airway surface liquid (asl) causing sticky mucin that inhibits normal ciliary motion and effective mucociliary clearance of organisms. this is due to a defect in the cystic fibrosis transmembrane conductance regulator (cftr) gene, located on chromosome that encodes a camp-activated channel which regulates the flow of chloride ions in and out of cells and intracellular vacuoles, helping to maintain the osmolality of the mucin. this protein is present predominantly on the apical membrane of the airway epithelial cells, though it is also involved in considerable subapical, intracellular trafficking and recycling during the course of its maturation within these cells. this genetic disease manifests in multiple other organs that depend on chloride ion transport to maintain normal secretions, including the pancreas, intestine, liver, reproductive organs, and sweat glands [ ] . the genetic mutations in cf influence the cftr trafficking in the distal compartments of the protein secretary pathway, and various genetic mutations produce different clinical phenotypes of the disease. over mutations of the cftr gene have been found. however, only four of these mutations occur at a frequency of greater than %. these mutations are grouped into five classes according to their functional deficit: group i, cftr is not synthesized; group ii, cftr is inadequately processed; group iii, cftr is not regulated; group iv, cftr shows abnormal conductance; group v, cftr has partially defective production or processing. approximately % of cf patients are in group ii and have the same mutation, f d cftr, a deletion of phenylalanine at codon [ ] . in these patients, most of the cftr protein is misfolded and undergoes premature degradation within the endoplasmic reticulum, though a small amount of the cftr protein is present on the apical membrane and does function normally. cf patients may have a combination of genetic mutations from any of the five groups. however, those patients with the most severe disease involving both the lungs and pancreas usually carry at least two mutations from group i, ii, or iii [ ] . systemic immune deficiencies cause bronchiectasis through the establishment of persistent infection and inflammation. there are four major categories of immune deficiencies. the first category consists of a number of genetic diseases that cause either agammaglobulinemia or hypogammaglobulinemia. these include xlinked agammaglobulinemia (xla) and common variable immunodeficiency (cvi). xla is caused by a mutation of the bruton's tyrosine kinase (btk) gene that results in the virtual absence of all immunoglobulin isotypes and of circulating b lymphocytes. in cvi there is a marked reduction in igg and iga and/or igm, associated with defective antibody response to protein and polysaccharide antigens. as expected, both of these diseases increase susceptibility to infections from encapsulated bacteria. the second category of immune deficiency is hyper-ige syndrome, a disease with markedly elevated serum ige levels that is characterized by recurrent staphylococcal infections. the third category is chronic granulomatous disease (cgd), a genetically heterogeneous group of disorders that have a defective phagocytic respiratory burst and superoxide production, inhibiting the ability to kill staphylococcus spp. and fungi such as aspergillus spp. finally, severe combined immune deficiency (scid) comprises a group of disorders with abnormal t-cell development and b-cell and/or natural killer cell maturation and function, predisposing these patients to pneumocystis jiroveci and viral infections [ ] . after the initial insult, the subsequent steps in the development of bronchiectasis include destruction of the epithelial cells and bronchial wall connective tissue matrix by the proteases and ros secreted by the neutrophils. this proinflammatory milieu is produced by multiple factors. first, infections can persist in these lungs due to defective host immune systems and mechanisms certain organisms have developed to evade these immune defenses. for example, pseudomonas aeruginosa, changes from a nonmucoid to a mucoid variant and also releases virulence factors to protect against phagocytosis [ ] . second, in the case of cystic fibrosis, neutrophils are directly recruited by proinflammatory cytokines, such as interleukin- (il- ), released from the bronchial epithelial cells as a result of the defective cgft protein [ ] . finally, the necrotic cellular debris and other breakdown products act as chemoattractants that recruit more inflammatory cells to the airway wall, further exacerbating the damage. the final phase of the repair and remodeling begins when macrophages invade and recruit fibroblasts that secrete collagen, leading to the fibrosis seen in the pathology. however, in the absence of effective airway clearance mechanisms, these ectatic airways remain a reservoir of infection that continues the cycle of inflammation and tissue destruction. the idiopathic interstitial pneumonias (iips) comprise a group of diffuse infiltrative pulmonary diseases with a similar clinical presentation characterized by dyspnea, restrictive physiology, and bilateral interstitial infiltrates on chest radiography [ ] . pathologically, these diseases have characteristic patterns of tissue injury with chronic inflammation and varying amounts of fibrosis. by recognizing these patterns, a pathologist can classify each of these entities and predict prognosis. however, the pathologist cannot establish the etiology, since these pathologic patterns can be seen in multiple clinical settings. the pathologic classification of these diseases, originally defined by liebow and carrington in [ ] , has undergone important revisions over the past years with the latest revision by the american thoracic society/european respiratory society in [ ] . the best known and most prevalent entity of the iips is idiopathic pulmonary fibrosis (ipf), which is known pathologically as usual interstitial pneumonia (uip). uip is a histologic pattern characterized by patchy areas of chronic lymphocytic inflammation with organizing and collagenous type fibrosis. these patients usually present with gradually increasing shortness of breath and a nonproductive cough after having had symptoms for many months or even years. imaging studies usually reveal bilateral, basilar disease with a reticular pattern [ ] . therapy begins with corticosteroids, advancing to more cytotoxic drugs such as methotrexate and cytoxan, but most current therapies are not effective in stopping the progression of the disease. the current estimates are that / , males and / , females have the disease, most of whom progress to respiratory failure and death within years [ ] . the pathology is characterized by a leading edge of chronic inflammation with fibroblastic foci that begin in different areas of the lung at different times. these processes produce a variegated pattern of fibrosis, usually referred to as a temporally heterogenous pattern of injury [ ] . because it occurs predominantly in the periphery of the lung involving the subpleura and interlobular septae, the gross picture is one of more advanced peripheral and basilar disease (figure . ) . the progression from inflammation to fibrosis includes interstitial widening, epithelial injury and sloughing, fibroblastic infiltration, and organizing fibrosis within the characteristic fibroblastic foci. deposition of collagen by fibroblasts occurs in the latter stages of repair. the presence of the abundant collagen produces stiff lungs that are unable to clear the airway secretions, leading to recurrent inflammation of the bronchiolar epithelium with eventual fibrosis and breakdown of the airway structure. this remodeling produces mucousfilled ectatic spaces giving rise to the gross picture of honeycomb spaces, which is seen in the advanced pathology ( figure . ) [ ] . theories of the pathogenesis of ipf have evolved over the past decade. early theories favored a primary inflammatory process, while current theories favor the concept that the fibrosis of the lung proceeds independently of inflammatory events and develops from aberrant epithelial and epithelial-mesenchymal responses to injury to the alveolar epithelial cells (aecs) [ ] . the aecs consist of two populations: the type pneumocytes and the type pneumocytes. in normal lungs, type pneumocytes line % of the alveolar wall, and type pneumocytes line the remaining %. however, in lung injury, the type cells, which are exquisitely fragile, undergo cell death, and the type pneumocytes serve as progenitor cells to regenerate the alveolar epithelium [ ] . though some studies have suggested that repopulation of the type cells depends on circulating stem cells, this concept remains to be fully proven. according to current concepts, the injury and/or apoptosis of the aecs initiates a cascade of cellular events that produce the scarring in these lungs. studies of aecs in lungs from patients with ipf have shown ultrastructural evidence of cell injury and apoptosis as well as expression of proapoptotic proteins. further, inhibition of this apoptosis by blocking a variety of proapoptotic mechanisms such the fas-fas ligand pathway, angiotensin, and tnfa production, and caspase activation can stop the progression of this fibrosis [ ] . the result of the aec injury is the migration, proliferation, and activation of the fibroblasts and myofibroblasts that leads to the formation of the characteristic fibroblastic foci of the uip pathology and the deposition and accumulation of collagen and elastic fibers in the alveoli (figure . ). this unique pathology may be a result of the increased production of profibrotic factors such as transforming growth factor-a (tgfa) and tgfb, fibroblastic growth factor- , insulin-like growth factor- , and platelet-derived growth factor. an alternative pathway might involve overproduction of inhibitors of matrix degradation such as timps (tissue inhibitors of matrix production) [ ] . in support of the former mechanism, fibroblasts isolated from the lungs of ipf patients exhibit a profibrotic secretory phenotype [ ] . multiple factors, such as environmental particulates, drug or chemical exposures, and viruses may trigger the initial epithelial injury, but genetic factors also play a role. approximately %- % of patients with ipf have a family history of the disease with an inheritance pattern of autosomal dominance with variable penetrance. two genetic mutations have been implicated in this familial form of ipf. one large kindred has been reported with a mutation in the gene encoding surfactant protein c, and six probands have been a b reported with heterozygous mutations in genes htert or htr, encoding telomerase reverse transcriptase and telomerase rna, respectively, resulting in mutant telomerase and short telomeres [ ] . adult respiratory distress syndrome (ards) represents a constellation of clinical, radiologic, and physiologic features in patients with acute respiratory failure that can occur after a variety of insults. ards is defined by clinical criteria that include a rapid onset of severe hypoxemia that is refractory to oxygen therapy, the presence of abnormal chest radiographs with evidence of bilateral alveolar filling and collapse, increased pulmonary artery occlusion pressure, and a resistance to improved oxygenation regardless of mechanical ventilation therapy [ ] . treatment of ards includes eliminating the underlying cause, protective ventilation strategies that improve oxygenation, and supportive treatment that may include administration of corticosteroids. the pathology of ards is diffuse alveolar damage (dad), whose histologic picture is one of inflammation and fibrosis that diffusely involves all of the structures of the alveolus and is similar throughout the affected areas of the lung [ ] . dad is divided into three major phases that follow each other chronologically after the original insult. these are exudative, proliferative, and fibrotic dad. the initial injury primarily involves the epithelium of the alveolar wall and the endothelium in the capillary, causing the destruction and sloughing of the type pneumocytes into the alveolar space and a breakdown of the tight junctions of the endothelium. in combination, these two events result in the loss of the epithelial-endothelial barrier of the alveolus and leakage of plasma from the capillary into the alveolar space. this flooding of the airspace with fluid markedly decreases oxygen exchange and causes the hypoxia that these patients experience. in addition, acute inflammatory changes of the endothelium also cause thrombi to form in vessels, adding to a decreased amount of blood circulating through the lung and further compromising gas exchange. as air is brought into the alveoli, the positive pressure within the alveolar space forces the plasma against the alveolar wall, producing a membranous morphology referred to as hyalin membranes characteristic of the first phase of dad, referred to as exudative dad (figure . ) . this initial injury is followed by a sequence of events that represent the lung's efforts to repair itself. first, type pneumocytes undergo hyperplasia and re-epithelialize the alveolar wall after the loss of the type cells. this re-establishes the epithelial barrier and, because these cells secrete surfactant, results in increased surfactant production, which lowers the surface tension of the alveolus and inhibits its collapse. because of the increased numbers of type pneumocytes, this is known as the proliferative phase of dad (figure . ) . in the final phase of dad, fibrotic dad, fibroblasts migrate in from the adjacent interstitium to the alveolar space and produce organizing and irreversible fibrosis within both the alveolar space and the interstitium. in addition to this mechanism, fibrosis may also occur in those areas where alveolar walls collapse when surfactant is decreased during the initial insult. the histopathologic picture during this fibrotic phase is one of thickened alveolar septa, intra-alveolar granulation tissue, microcyst formation, and areas of irregular alveolar scarring. in rare cases, these microcysts progress to large cysts, an adult equivalent of bronchopulmonary dysplasia. the cellular events of dad are complex and incompletely understood. in general, the disease can be broken down into two phases. in the first, a large influx of neutrophils and plasma enter the alveolar space. the role the neutrophils play in the initial cellular injury and death is unclear, but it is known that they are necessary for this injury to occur. in addition, clinical studies have shown that within the peripheral blood and bronchoalveolar lavages (bal) of these patients, neutrophils are present along with a myriad of proinflammatory cytokines, such as il- , il- , and tgfa, all of which are capable of recruiting them to the lung. also present in these fluids are mediators that recruit fibroblasts such as tgfb. all of these mediators are probably the result of upregulation of nfkb, a proinflammatory transcription factor, in alveolar macrophages. the adherence of neutrophils to the capillary endothelium in the lung occurs through adhesion molecules such as selectin, integrin, and immunoglobulins. neutrophil adherence and subsequent transmigration through the endothelium of the lung capillaries may cause some endothelial damage. however, most speculate that ros and reactive nitrogen chapter molecular basis of pulmonary disease species (rns) secreted by the neutrophils modulate the majority of this injury [ ] . this is supported by the finding that patients with ards have products of oxidative damage such as hydrogen peroxide (h o ) in the exhaled breath and myeloperoxidase and oxidized aat in the bal. the cell injury and death of the type pneumocytes most likely occurs via two mechanisms: lipopolysaccharide (lps)-induced caspase-dependent apoptosis and hyperoxia-induced cell death through apoptosis and nonapoptotic mechanisms [ ] . in the former, lps, an immunogenic component of the outer membrane of gram-negative bacteria, may trigger innate immune and inflammatory responses via toll-like receptors that bind fas-associated death domain protein and caspase- , leading to epithelial cell death. in hyperoxia-induced cell death, hyperoxia may induce the expression of angiopoietin (ang ) in lung epithelial cells. ang is an angiogenic growth factor that can activate caspase pathways and lead to apoptotic cell death [ ] . cell death in ards is not limited to these mechanisms, and further study of many of pathways by which this can occur is needed. lymphangioleiomyomatosis (lam) is a rare systemic disease of women, usually in their reproductive years (average age of years), that is characterized by a proliferation of abnormal smooth muscle cells giving rise to cysts in the lungs, abnormalities in the lymphatics, and abdominal tumors, most notably in the kidneys. in addition to sporadic cases (denoted as s-lam), lam also affects % of women with tuberous sclerosis (denoted as tsc-lam), a genetic disorder with variable penetrance associated with seizures, brain tumors, and cognitive impairment [ , ] . global estimates indicate that tsc-lam may be as much as -fold to -fold more prevalent than s-lam, though at least some suggest that tsc-lam may have a milder clinical course than s-lam [ ] . clinically, lam patients usually present with increasing shortness of breath on exertion, obstructive symptoms, spontaneous pneumothoraces, and chylous effusions or with abdominal masses consisting of either angiomyolipomas and/or lymphangiomyomas. chest imaging studies characteristically reveal hyperinflation with flattened diaphragms and thin-walled cystic changes. mortality at years from the onset of symptoms is %- % [ ] . lam appears as small, thin-walled cysts ( . - . cm) randomly throughout both lungs [ ] (figure . ) . microscopically, lam lungs contain a diffuse infiltration of smooth muscle cells, predominantly around lymphatics, veins, and venules. most notably, one finds smooth muscle cells in the subpleural with hemosiderin-laden macrophages in the adjacent field, and the macrophages are also seen on bronchoalveolar lavage specimens from these patients. the hemosiderin pigment in these lungs is thought to be secondary to microhemorrhages from the obstruction of the veins ( figure . ) [ ] . the smooth muscle cells in lam react to antibodies to hmb- , a premelanosomal protein. other melanosome-like structures are also found in lam cells, suggesting that these cells have characteristics of both smooth muscle and melanosomes [ ] . the lesional cells in lam are smooth muscle-like with both spindled and epithelioid morphology [ ] . these cells are the same in both s-lam and tsc-lam part iv molecular pathology of human disease and are a clonal population although they lack other features of malignancy [ ] . molecular studies reveal that the abnormal lam cell proliferation is caused by mutations in one of two genes linked to tuberous sclerosis: tuberous sclerosis complex or (tsc or tsc ). these two genes control cell growth and differentiation through the akt/mammalian target of rapamycin (mtor) signaling pathway [ ] . in this pathway, a growth factor receptor (such as insulin or pdgf receptors) becomes phosphorylated when an appropriate ligand binds, resulting in activation of downstream effectors and ultimately akt. the gene products of tsc and tsc are hamartin and tuberin, which act as dimers to maintain rheb (a member of the ras family) in a gdp-loaded state via statins, acting as a break to the akt/mtor pathway, thereby retarding protein synthesis and cell growth. in lam cells, loss-of-function mutations in these two genes remove this inhibition, leading to enhanced rheb activation, mtor activation (with raptor), and subsequent phosphorylation of downstream molecules which result in uncontrolled cell growth, angiogenesis, and damage to the lung tissue ( figure . ) [ ] . the abnormal proliferation of lam cells is thought to damage the lung through overproduction of matrix metalloproteinases (mmps), which degrade the connective tissue of the lung architecture, destroy the alveolar integrity, and result in cyst formation with air trapping [ ] . these destructive capabilities of the lam cells are enhanced by their secretion of the angiogenic factor vegf-c, which is thought to cause the proliferation of lymphatic channels throughout the lung [ ] . sarcoidosis is a multisystemic disease that involves the lung in over % of the cases [ ] . it is most common in the - -year age group and among females. in the united states, african americans are more commonly affected than caucasians [ ] . the clinical picture of sarcoidosis is variable, but most patients present with systemic symptoms including fatigue, weight loss, and fever. the most common finding on chest imaging studies is bilateral hilar lymph node enlargement and reticular, reticulonodular, and focal alveolar opacities within the lung parenchyma [ ] . pulmonary sarcoidosis is characterized by granulomas which consist of activated histiocytes, called epithelioid histiocytes that form nodules ranging in size from - microns (figure . ) [ ] . unlike infectious granulomas that usually contain areas of central necrosis, the granulomas in pulmonary sarcoidosis are predominantly non-necrotizing [ ] . also, the granulomas in sarcoidosis follow a distribution along the lymphatics, which includes the area in the subpleural, along the interlobular septae and around the bronchovascular area containing the bronchiole and branch of the pulmonary artery (figure . ). the granulomas occur much more commonly in the upper lobes, leading to the predominant upper lobe fibrosis and bronchiectasis that can be seen in longstanding sarcoidosis [ ] . despite over years of research on sarcoidosis, the etiology remains unknown. most agree that the disease is probably a result of environmental triggers acting on a genetically susceptible host [ , ] . a genetic basis of sarcoidosis has been suggested by studies that demonstrate familial clustering and racial variation [ , ] . further, complex inheritance patterns for the disease suggest that more than one gene may be involved [ ] . several genes of the major histocompatibility complex (mhc) region of the genome have been implicated. most are clustered on the short arm of chromosome that encompasses the human leukocyte antigen (hla) domain. the hla class i mhc molecules associated with sarcoidosis are the hla-b and hla-b class i alleles [ , ] . hla class ii molecules implicated in susceptibility include the hla-dr alleles [ , ] . genes other than mhc genes thought to regulate the susceptibility to sarcoidosis include those for chemokines such as macrophage inflammatory protein- a and rantes (ccr and ccr ) [ , ] . environmental factors that have been implicated are those that are aerosolized. therefore, these environmental agents have a mode of entry into the lungs and can cause granulomas in the lung, similar to sarcoidosis. these factors can be divided into two major categories, which include infectious and noninfectious agents. the mycobacteria have been the most extensively studied organisms. however, their role in this disease remains controversial due to the difficulty in identifying them by either culture or histochemical stains in sarcoid tissue. recently, molecular techniques have been able to demonstrate mycobacterial nucleic acid in sarcoid tissue [ , ] . however, even studies using this technology have not produced consistent results, and the role of these organisms in the disease requires further study. the immune response in sarcoidosis has two major features: (i) the initial event leading to granuloma formation and (ii) the progression of this granulomatous response to either resolution or fibrosis [ ] . the formation of the granulomas, triggered by activation of tcells and antigen-presenting dendritic histiocytes, results in a release of proinflammatory cytokines and chemokines, and recruitment, activation, and proliferation of mononuclear cells, predominantly t-cells. these activated t-cells are predominantly cd -expressing t-helper (th) cells, which release ifn-g and il- . alveolar macrophages at the site release tnfa, il- , il- , and other growth factors. this results in the granuloma formation and alveolitis, the characteristic morphologic features of the disease [ ] . the second phase of this immunologic response that leads to either resolution of the disease or persistence of the granulomas and fibrosis is less well characterized. ongoing granuloma formation and inflammation may be a result of the persistent presence of antigens, the excessive synthesis of chemotactic factors, or the part iv molecular pathology of human disease persistence of the mononuclear cells within the granulomas. importantly, the role of the t-cells in these granulomas is to secrete cytokines that attract, stimulate, and ultimately deactivate the fibroblasts that are responsible for the fibrosis that is seen in the chronic disease. the balance between the profibrotic mediators such as tgfb, insulin-like growth factor-i, platelet-derived growth factor (pdgf), and the antifibrotic mediators, such as ifn-g, probably dictates the natural history of sarcoidosis in the lung [ ] . genes involved in macrophage-derived cytokines, chemokines, and mediators of fibrosis are all possible candidates for the underlying genetic cause of this complicated disease. pulmonary alveolar proteinosis (pap) is a rare disease of the lungs characterized by accumulation of surfactant in the alveolar spaces. the names alveolar proteinosis, lipoproteinosis, or perhaps most accurately phospholipoproteinosis, apply equally to this entity. pap takes three forms clinically: (i) congenital ( %), (ii) secondary ( %- %), and (iii) idiopathic or primary ( %- %) [ ] [ ] [ ] . pap arises in previously healthy adults with the median age at diagnosis of approximately years and a male-to-female ratio of . : . the clinical presentation is variable and usually includes an insidious onset of slowly progressive dyspnea, a dry cough, and other symptoms of respiratory distress, including fatigue and clubbing. however, almost one-third of patients are asymptomatic and are found clinically by abnormal chest x-rays [ , ] . the secondary form of pap can be found in patients with environmental exposures, including fine silica, aluminum, titanium dioxide, and kaolin dust [ ] . also, secondary pap may be found in patients with malignancies, most commonly hematologic malignancies such as myelogenous leukemia [ , ] . chest imaging studies in both the idiopathic and secondary forms most commonly show fine, diffuse, feathery nodular infiltrates, centered in the hilar areas, sparing the peripheral regions [ ] . on chest computerized tomographs, the infiltrates may have a geometric-type shape, sometimes referred to as crazy paving [ ] . the most prominent microscopic feature of both idiopathic and secondary pap is the filling of the alveoli with finely granular period acid-schiff-positive diastaseresistant (pasd) acellular material (figure chapter molecular basis of pulmonary disease material consists of phospholipids ( %); surfactant proteins a, b, c, and d ( %); and carbohydrate (< %) [ ] . alveolar macrophages (ams) with prominent foamy cytoplasm are commonly seen, while alveolar septa are remarkably normal in appearance. in some alveolar spaces there are denser, more solid clumps of pas-d-positive material. definitive pathologic differences between the idiopathic and secondary forms of pap have not been well documented [ , ] . the etiologies of the two adult forms of pap have been well studied with the most known about the idiopathic variant. theories of the pathogenesis of this form have focused on the abnormal accumulation of the surfactant-like material within the alveolar spaces. since the regulation of surfactant levels in the alveoli depends on appropriate synthesis, recycling, and catabolism, the two opposing hypotheses have included overproduction versus decreased degradation of this material. in normal hosts, surfactant is essential to maintaining the low surface tension needed for proper alveolar inflation and gas exchange. the critical role of maintaining the proper composition and amount of surfactant in the alveoli is performed by two cell types: type pneumocytes and alveolar macrophages [ ] . the type pneumocytes synthesize surfactant in the endoplasmic reticulum and golgi, and store it as lamellar bodies [ ] , which are then delivered to and fuse with the apical plasma membrane, secreting the surfactant into the airways [ ] . catabolism of surfactant is carried out by type pneumocytes and ams. in pap, most evidence suggests that the clearance of surfactant by the am is decreased [ , ] . the first clue as to the underlying mechanism for this defect in am function came in when studies revealed that knockout mice deficient in granulocytemacrophage colony-stimulating factor (gm-csf) develop lung lesions similar to those in patients with pap [ ] . this rather serendipitous finding prompted explorations centered on the am and the effect diminished gm-csf might have on its cellular functions. subsequent studies from humans with pap revealed an autoimmune mechanism by which a circulating neutralizing antibody to gm-csf blocked its binding to the gm-csf receptor, depressing the effect of gm-csf on the ams [ ] [ ] [ ] . neutralizing antibodies to gm-csf have most often been identified in the idiopathic variant of pap. however, recently these antibodies have also been reported in patients with secondary pap [ ] . genes that control many functions in the am are controlled by signaling pathways initiated by gm-csf binding to the am. one pathway is mediated through a transcription factor pu. that controls genes involved in surfactant degradation, among other bactericidal functions [ , ] . another transcription factor, peroxisome-proliferator-activated receptor g (pparg), is also part of a pathway activated by gm-csf. pparg controls the expression of genes involved in intracellular lipid metabolism. ams from patients with pap have a deficiency of this transcription factor, which is correctable by gm-csf therapy [ ] . overall, the lack of gm-csf-initiated signaling in ams from patients with pap leads to inhibition of both pparg and pu. pathways. this results in decreased surfactant catabolism, intracellular lipid metabolism, and the accumulation of surfactant in the alveoli (figure . ). pulmonary hypertension consists of a group of distinct diseases whose pathology is characterized by abnormal destruction, repair, remodeling, and proliferation of all compartments of the pulmonary vascular tree, including arteries, arterioles, capillaries, and veins. the classification of these diseases has undergone a number of revisions. the most recent revision (in ) groups these diseases based on both their pathologic and clinical characteristics [ ] . there are five major disease categories in the current classification system: (i) pulmonary arterial hypertension (pah); (ii) pulmonary hypertension with left heart disease; (iii) pulmonary hypertension associated with lung disease and/or hypoxemia; (iv) pulmonary hypertension due to chronic thrombotic and/or embolic disease; and (v) miscellaneous causes, including sarcoidosis, histiocytosis x, and lymphangioleiomyomatosis. the clinical course of most patients with pulmonary hypertension begins with exertional dyspnea, and progresses through chest pain, syncope, increased mean pulmonary artery pressures and, eventually, right heart failure. the rate of this clinical progression varies among patients, from a few months to many years [ ] . treatment of these diseases focuses on blocking the mediators involved in the pathogenesis of the diseases. however, current therapies rarely prevent progression of the disease, and lung transplantation provides the only hope for long-term survival. the major group of this classification, pah, can be subdivided into familial pah, idiopathic pah, pah associated with other conditions (such as connective tissue diseases, hiv, congenital heart disease), and pah secondary to drugs and toxins (such as anorexigens, cocaine, and amphetamines). in these diseases, the primary pathology is localized predominantly in the small pulmonary arteries and arterioles. however, two other diseases in this group, pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, involve predominantly other components of the pulmonary vasculature, the veins, and the capillaries, respectively. the pathologic changes seen in the pulmonary vessels of these patients primarily reflect injury to and repair of the endothelium. early pathologic changes include medial hypertrophy and intimal fibrosis that narrows and obliterates the vessel lumen. these are followed by remodeling and revascularization, producing a proliferation of abnormal endothelial-lined spaces. these structures are known as plexogenic lesions and are the pathognomonic feature of pah (figure . ) . in the most severe pathologic lesions, these abnormal vascular structures become dilated or angiomatoid-like and may develop features of a necrotizing vasculitis with transmural inflammation and fibrinoid necrosis. though the exact pathogenetic mechanism of pah remains unknown, research over the past years has begun to offer some clues. the familial form of pah, with a : female-to-male prevalence, has an autosomal dominance inheritance pattern with low penetrance. the genetic basis for this has been found to be germline mutations in the gene encoding the bone morphogenetic protein receptor type (bmpr ). these mutations account for approximately %- % of familial pah and %- % of patients with sporadic pah [ ] . approximately bmpr mutations have been identified in familial pah, each resulting in a loss of receptor function, either through alteration in transcription of the gene through missense, nonsense, or frameshift alterations in the codon or by rna spicing mistakes [ ] . the mechanism by which a single mutation to the bmpr gene induces vascular smooth muscle proliferation and decreased apoptosis that is not completely understood, but it most likely involves defects in the bmpr signaling pathway. bmpr is a receptor for a family cytokines (bmps) that are members of the tgfb superfamily of proteins that play a role in the growth and regulation of many cells, including those of the pulmonary vasculature. in the vascular smooth muscle cells of the lung, tgfb signaling causes a proliferation of smooth muscle in pulmonary arterioles, while bmpr signaling causes an inhibition of the proliferation of these cells, favoring an apoptotic environment. the bmpr signaling occurs through an activation of a receptor complex (bmpr and bmpr ) that leads to phosphorylation and activation of a number cytoplasmic mediators, most notably the smad proteins (mothers against decapentaplegic). these smad proteins, especially the smad , smad , and smad complex with smad , translocate to the nucleus where they target gene transcription that induces an antiproliferative effect in the cell. in familial pah, the bmrpr gene mutation may lead to insufficient protein product and subsequent decreased protein function, in this case decreased bmpr receptor function, decreased smad protein activation, and decreased antiproliferative effects in the vascular smooth muscle cells. the imbalance between the proproliferative effects of the tgfbs and the antiproliferative effects of the bmps results in the formation of the vascular lesions of pah (figure . ) [ , ] . despite these advances, questions regarding the pathogenesis of pah remain. most notably, why do only %- % of patients with the mutation develop clinical disease? some speculate that genes confer susceptibility but a second hit is required to develop the clinical disease, such as modifier genes or environmental triggers, perhaps drugs or viral infections [ , ] pulmonary vasculitides present as diffuse pulmonary hemorrhage and are usually caused by one of three major pulmonary vasculitis syndromes: wegener's granulomatosis, churg-strauss syndrome, and microscopic polyangiitis. all three diseases have similar clinical presentations and considerable overlap in their pathologic features as small vessel systemic vasculitides that affect the lung as well as other organs, most notably the kidney. wegener's granulomatosis (wg) is an unusual disease that affects the upper and lower respiratory tract and the kidneys. it usually presents between and years of age and is slightly more common in men than women. the clinical presentation depends on the affected organ, but when the lung is involved, hemoptysis is the major presenting symptom. chest imaging studies may show a variety of patterns, most commonly bilateral ground glass opacities with masses, usually in the lower lobes that may cavitate. immunologic testing of peripheral blood or end organ tissue can be helpful in revealing characteristic immunofluorescent staining patterns for antineutrophilic cytoplasmic antibody (anca), an antibody that targets two substances: proteinase (pr ) and myeloperoxidase (mpo). when present in either the blood or the tissue, the pattern of immunofluorescent staining can be cytoplasmic (canca) or perinuclear (panca). the former pattern is more commonly seen in wegener's granulomatosis, and the latter is more commonly seen in microscopic polyangiitis and churg-strauss syndrome (css). css is a systemic disorder defined by the presence of asthma, peripheral blood eosinophilia, and systemic vasculitis. similar to wg, it usually presents between and years of age, and a clinical diagnosis requires a history of asthma, a peripheral blood eosinophilia, neuropathy, an abnormal chest imaging study, and sinusitis. other organs involved include the heart, the central nervous system, kidneys (though less commonly than wg), gastrointestinal tract, and skin. chest imaging usually shows patchy, multifocal infiltrates; masses and cavitation are rare. laboratory tests reveal positive panca tests in % of patients. microscopic polyangiitis (mpa) is similar to both wg and css in that it is a systemic vasculitis that involves the lung and usually presents in the fourth or fifth decade of life. the clinical onset is usually sudden with fever, weight loss, myalgias, and arthralgias. the kidney is the main organ involved, and mpa is the most common cause of pulmonary-renal syndrome. lung involvement occurs in approximately % of the patients, and skin and upper respiratory tract are other common sites. similar to wg and css, anca testing is helpful with positive panca in % of patients. chest imaging usually shows bilateral infiltrates without masses, similar to css. treatment for all three diseases is immunosuppression with glucocorticoids or cyclophosphamide, and all three usually respond well, although wg has a greater relapse rate after treatment than either css or mpa [ ] . the pathology of wg, css, and mpa have overlapping features of an acute and chronic vasculitis that involves medium-and small-sized vessels in the lung. the inflammatory cell infiltrate that destroys the blood vessels is both lymphocytic and neutrophilic, and areas of fibrinoid necrosis are seen. however, in wg, there are characteristic areas of microabscesses that lead to masses of geographic necrosis with basophilia. scattered multinucleated giant cells are present, but no wellformed granulomas are seen. this helps to distinguish it from other vasculitides and infection (figure . ) . similarly, the pathology of css has distinguishing features, with the early pathology characterized by an eosinophilic pneumonia with areas of loosely formed granulomas with central necrosis containing degenerating eosinophils (figure . ). the infiltrate is predominantly eosinophils, but neutrophils, lymphocytes, and plasma cells are also present. capillaritis can be seen in wg, csg, and mpa, and all three have hemosiderin deposition present, both within alveolar macrophages and deposited in the connective tissue of the interstitium and the vessel walls. the pathogenesis of these three pulmonary hemorrhage syndromes is similar to the mechanisms of these diseases in the kidney. in general, these diseases in the lung and the kidney represent immune-mediated these lesions are thought to be the early form of the larger areas of geographic necrosis that produces the mass-like nodules found in these lungs. chapter molecular basis of pulmonary disease necrotizing vasculitides that have few or no immune deposits in the vessels but exhibit the presence of anca autoantibodies to myeloperoxidase (mpo) and proteinase (pr ), the components of primary granules of neutrophils. mpa and css are primarily diseases of mpo antibodies, and wg is primarily a disease of pr antibodies. the mechanism by which the ancas are induced is not known but may be part of an autoimmune response to environmental exposures early in life. these autoantibodies then inflict damage on the vessels through a mechanism that is not yet completely understood. one theory suggests that circulating ancas bind to pr and mpo on the surface of neutrophils and initiate a respiratory burst, degranulation, and apoptosis. ros and proteases are released and inflict endothelial and tissue damage on the adjacent vessel. the anca binding may also induce the release of proinflammatory cytokines and chemokines such as il- and tnfa that further contribute to the vascular inflammation. the second theory postulates that circulating immune complexes of excess anca antigen (mpo or pr ) and anca autoantibodies attach to the vascular endothelium and activate complement that results in the chemotaxis and adhesion of inflammatory cells, causing these cells to undergo a respiratory burst and, as in the first theory, release of ros and proteases that cause the vascular endothelial damage. in both theories, it is important to remember that mpo and pr are also present in monocytes and that anca autoantibodies may be involved with monocytes in similar ways to release inflammatory mediators [ ] . infectious diseases of the lung are a common cause of pulmonary disease given the constant exposure of the lungs to the environment. various organisms are capable of causing these infections, including common viruses and bacteria, as well as more uncommon fungi, parasites, and protozoa. the diagnosis of the specific etiologic agent can be challenging given that most have similar clinical features and many are difficult to identify in the lung tissue. this brief overview of the defense mechanisms the lung uses to protect itself will serve to introduce the pathology of these lung infections. the lung has multiple anatomic mechanisms by which it defends itself against invasion by various pathogens. first, the upper nasal cavities and respiratory tract serve as anatomic barriers to inhaled organisms. the ciliated epithelium and torturous cavities of the sinuses screen large organisms (typically larger than microns). for those particles that venture further down the respiratory tract, the cough reflex that the upper trachea elicits serves to expel them up and out. second, the mucociliary tree of the upper respiratory tract captures organisms that evade these two mechanisms. the bronchial epithelium contains cilia of up to microns in length that extend into the air surface liquid (asl). the asl is a bilayer of - microns in thickness consisting of a low-viscosity or watery lower layer that is covered by a high-viscosity or gel upper layer secreted by adjacent goblet cells. this sticky upper layer serves to trap organisms, and the coordinated beating of the cilia moves these entrapped invaders up this mucociliary escalator to the larynx, where they can be expectorated. present in the secretions of the large airways and within the surfactant lining the alveolar walls are soluble mediators secreted by various cells. these mediators include lysozyme and lactoferrin, which lyse bacteria and inhibit their growth; the defensins and cathelicidins, small peptides both with microbicidal properties; and surfactant proteins a and d at the alveolar level, which bind to microorganism and enhance phagocytosis and also have direct bactericidal activity [ ] . the major cells of the innate immune response of the lung are the alveolar macrophages (am) and the polymorphonuclear leukocytes (pmn). neutrophils phagocytize and destroy bacteria such as s. aureus, s. pneumoniae, and h. influenzae through a respiratory burst that generates nadph oxidase-dependent ros. in some instances, ams may ingest but not kill an organism. this occurs with such organisms as mycobacterium spp., nocardia spp., and legionella spp. because of the ability of these organisms to continue to replicate within part iv molecular pathology of human disease the am, cell-mediated immunity is required for their complete elimination. patients with defects in nadph oxidase are especially prone to respiratory infections by such organisms as s. aureus, nocardia spp. and aspergillus spp. bronchial epithelial cells are important in innate immunity through secretion of cytokines and molecules including il- , il- , il- , il- , and granulocytemacrophage colony-stimulating factor (gm-csf). these molecules attract macrophages as well as neutrophils and other inflammatory cells to the area to enhance the inflammatory response to the organism [ ] . bronchial epithelial cells also serve an important role in recognizing pathogens through patternrecognition receptors (prrs). natural killer (nk) cells are involved in the innate immune response with surface receptors that recognize cells infected with viruses such as rsv, influenza, parainfluenza, and rhinovirus. the nk cells release ifn-g, which recruit other immune cells to add to the antiviral response. dendritic cells are tissue histiocytes positioned around the airways and lymphatics in the lung that recognize pathogens and their antigens and trigger the proliferation and amplification of antigen-specific tcells. this immune response bridges the innate immune response to the adaptive immune responses and is especially important in fungal infections. this mechanism is mediated through toll-like receptors (tlrs) that are able to distinguish pathogens from self-components by triggering cytokine production through nfkb and ap- and expressing co-stimulatory molecules necessary for this t-cell activation [ ] . for those organisms that evade the basic, innate immunity of the lung, there are adaptive immune mechanisms that encompass both humoral and cellular immune mechanisms. humoral immunity is an important defense against encapsulated bacteria, most notably s. pneumoniae, and for other pyogenic bacteria such as h. influenzae, and staphylococci spp., and resolution of these infections requires the production of igg antibodies to the organisms. cellular immunity is especially important against such respiratory viral infections as influenza, rsv, cmv, varicella, and also against opportunistic infections. these viruses induce a cd þ and cd þ t-cell response that clears the lung of these viruses within - days post infection. granulomas are a common inflammatory response to both pathogens and foreign material. the most notable granulomatous infections in the lung are due to mycobacteria and fungal organisms. activation of cd þ t-cells by these organisms leads to proliferation and differentiation of these cd þ t-cells into t-helper- cells. the release of ifn-g by the th- cells activates lung macrophages to form epithelioid macrophages that have an increased ability to kill the microorganisms and express surface molecules that promote cell-to-cell fusion into giant cells. in addition, activation of these macrophages results in the release of numerous cytokines including ifn-g and tnfa. in patients who are deficient in cd þ t-cells or ifn-g, granuloma formation is very poor, altering the pathologic picture of these infections. this effect is most obvious in the nontuberculous mycobacterial infections, which have numerous patterns of injury depending on the immune status of their host. pneumonias can be broadly categorized into one of five major clinicopathologic categories, including (i) community-acquired pneumonias (acute and atypical), (ii) nosocomial pneumonias, (iii) aspiration pneumonias and lung abscess, (iv) chronic pneumonias, and (v) pneumonias in immunocompromised hosts. each type presents with a characteristic clinical pattern and may be caused by any of several pathogens so that treatment is many times empiric. the first category comprises community-acquired pneumonias (cap). these represent the majority of the lung infections that receive medical treatment, usually on an outpatient basis, with low (< %) mortality. patients hospitalized for these infections typically have other comorbidities. the responsible organisms include respiratory syncytial virus (rsv); rhinovirus, parainfluenza, and influenza virus; bacteria, including mycoplasma pneumoniae and rickettsia; and most notably chlamydia pneumonia. chlamydia causes what is termed atypical pneumonia with a clinical course characterized by a progressive onset of fever without chills, a dry cough, and chest imaging that reveals focal infiltrates. acute or typical cap presents abruptly with high fever, chills, productive cough, and radiographs with lobar or segmental consolidation. the most common pathogens are streptococcus pneumoniae, haemophilus influenza, staphylococcus aureus, and moraxella catarrhalis. the second category, nosocomial pneumonias, consists of infections acquired within the hospital or from healthcare associated facilities. these infections are usually found in patients with predisposing risk factors and are a major source of morbidity and mortality, with some studies reporting a mortality range of %- %. the most common risk factors include respiratory ventilation, artificial airways, nasogastric tubes, supine positioning, and medications that alter gastric emptying. the responsible organisms include klebsiella spp., legionella spp., staphylococcus aureus, and pseudomonas aeruginosa. the third category includes aspiration pneumonias and lung abscesses. these infections occur in the setting of patients with aberrant swallow or gag reflexes that allow gastric or oral contents into the airways. the organisms where necrosis and cavity formation occurs include s. aureus, k. pneumoniae, the anaerobic oral flora, and mycobacteria. clinically, these infections may have an acute course with fever and dyspnea or a more insidious course, many times with patients first presenting with lung cavities, empyemas, or necrotizing pneumonias. the fourth category, chronic pneumonias, includes indolent infections that cause a localized mass-like lesion in an otherwise healthy host. nocardia and actinomyces spp. are the most common pathogens, but mycobacteria and fungi may also cause these pneumonias. the fifth category includes pneumonias that occur in the setting of an immunocompromised patient. these include a number of organisms that otherwise would not act as pathogens such as the viruses cmv and hsv, the fungi aspergillosis and pneumocystis pneumonia, and the bacterium mycobacterium avium complex. streptococcus pneumoniae streptococcus pneumoniae, a gram-positive diplococcus also known as pneumococcus or diplococcus pneumonia, is a common cause of bacterial pneumonia in infants and elderly patients, alcoholics, diabetics, and patients with immunosuppression. this pneumonia usually presents abruptly with chills, a cough with rust-colored sputum and pleuritis, with high fevers, tachycardia, and tachypnea. the characteristic gross pathology is a lobar pneumonia that progresses from a red acute phase to a gray organizing phase. a fibrinous pleuritis is common, which eventually organizes to entrap the lung parenchyma in a fibrous capsule [ ] . the microscopic examination reveals abundant fibrin, neutrophils, and extravasated red blood cells within the alveolar space and congested capillaries. hemophilus influenzae hemophilus influenzae is a gramnegative bacillus that inhabits the upper respiratory tract and can cause otitis media, epiglottitis, and meningitis, and usually enters the lung through aspiration or hematogenous spread. six serotypes are defined based on their capsular antigens, with type b the most common cause of pneumonias. this type of pneumonia is most commonly found in children or in the elderly with underlying chronic lung disease such as emphysema, cystic fibrosis, bronchiectasis, in patients with hiv infection, or in alcoholics. this bacterial pneumonia is usually preceded by a viral or mycoplasma infection that damages the mucociliary elements in the airways and allows for colonization by h. influenzae. the symptoms include fever; a productive, purulent cough; and myalgias. the incidence of this pneumonia as a common community-acquired pneumonia in children is quite low due to the advent of effective vaccines. however, it is increasing in incidence as a nosocomial infection [ ] . like pneumococcal pneumonia, the pathology of h. influenzae pneumonia is in a lobar distribution with a neutrophilic-rich infiltrate and a pleural effusion. necrosis and empyema may occur but are uncommon. staphylococcus aureus staphylococcal pneumonia is caused by staphylococcus aureus, gram-positive cocci that usually spread to the lung through the blood from other infected sites, most often the skin. though a common community pathogen, it is found twice as frequently in pneumonias in hospitalized patients. it often attacks the elderly and patients with cf and arises as a co-infection with influenza viral pneumonia. the clinical course is characterized by high fevers, chills, a cough with purulent bloody sputum, and rapidly progressing dyspnea. the gross pathology commonly reveals an acute bronchopneumonia pattern (figure . ) that may evolve into a necrotizing cavity with congested red/purple lungs and airways that contain a bloody fluid and thick mucoid secretions. the histologic pattern is characterized by a bronchopneumonia that spreads distally from the small airways into to the alveolar spaces (figure . ) to form abscesses that connect with the pleural surface and may result in empyemas. the treatment of this organism has become increasingly problematic due to antibioticresistant strains, most notably methicillin-resistant s. aureus. legionella pneumophila legionella are gram-negative bacilli found predominantly in aquatic habitats such as lakes, rivers, and ponds. standing pools of water from humidifiers and other water outlets may be other sources. approximately % of air conditioners contain these bacilli. though serogroups of legionella have been identified, cause the overwhelming majority of human pneumonia. the clinical disease takes two forms: (i) legionnaires' disease, named after the outbreak of pneumonia at the american legion convention in philadelphia; and (ii) pontiac fever, a self-limiting flu-like disease with nonspecific symptoms. legionella pneumonia presents as a severe infection of the lung with chills and rigors with a nonproductive cough. it can progress rapidly to systemic symptoms of nausea, vomiting, and diarrhea and can lead to renal failure and death without immediate antibiotic therapy. the infected lungs are remarkably red and congested and appear to be distended with fluid. the microscopic picture reveals fibrinopurulent exudates that fill the alveolar space mixed with a necrotic, cellular infiltrate of degenerating neutrophils and monocytes (figure . ). hyaline membranes may form in the periphery of the lesions, and pleural effusions consisting of fibrinoserous exudates are common. pseudomonas aeruginosa pseudomonas aeruginosa is a gram-negative bacillus that is found throughout the environment and in % of the airways of hospitalized patients. it usually enters the body through a disruption of the epithelial surface by cuts, burns, or therapeutic devices such as mechanical ventilators or intravascular catheters. pneumonias caused by this organism are usually found in intensive care units of hospitals and burn units, in patients with underlying chronic lung diseases including cystic fibrosis, emphysema, and in patients with prolonged hospitalization. the pathology is necrosis with a bronchopneumonia pattern that usually consists of an area of congestion and hemorrhage that is surrounded by a halo of tan/white consolidation (figure . ) . a necrotizing vasculitis with abundant organisms in vessel walls can be seen, and cavitation is common ( figure . ). in treated lungs, healed cavities or pneumatoceles may appear as smooth-walled fibrous cysts. other gram-negative bacilli gram-negative bacilli such as klebsiella pneumoniae, acinetobacter, and various enterobacteriaceae spp. are common nosocomial pathogens. similar to p. aeruginosa, these pathogens colonize the oropharynx and are usually introduced into the lung by inhalation or aspiration of oral contents. the most notable of these is friedlander's pneumonia caused by k. pneumoniae, the most common cause of gramnegative bacterial pneumonia. this typically occurs in men over years of age, usually in the setting of alcoholism, diabetes mellitus, or chronic lung disease. these patients produce large amounts of thick, bloody sputum, a product of the viscous mucopolysaccharide capsule of the organism, and present with severe systemic symptoms of hypotension and generalized weakness. the pathology of these pneumonias is similar to pseudomonas pneumonia with marked cavitation and abundant organisms on microscopic examination. nocardia spp. nocardiosis of the lung is caused by nocardia asteroides, a gram-positive rod found in the soil or organic matter. this infection is most common in immunocompromised adult patients and can be seen in the setting of pulmonary alveolar proteinosis, chronic lung diseases, and mycobacterial and other granulomatous diseases that affect the lung. its clinical course is indolent and usually begins - weeks before the patient presents for medical therapy. cough is common, often with thick, purulent sputum. in the immunocompromised setting, fever, chills, dyspnea, and hemoptysis are common, and weight loss may occur as the disease progresses. the pathology is remarkable for suppurative abscess formation with multiple cavities filled with green, thick pus. the inflammatory infiltrate consists of neutrophils, macrophages, and abundant necrotic debris with epithelioid histiocytes and giant cells within the wall of the cavity (figure . ). empyema and pleura involvement occur in the majority of cases. mycoplasma and rickettsia pneumonias mycoplasma pneumoniae pneumonia is among the most common infections of the lower respiratory tract and usually occurs in small epidemics in closed populations. it often presents with atypical features of a progressive onset, fever without chills, a dry cough, diffuse crackles on physical examination, and chest imaging studies that reveal patchy interstitial infiltrates. the pathologic features are a result of the attachment of the organisms to the bronchiolar epithelium where they cause epithelial injury and ulcerations through secretion of peroxide [ ] . in cases of severe infection, diffuse alveolar damage may be present. chlamydial pneumonia chlamydia spp. causes pneumonia in a variety of clinical settings. chlamydia trachomatis is an infection found predominantly in the postnatal period, chlamydia psittaci is the result of direct transmission from infected birds, including parakeets, parrots, and pigeons. chlamydia pneumoniae is the most common of the three and is a frequent cause of community-acquired pneumonia. it typically causes a very mild or asymptomatic infection with fever, sore throat, and nonproductive cough. the course of this infection may be severe in the elderly. chest imaging studies show alveolar infiltrates, and pleural effusions are present in the majority of cases. the pathology has not been well defined since the infection is usually self-limited. however, in experimental animal models there is a neutrophilic response in the early stages, and an interstitial, peribronchiolar, and perivascular infiltrate of lymphocytes, macrophages, and plasma cells in the latter stages of the infection. mycobacteria, a major cause of lung infections, are nonmotile, aerobic, catalase-producing, acid-fast bacilli. clinically significant lung infections can be caused by m. tuberculosis and by a group of nontuberculous mycobacteria (ntm). the latter group consists of over species, of which three cause the overwhelming majority of pulmonary disease. these are m. avium-intracellulare (m. avium complex), m. kansasii, and m. fortuitum-chelonae. throughout history, tuberculosis (infection with m. tuberculosis) was the major disease caused by these organisms and was responsible for worldwide morbidity and mortality. however, over the past two decades lung diseases caused by ntm have become much more common and now represent the majority of the pulmonary mycobacterial disease. mycobacterium tuberculosis pulmonary tuberculosis is spread by interpersonal contact through aerosolized droplets. once in the alveoli, the bacteria cause a cell-mediated inflammatory response that is capable of inducing granuloma formation and necrosis. as in all infections, the extent of the disease is a function of the host's immune response. the most susceptible part iv molecular pathology of human disease patients are those with certain conditions that include immunosuppression, diabetes, malignancy, renal failure, among others. clinically, an infected patient has a productive cough, fever, and weight loss, and may develop hemoptysis as the cavitation progresses and erodes into the pulmonary vessels. extensive involvement of the lung can produce significant dyspnea and pleuritic chest pain. the pathology of tuberculosis is primarily that of granuloma formation and acute pneumonia. the granulomas are predominantly necrotizing, and the pneumonia usually contains abundant fibrin and neutrophils that fill the alveolar spaces. the gross lesions are referred to as caseous or cheese-like, because of the amount of necrosis present. this caseous material can extend into airways and is commonly coughed up during the active disease. in chronic forms of the disease, the area can undergo fibrosis and involute into a firm, hard scar. there are three major clinicopathologic variants of the disease: (i) primary tuberculosis, (ii) postprimary or reactivation tuberculosis, and (iii) progressive fibrocavitary disease. primary tuberculosis. in this form of the disease, the initial site of infection can be anywhere in the lung, but is usually in the lower lobe or anterior segment of the upper lobe, the areas that receive the most ventilation. the lesion usually consists of a dense consolidation with acute pneumonia and necrotizing granulomas. cavitation may occur, especially in the setting of immunocompromised hosts. from these foci, the organisms may spread through the lymphatics to elsewhere in the lung, the hilar lymph nodes, and the bloodstream, and lay dormant for long periods of time. the combination of the primary site of infection and the involved hilar lymph nodes is known as a ghon complex [ ] . postprimary tuberculosis. this form of tuberculosis represents reactivation of old, scarred primary lesions long after the initial insult. the lesion can occur anywhere in the lung where the bacteria from the primary lesion have spread, but is usually apical. it consists of a focus or organizing pneumonia and fibrosis with central caseation. in an active lesion, the typical parenchymal pattern is an acute pneumonia with cavitation that expands to include the surrounding lung with aggregates of granulomas. the controversy surrounding this lesion arises as some evidence suggests that these lesions represent exogenous reinfection. the pathology of reactivation or reinfection may be indistinguishable, although reactivation tuberculosis may appear to arise out of a fibrotic, calcified chronic lesion [ ] . progressive fibrocavitary disease. this form of the disease may arise out of either primary or postprimary tuberculosis. however, the latter is the more common scenario. the cavities that develop in this form of the disease begin as a slowly progressive, necrotizing pneumonia with abundant granulomas (figure . ). the active disease may spread through the airways, causing ulceration, necrosis, and fibrosis of the surrounding bronchi and bronchioles. the extension of the disease in this way depends on the host, and patients with depressed immune systems can have large areas of the lung involved with massive pulmonary necrosis. usually, a fibrous capsule develops in the area of the cavitation, although inspissated necrotic material into the adjacent airways remains a continuous source of inflammation that can lead to reinfection and ongoing scarring [ ] . nontuberculous mycobacteria the nontuberculous mycobacteria (ntm) are ubiquitous inhabitants of our environment, isolated from soil, fresh and brackish water, house dust, birds, animals, and food, and are increasingly important in causing pulmonary disease. there are currently more than ntm species known. those organisms thought to be pathogenic to the lung include the clinical presentation of these lung infections can vary from minimally symptomatic small lesions discovered by routine radiography to sudden hemoptysis from advanced disease with severe cavitation (table . ). the two most characteristic lesions are those of diffuse infiltrates in an immunocompromised patient, seen most commonly in the hiv-positive population and an viruses most pulmonary infections are due to viruses from four major groups: influenza, parainfluenza, respiratory syncytial virus (rsv), and adenovirus (table . ) [ ] . the clinical presentations of these infections have some common features, including insidious onset, nonproductive cough, fever, and chest pain. chest imaging studies usually reveal bilateral, multifocal infiltrates, most without evidence of cavitation or pleural involvement. these infections are mild, self-limiting, and require no more than supportive therapy except in immunocompromised hosts, where the clinical course can be much more serious. also, immunocompromised patients are susceptible to other viruses such as herpesvirus and cytomegalovirus pneumonias, which are not common pathogens in normal hosts [ ] . since the s, a subset of pulmonary viral infections has emerged with a much more aggressive clinical course, most notably sars, coronavirus, and hantavirus. these viruses present with systemic symptoms of headache, myalgias, and weakness followed by a deteriorating clinical course with respiratory distress, shock and, in over % of the cases, death [ , ] . therapy for most respiratory viral infections is supportive, although antivirals are available for some viruses, mostly used in the setting of immunocompromised patients. ribavirin, a guanosine analogue, is the main antiviral used for rsv; m inhibitors or adamantanes (amantadine and rimantadine) are used against influenza a and neuraminidase inhibitors (oseltamivir and zanamivir) are used against both influenza a and b [ ] . cytomegalovirus is treated with ganciclovir, foscarnet, or cidofovir, while herpesvirus is treated with acyclovir [ ] . the pathologic patterns of injury for most viruses are similar, making morphologic distinctions among them difficult. however, some characteristic patterns emerge, most notably in those viruses that cause cytopathic changes. influenza, adenovirus, sars, coronavirus, and hantavirus all cause an acute lung injury pattern with diffuse alveolar damage, and in the case of the latter two viruses, evidence of hemorrhage and edema. influenza and adenovirus will also cause a necrotizing bronchiolitis due to their preferential infection of bronchial epithelial cells. finally, some viral infections can be distinguished by their characteristic cytopathic inclusions. adenovirus can be identified by characteristic smudge cells that present in advanced stages of the disease and represent adenovirus particles in the nucleus of an infected cell (figure . ). cytomegalovirus has both nuclear owl's eye inclusions, as well as cytoplasmic inclusions (figure . ). herpesvirus has glassy intranuclear inclusions and can also have multinucleation (figure . ). fungi are larger and more complex than bacteria, and their patterns of injury in the lung are different and in general more destructive. these pathogens are common in our environment and enter the lungs through inhalation. though many fungi are capable of causing pulmonary disease, most only inhabit the lung as colonizers. those of most concern for causing clinical disease include the endemic fungi of north america-histoplasma capsulatum, blastomyces dermatitidis, and coccidioides immitis-and two fungi that are commonly seen in immunocompromised hosts-aspergillus fumigatus and pneumocystis jiroveci. histoplasma capsulatum histoplasma capsulatum is a dimorphic fungus most prevalent in the middle portion of the united states from the great lakes to tennessee. the fungus is present in soil that has been contaminated with guano and other debris by nesting birds, most commonly blackbirds and chickens, and by bats. the organism lives in the environment as spores or conidia and germinates to form hyphae. these structures divide to create the yeast forms, which, when inhaled, induce granuloma formation in the lung. approximately % of people have skin tests that are positive for exposure to h. capsulatum, but most exposures do not cause clinical disease. disease typically occurs in people exposed to large amounts of organisms, such as construction workers who move large volumes of dirt or spelunkers who venture into bat-ridden caves. the acute disease has flu-like symptoms which are self-limiting. healed disease may leave behind calcified granulomas in the lung that appear as buckshot on chest imaging studies. the most chronic forms of this disease may slowly progress, giving rise to cavitating and fibrous lesions. in the immunocompromised host, disseminating histoplasmosis can be seen, although reactivation is uncommon [ ] . the pathology reveals characteristic necrotizing granulomas distributed around the airways (figure . ), which contain silver-positive yeast forms of - microns. these granulomas may resolve into scarred nodules, which can calcify and produce the characteristic chest images. cavities may form in the apices with progression of the disease, and the disseminated form of the disease has an abundance of organisms both within macrophages in the lung and throughout many organs in the body. blastomyces dermatitidis blastomyces dermatitidis is also endemic to the middle united states, including the ohio and mississippi river valleys. it is found in wooded terrain, usually during the wet seasons, putting campers and outdoorsmen at risk. the clinical disease takes two forms, cutaneous and systemic, the latter beginning in the lungs through inhalation. the acute pulmonary infection takes a nonspecific form with fever, malaise, and chest pain. imaging studies may show either infiltrates or a mass-like infiltrate. thus, blastomyces infection may mimic other diseases, and the diagnosis may be delayed. some patients go on to chronic disease with cavitation or progressive pulmonary blastomycosis, which manifests as acute respiratory distress syndrome, cavitary lesions, and a poor prognosis [ ] . the pathology of blastomyces infection is similar to histoplasmosis with necrotizing granulomas. however, the lesions are larger, showing more neutrophilic necrosis. the organisms are also larger ( - microns), with prominent broad-based budding, and are apparent on routine hematoxylin and eosin staining (figure . ). coccidioides immitis coccidioides immitis is found in the semi-arid desert climate of the southwestern united states. the organisms are inhaled as spores, causing an acute disease characterized by fever, chills, chest pain, dyspnea, and hemoptysis. chest imaging studies typically show consolidation and cavitation, and hilar lymphadenopathy is common. reactivation and dissemination are possible in patients with previous infection, whether or not they are immunocompromised patients [ ] . the pathology of pulmonary coccidioidomycosis is neutrophilic, suppurative, and granulomatous. the organisms appear as large spherules containing endospores, visible on silver stains. the spherules are - microns in diameter and the endospores that are released into the surrounding tissue proceed to mature into new spherules (figure . ) . as in histoplasmosis, cavitating lesions may have hyphal forms that begin to germinate. aspergillus fumigatus aspergilli are asexual mycelial fungi that are ubiquitous in the environment as airborne aspergillus spores. they are weak pathogens that produce invasive infections predominantly in immunocompromised hosts or in those with significant chronic lung diseases. in tissue, aspergilli form septate hyphae, - microns in diameter, with characteristic acute-angle, dichotomous branching (figure . ) . these organisms affect the lung in three major ways: (i) saprophytic growth in bronchi or pre-existent cavities; (ii) as an allergic or hypersensitivity reaction, predominantly in asthmatics; and (iii) invasive aspergillosis in immunocompromised hosts [ , ] . as a saprophyte, aspergillus produces surface growths or minute masses of hyphae, usually in bronchiectatic cavities, emphysematous bullae, or scars from previous lung diseases such as tuberculosis or sarcoidosis. the pathology is usually that of a fibrous-walled cavity containing degenerating hyphae (figure . ). in this setting, hyphae do not invade into the lung tissue, but surface erosion of a vascularized cavity may cause hemoptysis. aspergillus causes an immunologic response resulting in mucoid impaction or eosinophilic pneumonia in asthmatics, an entity known as allergic bronchopulmonary aspergillosis (abpa). pathologically, one sees mucoid plugs and superficial erosions of the airways with histiocytic inflammation, with only rare hyphal fragments present. the final form of the disease, invasive pulmonary aspergillosis, is found in severely immunocompromised, neutropenic patients. the hyphae, which disseminate through the blood, invade the blood vessels causing thrombosis, hemorrhage, and infarction to form typical targetoid lesions. this form of the disease has a poor prognosis despite aggressive antifungal therapy. pneumocystis jiroveci the taxonomy of pneumocystis jiroveci (formerly pneumocystis carinii) has changed over the past decade. previously thought to be a protozoan based on the histological characteristics of its trophozoite and cyst life forms, it has recently been placed in the fungal kingdom after ribosomal rna was found to have sequences compatible with the ascomycetous fungi [ ] . the inability to culture pneumocystis jiroveci has slowed the understanding of this organism. animal models have helped in defining the antigenic and genotypic differences among the various pneumocystis organisms, which has led to the proposal for species-specific strains, with p. jiroveci found in human infections [ ] . the molecular methods used for the typing these species examine a number of gene loci. most importantly, sequence analysis of the thymidylate synthase (ts) and superoxide dismutase (soda) gene loci, the epsp synthase domain of the multifunctional arom gene, and the mitochondrial small subunit ribosomal rna (mtssu rrna) locus have been used to distinguish the various pneumocystis species that infect different mammalian hosts [ ] . clinically, p. jiroveci causes disease predominantly in the immunocompromised setting. pneumocystis pneumonia (pcp) has been found during recent times most commonly in the aids population, but prior to this epidemic, it was found in malnourished infants and other severely immunocompromised hosts. because this organism has not been cultured, the diagnosis of pcp continues to be challenging. the clinical characteristics are nonspecific and vary with the patient's immune status. in the hiv population, patients typically develop a subacute onset of progressive dyspnea, a nonproductive cough, malaise, and a low-grade fever. in the non-hiv population, the presentation is more acute, with fulminant respiratory failure associated with cough and fever, and usually requiring mechanical ventilation [ ] . chest imaging studies typically show bilateral, symmetric, fine reticular interstitial infiltrates involving the perihilar area, which spread to involve the entire lung. figure . aspergillosis. aspergillus fumigatus grows within necrotizing cavities of the lung as branching septated fungal hyphae, as seen on this grocott methenamine silver stain. figure . aspergilloma. fungal hyphae from aspergillus fumigatus can colonize chronically inflamed lungs with cavities and may grow to form fungal balls with a dark, green color that are treated by surgical resection, as seen in this case of a lobectomy specimen. treatment is usually with trimethoprim/sulfamethoxazole and intravenous pentamidine. survival is %- % even in severely immunocompromised patients. the life cycle of p. jiroveci consists of three stages: trophozoite, cyst, and sporozoite. the trophozoite form, which adheres to the type epithelium, replicates and enlarges through three precyst stages before maturing into a cyst form that is found in the alveolar space. sporozoites develop within immature cysts through meiosis and mitosis. the mature cyst contains eight haploid sporozoites. the rupture of the cyst wall releases sporozoites into the surrounding environment where they mature into trophozoites. the pathology of the infection is predominantly due to the interaction of the organism with the epithelium. the attachment of the organism to the lung epithelium is via glycoprotein a present on the surface of the organism. the binding of the organism to the type cell occurs via surface receptors on the type cell that include macrophage mannose receptors. these interact with glycoprotein a and activate pathways in the organism that induce genes encoding for pathways that induce mating and proliferation responses, and for the formation of pheromone receptors, transcription factors, and heterotrimeric g-protein subunits [ ] . in addition to these genetic effects, the cyst wall contains chitins, polymers, and other substances, in particular, , -glucan, that maintain its integrity and induce the inflammatory response of the host. the , -glucan in the wall of the organism stimulates the release by the macrophages of reactive oxidant species and the generation of potent proinflammatory cytokines, such as tnfa, which bind to the organism and exert a toxic effect. once inside the macrophage, the organism is incorporated into the phagolysosome and degraded. tnfa also directly recruits other inflammatory cells including neutrophils, lymphocytes, and circulating monocytes, and induces the release of il- and ifn-g that recruit and activate inflammatory cells [ ] . in aggregate, the recruitment of these inflammatory cells and the mediators they release is responsible for the damage to the lung epithelium and endothelium that is seen in this disease [ ] . the pathology of pcp has typical and atypical variants. typically, the lung contains a dense interstitial plasma cell pneumonia that expands alveolar walls. the epithelium consists predominantly of type pneumocytes, and the alveolar spaces contain an eosinophilic, frothy exudate, which contains fine, hemoxylin-stained dots that represent a thickening in the cyst wall (figure . ) . in this form of the disease, the organisms are abundant and the diagnosis can usually be made by bronchoalveolar lavage. atypical pathologic variants include a necrotizing variant that has a pattern similar to the typical form with exudative alveolar infiltrates, but which undergoes necrosis and cavity formation. these cavities heal into fibrous-walled cysts, similar in gross appearance to those found in pseudomonas pneumonia. a third variant has wellformed granulomas involving the airways, a pattern common to histoplasmosis and tuberculosis. in this form, the organisms are rare and very difficult to find, even with tissue organismal stains. in general, the pathologic pattern of injury depends on the host's immune status, with the typical pathology found in severely immunocompromised hosts as the aids population and the atypical forms found in hosts with immune systems that are less compromised. pulmonary langerhans cell histiocytosis (plch) and erdheim-chester disease are histiocytic diseases that primarily affect the lung. other histiocytic diseases may affect the lung, such as niemann-pick disease, gaucher disease, hermansky-pudlak and rosai-dorfman disease, but these are not considered primarily lung histiocytic diseases. pulmonary langerhans' cell histiocytosis (plch) is a disease of the dendritic histiocytes of the lung referred to as langerhans' cells (lcs). this disease is part of a group of diseases that are characterized by a proliferation of langerhans cells in organs throughout the body that range from a malignant systemic disease as is seen in children [ ] to the pulmonary variant that is seen in adolescents and adults. plch is usually the result of inflammatory or neoplastic stimuli in lungs of smokers or in lungs involved by certain neoplasms [ ] . chest radiographs from patients with plch usually reveal bilateral nodules, predominantly in the upper lobes, which are worrisome for metastatic disease. treatment involves smoking cessation and steroid therapy. typically, the disease undergoes spontaneous regression. approximately %- % of patients will progress to irreversible end-stage fibrosis [ ] . the pathology of plch consists of airway-based lesions with a proliferation of lcs. the early cellular lesions contain a mixture of cells including langerhans' cells, lymphocytes, plasma cells, and eosinophils ( figure . ). though it was previously referred to as eosinophilic granuloma, eosinophils are not the major cell type present, and the lesion is, at best, a loosely formed granuloma. immunohistochemistry reveals the lcs to be diffusely, strongly immunoreactive to s- protein and cd a. ultrastructural analysis reveals intracytoplasmic organelles called birbeck granules, a normal constituent of langerhans' cells, in greater numbers in plch [ ] . the pathogenetic mechanisms of plch focus on defects in the homeostasis of dendritic cells (dcs) in the lungs of smokers and the role tobacco smoke may play in stimulating the proliferation of these cells [ ] . some studies suggest that stimulation of alveolar macrophages by chemicals in smoke results in secretion of such cytokines as gm-csf, tgfb, and tnfa [ ] . in transgenic mice, accumulation of dcs around airways may be a result of excess gm-csf [ ] . other theories suggest that cigarette smoke stimulates the secretion of bombesin-like peptide by the neuroendocrine cells in the bronchiolar epithelium and leads to a similar stimulation of alveolar macrophages and a cytokine milieu that promotes the proinflammatory proliferative changes [ ] . not all smokers get plch, leading to the suggestion that only smokers with an underlying genetic susceptibility will develop the disease. studies have established that in some cases the lcs in plch are clonal, suggesting that cellular abnormalities must play some part in the pathogenesis of the diseases [ ] . to support this, studies have shown genetic mutations and allelic loss of tumor suppressor genes in smokers with plch [ ] . the mechanisms by which this proliferation of lcs leads to the destruction of the bronchiolar epithelium and the other observed pathology are unclear. lcs in normal lungs have little ability to interact with t-cells or act as effective antigen-presenting cells, but the lcs of plch have a mature immunophenotype, expressing b - and b - , the co-stimulatory molecules needed for lymphostimulatory activity [ ] . whether this more mature immune phenotype leads to an unregulated immune response and destruction of the bronchial epithelial cells is not known. however, some studies have shown that bronchiolar epithelial cells may induce the expression of this mature phenotype by secreting cytokines in response to environmental stimulants such as cigarette smoke or viral infections, or by the development of hyperplastic or dysplastic lesions that express new foreign antigens [ ] . erdheim-chester disease (ecd) is a systemic non-langerhans' cell histiocytosis of adults that most commonly involves the long bones. involvement of other organs, including the lung, has been reported. lung involvement occurs in approximately %- % of the cases, and the patients usually present with cough, dyspnea, rhonchi, and pleuritic pain. radiographically, the lungs reveal infiltrates in a lymphatic distribution, predominantly upper lobe, with prominent interstitial septal markings that can mimic sarcoidosis [ ] [ ] [ ] [ ] [ ] [ ] [ ] . pulmonary involvement by ecd may have an unfavorable prognosis, and the fibrosis that ensues is one of the most frequently reported causes of death [ , ] . the treatment of ecd is variable with corticosteroids, chemotherapy, surgical resection, and radiation therapy reported [ ] . non-langerhans' cell histiocytes of dendritic cell phenotype are the main cells present in this disease. this infiltrate contains foamy histiocytes with scattered giant cells, a scant number of lymphocytes or plasma cells, and some fibroblasts. the histiocytes express cd (macrophage antigen) and factor xiiia (dendritic cell antigen), but express s- protein weakly or not at all, and do not express cd a. ultrastructural analysis reveals phagolysosomes, but no birbeck granules are present [ ] . this infiltrate that involves the lung is usually present in the pleura and subpleura, within the interlobular septa and around the bronchovascular structures. the remainder of the lung parenchyma is unremarkable, though fibrosis and paracicatricial emphysema can appear in the late stages of the disease [ ] . the etiology of ecd is not known, but this rare disease has been established as primarily a macrophage disorder [ ] . these histiocytes have abundant phagolysosomes and express the antigen cd a and are consistent with a phagocytic cell, most likely closely related to alveolar macrophages. the peripheral monocytosis and the proinflammatory cytokine profile that is found in these patients might suggest that the histiocytic infiltrate is a result of systemic monocytic activation and invasion of circulating monocytes into the tissues throughout the body [ ] . recently, an ecd patient was successfully treated by an agent toxic to monocytes, supporting the theory that these cells play a part in the disease [ ] . alternatively, end organ cytokine production by local inflammatory cells resulting in proliferation and differentiation of resident immature histiocyte populations may produce a similar picture. another interesting observation is that erdheim-chester has been reported to occur in patients with langerhans' cell histiocytosis [ ] , which may suggest that this is a disease where macrophages transition between two different phenotypes along the differentiation spectrum of tissue dendritic cells [ ] . whether this is a benign or malignant proliferation has not been established. of patients studied, clonality has been demonstrated in by polymerasechain reaction [ ] . environmental exposures are a major cause of lung disease and can cause a wide spectrum of both acute and chronic pathology. many organic and inorganic materials can cause lung damage, and because of their similar patterns of injury and long latent periods, it can be difficult to isolate the exact offending agent without a thorough clinical history. the two occupational lung diseases presented here-asbestosis and silicosis-represent pneumoconiosis, which are defined as diseases which result in diffuse parenchymal lung injury due to inhaled inorganic material. both have many pathologic patterns of injury that depend on the amount and length of time of exposure, and both can also cause neoplastic diseases of the lung. asbestos fibers are naturally occurring silicates that are commonly used in construction materials such as cement and insulation and in many textiles. they can be separated into two groups based on their mineralogic characteristics. serpentine fibers, named as such because they are long and curly, include chrysotile asbestos. amphibole fibers, more straight and rodlike, include predominantly amosite and crocidolite asbestos. in the united states most of the asbestos is chrysotile. the amphiboles are more pathogenic and are responsible for most of the neoplastic and non-neoplastic pulmonary diseases associated with asbestos exposure. by definition, asbestosis is bilateral diffuse interstitial fibrosis of the lungs that can be attributed to asbestos exposure. the disease, which mostly affects textile and construction workers, is usually the result of direct exposure over - years. the latency to clinical disease is inversely proportional to the level of exposure. the symptoms are a gradual onset of shortness of breath, a cough with dry rales at the bases on inspiration, and digital clubbing. in the early disease, the chest x-ray shows basilar disease that begins predominantly as thickening of the subpleural, but progresses as infiltrates and fibrosis that involve the middle zone, eventually leading to thickening of the airways and traction bronchiectasis. the apex of the lung is usually spared. the clinical findings are nonspecific and have considerable overlap with uip, so the diagnosis is usually made only when a history of significant exposure is discovered. the gross picture includes a bilateral lower lobe gray/tan fibrosis with honeycomb changes in late disease. microscopically, asbestosis can cause many patterns of injury in the lung, but the most common is collagenous deposition in the areas of the lymphatics where the fibers are in the highest concentration. these areas include the subpleural, interlobular septae, and around the bronchovascular areas that contain a bronchiole and a branch of the pulmonary artery. hyalinized pleural plaques are a common manifestation of asbestos exposure but are not specific for asbestos and can be found in the absence of pulmonary parenchymal disease. eventually, the fibrosis involves the alveoli beyond the bronchioles and causes distortion of the lung architecture to form remodeled, dilated airspaces similar to those seen in uip. distinguishing this fibrosis from other forms of fibrosing lung disease can be difficult, but the presence of ferruginous bodies, asbestos fibers coated by iron, proteins, and a mucopolysaccharide coat are indicative of significant asbestos exposures and support this diagnosis (figure . ) [ ] . figure . asbestosis. this cytopathologic preparation from a bronchoalveolar lavage specimen illustrates an asbestos fiber coated by an iron-protein-mucopolysaccharide substance and appears as a golden brown, beaded structure known as a ferruginous body. silicosis results from chronic, high-dose exposure to crystalline silica, which consists of silicon and oxygen with trace amounts of other elements, usually iron. the most common silica is quartz, which is present in large amounts in such rocks as granite, shale, and sandstone and is among the more fibrogenic of all silica types. thus, occupations most at risk for silicosis include sandblasting, quarrying, stone dressing, and foundry work where exposure to quartz is high. the disease takes three major clinical and pathologic forms that have different clinical characteristics. simple or nodule silicosis is marked by the presence of fine nodules cm, on chest imaging studies, usually in the upper lobes. patients with this condition are typically asymptomatic, with normal respiratory physiology. the pathology in these lungs reveals discrete, hard nodules that have a green/gray color, centered either on the small airways or in the subpleura. microscopically, these nodules have an early stellate shape that eventually transforms to a more whorled appearance with dustladen macrophages scattered throughout it. polarized light examination reveals weakly birefringent material. complicated pneumoconiosis represents similar pathologic findings only with larger and more circumscribed nodules, which coalesce into a large upper lobe mass, a condition known as progressive, massive fibrosis ( figure . ) . these patients are symptomatic with a productive cough and mixed pulmonary function tests with a reduced diffusing capacity as the fibrosis increases. diffuse interstitial fibrosis may occur; however, unlike asbestosis, this pattern is found in pneumoconiosis. when complicated pneumoconiosis is found with rheumatoid nodules in the setting of a patient with rheumatoid arthritis, this is known as caplan's syndrome. the pathogenesis of both asbestosis and silicosis depends upon inflammation and fibrosis caused by the inhaled fibers. in humans, the amount of fiber needed to cause fibrosis varies from person to person. this may be related to a difference in fiber deposition based on the size of the lungs or to the efficacy with which the lung clears these fibers [ ] . some studies have also suggested that fiber length determines the amount of pathology. however, this association has not been confirmed in humans for either asbestosis or silicosis. in both diseases, it is known that other factors increase the risk of developing disease. for example, smokers exhibit worse disease than nonsmokers with similar exposures to asbestosis. the mechanism for this effect is unclear, although speculation centers on the inhibition of fiber clearance in smokers. also, it is known that smoking enhances the uptake of fibers by pulmonary epithelial cells and in this way may increase the fibrogenic and inflammatory cytokine production by these cells. the cellular mechanisms by which both asbestos and silica fibers induce the inflammation and fibrosis are mediated predominantly through alveolar macrophages. in the case of silica, it is known that the uptake of these fibers into the alveolar macrophages is by way of a scavenger receptor expressed on the surface of the cell known as marco (macrophage receptor with a collagenous structure). once inside the cells, the fibers activate the release of ros that can lead to cellular and molecular damage through a number of pathways. first, ros can directly cause lipid peroxidation, membrane damage, and dna damage. second, silicainduced free radicals can trigger phosphorylation of cellular proliferation pathways through mitogen-activated protein kinases (mapks), extracellular signal regulated kinases (erks), and p . these pathways are also involved in the proliferation of fibroblasts in asbestosis and of mesothelial and epithelial cells in the neoplastic diseases associated with the inhalation of these fibers [ ] . in addition, these fibers can activate proinflammatory pathways controlled by such transcription factors as nuclear nfkb and activator protein (ap- ). these pathways result in the activation of the early response genes c-fos and c-jun and the release of proinflammatory cytokines such as il- as well as fibrogenic factors such tnfa [ ] . tnfa plays a prominent role in both diseases, and its regulation has been studied in animal models exposed to silica. it is now known that a transcription factor labeled nuclear factor of activated t-cells (nfat) plays a key role in the regulation of tnfa. figure . complicated pneumoconiosis/ progressive massive fibrosis. this sagittal cut section of lung reveals a large gray/black mass that extends from the apex to include the majority of the lung. the patient had a long history as a coal mine worker, and the microscopic sections revealed abundant anthracotic pigment and scarring in this area. binding sites for nfat have been found in the promoter region of the tnfa gene. the mediation of silica-induced tnfa transcription is probably via o -but not h o [ , ] . atresia of the lung represents a premature closure of the airway at any level of the bronchial tree including the lobar, segmental, or subsegmental airways. clinically, these children usually present between and years of age for symptoms of dyspnea, wheezing, recurrent pneumonias, or for incidental findings on a chest imaging study. these lesions are more common in the proximal segmental bronchi, right more often than left. when atresia is associated with anomalies of the vascular supply to the affected airway, the lesion represents a separate, aberrant segment of lung known as a sequestration, either intralobar or extralobar type. the pathology of bronchial atresias and sequestrations represents sequelae of chronic inflammation due to the accumulation of secretions in these blind-end airways. these features consist of cystically dilated airways with mucus and parenchymal fibrosis with honeycomb changes. in intralobar sequestrations (ils), the anomalous vessel is a muscular artery that enters through the pleura from an aortic source, usually from the thoracic area. ils are separate, isolated areas of lung invested with the normal visceral pleura without bronchial or arterial connections (figure . ). extralobar sequestrations (els) are pyramid-shaped accessory pieces of lung that have their own pleura with an artery from the lung but without airway connections. the category of congenital pulmonary cystic diseases represents the majority of congenital pulmonary disease and includes foregut cysts and cystic adenomatoid malformations. foregut cysts include bronchogenic, esophageal, and thymic cysts that form from defects in the foregut branching. clinically, these cysts are usually incidental findings on chest imaging studies, but they can present with complications due to infection or hemorrhage. pathologic features of these cysts include subtle differences that are usually only apparent after microscopic examination. grossly, these cysts usually arise proximally either within the mediastinum (over %) or in the proximal regions of the lungs, right more commonly than left, along the esophagus, and rarely within the lung parenchyma or below the diaphragm [ ] . microscopically, each cyst contains a simple cuboidal or columnar epithelium, ciliated or nonciliated, that may undergo squamous metaplasia. distinguishing among the three types of cysts requires the presence of other elements. bronchogenic cysts have submucosal glands and/or hyaline cartilage within their walls, and thymic cysts may contain residual thymus. congenital cystic adenomatoid malformations (ccam), now more commonly referred to as congenital pulmonary airway malformations (cpam), are segments of lung with immature airways and alveolar parenchyma. these are usually classified by their predominant cyst size into types - . type cysts, which contain a main large cyst of up to cm, are the most common. these cysts are distinguished from foregut cysts upon the recognition in the cpam of immature alveolar duct-like structures connecting to the surrounding lung parenchyma. this type of cpam is also notable, as it is known to undergo malignant transformation, usually to mucinous bronchioloalveolar cell adenocarcinomas. these anomalies arise due to defects during the various stages of development and are best considered within these developmental stages. the embryonic stage occurs within the first - weeks of life when the ventral wall of the foregut separates into the trachea and esophagus and branches to form the left and right lungs. the splanchnic mesenchyme that surrounds this foregut forms the vascular and connective tissues of the lungs. defects in this phase result in complete lack of lung development known as pulmonary agenesis and incomplete separation of the trachea and esophagus, causing tracheal-esophageal atresias and fistulas. the pseudoglandular stage, between weeks - of development, is a time of rapid development of the conducting airways including the bronchi and bronchioles and the expansion of the peripheral lung into the acinar buds. the mesenchymal tissue figure . intralobar sequestration. the tan and white mass involving this left lower lobectomy specimen represents chronic pneumonia and fibrosis in the sequestered area of the lung. the dilated airways are features of an endstage fibrosis that is commonly found in this entity. part iv molecular pathology of human disease that surrounds these buds begins to thin, becomes vascularized, and forms the cartilage that surrounds the more proximal branching airways. during the canalicular (week [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , saccular (weeks [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and alveolar (weeks to maturity) stages of development, the acinar buds continue to expand, and the mesenchyme surrounding this continues to thin. during the canalicular stage, the pulmonary vascular bed begins to organize, the distance between the blood in the vascular spaces and the air in the alveoli narrows, and the respiratory epithelium begins to form. the gas exchange unit of the alveolus becomes functional during the saccular stage with further differentiation of the respiratory epithelium to include clara cells, ciliated and nonciliated cells, and type cells with the first production of surfactant occurring during this period. this gas exchange unit continues to mature during the alveolar stage with the growth and septation of the alveoli. this process continues postnatally through - years of age. the different types of cpams arise at different stages of development. cpams , , and are a result of defects during the early embryonic and pseudoglandular stages of development, producing pathology with features of primitive alveolar buds and immature and abnormal airway cartilage structures. cpams and result from abnormal formation of the more distal airways and pulmonary parenchyma during the canalicular, saccular, and alveolar phases, causing pathology with immature alveolar, or alveolar simplification with enlarged alveoli [ ] . various genetic defects in the pathways that control lung morphogenesis have been associated with these congenital lung diseases. two major transcription factors are responsible for the normal branching morphogenesis. the first, thyroid transcription factor- (ttf- ), is a member of the nkx . family of hemeodomain-containing transcription factors. this factor plays a role in the lung epithelial-specific gene expression and proper lung bud development in the embryonic stage, as well as in the maturation of the respiratory epithelium. the second major factor is somatic hedgehog (shh)/gli, expressed by endodermally derived cells and required for branching morphogenesis. the development of the lung bud from the foregut endoderm depends on the appropriate expression of these lung-specific genes at the correct time in development. in the presence of genetic defects, aberrant lung development may occur. for example, mutations of various types in the shh/gli gene have been found to cause tracheoesophageal fistulas, anomalous pulmonary vasculature, and aberrant airway branching. also, deletions in the ttf- gene are associated with tracheoesophageal fistulas and a variety of forms of lung dysgenesis [ ] . finally, factors present in the surrounding mesenchyme play a role in inducing the proper development of the pulmonary endoderm. a prominent mesenchymal factor in this process is fibroblast growth factor (fgf), which modulates both the proximal and distal lung branching morphogenesis. deletions in this gene may cause lung agenesis and tracheal malformations [ ] . surfactant dysfunction disorders represent a heterogenous group of inherited disorders of surfactant metabolism, found predominantly in infants and children. pulmonary surfactant includes both phospholipids and surfactant proteins, designated surfactant proteins a, b, c, and d (sp-a, sp-b, sp-c, sp-d), synthesized and secreted by type cells beginning in the canalicular stage of lung development. damage to type cells during this time period can lead to acquired surfactant deficiencies. however, more commonly these deficiencies are the result of genetic defects of the surfactant proteins themselves. the major diseases are caused by genetic defects in the surfactant protein b (sftpb, chromosome p -p . ); surfactant protein c (sftpc, chromosome p ); and adenosine triphosphate (apt)-binding cassette transporter subfamily a member (abca , chromosome p . ). defects in sftpb and abca have an autosomal recessive inheritance pattern, and defects in sftpc have an autosomal dominant pattern. sp-b deficiency is the most common. it presents at birth with a rapidly progressive respiratory failure and chest imaging studies showing diffuse ground glass infiltrates. the gross pathology in these lungs consists of heavy, red, and congested parenchyma with microscopic features that range from a pap-like pattern to a chronic pneumonitis of infancy (cpi) pattern. in sp-b deficiency, the pap pattern predominates with a histologic picture of cuboidal alveolar epithelium and eosinophilic pas-positive material within the alveolar spaces that appears with disease progression. in the late stages of the disease, the alveolar wall thickens with a chronic inflammatory infiltrate and fibroblasts. this alveolar proteinosis-type pattern of injury can be confirmed with immunohistochemical studies that establish the absence of sp-b within this surfactant-like material. diseases due to abca or sftpc deficiency may present within a week of birth or years later; the former has a poor prognosis, but the latter has a more variable prognosis with some patients surviving into adulthood. indeed, sp-c mutations have also been recognized in some families as a cause of interstitial pneumonia and pulmonary fibrosis in adults [ ] . the pathology of sp-c deficiency has more cpi features and less proteinosis. in contrast, abca deficiency can have either pap or cpi features, with the former present early in the disease and the latter present in more chronically affected lungs [ ] . the sp-b gene (sftpb) is approximately kb in length and is located on chromosome . there are over recessive loss-of-function mutations associated with the sftpb gene. however, the most common mutation is a gaa substitution for c in codon , found in about % of the cases. the lack of sp-b leads to an abnormal proportion of phosphatidylglycerol and an accumulation of a pro-sp-c peptide, leading to the alveolar proteinosis-like pathology. sp-c protein deficiency is due to a defect in the sftpc gene localized to human chromosome . there are approximately dominantly expressed mutations in sftpc that result in acute and chronic lung disease. approximately % of them arise spontaneously, and the remainder are inherited. the most common mutation is a threonine substitution for isoleucine in codon (i t), found in % of the cases, including both sporadic and inherited disease [ ] . this mutation leads to a misfolding of the sp-c protein, which inhibits its progression through the intracellular secretory pathway, usually within the golgi apparatus or the endoplasmic reticulum [ ] . the absence of sp-c within the alveolar space causes severe lung disease in mouse models. infants with documented mutated prosp-c protein, the larger primary translation product from which sp-c is proteolytically cleaved, can have respiratory distress syndrome (rds) or cpi. in older individuals, pathologic patterns observed in the lungs with these mutations include nonspecific interstitial pneumonitis (nsip) and uip. in this affected adult population, the pathology and age of disease presentation vary even within familial cohorts, suggesting the involvement of a second hit, perhaps an environmental factor [ ] . the abca protein is a member of the family of atpdependent transporters, which includes the cftr, and is expressed in epithelial cells. mutation in this gene results in severe respiratory failure that is refractory to surfactant replacement. the cellular basis for the lack of surfactant in patients with this genetic mutation is not known. the presence of abnormal lamellar bodies within the type cells by ultrastructural analysis suggests a disruption in the normal surfactant synthesis and packaging in this disease. there is some evidence that this gene contains promoters that share elements consistent with their activation by the 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patients with end-stage liver disease. hence, anesthesiologists, armed with a comprehensive understanding of pathophysiology and physiologic effects of liver transplantation on recipients, are expected to maintain homeostasis of all organ function. specifically, patients with fulminant hepatic failure develop significant changes in cerebral function, and cerebral perfusion is maintained by monitoring cerebral blood flow and cerebral metabolic rate of oxygen, and intracranial pressure. hyperdynamic circulation is challenged by the postreperfusion syndrome, which may lead to cardiovascular collapse. the goal of circulatory support is to maintain tissue perfusion via optimal preload, contractility, and heart rate using the guidance of right-heart catheterization and transesophageal echocardiography. portopulmonary hypertension and hepatopulmonary syndrome have high morbidity and mortality, and they should be properly evaluated preoperatively. major bleeding is a common occurrence, and euvolemia is maintained using a rapid infusion device. pre-existing coagulopathy is compounded by dilution, fibrinolysis, heparin effect, and excessive activation. it is treated using selective component or pharmacologic therapy based on the viscoelastic properties of whole blood. hypocalcemia and hyperkalemia from massive transfusion, lack of hepatic function, and the postreperfusion syndrome should be aggressively treated. close communication between all parties involved in liver transplantation is also equally valuable in achieving a successful outcome. dr. thomas starzl of denver, colorado, usa, who believed that "liver transplantation is an effective treatment providing exactly what is needed for patients with end-stage liver disease (esld)," performed the first successful orthotopic liver transplantation (olt) in a -year-old boy with biliary atresia in (starzl et al. ) . during the first two decades of the procedure's history, liver transplantation led by starzl and sir roy calne of cambridge encountered almost insurmountable challenges, including complexity of surgical technique, primitive anesthesia and intensive care, less-than-adequate immunosuppression and organ preservation, and devastating infection. the number of procedures performed was relatively few, and the success rate was low. however, their keen observations on these early clinical experiences laid the foundation of modern liver transplantation (starzl and putnam ; calne ) . breakthroughs were made in each decade following the first transplantation. in the s, venovenous bypass was introduced to maintain better hemodynamic stability (shaw et al. ) , cyclosporine was found to be a superior immunosuppressant to azathioprine, and anesthesiologists answered important clinical questions, including those relating to the monitoring and treatment of coagulopathy, hemodynamic changes, and the role of the electrolyte imbalance. in the s, fk (tacrolimus) became the immunosuppressant of choice ), university of wisconsin solution was introduced to extend the safe cold ischemia time to h (kalayoglu et al. ) , and the piggyback technique simplified surgery in select patients (tzakis et al. ). in the past years, liver transplantation has been performed in most major medical centers with a -year survival rate of greater than %, and living donor liver transplantation has become a valuable alternative. liver transplantation requires a true multidisciplinary approach, and anesthesiologists and intensivists have played a major role in the successful outcome of liver transplantation. in support of the important role of anesthesiologists in liver transplantation, the american society of anesthesiologists (asa) developed the guidelines for director of liver transplant anesthesia in . the guidelines specified that the director should have fellowship training in critical care medicine, cardiac anesthesiology, or transplantation anesthesiology that includes the perioperative care of at least ten liver transplant recipients or experience in the perioperative care of at least liver transplant recipients in the operating room. in addition, the director is expected to obtain a minimum of h of accreditation council for continuing medical education (accme) category i continuing medical education (cme) credit in transplantation-related educational activities within the most recent -year period. in this chapter, physiology and pathophysiology of liver disease and anesthesia care of liver transplantation are described based on clinical experience at the university of pittsburgh (pittsburgh, pa, usa) and thomas jefferson university (philadelphia, pa, usa). the liver, which weighs - g in adults, is traditionally divided into the right and left lobe in reference to the location of the falciform ligament. couinaud, however, divided the liver into the right and left hemiliver using the cantlie's line, which extends from the inferior vena cava (ivc) to the gall bladder, and each hemiliver is further divided into four segments (couinaud ) . the left hemiliver is composed of the traditional left lobe along with the caudate and quadrate lobe. liver resections based on these segmental definitions are right hepatectomy (segments - ), right lobectomy (segments - ), left hepatectomy (segments - ), and left lobectomy (segments - ) ( fig. ) (bismuth ) . the liver has a unique dual blood supply: arterial supply from the hepatic artery, a branch of the celiac axis, and venous supply from the portal vein formed by the union of the splenic and superior mesenteric vein. despite liver mass constituting only . % of the total body weight, the total hepatic blood flow is approximately ml/ g/min, or % of cardiac output. the hepatic artery supplies approximately - % of hepatic blood flow and - % of the oxygen requirement, while the portal vein supplies - % of hepatic blood flow and - % of oxygen. the venous drainage is through the right, middle, and left hepatic veins, which merge into the ivc. the valveless portal vein is a low pressure/low resistance circuit, while the hepatic artery is a high pressure/high resistance system. hepatic - , copyright ( ) , with permission from elsevier) blood flow is primarily regulated by local metabolic demand with an inverse relationship between portal venous and hepatic arterial flow: an increase in the hepatic adenosine level triggered by a reduced portal venous flow increases hepatic arterial blood flow (gelman and ernst ; lautt et al. ) . the hepatic artery buffer response appears to be functional even after liver transplantation (payen et al. ) , and this response may be responsible for the development of the small-for-size syndrome after living donor or split liver transplantation (kiuchi et al. ). small-for-size syndrome develops in a patient who received a donor graft that was less than % of the recipient's body weight and is caused by decreased hepatic arterial flow in response to increased portal venous flow and pressure. subsequently, a prolonged postoperative reduction in hepatic arterial flow can lead to centrilobular tissue necrosis, biliary ischemia, and hepatic arterial thrombosis (smyrniotis et al. ) . there is no buffer response in the portal system because the portal vein cannot regulate its blood flow. therefore, alterations in the hepatic arterial blood flow do not induce compensatory changes in the portal blood flow (lautt ) . the mean pressure in the hepatic artery is similar to that in the aorta, while portal vein pressure ranges between and mmhg. the portal pressure depends primarily on the degree of constriction or dilatation of the splanchnic arterioles and on intrahepatic resistance. both afferent systems merge at the sinusoidal bed, where the pressure is estimated to be - mmhg higher than that in the ivc. the liver serves as a blood reservoir, and it replenishes blood volume of up to % rapidly in the case of an acute bleeding episode (lautt ) . hepatic blood volume may expand considerably in cardiac failure by venous congestion. the liver is innervated by the left and right vagi, the right phrenic nerve, and fibers from the t -t sympathetic ganglia. the hepatic artery is innervated mainly by sympathetic fibers, and hepatocytes, by the unmyelinated sympathetic fibers. the bile ducts are innervated by both sympathetic and parasympathetic fibers. the role of hepatic innervation is unclear, as denervation of the transplanted liver does not affect its function (kjaer et al. ) . bile flow begins from the bile canaliculi to the common bile duct. hepatic lymph forms in the space between the sinusoid and the hepatocyte (space of disse) and flows to lymph nodes in the hilum and ivc. the transdiaphragmatic lymphatic flow is the cause of pleural effusions in the presence of large ascites. the liver is made of parenchymal cells (hepatocytes) and non-parenchymal cells (sinusoidal endothelial, kupffer, stellate, dendritic, and lymphocyte) . hepatocytes make up - % of liver cells and carry out hepatic metabolic, synthetic, and detoxification functions. polyhedral hepatocytes are arranged in one-cell thick plates with endothelium-lined sinusoids on both sides. each hepatocyte cell membrane has three distinct membrane domains. the sinusoidal membrane is adjacent to the sinusoidal endothelium and has numerous microvilli abutting into the space of disse. fenestrae within the sinusoidal endothelium without the basement membrane permit intimate contact between sinusoidal blood and the hepatocytes to allow the passage of big molecules, including lipoproteins. liver sinusoidal endothelial cells make up - % of liver cells and release nitric oxide to regulate vascular resistance. they are, along with dendritic cells and lymphocytes, part of the innate immune system. the space of disse contains phagocytic kupffer cells that participate in the hepatic inflammatory process. the ito cells, also known as stellate cells, are the major site of vitamin a storage, and their activation results in hepatic fibrosis and cirrhosis. reticulin fibers in the space of disse support the sinusoidal framework, and weakening of these supporting fibers results in rupture of sinusoidal walls and formation of blood-filled cysts known as peliosis hepatis, a forerunner of cirrhosis. the apical membrane circumscribes the canaliculus, the earliest component of the biliary system. the lateral hepatic membrane is found between adjacent hepatocytes. the functional unit of the liver is the acinus. terminal portal veins communicate with terminal hepatic venules, with sinusoids bridging the gap between the two vessels ( fig. ) . each sinus contains three zones with equal blood pressure and oxygen content. the periportal zone (zone ) receives blood highest in oxygen content and the pericentral or perivenular zone (zone ) receives blood lowest in oxygen content. as a result, the hepatocytes in the perivenular zone (zone ) are more vulnerable to ischemic damage and nutrient depletion. oxidative and reductive functions are predominantly performed by hepatocytes at the periportal zone and glucuronidation is performed by those at the perivenular zone, although hepatocytes of the two different zones are functionally integrated (lamers et al. ). the unique structure of the liver acinus is well-suited for bidirectional transfer of nutrients. the low pressure in the portal venous system allows blood to flow slowly through the sinusoids. hepatic arterial blood flows mainly to the terminal bile canaliculi, although it augments sinusoidal flow to give a gentle pulsatility. in patients with liver cirrhosis, the sinusoids acquire features of systemic capillaries: the space of disse widens with collagen deposits at the basement membrane, endothelial fenestrations become smaller and fewer, and hepatic microvilli efface. all of these changes reduce transport across the sinusoidal walls and result in hepatic dysfunction. furthermore, widespread fibrosis and scarring reduce the number and size of the small portal and hepatic veins and increase intrahepatic vascular resistance to the development of portal hypertension (popper ) . the sluggish blood flow in the altered vascular architecture promotes thrombosis, causing further cell necrosis and fibrosis (wanless et al. ) . the liver undergoes rapid regeneration through proliferation of hepatocytes to maintain the critical mass necessary for normal liver function. for example, the newly transplanted hemiliver from a living related donor regenerates to about % of its original whole liver size in - days. the major hepatic growth factors are epidermal growth factor and hepatocyte growth factor (michalopoulos ) . administration of the epidermal or hepatocyte growth factor to normal rats, however, does not cause hepatocyte replication. this negative response suggests that liver regeneration involves a two-step process: the initial signal generated by an acute increase in metabolic demand associated with the loss of hepatocytes triggers a set of early response genes that prime hepatocytes to respond to various growth factors. in apoptosis or programmed cell death, aging hepatocytes are removed and new cells are produced in a continuous manner (ellis et al. ). the liver has three major functions: metabolism, bile production and secretion, and filtration of harmful substances. the principal role of the liver is to provide the body with normal glucose levels, which are regulated by insulin, glucagon, growth hormone, and catecholamines (pilkis and granner ) . the liver converts glucose into glycogen (glycogenesis) and utilizes glucose for the synthesis of fatty acids. cirrhotic patients are frequently hyperglycemic although their insulin level is elevated (petrides and defronzo ) . this insulin resistance is caused by multiple mechanisms. cirrhotic patients have an increased basal metabolic rate and use preferentially fatty acids as an energy source. reduced glucose uptake and limited glucose storage in the liver and muscle lead to hyperglycemia. other contributing factors are increased serum fatty acids, which inhibit glucose uptake by muscle; altered second messenger activity after insulin binding to its receptors; an increased concentration of serum cytokines associated with elevated levels of endotoxins; and increased levels of glucagon and catecholamines. the liver is the major organ for protein synthesis, and albumin is the most important protein product. albumin is the major contributor to plasma oncotic pressure and binds and transports bilirubin, hormones, fatty acids, and other substances. hypoalbuminemia is commonly caused by decreased hepatic synthetic function, although it can be secondary to an enlarged volume of distribution, reduced level of amino acid precursors, and losses into the urine, peritoneum and pleural cavity, and leads to peripheral edema, ascites, and pleural effusions. the low serum oncotic pressure stimulates the hepatic albumin synthesis in healthy subjects, but this is impaired in patients with cirrhosis (pierrangelo et al. ) . the liver synthesizes all coagulation factors (except von willebrand factor) and protein c and s. factors ii, vii, ix, and x undergo a posttranslational vitamin k-dependent modification involving γ-carboxylation of specific glutamic acid residues in the liver. the liver is the primary site of interconversion of amino acids. anabolic processes synthesize proteins from amino acids, while catabolic processes convert amino acids either to keto acids by transamination or ammonia by oxidative deamination. ammonia, in turn, is converted to urea by the krebs-henseleit cycle. in patients with liver disease, derangement of both anabolic and catabolic processes results in decreased production of blood urea nitrogen (bun) and accumulation of ammonia, a contributing factor in the development of hepatic encephalopathy. the liver produces acute-phase reactants, such as α-fetoprotein, ceruloplasmin, fibrinogen, transferrin, complement, and ferritin. they are expressed during acute and chronic systemic inflammation, and their activation is mediated by interleukin- , tumor necrosis factor, interferon-γ, and glucocorticoids. the liver takes up fatty acids and cholesterol from diet and peripheral tissues to produce and release lipoprotein complexes into circulation. fatty acids released from adipocytes are bound to serum albumin and transported to the liver for the synthesis of phospholipids and triglycerides. the liver produces fatty acids from small molecular weight precursors, and cholesterol synthesis is regulated by the ratelimiting enzyme -hydroxyl- methylglutaryl coenzyme a reductase (hmg-coa reductase). lipids are exported out of the liver by very low-density lipoprotein (vldl) particles, which are the major carriers of plasma triglycerides during non-absorptive states. lipids are temporarily stored in the liver as fat droplets, or as cholesteryl esters in the case of cholesterol, and are directly excreted into bile or metabolized into bile acids. the liver is the major site for sterol excretion and production of bile acids. various abnormalities in lipid metabolism are common in liver disease. hypertriglyceridemia ( - mg/dl) is the most common presentation and may be caused by decreased synthesis of lipoproteins, decreased hepatic clearance of lipoprotein complexes, or re-entry of biliary content into the serum. alcoholic liver injury results in increased fatty acid synthesis and steatosis (lieber ) . paradoxically, an increased high-density lipoprotein (hdl) level has been noted with moderate alcohol consumption, which may explain the reduced risk of atherosclerosis in these patients (chait and brunzell ) . patients with cholestatic liver diseases have elevated total serum cholesterol and triglycerides because the bile is rich in cholesterol, phospholipids, and lecithin. the liver eliminates drugs through two types of reactions. the phase reactions include oxidation, reduction, hydroxylation, sulfoxidation, deamination, dealkylation, and methylation of reactive substances. these reactions involve systems such as cytochrome p and typically occur in the periportal area of the liver. the phase reactions, which transform lipophilic agents into more water-soluble compounds, take place in the pericentral area. in patients with liver disease, hepatic drug clearance is usually reduced due to the enlarged volume of distribution and decreased hepatic metabolism. as a result, a large initial dose of medications followed by small, titrated maintenance doses are required to achieve the desired pharmacologic effects. several hormones are deactivated or altered in the liver. the deactivated hormones are insulin, glucagon, steroid hormones, aldosterone, thyroxine, and triiodothyronine. the liver converts testosterone into androsterone and estrogen into estrone and estriol. abnormal levels of estrogen and testosterone in patients with liver disease lead to testicular atrophy, loss of pubic and axillary hair, spider angioma, and gynecomastia. the liver removes various substances from the body, and bile formation is one of the most important excretory functions. when membranes of old erythrocytes rupture, the released hemoglobin is taken up by the reticuloendothelial cells and is split into heme and globin. heme converts to biliverdin, which, in turn, is reduced to free bilirubin and released into the plasma. the free bilirubin-albumin complex is taken up by the hepatocytes. bilirubin conjugates primarily with glucuronic acid and is actively transported into the bile. a small portion of conjugated bilirubin returns to the plasma directly from the sinusoids or indirectly by absorption from the bile ducts and lymphatics. bilirubin is converted into urobilinogen by the intestinal bacterial flora. some urobilinogen is reabsorbed through the intestinal mucosa and is re-excreted into the intestine. bile acids, which enhance absorption of vitamin k, are also excreted into the bile by the liver. the liver, located between the splanchnic and systemic venous system, acts as a vascular filter. kupffer cells phagocytose immune complexes, endotoxins, and bacteria in the portal venous blood and process antigens for presentation to immunocompetent cells. the liver also removes activated coagulation elements from circulation to prevent excessive coagulation or fibrinolysis. liver cirrhosis is defined as progressive fibrosis and the formation of regenerative nodules, and is the final common pathway in which hepatocytes are replaced by connective tissue after various, repetitive insults. the amount of remaining functional hepatic mass and the degree of architectural distortion determine the functional state of the liver. portal hypertension is inevitable in advanced cirrhosis and leads to ascites, variceal bleeding, and encephalopathy. the severity of cirrhosis is frequently classified using the child-pugh score (table ) , and a score of > suggests a short life expectancy. hepatic encephalopathy is a reversible neuropsychiatric condition in both acute and chronic liver failure. in chronic liver disease, hepatic encephalopathy develops in % of patients within years of compensated cirrhosis and is associated with spontaneously developed or surgically created portosystemic shunting (butterworth ) . the degree of encephalopathy is stratified by a coma scale: grade , subtle confusion; grade , somnolence; grade , unconsciousness with response to pain stimulation; and grade , deep coma. clinically, asterixis, flapping tremor, and fetor hepaticus (musty, sweet breath odor) are confirmatory of hepatic encephalopathy. the main cause of hepatic encephalopathy is the altered expression of several genes for various neurotransmitter proteins in the brain (butterworth ) . decreased expression of the glutamate transporter (glt- ) increases extracellular brain glutamate. an increased expression occurs in some receptors: monoamine oxidase increases degradation of monoamine transmitters, the peripheral-type benzodiazepine receptor increases inhibitory neurosteroids, and neuronal nitric oxide synthase increases nitric oxide production. although its plasma level is not closely related to the severity of encephalopathy, ammonia is still considered to be a major contributing factor. ammonia and manganese are known to alter the expression of the peripheraltype benzodiazepine receptor and neuronal nitric oxide synthase in exposed cells (warskulat et al. ) . magnetic resonance spectroscopy reveals brain edema and increased brain glutamine/glutamate in the frontal and parietal lobes; histologic findings are swelling and glycogen deposition in astrocytes. these changes in the brain coincide with impairment in the visuopractic capacity, visual scanning, and perceptual-motor speed on neuropsychiatric testing (tarter et al. ) . subclinical hepatic encephalopathy can be detected by having patients perform a simple timed connect-the-numbers test. treatment of hepatic encephalopathy is based on the ammonia-lowering strategy, such as protein restriction, oral non-absorbable antibiotics, and lactulose. rifaximin reduces the plasma ammonia level by destroying intestinal bacteria that produce urease. metronidazole ( mg/day) is another antibiotic, although its adverse effects limit its use to week at a time. lactulose is a substrate for gut bacteria and reduces the formation of ammonia by lowering intestinal ph. rifaximin class a = - points, b = - points, and c = - points inr international normalized ratio and lactulose are commonly used together, and the antibiotic is discontinued once eradication of disaccharide-metabolizing intestinal bacteria is indicated by an increase in stool ph. oral or parenteral ornithine aspartate, a substrate for the conversion of ammonia to urea and glutamine, has effects similar to those of lactulose, but with fewer adverse effects. in patients with severe encephalopathy, the molecular-absorbent recycling system (mars) may be utilized to remove small and middle molecular weight water-soluble substances (sorkine et al. ) . the system appears to increase blood pressure and systemic vascular resistance, possibly by removing nitric oxide. in fulminant hepatic failure, progressive hepatic coma is accompanied by a gradual increase in cerebral blood flow and intracranial pressure (icp) (see ▶ chap. , "fulminant hepatic failure: diagnosis and management"). subsequently, vasogenic cerebral edema and severe intracranial hypertension develop and approximately - % of patients die of brain herniation. monitoring of icp using a ladd epidural sensor is useful in detecting intracranial hypertension, monitoring the therapeutic effects, and identifying patients who would survive after transplantation without neurologic damage (lidorsky et al. ) . non-invasive neurologic assessment includes transcranial doppler (tcd) to measure cerebral bloodflow velocity, determination of the cerebral metabolic rate for oxygen by calculating the oxygen content difference between arterial and jugular bulb venous blood, evoked potentials, and serial computed tomography (ct) scans (aggarwal et al. ) . treatment includes osmotic and loop diuretics, barbiturateinduced coma, and hypothermia. the definitive treatment is usually transplantation. the presence of hyperdynamic circulation with a markedly increased cardiac output and decreased systemic vascular resistance was first described by kowalski and abelmann in the early s (kowalski and abelmann ) . several hypotheses have been proposed to explain this phenomenon, including an overactive sympathetic nervous system, inadequate clearance of vasoactive substances by the diseased liver, the presence of arteriovenous shunts, nitric oxide-induced vasodilation, and relative hypoxia in peripheral tissues (benoit et al. ; yokoyama et al. ; kalb et al. ; d'souza et al. ) . although cardiac output is frequently two to three times normal, impaired systolic and diastolic function together with attenuated cardiac responsiveness to stimuli suggests that cardiomyopathy is present in cirrhotics (cirrhotic cardiomyopathy) (lee ) . caramelo et al. noted a % decrease in cardiac output with volume expansion in a ccl -induced cirrhotic rat model (caramelo et al. ) . in another rat model, the chronotropic response to isoproterenol was attenuated compared with that in control animals (lee et al. ). cardiac response to physical exercise is blunted in patients with cirrhosis, indicated by alterations in the pre-ejection period, isometric contraction time, and ratio of the pre-ejection period to left ventricular ejection time. in addition, abnormalities in myocardial diastolic indices suggest non-compliant ventricles. histologically, myocardial fibrosis, mild subendocardial edema, and vacuolation of myocyte nucleus and cytoplasms are observed. the development of cirrhotic cardiomyopathy is multifactorial. it appears that the β-receptor system, the main stimulant of the ventricle, is dysfunctional. in humans, lymphocyte β-receptor density, which reflects cardiac β-receptor status, is reduced in patients with severe ascites (gerbes et al. ) , and β-receptor density of the cardiomyocyte sarcolemmal plasma membrane is reduced in cirrhotic rats (liu and lee ) . further, the β-receptor signal transduction pathway is impaired at several levels (ma et al. ) . although cardiac contractile impairment may result from overactivity of the muscarinic m receptor, the receptor density and binding affinity are unchanged, suggesting normal parasympathetic function (jaue et al. ) . high serum catecholamine levels, a result of desensitization and down-regulation of β-receptors, may lead to myocardial dysfunction in the presence of α-mediated coronary vasoconstriction. additionally, overproduction of nitric oxide inhibits β-receptor-stimulated cyclic adenosine monophosphate (camp) release, causing myocardial dysfunction and vasodilation (hare and colucci ) . coronary artery disease (cad) was previously believed to be relatively uncommon in patients with cirrhosis as a result of generalized vasodilation and elevated levels of hdl and estrogen. in addition, autopsy findings showed relatively fewer atherosclerotic changes and myocardial infarction. however, studies have shown that cad is not uncommon, and moderate-to-severe cad was found in approximately % of patients who underwent coronary artery catheterization as a part of liver transplantation workup (carey et al. ) . in another study of liver transplantation candidates who were at risk for cad and referred for coronary angiography, % of patients had at least one moderate or severe (> %) coronary stenosis (tiukinhoy-laing et al. ) . endocarditis is three times more common in patients with liver disease (snyder et al. ) . this is attributed to translocation of intestinal bacteria through the intestinal wall and portosystemic collaterals, and reduced immune response. the incidence of pericardial effusion in cirrhotic patients is approximately - % and correlates with the degree of liver failure (shah and variyam ) . the effusion is usually small and may require drainage if it affects cardiac function. patients with liver disease exhibit three common cardiac electrophysiological disturbances: electromechanical dissociation, prolongation of ventricular repolarization (the q-t interval), and chronotropic incompetence (milani et al. ) . pulmonary hypertension associated with portal hypertension was first described in (mantz and craige ) . pulmonary hypertension defined as a mean pulmonary artery pressure of > mmhg and pulmonary vascular resistance of > dyn/s/cm À ( wood units) is more common in patients with liver disease, with a prevalence of . - . % (lebrec and capron ; mcdonnell et al. ) . pulmonary artery pressure is a function of pulmonary venous pressure, pulmonary vascular resistance, and cardiac output [(pulmonary artery pressure = pulmonary venous pressure + (pulmonary vascular resistance  cardiac output)]. therefore, pulmonary hypertension is not uncommon in patients with liver disease because of their poor left ventricular compliance, increased pulmonary vascular resistance, and increased pulmonary blood flow from portosystemic shunting. the pathophysiology and management of pulmonary hypertension are well-described in ▶ chap. , "hepatopulmonary syndrome and portopulmonary hypertension". portal hypertension is caused by an increased intrahepatic vascular resistance and increased splanchnic blood flow. endothelin- , a powerful vasoconstrictor produced by the sinusoidal endothelial cells, is known to increase intrahepatic vascular resistance and activates stellate cells, and its level increases as cirrhosis progresses (kojima et al. ; gandhi et al. ) . normally, vasodilatory compounds, such as nitric oxide, counterbalance the increased intrahepatic vascular resistance induced by endothelin. in liver cirrhosis, however, nitric oxide production is inhibited by caveolin- , a hepatic membrane protein that binds with endothelial nitric oxide synthase. hypoxemia of varying severity is present in - % of patients with significant liver disease (krowka and cortese ) . the common causes are pleural effusions, impaired diffusion capacity, arteriovenous shunting, atelectasis caused by ascites or diaphragmatic dysfunction, aspiration secondary to encephalopathy, and deconditioning (hourani et al. ) . ventilation-perfusion mismatch, pulmonary vasodilation, and infection also contribute to hypoxemia. mild forms of hypoxemia are most common, although moderate-tosevere hypoxemia may be found in patients with advanced liver disease complicated by adult respiratory distress syndrome (ards), infection, and multiple organ failure. hepatopulmonary syndrome, first described by fluckiger in (fluckiger ) , may cause severe hypoxemia in a subset of patients with liver disease. the syndrome consists of a triad of liver dysfunction, severe hypoxemia (pao < mmhg in room air), and pulmonary vasodilation, and is characterized by dyspnea, cyanosis, clubbing of the digits, exercise desaturation, and orthodeoxia (hypoxemia in upright position). other concomitant clinical signs are a markedly increased alveolar-arterial oxygen gradient, portal hypertension, and vascular abnormality such as spider angioma and pulmonary vasodilation. the pulmonary vascular dilation (from - μ to - μ) at the precapillary level is believed to be the main pathology of the hepatopulmonary syndrome, which is caused by decreasing erythrocyte transit time and impairing diffusion of oxygen to the erythrocytes at the center of the bloodstream (genovesi et al. ). in contrast with other pulmonary diseases, oxygenation improves dramatically with a high inspired oxygen concentration (fio ), because a high alveolar concentration of oxygen overcomes the diffusion barrier and oxygenates the erythrocytes in the center of the bloodstream. the pathophysiology and management of hepatopulmonary syndrome are described in ▶ chap. , "hepatopulmonary syndrome and portopulmonary hypertension". non-cardiogenic pulmonary edema occurs in - % of patients with advanced liver disease, particularly in those with fulminant hepatic failure, and appears to be associated with sepsis and a neurogenic mechanism. the presence of this complication is ominous: matuschak and shaw reported that all patients who developed non-cardiogenic pulmonary edema died before liver transplantation (matuschak and shaw ) . in contrast, a rapid reversal of ards after liver transplantation has been reported (doyle et al. ) . pulmonary edema caused by fluid overload responds to diuretics and has a relatively benign course. pleural effusions are found on chest x-rays in about % of patients. these are caused by the unidirectional passage of ascites via diaphragmatic defects into the pleural space. diagnostic thoracentesis is necessary to confirm the transudative nature and to exclude infection, malignancy, or embolic disease. optimal control of ascites may prevent symptomatic pleural effusions, and transjugular intrahepatic portosystemic shunt (tips) is effective in treating refractory hydrothorax in % of patients (siegerstetter et al. ). approximately % of hospitalized cirrhotic patients with ascites develop the hepatorenal syndrome, which is a form of acute pre-renal kidney injury caused by circulatory dysfunction secondary to an imbalance between circulating vasodilatory and vasoconstrictive substances. the primary contributing factor for the hepatorenal syndrome is nitric oxide-induced vasodilation of the splanchnic vascular bed causing systemic arterial underfilling and relative hypovolemia (arroyo et al. ) . this relative hypovolemia activates baroreceptor-mediated sympathetic and the renin-angiotensin system to constrict all vascular beds including the renal vasculature (guevara et al. ). the initial prostaglandin-mediated compensatory renal vasodilation is followed by renal arterial vasoconstriction and renal hypoperfusion. a striking feature of the hepatorenal syndrome is the lack of any histologic change and its reversibility: the affected kidneys resume their function after successful liver transplantation. the renal failure may be rapid (type ) or insidious (type ) and results in sodium and water retention and dilutional hyponatremia. since the hepatorenal syndrome is a functional renal failure, the urine is similar to that found in pre-renal azotemia: oliguria, low urinary sodium, and an increased urine osmolality and urine to plasma osmolality ratio. the major criteria for the diagnosis of the hepatorenal syndrome are as follows: ( ) advanced hepatic disease and portal hypertension; ( ) low glomerular filtration rate (serum creatinine > . mg/dl or creatinine clearance < ml/ min); ( ) absence of nephrotoxic drug use, shock, systemic infection, or recent fluid losses; ( ) lack of sustained improvement after diuretic withdrawal and volume resuscitation with . l of normal saline; ( ) proteinuria (< mg/dl); and ( ) no ultrasound evidence of urinary obstruction or parenchymal disease. minor criteria include oliguria (< ml/day), urinary sodium < meq/l, urinary osmolality greater than plasma osmolality, urinary red blood cells (rbcs) < /hpf, and serum sodium < meq/l. it is noteworthy that conventional renal function tests, such as bun and creatinine levels, overestimate renal function in patients with liver failure because malnutrition and muscle wasting contribute to a low creatinine level and liver dysfunction impairs urea synthesis. the hepatorenal syndrome is treated with the administration of vasopressin- agonists (i.e., terlipressin), tips, and, most reliably, liver transplantation. one uncontrolled trial using terlipressin with albumin for a median duration of days (range - days) showed improvement in serum sodium as well as a decrease in the creatinine level below mg/dl (mulkay et al. ) . hemodialysis is a temporary measure and its efficacy is not reliable. the only primary preventive measure showing some promise is the administration of albumin along with antibiotics as soon as the presence of spontaneous bacterial peritonitis is diagnosed; this possibly works by preventing hypovolemia and subsequent activation of vasoconstrictor systems. all phases of hemostasis are impaired in patients with liver disease, including clot formation, fibrinolysis, and their inhibitory processes. thrombocytopenia is found in - % of cirrhotic patients, and platelet count is commonly below , /mm . thrombocytopenia is primarily caused by splenomegaly associated with portal hypertension, which pools up to % of platelets in the spleen. however, the degree of thrombocytopenia does not closely correlate with the size of the spleen. impaired hepatic synthesis of thrombopoietin also leads to thrombocytopenia. thrombopoietin is involved in the maturation and formation of platelets, and its return to a normal level coincides with a gradual increase in platelet count by the fifth day after liver transplantation (kawasaki et al. ) . other contributing factors are increased destruction of platelets by immune mechanisms, excessive activation of coagulation, and direct bone marrow suppression by toxins such as ethanol and folate deficiency. additionally, platelet dysfunction is common, as demonstrated by impaired platelet aggregation to adenosine diphosphate (adp), collagen, and thrombin (rubin et al. ) . the liver produces all coagulation factors except for von willebrand factor. therefore, plasma levels of clotting factors are directly related to the severity of liver disease, and prothrombin time (pt) is considered to be one of the most sensitive hepatic synthetic function tests. the plasma fibrinogen level, being an acutephase reactant, typically is normal or increased in chronic liver disease. a reduction in the fibrinogen level may indicate either a greatly reduced hepatic reserve or significant extravascular loss to ascites. markedly prolonged thrombin time indicates the presence of dysfibrinogenemia in some patients. dysfibrinogenemia is characterized by an excessive number of sialic acid residues in the fibrinogen molecule and abnormal polymerization of fibrin monomers. its clinical significance is unclear. patients with liver disease have a tendency to develop fibrinolysis due to decreased hepatic clearance of plasminogen activators, especially tissue plasminogen activator (tpa), and reduced production of α -antiplasmin and thrombin activatable fibrinolysis inhibitors (van thiel et al. ) . elevated levels of d-dimers, fibrin degradation products, and plasminogen are present in ascitic fluid, indicating that absorption of ascitic fluid may contribute to the hyperfibrinolysis. on the other hand, excessive activation of coagulation is common in liver disease because of inadequate hepatic clearance of activated coagulation factors, reduced level of coagulation inhibitors, and enlarged vascular beds. the hypercoagulable state may lead to localized or disseminated intravascular coagulation (dic), particularly in the presence of sepsis, trauma, or major surgery. the diagnosis of excessive activation of coagulation is based on the presence of a known triggering factor and the progressively worsening of coagulation with thrombocytopenia. an anesthesia consultation is performed once a patient with esld is referred to the liver transplantation center. the type of liver disease is identified because patients with hepatocellular disease may have more pronounced hepatic dysfunction than those with cholestatic disease or hepatocellular cancer, and certain types of liver disease may affect other vital organ function (i.e., hemochromatosis, familiar amyloidosis, etc.). the anesthesia consultation is focused on evaluation of the functional reserve of extrahepatic organs, and various tests or specific consultations may be requested (table ) . cardiovascular assessment is performed to determine two things: ( ) whether a patient can be expected to survive the operation and immediate postoperative period; and ( ) whether transplantation in patients with severe cardiopulmonary disease would be futile and an inappropriate use of a scarce donor organ (lentine et al. ) . a suggested strategy for cardiac assessment is shown in fig. (raval et al. ) . overall cardiac performance is evaluated by transthoracic echocardiography to assess myocardial contractility, abnormality in cardiac anatomy, intracardiac or intrapulmonary shunting, and pulmonary artery pressure. most patients over age years undergo non-invasive stress testing because they may have multiple cad risk factors (i.e., diabetes, hypertension, hyperlipidemia, and pre-existing cardiovascular disease), and limited physical activity masks underlying ischemic heart disease. an exercise stress test may not be feasible in many patients with advanced liver disease, and dobutamine stress echocardiography (dse) is commonly used, although adenosine or dipyridamole may be used when dobutamineinduced tachycardia is not desirable. dse, with its high sensitivity and specificity, appears to be the most reliable screening test (plotkin et al. ) , and dobutamine-induced tachycardia may mimic intraoperative stress on the cardiovascular system. on the contrary, dse has been reported to have poor sensitivity (as low as %) and negative predictive value (as low as %) (harinstein et al. ) , and its results may not correlate with adverse cardiac events within days after transplantation (safadi et al. ). cardiac ct scan is a non-invasive technique measuring calcium deposits within the coronary vasculature. the total amount of calcium, adjusted to the age and gender of the patient, is reported as a calcium score. high scores suggest a greater potential for coronary artery stenosis (shaw et al. ; o'rourke et al. ) , and a calcium score of > has a predictive value of cardiac complications within month after transplantation (kemmer et al. ). this test, however, may have limited predictive value as a single screening study for cad. cardiac ct angiography is an alternative to invasive coronary angiography. it does appear to have negative predicting value of % for clinical coronary events in patients undergoing liver transplantation (cassagneau et al. ) but may not be suitable for the diagnosis of obstructive lesions at this time. because of the difficulty in diagnosing cad using non-invasive testing methods, coronary angiography is recommended for patients with a positive dse or multiple high-risk factors to identify the degree and type of obstruction. in addition, coronary angiography should be able to detect non-obstructive lesions (coronary artery stenosis < %), which are unlikely to be detected by stress tests but can be responsible for acute coronary syndromes (unstable angina, myocardial infarction, or sudden cardiac death) (rubin et al. ; gulati et al. ). cardiac catheterization, however, can be difficult in patients with severe liver disease due to bleeding complications and the increased risk of contrast-induced nephropathy (sharma et al. ). if significant coronary artery stenosis (> % stenosis) is detected, revascularization may be table liver transplantation evaluation at the thomas jefferson university hospital attempted before liver transplantation. bare metal stents are favored over drug-eluting stents to avoid the need for long-term antiplatelet therapy ( weeks vs. year). when angioplasty is not amenable, coronary artery bypass grafting (cabg) is performed. it is clear that -year survival after cabg is greater in patients with child-pugh class a ( %) than with child-pugh class b ( %) and c ( %) (filsoufi et al. ). therefore, patients with child-pugh class a can undergo cabg relatively safely while waiting for liver transplantation. on the other hand, patients with child-pugh class b and c may require simultaneous cabg and liver transplantation. patients with mild-to-moderate valvular disease undergo liver transplantation without excessive complications. similar to that of cabg, mortality after corrective valvular surgery depends on the severity of liver disease. therefore, child-pugh class c patients with severe aortic or mitral valve stenosis may undergo percutaneous balloon valvuloplasty or simultaneous valve replacement with cardiopulmonary bypass and liver transplantation. myocardial disease is commonly detected by transesophageal echocardiography (tee). patients with chronic cardiomyopathy may have attenuated systolic contraction and diastolic relaxation, altered repolarization, and reduced cardiac response to β stimulation (liu et al. for pulmonary evaluation, results of chest x-ray, arterial blood oxygen tension in % oxygen, and spirometry are reviewed to identify the degree of pulmonary shunting, obstructive, or restrictive disease. when the hepatopulmonary syndrome is suspected, contrast tee or tc- m macro aggregated albumin scintigraphy may be performed for its definitive diagnosis (krowka et al. ) . for evaluation of renal function, results of bun, creatinine, glomerular filtration rate, levels of serum and urine electrolytes, urine output, and renal ultrasound are reviewed. the diagnosis criteria of the hepatorenal syndrome have been described earlier. in patients with chronic renal failure, simultaneous liver and kidney transplantation is performed, the criteria for which are end-stage renal disease with dialysis, no dialysis but a glomerular filtration rate < ml/min and proteinuria > g/day with a -h urine protein/creatinine ratio > , and acute kidney injury requiring dialysis at least twice per week for more than weeks (charlton et al. ). in patients with fulminant hepatic failure, reversibility of the neurologic function should be investigated using clinical signs, eeg, brain ct scan, the cerebral metabolic rate of oxygen, and tcd. in addition, icp monitoring is recommended when a high icp (> mmhg) is suspected, although its benefit should be weighed against potential complications (vaquero et al. ) . poor prognostic indicators of fulminant hepatic failure are progressive hepatic failure for - days, grade - encephalopathy, intracranial hypertension, cerebral swelling, severe coagulopathy, rapid shrinkage of the liver, metabolic acidosis, hemodynamic instability, and sepsis. for the coagulation system, pt, activated partial thromboplastin time (aptt), and platelet count are reviewed. in general, no specific coagulation therapy is requested because of the potential long waiting period and fluid overloading. abdominal magnetic resonance imaging (mri) is reviewed to assess the degree of portosystemic shunting and anatomy of hepatic vasculature. additional consultation may be requested from various specialists to identify the type and severity of the specific organ dysfunction. after the evaluation, all information of the potential recipient is compiled to stratify whether the patient's condition can be optimized or meet the criteria of contraindications. contraindications are diseases or conditions patients could have that may not improve survival after liver transplantation. they include malignancy with poor prognosis, active bacterial and viral infection, severe cardiopulmonary dysfunction, and technical difficulties. active alcoholism is a contraindication, although demonstrable abstinence for months is considered acceptable. the presence of multiple organ dysfunction is a relative contraindication for liver transplantation as the -year survival is approximately %. indications and contraindications of liver transplantation, however, have evolved over the past years, and further modifications are expected to occur. anesthesiologists participate in the transplantation candidate selection committee for discussion of the hepatic disease, its complications, and the extrahepatic organ function of each patient. once the patient is placed on the active candidate list, the united network for organ sharing (unos) is notified and the patient is given a meld (model for end-stage liver disease) or peld (pediatric end-stage liver disease) score for fair distribution of donor livers. although surgical techniques are fully described elsewhere, a brief description of their physiologic effects is warranted here. in olt, after removal of the diseased liver, the donor liver is placed anatomically in the right upper quadrant. for the convenience of description, the procedure is divided into three stages: stage (dissection stage), stage (anhepatic stage), and stage (neohepatic stage). the dissection stage begins with an inverted y-shaped bilateral subcostal skin incision and ends with the skeletonization of the diseased liver. the anhepatic stage begins with the occlusion of the hepatic artery, portal vein, and ivc for hepatectomy. however, the patient is virtually anhepatic once the hepatic artery or portal vein is occluded. three surgical techniques are used for hepatectomy and vascular reconstruction during the anhepatic stage: olt with simple venous crossclamping, olt with venovenous bypass, and the piggyback technique. in olt with simple venous cross-clamping, the diseased liver is removed together with the retrohepatic portion of the ivc after crossclamping of the suprahepatic and infrahepatic ivc, hepatic artery, and portal vein (fig. ) . after surgical hemostasis of the hepatic bed, the donor liver is placed in the right upper quadrant, and sequential anastomoses of the suprahepatic ivcs, infrahepatic ivcs, portal veins, and hepatic arteries are performed. during the infrahepatic ivc anastomosis, the liver allograft is flushed with ml of cold lactated ringer's solution or % albumin solution through a cannula in the portal vein. this flush technique allows preservation solution, metabolites, and air in the donor liver to escape through the incompletely anastomosed infrahepatic ivc. a second flush may be used by allowing - ml of blood to escape through the incompletely anastomosed portal vein by unclamping the infrahepatic ivc (back-bleeding technique). when the portal vein of the recipient is less than optimal, the superior mesenteric vein, collateral vein, or venous graft may be used for portal blood supply. the hepatic artery is reconstructed by end-to-end hepatic arterial anastomosis. however, an arterial graft is placed between the graft hepatic artery and the infrarenal aorta of the recipient with a side clamp on the aorta when the size or anatomy of the recipient hepatic artery is less than optimal. the liver is reperfused by the sequential unclamping of the infrahepatic ivc, portal vein, suprahepatic ivc, and hepatic artery. after hemostasis, choledochocholedochostomy is performed frequently with a t-tube. choledochojejunostomy using a roux-en-y loop is performed when the bile ducts are diseased or mismatched in size. the abdomen is closed once the absence of foreign bodies in the peritoneal cavity is confirmed. in patients with a large graft or swollen intestine, the abdomen may require secondary closure. olt with venovenous bypass was developed in to minimize reduction of venous return associated with the cross-clamping of the ivc and portal vein by diverting blood from the ivc and portal vein to the axillary vein using a centripetal magnetic pump (shaw et al. ) . once the hepatic hilum is dissected, cannulas are inserted into the left superficial femoral vein ( mm) and portal vein ( mm) for outflow from the patient and into the left axillary vein ( mm) for venous inflow. the cannula site and size may vary depending on the preference of the surgical team or anatomic variations. the cannulas and heparin-bonded tubings are flushed with heparin solution ( u/l) to avoid thrombosis during preparation. systemic heparinization is not used because of the presence of pre-existing coagulopathy and the use of heparin-bonded tubings. the bypass run begins by unclamping all cannulas while the pump speed is gradually increased to achieve the maximal flow rate. hepatectomy and anastomoses of the suprahepatic and infrahepatic ivc are performed once full bypass is achieved. the removal of the portal cannula for portal venous anastomosis leads to a partial bypass, which reduces venous return. bypass is terminated after the engrafted liver is reperfused, and cannulas are removed. the advantages of venovenous bypass are ( ) well-preserved cardiac output by uninterrupted venous return from the viscera and lower extremities; ( ) effective decompression of the portal venous system, which decreases bleeding and intestinal congestion; ( ) avoidance of renal congestion, oliguria, and hematuria; and ( ) simplified anhepatic stage allowing meticulous hepatectomy and vascular anastomoses. long-term complications are neurovascular injury, thrombosis, infection, lymphocele, and seroma at the cannulation sites. as an alternative to the traditional venovenous bypass technique, percutaneous cannulation was introduced. in this technique, inflow to the patient is achieved by percutaneous cannulation of the right internal jugular vein ( - french) performed by the anesthesia team using a seldinger technique, and outflow from the patient by percutaneous cannulation of the left femoral vein ( - french) and a portal cannula by the surgical team. this technique is generally safe, but the inadvertent extravascular placement of an inflow cannula may cause a massive hemothorax (sakai et al. ). the piggyback technique was originally designed for patients with significant cardiovascular disease, portacaval shunt, superior vena caval syndrome, or small donor livers (tzakis et al. ) . in this technique, the diseased liver is removed without the retrohepatic portion of the ivc by peeling the diseased liver off the ivc after transaction of the hepatic veins, hepatic artery, and portal vein. therefore, systemic venous return can be relatively well preserved via the intact ivc during the anhepatic stage. vascular anastomoses are made between the reconstructed ostia of the recipient by combining hepatic veins and the suprahepatic ivc of the graft for the drainage of the hepatic venous blood. the portal vein of the recipient and the graft are anastomosed for portal blood supply, and the infrahepatic ivc of the graft is ligated. the neohepatic stage begins with reperfusion of the grafted liver by sequential unclamping of the infrahepatic ivc, portal vein, suprahepatic ivc, and hepatic artery, although the sequence of unclamping may vary depending on the surgical technique. reperfusion is followed by hepatic arterial anastomosis (if it has not been performed already), biliary reconstruction, and closure of the abdomen. immediate preoperative consultation is made when a donor organ is identified. the patient is re-evaluated to identify any interval changes during the waiting period. anesthetic and postoperative management and their risks are explained to the patient one more time. in general, pre-medication is withheld in most cases because of potential encephalopathy and hypovolemia, and narcotics (e.g., fentanyl - μg/kg) are commonly administered intravenously in the operating room. necessary medications and anesthesia equipment are listed in table . a device that delivers fluids and blood rapidly on demand is considered standard equipment (i.e., fms ® fluid warming system, belmont instrument corp., billerica, ma, usa) (elia and kang ). an autotransfusion system is helpful in minimizing the need for bank blood (dzik and jenkins ; kang et al. ) . a system that monitors coagulation, either a conventional coagulation profile, thromboelastography r with circle (teg; haemonetics, braintree, ma, usa), or (kang (kang , . teg and rotem provide similar physical properties of blood coagulation, although teg monitors shear elasticity and rotem monitors viscoelasticity. in general, units each of cross-matched packed rbcs (prbcs) and fresh frozen plasma (ffp) are available at all times, and units of each are prepared in the operating room. platelets ( - units) should be available on demand. two large-bore intravenous (iv) catheters (up to . or french) are secured, typically in the right antecubital and right or left internal jugular vein. when the antecubital vein is unavailable, two catheters may be placed in the same internal jugular vein. catheter patency is confirmed by noting the line infusion pressure of < mmhg during fluid infusion at ml/ min. sterile technique should be followed during catheterization, and antiseptic ointment or antiseptic patch is applied at the skin puncture site. a nasogastric tube is placed with copious lubrication and topical vasoconstrictor to avoid nasal or esophageal variceal bleeding. proper monitoring is prerequisite to a successful outcome because patients undergoing liver transplantation develop clinically significant hemodynamic, hematologic, metabolic, and other homeostatic abnormalities. non-invasive monitoring is similar to that for patients undergoing any major surgery. for invasive monitoring, two intra-arterial catheters ( gauge in the left radial artery and - gauge in the right femoral artery) are used at the thomas jefferson university hospital. femoral arterial pressure monitoring is preferred because it reflects central arterial blood pressure more accurately in the presence of low systemic vascular resistance, particularly after reperfusion (lee et al. ) . radial arterial pressure monitoring is useful for blood sampling and backup pressure monitoring when the aorta is partially or completely clamped during aorta-tohepatic artery anastomosis. a pulmonary artery catheter (pa catheter) is inserted via the right internal jugular vein to monitor cardiac output, intracardiac pressures, and core temperature. carotid artery puncture should be assiduously avoided because of the presence of coagulopathy. an oximetric-type pa catheter provides additional information on mixed venous hemoglobin oxygen saturation (svo ). the right ventricular ejection fraction-type pa catheter monitors the right ventricular ejection fraction and right ventricular end-diastolic volume. it has been shown that central venous pressure (cvp) and pulmonary capillary wedge pressure (pcwp) are not as sensitive as right ventricular end-diastolic volume in estimating preload, particularly during the anhepatic stage (dewolf et al. b ). recently, non-invasive, continuous cardiac output monitoring was introduced; however, the technique is not reliable in monitoring cardiac output in hyperdynamic patients. in some centers, a cvp catheter is used instead of a pa catheter. this, of course, is justified if hemodynamic derangement is kept minimal during the entire surgical procedure. however, most centers use a pa catheter for three reasons: ( ) hemodynamic instability can be unpredictable during liver transplantation; ( ) determination of cardiac output and preload is more clinically significant than cvp monitoring; and ( ) it is an important educational tool for trainees. tee is used in all patients at the thomas jefferson university hospital to monitor myocardial contractility, ventricular end-diastolic volume, wall motion abnormality, air or thromboembolism, intrapulmonary shunting, and patency of the reconstructed major veins. a tee probe may cause esophageal variceal bleeding (burger-klepp et al. ) and it should therefore be placed gently. various laboratory tests are performed, including arterial blood gas tension and acid-base state, and serum level of electrolytes, ionized calcium, glucose, lactate, and ionized magnesium if available. typical test times are before and after induction of anesthesia, every hour during the dissection stage, min after the onset of the anhepatic stage, every min during the anhepatic stage, min before reperfusion, and min after reperfusion, and every hour thereafter. coagulation is monitored by conventional coagulation profile (pt, aptt, fibrinogen level, and platelet count) and teg or rotem at the following times: before induction of anesthesia, every hour during the dissection stage, and min after onset of the anhepatic stage, min before reperfusion, and min after reperfusion, and every hour thereafter. monitoring of teg or rotem and the platelet count is preferable as a conventional coagulation profile has several drawbacks when used during liver transplantation (kang ) . pt is a very sensitive hepatic function test and is prolonged in most patients undergoing liver transplantation. administration of ffp to correct the pt may not be possible or desirable in the course of surgery. aptt follows a similar time course to pt, and its correction may not be practical. it is a sensitive test for the heparin effect, and its prolongation indicates the presence of heparin released from the bypass circuit or grafted liver. the fibrinogen level is frequently maintained within the acceptable range, although severe hypofibrinogenemia may indicate either active fibrinolysis or excessive activation of coagulation. the level of fibrin(ogen) degradation products is usually elevated in most patients due to excessive activation of coagulation and reabsorption of defibrinated blood from the abdominal cavity and does not have any immediate clinical significance. further, coagulation profile results may not be available in a timely manner. teg/rotem has several advantages over a conventional coagulation profile and has been accepted as a standard coagulation monitoring tool by the asa (american society of anesthesiologists ). it rapidly and reliably measures blood coagulability (quality) instead of the quantity of each coagulation component. an accurate differential diagnosis can be made for replacement therapy and pharmacologic therapy by comparing teg/rotem of untreated blood with that of blood treated with various blood components (ffp, platelets, cryoprecipitate) or pharmacologic agents (protamine sulfate, heparinase, ε-aminocaproic acid [eaca], aprotinin) (fig. ) . lastly, circumferential identification tags around the wrists or ankles are removed to avoid the compartment syndrome. both arms are placed on padded arm boards in an abducted position, and excessive abduction should be avoided to prevent a plexus stretch injury. the extremities are protected with foam padding to avoid pressure injuries. a rapid-sequence induction is preferred because of uncertain gastric emptying. anesthesia is commonly induced with propofol ( - mg/kg) or etomidate ( . mg/kg), and fentanyl ( - μg/kg) is frequently added. succinylcholine ( - mg/kg) or rocuronium bromide ( . mg/kg) is used to facilitate intratracheal intubation. anesthesia is maintained using volatile inhalation agents and narcotics. isoflurane is the preferred inhalation agent because its effect includes less myocardial depression and biotransformation. nitrous oxide is avoided because it distends the bowel and increases the size of any entrained air. midazolam ( - mg) may be added for amnesia. for muscle relaxation, protamine-treated blood untreated blood min after reperfusion fig. effects of pharmacologic agents on pathologic coagulation immediately after reperfusion (from kang yg ( ) monitoring and treatment of coagulation. in: winter pm, kang yg (ed) hepatic transplantation, anesthetic and perioperative management. prager, new york, with the permission of the publisher) rocuronium bromide, vecuronium bromide, or cisatracurium besilate are commonly used. antibiotics and immunosuppressants administered during surgery may vary from center to center. at the thomas jefferson university hospital, unasyn ® (ampicillin/sulbactam g) is given before incision and every h thereafter. for patients allergic to cephalosporin or penicillin, vancomycin is administered within h before skin incision ( g for patients < kg and . g for those > kg). for immunosuppression, methylprednisolone ( mg iv) and basiliximab ( mg iv) are given during the anhepatic stage and tacrolimus is given in the postoperative period. liver transplantation imposes a great deal of physiologic stress on patients, and maintenance of physiologic homeostasis is essential to a successful outcome. the goal of hemodynamic management is to optimize tissue perfusion by maintaining the hyperdynamic state characteristic of esld. in general, there are two schools of thought about maintaining hemodynamic stability. the first endorses maintaining the hyperdynamic state to optimize cardiac output and tissue perfusion. patients with esld have generalized vasodilation and are known to have oxygen debt at the tissue level. therefore, maintaining the hyperdynamic state, instead of 'normal blood pressure,' ensures ample oxygen delivery to tissues and avoids tissue acidosis. this, in turn, optimizes tissue metabolism and hepatic blood flow. the second school of thought endorses maintaining arterial blood pressure within the normal range. this may include the use of various vasopressors (phenylephrine, norepinephrine, vasopressin, etc.) with or without hypovolemia. in extreme cases, blood is removed from the patient to induce hypovolemia, and blood pressure is supported by vasopressors (massicotte et al. ) ; it has been claimed that blood loss is minimal without increasing perioperative complications, although fluid restriction may lead to tissue ischemia, renal failure, and air embolism (melendez et al. ; schroeder et al. ). further, α-vasopressors (norepinephrine and phenylephrine) decrease hepatic blood flow by reducing portal venous flow dramatically in the presence of a limited hepatic arterial buffer response (mehrabi et al. ). hemodynamic instability represented by reduced cardiac output and hypotension is typically caused by hypovolemia associated with drainage of ascites, rapid third-space fluid loss, surgical bleeding, and inadvertent compression of major vessels (ivc, portal vein, hepatic veins, and aorta). intravascular volume is usually replenished by administration of a mixture of prbcs and ffp (typically, prbc:ffp: plasmalyte-a ® = : : ml) using a rapid-infusion device. this mixture yields hematocrit of - vol.% and coagulation factor levels of - % of normal. a low hematocrit is chosen to optimize microcirculation and minimize the rbc wastage. calcium-containing fluid (i.e., lactated ringer's solution) should not be used to prevent clot formation in the reservoir of the rapid-infusion device. continuous administration of ffp is necessary to compensate for the loss of coagulation elements (procoagulants, prolysins, and their inhibitors) by surgical bleeding and excessive activation of coagulation. in patients with minimal blood loss, colloids (albumin or ffp) and crystalloids may be required to compensate for the third-space fluid loss and continuous production of ascites. close communication with the surgical team is essential to identify the cause of hemodynamic instability, as is communication with the blood bank to facilitate adequate supply of blood products. intraoperative autotransfusion has been shown to be effective and safe during liver transplantation, and its use may be considered when the prbc requirement is > units. its use is not recommended for patients with peritoneal infection or malignancy (liang et al. ). when lower cardiac output and/or hypotension persists even with adequate preload, dopamine or epinephrine may be infused for patients with hypotension, while dobutamine can be used when patients are normotensive. high venous pressures (cvp and pcwp) may be seen in patients with volume overload, large ascites, and pleural or pericardial effusion. drainage of ascites and effusion may decrease intrathoracic pressure and central venous pressures and improve cardiac performance. thoracentesis and pericardiocentesis can be performed after the abdomen is opened to minimize the risk of injury to the thoracoabdominal organs. unexpected pulmonary hypertension may be observed in some patients. because of the high perioperative mortality in patients with pulmonary hypertension, it deserves a thorough intraoperative investigation. the pa catheter should be able to differentiate between pulmonary hypertension with high pulmonary vascular resistance and pulmonary hypertension with fluid overloading. pulmonary hypertension caused by fluid overloading may dissipate gradually by intraoperative fluid loss, and phlebotomy may be required in severe hypervolemia. in portopulmonary hypertension with increased pulmonary vascular resistance, the presence of right ventricular function is investigated. a low cardiac output with a high cvp suggests the presence of right ventricular dysfunction. tee findings of right ventricle dysfunction are low fractional area change (fac), tricuspid annular plane excursion (tapse) of < mm, flattening of the ventricular septum, apicalization of the right ventricle, and right ventricular dilation. additionally, the pulmonary vascular response to various vasodilators (i.e., diltiazem, nitroglycerin, epoprostenol, and nitric oxide) may be evaluated. liver transplantation may continue when pulmonary hypertension is mild to moderate with normal right ventricular function. in such cases, right ventricular function is supported by maintaining optimal preload and improving myocardial contractility by inotropes. complications of massive blood transfusion (ionic hypocalcemia, ionic hypomagnesemia, hyperkalemia, and acidosis) may develop at this stage and should be treated aggressively. normothermia can be well-maintained even during massive transfusion when a rapid-infusion device is used. hemodynamic changes that occur during the anhepatic stage are caused primarily by interruption of venous return from the ivc and portal vein. in the simple cross-clamping technique, clamping of the ivc and portal vein reduces venous return by up to %, leading to low cardiac output, hypotension, and compensatory tachycardia (pappas et al. ) . calculated systemic vascular resistance is frequently elevated, although this is a reflection of the exclusion of the vascular tree of the lower extremities and splanchnic bed. it is noteworthy that cross-clamping of the ivc and the portal vein decreases the central blood volume and pressure (cvp and pcwp) but progressively increases total intravascular blood volume as blood is sequestered in the vascular bed of the gastrointestinal and pelvic organs, kidneys, and lower extremities. a prolonged low output state, portal hypertension, and renal venous congestion may lead to acidosis, intestinal swelling, and hematuria. we, at thomas jefferson university hospital, prefer to treat the low output state by administration of fluid and/or inotropes (dopamine or dobutamine - μg/kg/min). venovenous bypass is more physiologic technique than a simple cross-clamping technique as it returns venous blood from the portal and ivc system (shaw et al. ) . hence, hemodynamic changes that occur during the anhepatic stage with venovenous bypass are minimal when the bypass flow rate is greater than % of the baseline cardiac output and, therefore, the bypass flow should be monitored and adjusted as needed. improper positioning of the cannula tip in the femoral or portal vein, or a kinked bypass circuit, may not drain blood adequately and the surgical team should correct their positions. a low pump speed reduces venous return, while a high pump speed collapses the outflow venous wall and decreases the bypass flow. the perfusionist, therefore, should adjust the pump speed to maximize the bypass flow. in addition, hypovolemia decreases the bypass flow, and it should be corrected by the anesthesia team. the anesthesia and surgical teams should be prepared for potential acute complications of venovenous bypass. bleeding or air entry may result from venous laceration during cannulation or improperly secured cannulas. entry of a small volume of air (up to ml) into the bypass pump may not cause immediate systemic air embolism because it is trapped in the cone-shaped pump head by centripetal force. thromboembolism may be caused by the migration of pre-existing thrombi or those developed during a low bypass flow rate (< ml/min), particularly in hypercoagulable conditions (i.e., budd-chiari syndrome, neoplasms, and congenital protein c deficiency). most importantly, the bypass may have to be terminated unexpectedly when serious complications occur. therefore, the anesthesia team should be prepared for unexpected cross-clamping of the ivc and portal vein at all times. after completion of the ivc anastomosis, the portal cannula is removed to facilitate the portal venous anastomosis, resulting in partial bypass. low bypass flow and low cardiac output during this period can be improved by the administration of fluids or dopamine, but full correction of central hypovolemia, as reflected on cvp, pcwp, or tee, is avoided to prevent fluid overload on reperfusion. in the original description of the piggyback technique, adequate venous return is maintained through the intact ivc and portal vein using portoaxillary venovenous bypass (tzakis et al. ). currently, many transplantation centers do not incorporate the portoaxillary venovenous bypass in the piggyback technique, which makes patients vulnerable to significant hypovolemia. hepatectomy in the presence of portal hypertension can be difficult, and hypovolemia is not uncommon as a consequence of inadvertent compression of the ivc and portal vein, partial side-clamping of the ivc, and cross-clamping of the portal vein during portal anastomosis. hence, temporary portacaval shunt or portal-axillary venovenous bypass may be instituted in surgically challenging patients to maintain preload. as described earlier, ml of cold lactated ringer's solution or albumin ( %) is flushed through the portal vein and drained via the incompletely anastomosed ivc to remove preservative solution, metabolites, and air from the allograft. additionally, approximately - ml of blood may be allowed to escape through the incompletely anastomosed portal vein to enhance the washout by partial unclamping of the infrahepatic ivc (back-bleeding technique) immediately before reperfusion of the grafted liver. in this case, blood should be administered simultaneously to avoid hypovolemia. other factors that affect circulation during the anhepatic stage are similar to those of the dissection stage, although lactic acidosis, citrate intoxication, hypomagnesemia, hyperkalemia, and coagulopathy are more pronounced. hyperkalemia is treated by dextrose ( - g) and insulin ( - units) to move potassium intracellularly (dewolf et al. a ). in severe hyperkalemia, prbc or phlebotomized blood can be washed using an autotransfusion system to remove potassium before transfusion (ellis et al. ) . at the end of the anhepatic stage, all biochemical variables are normalized to prepare for reperfusion. significant hemodynamic changes occur on reperfusion of the grafted liver (fig. ) . unclamping of the infrahepatic ivc and portal vein results in transient hypovolemia and hypotension due to acute sequestration of the blood in the engrafted liver. unclamping of the suprahepatic ivc increases preload by mobilizing blood from the low extremities and splanchnic circulation. this is followed by severe hemodynamic changes, the so-called postreperfusion syndrome (aggarwal et al. ) . the postreperfusion syndrome, which occurs in approximately % of patients, is defined by abrupt hypotension (below % of the baseline value) that develops within min of reperfusion and lasts for more than min. other associated hemodynamic changes are bradycardia, high cvp and pcwp, low systemic vascular resistance, and conduction defects. acute reduction in myocardial contractility is observed in tee. the postreperfusion syndrome appears to be caused by a combination of several factors. for example, an acute increase in preload may result in right ventricular strain and an acute decrease in blood temperature ( - c) by the systemic entry of the cold preservation solution may decrease cardiac conduction and contractility. other physical factors are air embolism and thromboembolism, which may cause right ventricular strain or right ventricular outflow tract obstruction (ellis et al. ; suriani et al. ) . chemical factors involved are acute hyperkalemia and acidosis. systemic entry of hyperkalemic preservation solution increases serum potassium level to a very high level (up to mmol/l), causing severe bradycardia and conduction defects (martin ). return of the acidic blood from the viscera and lower extremities increases the base deficit by - mmol/l. in addition, unknown endogenous vasodilators or myocardial depressants (i.e., vasoactive intestinal polypeptide, nitric oxide, and eicosanoid) released from the allograft or congested viscera may decrease systemic vascular resistance and impair myocardial function. several measures may be taken to prevent the postreperfusion syndrome, although they are not always successful. at the end of the anhepatic stage, blood volume is adjusted to avoid fluid overloading on reperfusion, and ionic hypocalcemia, hyperkalemia, and metabolic acidosis are corrected. prophylactic administration of cac ( mg/kg), nahco ( . - mmol/kg), regular insulin ( units), % dextrose ( ml/kg), and epinephrine ( - μg) are recommended by some centers (ellis et al. ) . once the postreperfusion syndrome develops, severe hypotension and bradycardia are treated with small doses of epinephrine ( μg increments) to support contractility, heart rate, and vasomotor tone, followed by a dopamine or epinephrine infusion, if necessary. symptomatic hyperkalemia (tall, peaked-t wave, and widening qrs complex with bradycardia) is treated by administration of cac ( mg/kg) and nahco ( . - mmol/kg). arrhythmias are treated in the standard fashion. when pulmonary edema develops, positive end-expiratory pressure (peep) is applied and inotropes may be given. patients who develop intracardiac or pulmonary embolism are supported by inotropes. when severe fluid overloading is a concern, phlebotomy may be considered. the postreperfusion syndrome dissipates gradually over the next - min, although low ( )) systemic vascular resistance and hypotension with a high cardiac output may persist for several hours. when hypotension is suspected to cause tissue and myocardial ischemia, it may be treated with ephedrine, dopamine, or epinephrine. overzealous administration of fluids may result in hepatic congestion, while norepinephrine may interfere with hepatic blood flow by decreasing portal venous flow. octreotide and vasopressin may increase arterial blood pressure by decreasing portal pressure and flow, although its effects on hepatic circulation and metabolism are unclear (fayed et al. ; wagener et al. ) . hemodynamic changes that occur during hepatic arterial and biliary reconstruction are relatively minor, except for intermittent fluctuation of the preload associated with continuous third-space fluid loss and compression of the liver and great vessels. gas exchange is maintained satisfactorily in most patients. minute volume is gradually decreased during the anhepatic stage to match the reduced oxygen consumption and carbon dioxide production, and is increased during the neohepatic stage. alveolar recruitment maneuvers are performed intermittently to avoid atelectasis caused by pleural effusions, cephalad traction of the rib cage, and compression of diaphragm. intermittent endotracheal suctioning, using a suction catheter or bronchoscope, may be required to remove secretions. drainage of pleural effusions and ascites decreases intrathoracic pressure and improves oxygenation within h. patients with preoperative ards may require a high fio and a high level of peep to ensure adequate gas exchange, and a volume ventilator may be necessary to overcome the high airway pressure. frank pulmonary edema can develop, particularly after reperfusion, from the increased pulmonary capillary permeability or fluid overload. in such cases, patients are ventilated with a high level of fio and peep, while the underlying cause is treated. closure of the abdominal cavity may interfere with ventilation by increasing intrathoracic and airway pressures. primary closure with mesh or secondary closure may be necessary. in patients with fulminant hepatic failure, preoperative cerebral monitoring is continued as cerebral hyperemia and intracranial hypertension persist during surgery, although they are somewhat attenuated by general anesthetics. however, a sudden increase in preload may dramatically exacerbate intracranial hypertension on reperfusion of the grafted liver. hence, optimal preload should be maintained during the entire procedure. after reperfusion, cerebral hyperemia may gradually decrease as the liver begins to function. intraoperative changes in coagulation are summarized in table . surgical bleeding is common due to numerous collateral vessels associated with portal hypertension, difficulty in dissection of the diseased liver, pre-existing coagulopathy, and pathologic changes in coagulation. the average blood loss in adults is - units each of prbc and ffp, although blood loss may reach more than units each. during the dissection stage, dilutional coagulopathy develops as bleeding reduces the levels of coagulation factors and platelets (fig. ) . fibrinolysis may develop, particularly in patients with hepatocellular disease, as a result of a low level of inhibitors of fibrinolysis and impaired hepatic clearance of tpa (lewis et al. a) . excessive activation of coagulation, evidenced by a gradual increase in thrombin-antithrombin complex, develops at the end of the dissection stage (kratzer et al. ) . management of coagulation begins with normalization of physiologic variables, such as ionic hypocalcemia, hypothermia, and acidosis impair coagulation (rohrer and natale ) . this is followed by continuous infusion of coagulation factor-rich blood (rbc:ffp: plasmalyte-a ® or normal saline = unit: unit: ml) to maintain coagulation factor levels above the critical level ( - % of normal). specific blood components may be administered based on teg/rotem. in general, platelets ( - units) are administered for a small maximum amplitude (ma) (< mm). platelet administration, in addition to increasing ma, improves reaction time (r) and clot formation rate (α), because the coagulation cascade leading to fibrin formation occurs on the surface of platelets. its administration, however, is withheld during the anhepatic stage to avoid potential thrombosis and during massive blood transfusion (> ml/min) to minimize wastage. two units of ffp may be administered when the reaction time is prolonged (r> min) even after platelet administration cryoprecipitate ( units) containing factors i and viii are rarely required unless severe fibrinolysis is left untreated because plasmin selectively destroys factors i, v, and viii. however, cryoprecipitate may be used for patients with severe hypofibrinogenemia (< mg/dl). pathologic coagulation superimposes on dilutional coagulopathy during the anhepatic stage. the heparin effect is seen as a prolonged aptt and reaction time on teg/rotem at the onset of the venovenous bypass as a small dose of heparin ( - units) in the bypass circuit enters systemic circulation. this heparin effect dissipates over the next - min. the effects of the absence of the hepatic synthetic and clearance function begin to develop during this stage. the absence of hepatic clearance of tpa promotes fibrinolysis in approximately % of patients . similarly, the absence of hepatic clearance of activated coagulation factors results in excessive activation of coagulation evidenced by a progressive increase in thrombin-antithrombin complex and fibrin (ogen) degradation products. severe fibrinolysis (fibrinolysis time < min) may be treated by the administration of a single, small dose of eaca ( - mg) ). administration of a large or repeated dose of eaca is not recommended in order to avoid potential thromboembolism (gologorsky et al. ) . the postreperfusion syndrome occurs in coagulation at the onset of the neohepatic stage. a typical coagulation profile shows prolonged pt, aptt, reptilase time, and thrombin time. a generalized decrease in coagulation factors (i, v, vii, and viii) and platelets is accompanied by a sharp increase in the tpa level, a shortened euglobulin lysis time, and a moderate increase in fibrin(ogen) degradation products and thrombin-antithrombin complex. fibrinolysis is observed in up to % of patients and is severe in about % . fibrinolysis is caused by a -fold increase in tpa being released from the allograft and congested viscera, which overwhelms the activity of the plasminogen activator inhibitor (virji et al. ; porte et al. ). there are ample data to support the finding that fibrinolysis is primary in origin: a relatively steady antithrombin level, only moderate levels of fibrin(ogen) degradation products and d-dimers, selective decreases in factors i, v, and viii, and no known microthrombi formation (lewis et al. a, b) . fibrinolysis resolves over the min following reperfusion. the heparin effect occurs in approximately % of patients, as heparin is released from the allograft and dissipates over the next - min. to identify the presence of fibrinolysis and the heparin effect, teg/rotems of untreated blood (native), blood treated with antifibrinolytic agent (eaca or aprotinin), and blood treated with an agent neutralizing heparin (protamine sulfate or heparinase) are compared min after reperfusion. when fibrinolysis is present, early treatment using a single, small dose of eaca ( - mg) is recommended in order to reduce delayed oozing and to minimize the loss of factors i, v, and viii . prophylactic administration of eaca or tranexamic acid (amca) is a common practice in many centers, but has not shown scientific efficacy. fibrinolysis prophylaxis is not recommended by the authors, because the presence of fibrinolysis can easily be detected by teg/rotem and can be treated effectively with a small dose of eaca in most patients. when the heparin effect is present, a small dose of protamine sulfate ( - mg) may be given in severe cases. in addition, blood coagulability can be impaired by reperfusion hypothermia, acidosis, and ionic hypocalcemia. in contrast, excessive activation of coagulation leading to fatal intracardiac or pulmonary embolism may occur in some patients (gologorsky et al. ; warnaar et al. ). this complication appears to be associated with a massive transfusion, release of a large quantity of tissue thromboplastin from the less than optimal allograft, impaired tissue perfusion, and possibly antifibrinolytic therapy. intracardiac thrombosis can be treated by infusion of tpa ( - mg over h) while observing resolution of thrombi using tee (boone et al. ; jackson et al. ) . coagulopathy improves gradually after reperfusion. generalized oozing, however, may occur even in the presence of acceptable coagulation profiles and teg/rotem, possibly due to delayed bleeding caused by the loss of a poorly formed clot or by the residual effects of reperfusion fibrinolysis. several other pharmacologic agents are reported to improve coagulation. aprotinin ( , , kiu followed by , kiu/h), a non-specific inhibitor of plasminogen and serine protease, may reduce blood loss by inhibiting fibrinolysis and excessive activation of coagulation (neuhaus et al. ; cottam et al. ). however, clinical use of aprotinin declined even before the drug was withdrawn by the manufacturer: clinical reports did not show a significant reduction in blood loss (ickx et al. ; groh et al. ) , and fibrinolysis can be treated with eaca or amca more efficiently with negligible side effects boylan et al. ) . recombinant factor viia (rfviia) has been suggested to improve coagulation and reduces bleeding by actively enhancing coagulation and stimulating fibrin formation in the presence of tissue factor. its beneficial effects have been shown in patients with fulminant hepatic failure, "critical bleeding," and a ruptured liver (meadows et al. ; merchant et al. ; yamaguchi et al. ) . however, results of clinical trials are controversial (planinsic et al. ; gasperi and baudo ; niemann et al. ) and a european consensus concluded that a paucity of data from clinical trials with rfviia limits both the strength and the scope of clinical recommendations (vincent et al. ) . recently, the use of prothrombin complex concentrate has been assessed in a limited number of centers. prothrombin complex concentrate is prepared from ffp and contains clotting factors ii, vii, ix, and x, protein c, and protein s, and its use may improve coagulation without increasing preload (arshad et al. ). however, it has limited components of coagulation and its clinical advantage requires further investigation. desmopressin acetate (ddavp), a synthetic analog of -arginine vasopressin, increases the endothelial release of factor viii, von willebrand factor, and plasminogen. its beneficial effects have been demonstrated in vitro and in patients with liver disease, and it may be used to improve coagulation ( . μg/kg) . conjugated estro-gen has been reported to improve coagulation and reduce blood loss (frenette et al. ) , although its use has not been accepted widely. calcium metabolism patients with hepatic dysfunction invariably develop ionic hypocalcemia during massive blood transfusion, which is caused by chelation of serum calcium with citrate in the banked blood. ionic hypocalcemia begins to appear during the dissection stage (marquez et al. ) and becomes severe during the anhepatic stage. the serumionized calcium level is inversely related to the serum citrate level, as the absence of hepatic metabolism of citrate increases the serum citrate level close to that in the banked blood (fig. ) . significant hypocalcemia (ca + < . mmol/l) is associated with a prolonged q-t interval and decreases in the cardiac index, stroke-work index, and blood citrate level ca ++ level mg ++ level fig. intraoperative changes in serum calcium, magnesium, and citrate level (results of two studies (marquez et al. and scott et al. ) are superimposed, with the permission of the publisher) pressure. therefore, the ionized calcium concentration is monitored hourly or more frequently, and cac ( mg/kg) or calcium gluconate ( mg/kg) is administered to maintain a normal level (martin et al. ). ionic hypocalcemia improves gradually as the engrafted liver begins to metabolize citrate, unless the speed of the transfusion exceeds the metabolic function of the liver. hypokalemia is not uncommon in patients with liver disease due to poor dietary intake of potassium and its loss from chronic diuretic therapy and diarrhea. severe hypokalemia (< . mmol/l) is treated with potassium chloride to increase its level to . - . mmol/l. moderate hypokalemia (< . mmol/l) is not treated because it is welltolerated by patients and self-corrected by blood transfusion. hyperkalemia is a serious concern because it interferes with myocardial conduction and contractility, particularly in the presence of acidosis and hypocalcemia. progressive hyperkalemia (up to - mmol/l) may occur in patients with renal dysfunction or those requiring massive blood transfusion. mild hyperkalemia (up to . mmol/l) is treated with insulin ( units) and glucose ( . g). it has been shown that glucose and insulin therapy is effective in lowering the serum potassium level even in the absence of hepatic function (dewolf et al. a) . for moderate-to-severe hyperkalemia (> . mmol/l), in addition to insulin therapy, prbc or phlebotomized blood can be washed to remove potassium using an autotransfusion system before transfusion (ellis et al. ) . reperfusion hyperkalemia is caused by potassium influx from the preservation solution and hepatocytes, and its systemic effects and treatment have been described previously. acute hyperkalemia returns to a normal range within - min as a result of redistribution. the potassium level gradually returns to the baseline value as the rbcs and the engrafted liver take up excess potassium. hypokalemia (< . mmol/l), which occurs toward the end of procedure, is treated using a kcl infusion ( mmol increments). hyponatremia (< mmol/l) is a common occurrence in patients with liver disease, particularly those with fluid retention, ascites, diuretic therapy, and restricted sodium diet. the serum sodium level gradually increases towards normal during surgery via administration of blood products and a balanced salt solution. a rapid rise in the serum sodium level (> mmol/l) is a clinical concern because it may contribute to the development of central pontine myelinolysis, a serious neurological injury caused by the destruction of the myelin sheath in the pons (videira et al. ) . therefore, the preoperative serum sodium level should be raised to > mmol/l, if possible, and a rapid increase in sodium should be prevented by administration of low sodium-containing crystalloids during surgery. in addition, tromethamine (tham) is the preferred drug for treatment of metabolic acidosis as it does not contain sodium. hypernatremia may be seen in some patients who receive a large dose of nahco preoperatively. this hypernatremia is gradually normalized by administration of blood products and a balanced electrolyte solution. a clinical investigation showed that the serum ionized magnesium level, similar to the ionized calcium level, has an inverse relationship with the serum citrate level as magnesium ion chelates with citrate in banked blood (scott et al. ) . although the clinical significance of ionic hypomagnesemia during liver transplantation is unclear, mgso ( - g) can be administered to minimize potential cardiac irritability and myocardial depression. metabolic acidosis begins to appear during the dissection and anhepatic stages because of impaired hepatic metabolism of the acid load from the banked blood and the peripheral tissues. the base deficit and lactate level increase further (approximately mmol/l) on reperfusion due to the acid load from the graft and congested viscera and lower extremities. it gradually improves as hepatic function is restored and tissue perfusion improves during the neohepatic stage. persistent lactic acidosis (> mmol/l) appears to be associated with graft dysfunction (begliomini et al. ) . metabolic acidosis is aggressively corrected by administration of nahco to maintain base deficit levels < mmol/l because acidosis is frequently progressive and leads to myocardial depression, inadequate cellular respiration, and decreased sensitivity to catecholamines. as described earlier, tham is preferred in hypo-or hypernatremic conditions to minimize fluctuation of the serum sodium level: ml of . m tham is equivalent to mmol of nahco . alternatively, dichloroacetate ( mg/kg every h) appears to reduce lactate production by stimulating pyruvate oxidation (shangraw and robinson ) . metabolic alkalosis may develop during the neohepatic stage, and this was believed to be associated with nahco -administered and citrate metabolism-generating bicarbonate. however, it has been shown that the degree of metabolic alkalosis is unrelated to the citrate and nahco load (fortunato et al. ) and may be associated with residual hyperaldosteronism. body temperature may gradually decrease to c during the dissection stage as a result of the exposure of the abdominal contents to the cold environment, vasodilatation, and lack of shivering. hypothermia continues during the anhepatic stage as energy production decreases further. an abrupt decrease in core temperature ( - c) occurs on reperfusion as cold preservation solution enters systemic circulation. the temperature increases during the neohepatic stage, and the surgery ends with a body temperature of approximately - c. hypothermia is difficult to avoid, although raising the room temperature, application of forced warm air devices, use of a warming blanket, and a heat exchanger in the venovenous bypass system may be beneficial. the blood glucose level is relatively wellmaintained ( - mg/dl) with blood transfusion, as the banked blood contains glucose (approximately mg/dl). a gradual decrease in glycogenolysis reduces the blood glucose level during the dissection and anhepatic stages. in patients with fulminant hepatic failure or severe hepatocellular disease, the blood glucose level may decrease precipitously, making glucose supplementation necessary. hyperglycemia (up to mg/dl) occurs on reperfusion as glucose is released from the engrafted liver (dewolf et al. ). insulin does not appear to be effective in treating reperfusion hyperglycemia because glucose reuptake requires restoration of hepatic function. the insulin level is relatively steady during surgery, and the glucagon level increases after reperfusion. the blood glucose level usually returns to normal within - h. persistent hyperglycemia caused by impaired hepatic glucose reuptake and hormonal imbalance is an early sign of poor graft function (mallett et al. ). urine output is well-preserved in most patients once the intravascular volume is optimized. oliguria or anuria, however, may persist in patients with the hepatorenal syndrome or underlying renal disease. the presence of oliguria and hematuria during the anhepatic stage of the simple cross-clamping technique has been described earlier. urine output increases during the neohepatic stage as a result of the restoration of renal function and circulation. various agents have been tried to protect or improve renal function: the role of dopamine is controversial, dopexamine appears to be beneficial, and triple-drug therapy (dopamine [ - μg/kg/min], mannitol [ mg/kg], and furosemide) improves urine output but not renal function (gray et al. ; planinsic et al. ). when fluid overload or severe electrolyte imbalance is a concern, intraoperative venovenous ultrafiltration or hemodialysis may be utilized. the restoration of hepatic function is evident about h after reperfusion: levels of citrate and lactate decrease, the glucose level returns toward normal, coagulopathy improves, and bile production begins. persistent citrate intoxication, acidosis, hyperglycemia, coagulopathy, and pale-colored bile are poor prognostic signs. recently, tracheal extubation in the operating room has been successful in several centers when the patient meets the liver transplantationspecific extubation criteria, including the severity of pre-existing liver disease, blood loss, and hemodynamic stability (mandell et al. ; biancofiore et al. ; glanemann et al. ). however, most patients are still transported to the intensive care unit (icu) while receiving invasive monitoring and ventilatory support. upon arrival to the icu, the ventilator setting is reported to the respiratory therapist, the lungs are auscultated, and vital signs are displayed on the icu monitor. detailed intraoperative information is reported to the icu physician and nursing staff. primary non-function primary non-function is defined as graft failure occurring within days after liver transplantation in the absence of either rejection or technical factors such as hepatic arterial thrombosis (bzeizi et al. ) . this complication occurs in up to % of patients and is frequently caused by hepatic dysfunction of the donor liver or prolonged cold ischemia (> h). the patient develops progressive multi-organ failure including encephalopathy, coagulopathy, minimal bile production, and oliguria. supportive therapy may be helpful until the liver resumes its function, although urgent retransplantation is the only solution in many patients. worsening liver function without technical complications in the second week after liver transplantation suggests acute cellular rejection. biopsy findings are inflammation of the intrahepatic endothelium and bile duct and a mononuclear cell infiltration with eosinophilia (wiesner ) . hepatic arterial stenosis occurs in approximately % of patients, and is four times more common in children. common clinical signs are biliary tract breakdown, recurrent bacteremia, hepatic abscess, and occasionally massive hepatic necrosis (tzakis et al. ) . hepatic arterial stenosis is suspected when an ultrasound examination reveals increased focal arterial flow velocities and is confirmed by angiography. in the immediate postoperative period, direct repair or reconstruction using an infrarenal arterial conduit is usually successful. stenosis occurring several weeks after transplantation is treated with percutaneous hepatic arterial angioplasty, which has a success rate of more than % in achieving long-term patency. vena caval stenosis and thrombosis occur in - % of patients. in traditional liver transplantation, outflow obstruction is managed by balloon angioplasty with or without a metallic stent placement (simo et al. ) . in the piggyback technique, it is treated with end-to-side anastomoses between the donor infrahepatic ivc and the recipient retrohepatic ivc (stieber et al. ) . portal venous stenosis and thrombosis are relatively uncommon in the adult population and present with graft dysfunction, massive ascites formation, and hemodynamic instability. this complication is corrected by an urgent reconstruction of the portal vein or construction of a superior mesenteric venous graft to the liver, together with a ligation of large collaterals that may reduce the portal flow. biliary complications are more common in children and have an overall incidence of - %. early recognition is difficult, leading to high morbidity and mortality. bile leaks usually occur at the anastomotic site, although they may be found at the t-tube site or aberrant ducts. most biliary complications occur within the first months and are diagnosed by liver function tests (serum bilirubin, γ-glutamyltransferase, and alkaline phosphatase) and imaging techniques. these complications are treated by percutaneous or endoscopic drainage of bile collections. in cases of roux-en-y choledochojejunostomy, surgical reconstruction is required. intra-abdominal bleeding occurs in about - % of patients and requires exploration in about half of these cases (ozaki et al. ) . gastrointestinal bleeding may develop from ulcers, viral enteritis, varices, and an afferent roux-en-y loop. variceal bleeding is usually associated with portal vein thrombosis and requires an urgent ultrasound or angiographic evaluation. bleeding from the roux-en-y limb occurs week after surgery and is usually self-limited. additionally, bleeding can be caused by persistent thrombocytopenia associated with splenic sequestration, drug toxicity, heparin-induced thrombocytopenia, and immunologic reactions. intestinal perforation is caused by serosal injury to the intestines and usually occurs in patients who have had a technically difficult hepatectomy, prolonged portal venous clamping, or a massive blood transfusion. intestinal perforation or leakage is treated by urgent surgery and antifungal therapy. cardiac complications any type of cardiac complication can develop in the postoperative period. hypotension can occur due to hypovolemia, either from underresuscitation or ongoing bleeding, decrease in contractility secondary to the pre-existing myocardial disease, or new onset of dilated or ischemic cardiomyopathy. other potential causes are acidosis, hypocalcemia, or vasodilation from sepsis or graft failure. management of cardiac complications is based on the underlying cause. hypertension occurs in patients with pre-existing hypertension, inadequate pain control, hypoglycemia, and cerebral edema. restoration of normal liver function may increase systemic vascular resistance, and calcineurin inhibition can increase systemic blood pressure. calcium channel blockers (i.e., diltiazem and verapamil) are avoided because they can increase the levels of the calcineurin inhibitors. myocardial infarction is relatively rare due to thorough preoperative evaluation being undertaken to detect cad. however, when it does develop, a cardiologist should be consulted for possible emergent cardiac catheterization during surgery and revascularization. pulmonary edema is commonly seen postoperatively and may be caused by significant transfusion requirements, increased capillary permeability, prolonged intubation, and reversible dilated cardiomyopathy. reversible dilated cardiomyopathy with pulmonary edema may develop in the first days after transplantation. sampathkumar et al. reported that % of patients who did not have ventricular dysfunction developed dilated cardiomyopathy postoperatively, most of whom recovered completely without any long-term complications (sampathkumar et al. ) . the cause of this condition is unknown, although it may be a form of stress-induced cardiomyopathy. atrial fibrillation, ventricular tachycardia, and other arrhythmias may develop as a result of electrolyte abnormalities (i.e., hypomagnesemia, hyperkalemia, and hypocalcemia), cardiac ischemia, or irritation from cvp or pa catheters. in a study by xia et al., atrial fibrillation was observed in . % of patients and was associated with increased mortality, graft failure, and acute kidney injury (xia et al. ) . all arrhythmias are treated following the standard guidelines. thromboembolism is a common cause of sudden postoperative death. deep vein thrombosis should be prevented by early extubation and mobilization, use of compressive stockings, and administration of heparin (subcutaneous or low molecular weight). most patients require mechanical ventilation for only a few hours or days after transplantation. however, prolonged ventilatory support is required in some patients with atelectasis, pleural effusions, and central nervous system (cns) depression. intraoperative cross-clamping of the ivc occasionally results in right phrenic nerve crush injury and diaphragmatic paralysis in the immediate postoperative period (mcalister et al. ). ards may develop in patients with intra-abdominal infection, pancreatitis, hepatic necrosis, acute cellular rejection, and occasionally with muromonab-cd (okt ) treatment. bronchoalveolar lavage and bacterial culture are frequently performed to rule out pulmonary infection from any other pulmonary pathology. pre-existing pulmonary hypertension may persist postoperatively and is controlled by epoprostenol or nitroglycerin. neurological complications occur in - % of patients, mostly in the first week of transplantation (singh et al. ). these are more common in adults and present as mental status changes ranging from dysphasia to frank coma. dysfunction of the cns is commonly caused by medications, such as cyclosporine, tacrolimus, histamine h -blockers, acyclovir, and antibiotics such as imipenem. non-convulsive seizures may occur, and an eeg is performed for patients with unexplained mentation changes. intracranial hemorrhage and watershed infarcts are ruled out using ct scans. hyponatremia and hypomagnesemia can also delay awakening. central pontine myelinolysis may develop several days after transplantation, and recovery is often slow and incomplete (winnock et al. ) . hepatic encephalopathy may be present for several days after transplantation in patients with persistent portosystemic shunting. meningitis should be ruled out when the mental status change is accompanied by fever. disseminated aspergillosis is a devastating complication in a patient with multiple brain infarcts and fever. peripheral neuropathy presenting as weakness is usually myopathic in nature and is more common in patients with preoperative severe liver disease, poor graft function, high steroid doses, and uremia, and are confirmed by electromyography and muscle biopsy. in patients with fulminant hepatic failure, cerebral hyperemia and hypertension usually decrease gradually, and the patient regains consciousness as the liver begins to function. renal dysfunction is usually transient and is commonly associated with intraoperative hypovolemia and hypotension, allograft dysfunction, and nephrotoxicity of cyclosporine and tacrolimus. oliguria is an early sign of renal dysfunction and is managed by restoring intravascular volume and renal perfusion. the hepatorenal syndrome may persist after transplantation, and its recovery depends on its preoperative severity and allograft function. in some patients, addition of vasoconstrictive immunosuppressants (cyclosporine and tacrolimus) may lead to acute tubular necrosis. in general, renal function returns to the normal range in most patients, and approximately % of patients require temporary dialysis (mccaulley et al. ). long-term prognosis is fair, although hypertension, diabetes, and chronic nephropathy induced by steroids and the calcineurin inhibitors may result in chronic renal failure. more than half of the postoperative infections following liver transplantation are bacterial in origin. these infections typically occur in the first weeks, when blood levels of immunosuppressants are high. the most common sites of infection are the liver, biliary tract, peritoneal cavity, and pulmonary system. common organisms in the abdomen are aerobic gram-positive organisms (streptococci and staphylococci) and gram-negative bacilli (escherichia coli, enterobacter species, and pseudomonas), while pseudomonas infection is most common in the lungs. approximately % of infections are caused by fungus, with candida species accounting for more than % of all fungal infections. the risk factors are a high steroid dosage, usage of broad-spectrum antibiotics, and prolonged surgical time. candida infection is treated with amphotericin or fluconazole. aspergillus infection accounts for % of all fungal infections and is associated with a very high mortality; high-dose liposomal amphotericin b followed by prolonged itraconazole is the treatment of choice. viral infections are seen - months after transplantation, with cytomegalovirus and herpes simplex accounting for the bulk of these infections. epstein-barr virus is not usually seen until approximately months after transplantation, but is an important cause of lymphoproliferative disease. pneumocystis pneumonia, an opportunistic infection, responds to trimethoprim-sulfamethoxazole. late metabolic complications following liver transplantation include diabetes, hyperlipidemia, weight gain, and hypertension. diabetes is induced by steroids, cyclosporine, and tacrolimus and may respond to oral hypoglycemic agents or insulin. hyperlipidemia is associated with diabetes, obesity, steroids, and immunosuppressive drugs and is treated by diet and exercise. hypertension is seen in as many as % of patients after transplantation; the use of steroids or tacrolimus is the most likely cause. hypomagnesemia has been implicated as the cause of the hypertension in some cases. approximately % of all patients require retransplantation of the liver. early retransplantation is performed within several days after the primary transplantation to rescue patients from primary non-function (graft factor), acute rejection, and technical failure (vascular thrombosis), or secondary non-function (host factor) associated with poor hepatic perfusion. hepatic necrosis is the common pathway of graft non-function and results in progressive, severe encephalopathy, ards, lactic acidosis, coagulopathy, hypoglycemia, and significant circulatory instability. although infrequent, hepatectomy with a portacaval shunt may be performed to protect the patient from the ill effects of the necrotizing liver on extrahepatic organ functions. in such a case, retransplantation should be performed as soon as the donor organ is available. the surgical procedure itself is relatively simple because surgical dissection has already been made and adhesions have not yet formed. anesthetic management of these patients is similar to that of patients undergoing primary transplantation. late retransplantation is performed in patients with chronic rejection, vascular complications, and recurrence of the original disease. the physical condition of the patient may have improved, but complications of immunosuppression (i.e., hypertension, renal insufficiency) may be present. adhesions and the steroid-induced fragile tissues frequently complicate late retransplantation. anesthetic management is similar to that of primary liver transplantation, but a large amount of blood loss is anticipated. in pediatric liver transplantation, rapid-sequence iv induction is preferred, although mask induction is chosen in patients in whom there is difficulty obtaining iv access (borland et al. ) . large-bore iv catheters are placed in the upper extremities after induction of anesthesia. a central venous catheter with cvp monitoring is the usual procedure, and pulmonary arterial catheterization is rarely indicated. blood pressure is monitored using a femoral intra-arterial catheter. it appears that children tolerate cross-clamping of the ivc and portal vein reasonably well without significant hemodynamic changes, possibly by compliant vasomotor tone. therefore, venovenous bypass is rarely used in children under kg. coagulation changes that occur during liver transplantation are not as severe as those of adults, and this may be associated with more prevalent cholestatic diseases in children ). blood loss in children with biliary atresia can be large due to the technical difficulty associated with previous biliary surgery (i.e., ksai procedure). maintenance of body temperature is difficult, as the large surface area promotes heat loss. live-donor hepatectomy is usually a challenging procedure. the young and healthy donors (asa physical status [ps] or ) undergo a complete evaluation by hepatologists, surgeons, anesthesiologists, and psychologists. the anesthetic goals are minimizing surgical blood loss and allogeneic blood transfusion, maintaining liver blood flow, facilitating early extubation, preventing deep venous thrombosis and infection, and providing adequate postoperative pain control. preoperatively, donors may be given erythropoietin to boost rbc production and they can donate units of autologous whole blood - weeks before surgery. on the day of surgery, donors may be given heparin ( units, subcutaneous injection) to prevent deep venous thrombosis, and units of typed and cross-matched prbcs are prepared. in the holding area, a peripheral iv catheter is secured, anxiolytics are administered, and donors may elect to receive thoracic epidural anesthesia for postoperative analgesia. the need for epidural local anesthetics with or without narcotics is determined by the attending anesthesiologist and pain service. in the operating room, unasyn ® ( g iv) or vancomycin (if allergic to penicillin) is administered to prevent infection, and the patient is positioned with minimal stress to the brachial plexus to avoid neurologic injury (dulitz et al. ) . induction and maintenance of anesthesia follows the standard guidelines of any major surgical procedure. ultra-short-acting narcotics such as remifentanil may be beneficial for early extubation after surgery as it is rapidly metabolized by plasma esterase and does not have a prolonged effect in the presence of hepatic and renal dysfunction. intraoperative monitoring is similar to that of patients undergoing major surgery, and a radial arterial catheter and cvp are placed for hemodynamic monitoring. additional ivaccess is secured to prepare for the potential need for rapid infusion of fluids using a rapid-infusion system. immediately after induction of anesthesia, isovolemic hemodilution may be performed: units of the patient's whole blood is collected in cpda (citrate phosphate dextrose adenine) blood collection bags, agitated to prevent clot formation, stored at room temperature, and returned to the patient within h. intraoperatively, physiologic condition should be maintained at all times to ensure adequate perfusion of all tissues including the liver by monitoring the cardiopulmonary system and stat laboratory. metabolic acidosis should be avoided, and use of a balanced salt solution (lactated ringer's solution or plasmalyte-a ® ) is the preferred choice in order to avoid the acid load from normal saline (waters et al. ). blood loss is not excessive and pre-and intraoperatively donated autologous blood and intraoperative autotransfusion are sufficient in most patients. the relationship between the cvp level and surgical blood loss is controversial: chhibber et al. reported that intraoperative blood loss did not correlate with cvp (< mmhg) in their study (chhibber et al. ), while jones et al. demonstrated a significant reduction in blood loss with low cvp (jones et al. ). the authors recommend euvolemia to maintain hepatic blood flow during dissection of the liver. however, fluid overloading should be avoided after hepatectomy because relatively high portal venous flow to the reduced liver mass may lead to liver congestion and small-for-size syndrome (dahm et al. ) . at the conclusion of surgery, the patient can be extubated safely in the operating room and transported to the icu. all types of surgical procedures may be necessary in the early postoperative period. within the first months after transplantation, surgical procedures are performed to treat complications of transplantation, such as exploratory laparotomy for abdominal bleeding or reconstruction of the biliary system. some degree of hepatic dysfunction may still be present, and ventilatory and circulatory support and invasive monitoring may be required. regional anesthesia is not recommended because of potential bleeding and infectious complications. anesthesia care of these patients is similar to that of other urgent abdominal procedures. patients may return to the operating room at any time for biliary reconstruction, replacement of a hip joint, or almost any other procedure. liver function and drug metabolism are usually within the normal range, and anesthetic management differs little from that of other patients. side effects of immunosuppressants (hypertension and renal insufficiency) and drug interactions should be considered. the main goal of organ procurement is the maintenance of optimal conditions for all organ systems to promote as normal as possible an environment for the organs prior to harvesting. specifically, integrity of organs should be maintained by optimizing organ perfusion and preventing further damage associated with pre-existing illness or trauma. therefore, donor care during procurement is a continuum of the intensive care provided before brain death. the donor is reviewed and examined by the anesthesia team to evaluate their medical history and vital organ function. the equipment and medications necessary for multiple organ procurement are shown in table . a multiple-channel vital-sign monitor is an essential piece of equipment because of the unavoidable hemodynamic changes associated with the absence of brain stem function, surgical manipulation, and fluid shift. a volume ventilator may be required for donors requiring high levels of peep or airway pressure. a large volume of crystalloids and colloid solutions is prepared, and units of prbcs are frequently required. the transit from the icu to the operating room is a crucial period; the anesthesia care team directs the transportation while the donor is continuously monitored, ventilated, and treated. intraoperatively, blood pressure is monitored by an indwelling radial or brachial arterial catheter as abrupt changes in blood pressure are anticipated. cvp monitoring is essential, and a pa catheter may be used in unstable donors. general anesthesia is provided as donors respond to surgical stimulation by dramatic hemodynamic changes such as tachycardia, hypertension, perspiration, and involuntary movement (wetzel et al. ) . this so-called mass reflex is caused by the neurogenic vasoconstriction and stimulation of adrenal medulla by reflex spinal arc. isoflurane is the most commonly used agent, because its myocardial depression is relatively benign, and short-acting narcotics (i.e., fentanyl, up to μg/kg/min) may be used in unstable donors. rocuronium bromide or vecuronium bromide is administered for muscle relaxation. the specific goals of ventilatory care are to maintain normal pao ( - mmhg), arterial hemoglobin oxygen saturation (> %), and paco ( - mmhg) as well as to avoid pulmonary complications. this goal is frequently achieved by ventilating with a tidal volume of - ml/kg, fio of - %, respiratory rate of < /min, and a low level of peep (< cmh o). however, in donors with pulmonary complications, adjustments are made in tidal volume (up to ml/kg), respiratory rate (up to /min), and peep (up to cmh o). aggressive circulatory care is essential because hemodynamic instability may impair organ perfusion. specifically, hypotension (systolic blood pressure < mmhg or mean arterial pressure < mmhg) is associated with a high incidence of acute tubular necrosis, non-function of the graft kidneys, and poor hepatic function. it is generally agreed that systolic blood pressure should be within the normal range ( - mmhg) and cvp should be < cmh o with minimal vasopressor support. maintaining circulatory homeostasis, however, can be challenging. preload is frequently decreased because of blood loss, vasomotor paralysis, diuretic therapy, and diabetes inspidus, although fluid resuscitation may result in overload. the heart rate may vary depending on the degree of brain injury, ranging from tachycardia to bradycardia. arrhythmia is not uncommon, and myocardial contractility is frequently impaired by myocytolysis, myocardial necrosis, coronary spasm, and reduction of myocardial energy storage (novitzky et al. ). afterload may be high, from excessive sympathetic tone, or low, from vasomotor paralysis. volume deficit is usually corrected with lactated ringer's or colloid solution, and transfusion of prbcs ( - units) may be necessary to maintain hematocrit between and % (hardesty and griffith ) . once the fluid deficit is corrected, a glucose-containing hypotonic solution ( % dextrose in . % nacl ml/kg/h) is administered to replace urine output and insensible loss, guided by cvp and urine output. excessive urine output (> - ml/h) is replaced using a hypotonic electrolyte solution with supplementation of kcl ( meq/l). tachycardia with hypertension should be avoided as it may cause pulmonary edema, decrease organ perfusion, and increase myocardial oxygen consumption. a β-antagonist (i.e., labetalol hydrochloride or esmolol hydrochloride) or a calcium channel blocker (verapamil hydrochloride) is used to treat tachycardia and arrhythmia (novitzky et al. ) . for bradycardia, isoproterenol or epinephrine is used for positive chronotropic effects because donors are unresponsive to centrally acting chronotropic drugs (i.e., atropine). supraventricular or ventricular arrythmia is treated using antiarrhythmic drugs. low afterload is compensated for by increasing preload because α-vasopressors increase the myocardial work load and decrease splanchnic and coronary blood flow. in severely hypertensive donors, an α-blocker (hydralazine or sodium nitroprusside) may be given to reduce the afterload. when cardiac output and organ perfusion are impaired, inotropes (dopamine hydrochloride, dobutamine hydrochloride, and isoproterenol hydrochloride) are recommended to improve cardiac contractility. in brain-dead animal models, serum levels of triiodothyronine, insulin, and cortisol have been found to be low, and the administration of triiodothyronine may improve hemodynamic stability by maintaining myocardial high-energy stores and glycogen (james et al. ) . circulatory arrest, which occurs in % of potential donors (emery et al. ) , is managed in the standard fashion, except atropine is not effective. adequate diuresis (> . ml/kg/h, preferably - . ml/kg/h) is recommended as urine output (> ml/h) is the most significant factor that determines the outcome of the kidney and liver graft. oliguria is generally caused by hypovolemia and hypotension and frequently responds to fluid administration. diabetes insipidus leads to polyuria, hypovolemia, and electrolyte imbalance. in addition to the fluid replacement, ddavp ( . - units/h) may be administered (richardson and robinson ) , although an excessive dose of ddavp may increase the risk of acute tubular necrosis and reduce hepatic blood flow (burggraaf et al. ) . donors are poikilothermic, and hypothermia plays a major role in hemodynamic instability. body temperature should be kept above c by raising the operating room temperature, infusing all fluids through a blood warmer, and using heating lamps, a warming blanket, and a heated humidifier in the ventilation circuit. metabolic acidosis, caused by inadequate tissue perfusion, is corrected by administration of nahco or tham. commonly seen electrolyte imbalances are hypernatremia, hypokalemia, hypocalcemia, hypophosphatemia, and hypomagnesemia, and they are treated in a standard fashion. glucose metabolism is relatively well-maintained, and any abnormality in glucose metabolism is corrected by administration of insulin or glucose on the basis of the serum glucose level. dilutional coagulopathy is common, and consumption coagulopathy may develop secondary to the release of tissue thromboplastin from injured tissues and the ischemic organs (kaufman et al. ) . fibrinolysis is not uncommon in donors, possibly as a result of the release of tpa from the necrotic brain. replacement of coagulation factors and platelets or any pharmacologic therapy is rarely indicated as donors are fully heparinized when the aorta is cannulated. once cardiac arrest is induced by cardioplegia, no further supportive care is necessary. liver transplantation is one of the most stressful procedures for patients with multiple organ dysfunction and it is a challenge for anesthesiologists. it is remarkable that anesthesiologists have played a major role in the progress of liver transplantation and its successful outcome. it cannot be overemphasized, however, that a thorough understanding of pathophysiology and close communication and cooperation among hepatologists, surgeons, anesthesiologists, intensivists, and other healthcare workers are vital to successful outcomes and further progress in this field. ▶ hepatopulmonary syndrome and portopulmonary hypertension postreperfusion syndrome: hypotension after reperfusion of the transplanted liver cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study guidelines for director of liver transplant anesthesia practice guidelines for perioperative blood management: an updated report by the american society of anesthesiologists task force on perioperative blood management definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in 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identification of osmosensitive and ammonia-regulated genes in rat astrocytes by northern blotting and differential display reverse transcriptase-polymerase chain reaction normal saline versus lactated ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study hemodynamic responses in brain dead organ donor patients is hepatic histology the true gold standard in diagnosing acute hepatic allograft rejection pontine myelinolysis following liver transplantation: a report of two cases postoperative atrial fibrillation in liver transplantation successful anesthetic management of a patient with critical bleeding during hepatectomy using recombinant activated factor vii and intraoperative blood salvage endotoxemia and human liver transplantation key: cord- -bufbjdmw authors: clement, annick; nathan, nadia; epaud, ralph; fauroux, brigitte; corvol, harriet title: interstitial lung diseases in children date: - - journal: orphanet j rare dis doi: . / - - - sha: doc_id: cord_uid: bufbjdmw interstitial lung disease (ild) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. these disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. typical features of ild include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ild. consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. several classifications for ild have been proposed but none is entirely satisfactory especially in children. the present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. the following diagnostic grouping is used to discuss the various causes of pediatric ild: ) exposure-related ild; ) systemic disease-associated ild; ) alveolar structure disorder-associated ild; and ) ild specific to infancy. therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. the outcome is highly variable with a mortality rate around %. an overall favorable response to corticosteroid therapy is observed in around % of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy. interstitial lung disease (ild) in infants and children represents a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality (around %) [ , ] . these disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. typical features of ild include the presence of diffuse infiltrates on chest radiograph, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect (in older children) and/or impaired gas exchange [ ] . there have been many different approaches to the classification of ild, with major shifts based on clinical investigation, improvement in chest imaging, and collaboration with pathologists. in , katzenstein and myers proposed four histopathologically distinct subgroups of idiopathic interstitial pneumonias: usual interstitial pneumonia (uip), desquamative interstitial pneumonia (dip) and a closely related pattern termed respiratory bronchiolitis-associated ild, acute interstitial pneumonia (formerly hamman-rich syndrome), and non specific interstitial pneumonia (nsip) [ ] . in , an international multidisciplinary consensus classification of idiopathic interstitial pneumonias was proposed by the american thoracic society (ats)/european respiratory society (ers) [ ] . this classification defined a set of histologic pattern that provided the basis for clinico-radiologic-pathologic diagnosis, with the final pathologic diagnosis being made after careful correlation with clinical and radiologic features. however, as discussed in several reports, the classification schemes of adult ild are not satisfactory for the pediatric cases which seem to comprise a broader spectrum of disorders with a more variable clinical course [ ] . in addition, pediatric histologic patterns often do not resemble pathologic features of lung tissues from adults and some forms are only observed in children younger than years. among the proposed classifications for pediatric ild, one strategy frequently used is to separate the primary pulmonary disorders and the systemic disorders with pulmonary involvement. recently, an additional group has been introduced which is based on the concept that some pediatric ild are observed more frequently in infants, while others are more specific to older children. the last ers monography on ild provided a chapter on pediatric classification which is based on a clear distinction between children aged - years and children over years-old [ ] . indeed the stage of lung development and maturation should be taken into consideration when approaching a diagnosis of pediatric ild. in this view, a new term "diffuse lung disease" has recently been introduced that comprises a diverse spectrum of lung disorders with impaired gas exchange and diffuse infiltrates by imaging. these disorders, more prevalent in young children, include diffuse developmental disorders, lung growth abnormalities, neuroendocrine cell hyperplasia and pulmonary interstitial glycogenosis, surfactant dysfunction disorders, disorders related to systemic diseases, disorders of immunocompromised host, and disorders of normal host caused by various insults such as aspiration syndrome or infections [ ] . some diseases are mostly observed in older children such as systemic diseases, idiopathic disorders as described in adults (dip, uip, nsip and lymphoid interstitial pneumonia (lip)), unclassifiable ild and also infectious disorders [ ] . it is important to point out that the pathologic processes underlying the so-called diffuse lung diseases involve not only the alveolar structure but also the distal part of the small airways and the conducting zone, i.e. the terminal bronchioles. terminal bronchioles are lined with a simple cuboidal epithelium containing clara cells, basal cells and a limited number of ciliated cells. clara cells secrete nonsticky proteinaceous compounds to maintain the airway in the smallest bronchioles, which constitute the quiet zone between the conducting and the respiratory lung zones [ ] . the terminal bronchioles are surrounded by a spiral of smooth muscle. each of the terminal bronchioles divides to form respiratory bronchioles which contain a small number of alveoli. consequently, the term of diffuse lung disease refers to disorders that can affect both the distal part of the conducting and the respiratory lung zones, and include ild as well as pathological processes leading to obstruction/ obliteration of small airways [ ] . therefore, diffuse lung diseases encompass a broader group of diseases than ild which refers to disorders that affect the respiratory function of the lung and consequently the pulmonary structure responsible of the diffusion of gases between blood and air (i.e. the alveolar epithelium, the interstitium, and the pulmonary capillary endothelium). the present review focuses on ild in immunocompetent children, and excludes pulmonary consequences of previous lung injury in situations of chronic aspiration syndromes, resolving acute respiratory distress syndrome, and bronchopulmonary dysplasia. an estimated prevalence of . per million has been reported by dinwiddie and coworkers through a national survey of chronic ild in immunocompetent children in the united kingdom and ireland over a three year period ( ) ( ) ( ) ( ) [ ] . this prevalence is certainly under-estimated due to the lack of standardized definitions and the absence of organized reporting systems. from the limited published data composed mainly of case reports and small series, it seems that pediatric ild occurs more frequently in the younger age and in boys [ ] . in addition, nearly % of cases appear to be familial [ ] . the understanding of the mechanisms underlying the development and progression of ild remains elusive [ , ] . indeed, for a long time, chronic ild and pulmonary fibrosis were believed to result mainly from chronic inflammation following an initial injury to the alveolar epithelial lining [ , ] . in cases of limited injury, it was thought that the reparative attempt could reverse the trend toward fibrosis. by contrast, in situations of continuing injury, the repair process driven by inflammatory molecules produced by the local cells will result in scarring and structural changes. therefore, by targeting the inflammatory response, the belief was that fibrosis could be prevented or controlled. this theory explains the large use of anti-inflammatory therapy with, however, limited clinical efficacy. based on clinical and experimental observations, a new paradigm has progressively emerged with the alveolar epithelium being viewed as a key actor in the development of ild [ ] [ ] [ ] . following injury, alveolar epithelial cells (aec) may actively participate in the restoration of a normal alveolar architecture through a coordinated process of re-epithelialization, or in the development of fibrosis through a process known as epithelial-mesenchymal transition (emt) [ ] . complex networks orchestrate emt leading to changes in cell architecture and behaviour, loss of epithelial characteristics and gain of mesenchymal properties. the reasons for epithelial cell loss and inappropriate re-epithelialisation are still debated, but ongoing apoptosis is believed to be a key component in the progression of the disorder [ ] . prolonged denudation of the basement membrane contributes to altered interactions and cross-talk between aecs and mesenchymal cells, resulting in profound modifications of cell functions with imbalanced production of oxidants, proteases, and polypeptide mediators including cytokines and growth factors such as transforming growth factor (tgf)-β and endothelin (et)- . a consequence is the perpetuation of a vicious cycle with tgf-β promoting epithelial cell apoptosis, which in turn increases the local production of tgf-β [ ] . et- is also considered to be an important actor, based on the current knowledge of its numerous functions including fibroblast and smooth muscle cell mitogen, and stimulant of collagen synthesis [ , ] . recent studies showed that et- is produced by aec, and could induce alveolar emt via stimulation of endogenous tgf-β production. ild may be caused by myriad etiologies with differing prognoses and natural history. indeed, multiple factors may injure the alveolar epithelium and initiate the development of ild [ ] . the initiating injury can be introduced through the airways and the circulation, or can occur as a result of sensitization. consequently, the mechanisms underlying disease progression will be influenced by the causative event as well as by the host and the environment. these mechanisms are developed through interactions of multiple pathways, which include apoptotic pathways, developmental pathways, and endoplasmic reticulum (er) associated pathways ( figure ). apotosis plays a central role in lung remodeling associated with ild [ ] . an important molecule in the events associated with epithelial cell apoptosis is tgf-β, which is overexpressed in ild. downstream events linked to upregulation of tgf-β include modifications in the expression of various components of the cell cycle machinery, mainly the cyclin-dependent kinases (cdk) system that plays an essential role in ensuring proper cell cycle progression. recently, much work has been focused on the protein p cip , a member of the cdk inhibitor family. this protein promotes cell cycle arrest to apoptosis in cases of cellular dna damage. interestingly, upregulation of p cip has been reported in the lung tissues of patients with pulmonary fibrosis, primarily in hyperplastic alveolar epithelial cells [ ] the increased expression of p cip can favour the process of epithelial cell apoptosis. apoptotic cells can also produce tgf-β. a consequence would be the perpetuation of a vicious cycle with tgf-β promoting epithelial cell apoptosis, which in turn increases the local production of tgf-β. recently, it has been suggested that genes associated with lung development and embryonic pathways could be involved in aberrant epithelium-mesenchymal crosstalk and epithelial plasticity, and could therefore participate in the development of chronic ild. selman and coworkers reported that lung fibrosis is characterized by enrichment for genes associated with cell adhesion, extracellular matrix, smooth muscle differentiations, and genes associated with lung development [ ] [ ] [ ] [ ] . during emt in the embryonic period, cells undergo a switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype [ ] . molecular processes governing emt are induced by a cooperation of receptor tyrosine kinases or oncogenic ras (rtk/ras) pathway and tgf-β signaling [ ] . recently, additional pathways and effectors have been reported to play a role in the induction of emt, such as wnt//β-catenin, notch and sonic hedgehog signalling [ ] . recent reports strongly suggest that the er stress may represent an important mechanism of the altered repair process observed in the alveolar epithelium of fibrotic lung [ ] . situations associated with abnormal regulation of the cascade of events leading to the formation of mature protein result in either misfolding or mistargeting of the protein. these events trigger induction of intracellular aggregate formation and er stress, which can lead to cell death through apoptosis and autophagic pathways [ , ] . several stimuli including oxidant-antioxidant imbalance, viral proteins, inflammatory molecules, nutrient deprivation may induce er stress [ , ] ( figure ). among the cytoprotective mechanisms available are the er chaperones such as binding immunoglobulin protein (bip). interestingly, mutant bip mice have been reported to die within several hours of birth from respiratory failure due to impaired secretion of pulmonary surfactant by type aec. in these animals, expression of surfactant protein (sp)-c was reduced and the lamellar bodies were malformed, indicating that bip figure alveolar structure disorder-associated ild and er stress. the (endoplasmic reticulum) er and its protein maturation machinery allow the synthesis of mature secretory and membrane proteins with specific folded conformation. in situations of stress induced by genetic mutations or environmental factors, unfolded or misfolded proteins are retained in the er and induce a defence mechanism called the er stress response. the induction of er chaperones is critical to increase the er folding capacity allowing the production of correctly folded protein. when this defence mechanism is impaired, the misfolded proteins can either be degraded by the proteasome or form protein aggregates. protein aggregates are toxic and can cause conformational diseases. within the alveolar epithelium, misfolding of sp-c could trigger induction of intra-cellular aggregate formation and er stress, with consequently development of alveolar structure disorder-associated ild and conformational disease. plays a critical role in the biosynthesis of surfactant [ ] . several recent reports suggest the possible implication of er stress in ild, with activation of stress response markers in fibrotic lung tissues. it is now well established that surfactant dysfunction plays an important role in the development and progression of ild. pulmonary surfactant is a multimolecular complex constituted of phospholipids and proteins secreted by type aec into the alveolar space. it assures alveolar stability by reducing surface tension along the epithelial lining and this role involves mainly the lipids and the specific hydrophobic sp, sp-b and sp-c. other important players in surfactant metabolism include the atp-binding cassette, sub-family a, member (abca ) and the thyroid transcription factor (ttf- ). surfactant deficiency can be induced by a number of primitive and secondary mechanisms. among them are genetic defects with mutations in sp-b gene (sftpb) as well as genes coding for sp-c (sftpc), abca , and ttf- [ ] [ ] [ ] . more than sftpb (located on chromosome ) mutations have been identified among patients with a congenital deficiency in sp-b. for sftpc located on chromosome , at least mutations have been described, localized primarily in the coohterminal brichos domain [ , ] . a proposed function of the brichos domain is a chaperone-like activity, which could prevent misfolding and aggregation of the parent protein. alterations in the brichos domain could therefore lead to diseases through mechanisms related to abnormal protein processing and cell toxicity [ ] . recently, several studies have also documented the role of abca deficiency in ild. abca functions in the transport of surfactant lipids into lamellar bodies and is required to maintain pulmonary surfactant phospholipid homeostasis. another contributor of ild is ttf- (nk homeobox ) dysfunction. ttf- is a critical regulator of transcription for the surfactant protein sp-b and sp-c. it is encoded by a gene located on chromosome q and is composed of three exon and two introns [ ] . it is expressed in the thyroid, brain and lung. stem cell dysfunction represents a new domain of investigation. alveolar epithelium regeneration and repair requires activation and proliferation of tissue-resident (progenitor) cells and their differentiation to replace the damaged cells [ ] . however, unlike cancer cells, stem cells are not immortal and display decreasing telomere length with aging [ ] . telomere shortening has been documented to be associated with reduced capacity for stem cell renewal, and decreased activity of telomerase, the polymerase responsible for telomere maintenance. the stem cells of the alveolar epithelium are the type aec, and expression of telomerase has been documented in these cells [ ] . experimental studies have also indicated that telomerase is expressed mainly during lung development with a peak expression before birth followed by a decrease to nearly undetectable levels in mature alveolar epithelium. interestingly, telomerase expression and activity could be reinduced in normal quiescent type aec exposed to oxidative stress [ ] . the current understanding is that a population of type aec may have the capacity to survive injury through telomerase activation, and consequently may be responsible for repopulation of the damaged alveolar epithelium. on the basis of reports of pulmonary disorders in dyskeratosis congenita (a rare hereditary disease of poor telomere maintenance), recent and exciting findings have documented mutations in the telomerase gene in familial idiopathic pulmonary fibrosis [ ] . in addition, it is likely that environmental factors such as inflammation, oxidative stress, or virus infection may modify telomerase activity and account for the development of organ-specific disease associated with telomerase dysfunction. in this view, new data in chronic respiratory diseases support the concept that alveolar stem cell dysfunction may play an important role in the rate of progression or severity in ild [ ] . the question whether telomerase mutations or telomere dysfunction may be implicated in pediatric ild needs to be addressed in prospective studies, one possible tool being determination of telomere length in circulating leukocytes. the frequency of lung fibrotic disorders is much lower in children than in adults. some clinical situations have features certainly unique to children, but many of these diseases overlap their adult counterparts with the primary event being injury and damage of the alveolar epithelium [ , ] . yet, the overall outcome and prognosis of the diseases in children are thought to be less severe than in adult patients. in addition, pediatric ild is more responsive to therapeutic strategies than adult ild [ ] . these differences may be explained by the types of initial injury, which may not be similar due to changes in the host environment. another explanation is the modifications of the process of wound healing with age. comparison of the response to injury in foetal and adult skin shows clear differences [ ] . skin wound healing in the foetus is characterized by complete regeneration of the skin and the absence of scar formation. progressively with age, the skin looses the capacity to regenerate the original tissue architecture with the result being scar formation that extends outside the wound bed. the process of healing involves the coordinated regulation of cell proliferation and migration and tissue remodeling, predominantly by polypeptide growth factors [ ] . the slowing of wound healing that occurs in the aged may be related to changes in the activity of these various regulatory factors. in a study on the role of aging in the development of cardiac fibrosis in the rabbit, differences in the cascade of events leading to myocardial remodeling were observed, with mainly the presence of more myofibroblasts synthesising collagen and expressing high levels of tgf-β in older animals [ ] . a study of growth factors involved in skin wound healing in young and aged mice also showed age-dependent changes. expression of all the fibroblast growth factors was diminished in aged mice, even in healthy skin. in addition, the post-wound regulation of expression of these factors and of tgf-β was less pronounced and slower than in young mice. these findings are in agreement with data observed in muscle that indicated significant alterations in the tgf-β production with age [ , ] . other potential mechanism is linked to the observation that injury in adult tissues does in certain circumstances stimulate tissue regeneration, depending on the presence of small subsets of primitive stem cells. stem cells are the self-renewing, primitive, undifferentiated, multipotent source of multiple cell lineages [ ] . while such cells are critical for development and growth through childhood, residual pools of adult stem cells are hypothesized to be the source of the frequently limited tissue regeneration and repair that occurs in adults [ ] . unlike embryonic stem cells, adult stem cells are not immortal, and show decreasing telomere length with increasing age. the naturally limited replacement capacity of such endogenous stem cell pools may occur via exhaustion of the stem cell pool or arise as a consequence of inherited or acquired mutations that alter proper stem cell function [ ] . the limited life span of cells may result from replicative senescence in response to various stresses including dna damage, oxidants, and telomere erosion [ ] . all these forms of injury have been documented in the lung from adult patients with ild. the prevalence of children ild is higher in the younger patients: more than % of patients are less than years at diagnosis, as recorded by the recent ers task force. % have parental consanguinity and nearly % of case siblings were affected by similar diseases. there is a male predominance with a sex ratio of . . the presenting clinical manifestations are often subtle and nonspecific. the onset of symptoms is, in most cases, insidious and many children may have had symptoms for years before the diagnosis of ild is confirmed. however, the majority of patients has symptoms for less than one year at the time of initial evaluation. the clinical manifestations vary from asymptomatic presentation with radiological features suggestive of ild to more characteristic presence of respiratory symptoms and signs such as cough, tachypnea and exercise intolerance [ , ] . these varying presentations are also reflected in the report published by fan et al. who systematically evaluated the clinical symptoms and physical findings of consecutive children with ild [ ] . common symptoms at presentation included cough, dyspnea, tachypnea and chest wall retraction, exercise limitation and frequent respiratory infections. cough is observed in almost % of the patients, is normally non-productive and does not disturb sleep. tachypnea is observed in % of patients and is usually the earliest and most common respiratory symptom. unexplained fever is also reported in almost one third of infants. failure to thrive ( %), tiring during feeding and weight loss are also common symptoms, mainly in young patients. although a history of wheezing may be elicited in almost % of the patients, wheezing is documented by physical examination in only % of the cases. the frequent clinical findings are inspiratory crackles ( %), tachypnea and retraction. in a child with a normal birth history, these are strongly suggestive of ild. other findings associated with an advanced stage of lung disease include finger clubbing ( %) and cyanosis during exercise or at rest ( %) [ , ] . during physical examination it is essential to check the presence of associated non-respiratory symptoms such as joint disease, cutaneous rashes, and recurrent fever suggestive of collagen-vascular disorders. details should also be obtained on precipiting factors such as feeding history, infections, or exposure to dust and drugs. in addition, information on relatives or siblings with similar lung conditions should be gathered. plain radiographs are usually performed in a child suspected of ild at first presentation, but the information provided is often limited and the key chest imaging tool for diagnosis is the high resolution computed tomography (hrct), which can visualize the parenchymal structure to the level of the secondary pulmonary lobule. hrct technique for ild diagnosis has been extensively discussed [ ] [ ] [ ] . to optimise spatial resolution, there is a general agreement to use thin sections, the smallest field of view and a sharp resolution algorithm. the most common hrct feature of ild is widespread ground-glass attenuation. intralobular lines, irregular interlobular septal thickening and honeycombing are less common findings. large subpleural air cysts in the upper lobes adjacent to areas of ground-glass opacities have been also reported in young children with ild. these cysts are interpreted as paraseptal or irregular emphysema. hrct is useful for ild diagnosis and selection of lung area to be biopsied. it is proposed that it also may contribute to monitor disease activity and/or severity. however, evaluation is still needed to support a role of hrct as a follow up tool in pediatric patients. pulmonary function testing (pft) techniques are well established in children and adolescents. however, children aged - years represent a real challenge in pulmonary function assessment as they cannot be sedated and find it difficult to cooperate with all respiratory manoeuvres. in , an ats and ers statement on pft in preschool children summarized the current knowledge on the pft techniques suitable for young children [ , ] . although pft does not provide specific information, it represents a useful investigation for both the diagnosis and the management of ild [ ] . generally, in ild, pulmonary function abnormalities reflect a restrictive ventilatory defect with reduced lung compliance and decreased lung volumes [ ] [ ] [ ] . vital capacity (vc) is variably diminished; the decrease in total lung capacity (tlc) in general is relatively less than in vc. functional residual capacity (frc) is also reduced but relatively less than vc and tlc, and residual volume (rv) is generally preserved; thus the ratios of frc/tlc and rv/tlc are often increased. airway involvement is observed only in a minority of patients. lung diffusing capacity of carbon monoxide (dlco) or transfer factor (tlco) is often markedly reduced and may be abnormal before any radiological findings. however, dlco corrected for lung volume may also be normal in many children. hypoxemia as defined by a reduced resting arterial oxygen saturation (sao ) or a reduced resting arterial oxygen tension is often present. hypercarbia occurs only late in the disease course. during exercise the above described dysfunctions become even more pronounced. thus, gas exchange during exercise might be a more consistent and sensitive indicator of early disease [ ] . bronchoalveolar lavage (bal) usefully provides specimens for cytological examination, microbial cultures, and molecular analysis. besides infections, bal can be of diagnostic value in several situations. in the context of pulmonary alveolar proteinosis, bal abnormalities are characterized by milky appearance fluid, abundant proteinaceous periodic acid schiff positive material, and presence of foamy alveolar macrophages (am) [ ] . bal can also be diagnostic for pulmonary alveolar haemorrhage [ ] . this diagnostic is easy when the bal fluid has a bloody or pink color, but its gross appearance may be normal. microscopic analysis may then be of value by documenting the presence of red blood cells in am or haemosiderin laden am [ ] . among other situations, the diagnosis of langerhans cell histiocytosis can be performed with the use of the monoclonal antibodies revealing the presence of cd a positive cells (in more than % of the bal cells) [ ] . lipid disorders with lung involvement represent another indication of bal. this includes congenital lipid-storage diseases (gaucher's disease and niemann-pick disease) or chronic lipid pneumonia due to chronic aspiration [ , ] . however, in cases of aspiration syndromes, the presence of lipid laden am is sensitive but not specific [ ] . in other pathological situations, bal can usefully serve to direct further investigations. accumulation of bal t-lymphocytes with prevalence of cd + cells is suggestive of sarcoidosis, whilst prevalence of cd + cells is suggestive of hypersensitivity pneumonitis [ ] . also, an increase in bal eosinophils suggests pulmonary infiltrates associated with eosinophilia syndromes [ ] . depending of the underlying diseases, a number of cellular and molecular investigations can be proposed including the studies of various surfactant components, phospholipids and apoproteins [ ] . with increasing recognition of the different patterns of ild and their clinical significance, histological investigation has become increasingly important. depending on disorder presentation, biopsy may concern more accessible organs than the lung such as the skin or the liver in sarcoidosis. histological evaluation of lung tissue usually represents the final step in a series of diagnostic approaches. different methods may be used to obtain lung tissue. the major difference between individual methods lies mainly in balancing invasiveness against the potential for obtaining adequate and sufficient tissue for diagnosis. the techniques of choice are open lung biopsy and video assisted thoracoscopy biopsy. in children, open lung biopsy usually provides sufficient tissue with few complications related directly to the biopsy procedure [ ] . video assisted thoracoscopy biopsy is an alternative to open lung biopsy, and it has been shown that the procedure can be safely performed, even in small children [ ] . the place of other methods like transbronchial lung biopsy and percutaneous needle lung biopsy in appropriate diagnosis of pediatric patients with ild has to be established [ ] [ ] [ ] . the lung histological patterns that can be observed in ild have been reviewed by the ats/ers [ ] . in children, they include mainly: dip, nsip, and lip. dip is characterized by airspaces filled with am, thickened alveolar septa, scattered mixed inflammatory cells and minimal fibrosis. many alveolar spaces are lined by hyperplastic type aec. recently, association with surfactant disorders has been reported [ , [ ] [ ] [ ] . nsip encompasses a broad spectrum of abnormalities with varying degrees of alveolar wall inflammation or fibrosis. the cellular pattern of nsip is characterized by mild to moderate interstitial chronic inflammation and type aec hyperplasia in inflammation areas. it has been reported in a variety of underlying conditions including connective tissues diseases and surfactant disorders. lip features include a marked diffuse infiltrate of mature lymphocytes, plasma cells and histiocytes within the pulmonary interstitium, particularly the alveolar walls. they are often associated with either connective tissues disorders or immunodeficiency states, both congenital and acquired [ ] . another pattern described mainly in adults is diffuse alveolar damage (dad), which includes diffuse homogeneous thickening of alveolar interstitial walls with myofibroblast accumulation, prominent type aec hyperplasia and atypia, and hyaline membranes containing surfactant proteins and cellular debris [ ] . usual interstitial pneumonia (uip) is rare in children [ ] . it is characterized by severe remodeling of the alveolar structure with heterogeneous appearance consisting of contiguous areas of normal lung, dense scarring, and bronchiolar abnormal proliferation. interstitial inflammation is usually mild to moderate. histologic patterns of ild unique to infancy are described below. laboratory tests are used to exclude a number of respiratory diseases in childhood that does not typically present with ild such as chronic aspiration syndromes, resolving acute respiratory distress syndrome, tuberculosis, cystic fibrosis, bronchopulmonary dysplasia and diffuse pulmonary disease such as cystic fibrosis. laboratory tests also verify the absence of immunodeficiencies [ ] . when these conditions have been eliminated, the spectrum of investigations that should be performed for the diagnostic approach will be guided by the history and clinical presentation in each individual child. these investigations are discussed below for the various disorders. in addition, an increasing number of blood and bal biomarkers for evaluation of disease severity and progression is currently investigated. the studied molecules include various cytokines and chemokines, surfactant protein d, krebs von den lungen- antigen (kl- ), matrix metalloproteinases mmp and mmp and defensins [ ] [ ] [ ] [ ] . a large number of pathological situations can impair gas exchange and contribute to progressive lung damage and ild. consequently, diagnosis approaches need to be organized by cause, with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. indeed, in a number of pathological situations, no final diagnosis is proposed and the conclusion reported by the physician in charge of the patient is ild of unknown cause. however, information from recent studies highlights the concept that lung insults caused by substances from the environment or in the context of systemic diseases are largely under-estimated and should be more often discussed considered in the diagnostic process. based on this consideration, the following diagnostic grouping for pediatric ild can be considered ) exposure-related ild; ) systemic disease-associated ild; ) alveolar structure disorder-associated ild; and ) ild specific to infancy. accordingly, a step-by-step etiological diagnostic approach is required and is summarized in figure . once the diagnosis of ild is established on clinical, radiological, and functional findings, a careful history should be obtained for potential exposure-related diseases leading to discuss the need for specific serum antibodies against offending antigens. the following step focuses on the search for systemic disease associated ild, oriented by the presence of clinical and functional extra-pulmonary manifestations. in such situations, additional investigations should include specific serum antibodies and possibly tissue biopsies in organs other than the lung. finally, elimination of these groups of causes with a lung restricted expression of the disease allows discussing the potential interest of a lung biopsy. exposure-related disease refers to diseases caused by a sufficient level of exposure (dose) to components with target organ contact, and subsequent biologic changes and clinical expression. many agents have been associated with pulmonary complications of various types including ild. the adult literature has provided extensive lists of candidate molecules [ ] . in children, the potential involvement of these molecules is not similar as the environmental conditions and the use of therapeutic drugs differ. it is important to point out that exposure-related diseases are certainly under-estimated in the pediatric age. one reason is linked to the fact that the diagnosis is less often discussed than in adults as pediatricians and other child health care providers do not usually have the expertise necessary to take an environmental history. in this review, the most frequent causes of exposure-related ild are discussed. hypersensitivity pneumonitis (hp) is a cell-mediated immune reaction to inhaled antigens in susceptible persons [ , ] . in children, hp is often associated with exposure to antigens in the home environment as well as with certain hobbies. the most frequent types of hp include bird fancier's diseases, humidifier lung diseases, and chemical lung diseases. bird fancier's diseases are induced by exposure to birds with the antigens being glycoproteins in avian droppings, and on feathers. importantly, respiratory symptoms in exposed patients who have only one pet bird at home should raise the suspicion of hp [ ] . humidifier lung diseases (air conditioner lung, misting fountain lung, basement lung diseases) are caused mainly by free-living amoeba and nematodes, as well as bacteria and fungi. chemical lung diseases can be induced by various inorganic antigens such as those from vaporized paints and plastics. low-molecular-weight chemicals may react with proteins in the airways, thus forming complete antigens. once exposure history is obtained, additional information is required and includes biologic tests allowing measurements of environmental contaminants and interpretation of the results by environmental medicine experts. as hp is believed to be an adult disease, children are often diagnosed at the chronic stage of the disease resulting of a long-term exposure to low levels of inhaled antigens. children can develop subtle interstitial inflammatory reactions in the lung without noticeable symptoms for months [ ] . clinical features in the classic form include non productive cough, dyspnea, malaise, asthenia and occasional cyanosis [ ] . lung function abnormalities are not specific and appear similar to changes observed in other ild. hrct abnormalities vary from ground glass attenuation predominantly in the mid-upper zone to nodular opacities with signs of figure search for ild etiology in children. ild is defined by the presence of diffuse infiltrates on chest radiographs or chest high resolution computed tomography, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect (in older children) and/or impaired gas exchange. the search for etiology requires a systematic step-by-step diagnostic strategy for identifying: exposure-related ild; systemic disease-associated ild; alveolar structure disorder-associated ild; and ild specific to infancy. air-trapping [ , , ] . laboratory tests focus mainly on the search for serum-precipitating igg antibodies against the offending antigen [ ] . however, the presence of these antibodies is considered to be of questionable clinical relevance for diagnosis, as it is observed in up to % of serum samples of exposed but asymptomatic individuals. bal cell profile study typically shows an increase in total cell count with a remarkable elevation in the percentage of lymphocytes often over % with a decreased cd /cd ratio [ , ] . however, in contrast to studies in adults, the cd /cd ratio could be within the normal range for children [ ] . histopathologic evaluation of lung tissue is usually not necessary for the diagnosis of hp. at the present time, there is no diagnostic test that is pathognomonic for hp, and only significant predictors of hp are identified. the most significant diagnostic tool is a detailed environmental exposure history. other diagnostic features include: positive precipitating antibodies to the offending antigen; recurrent episodes of symptoms; symptoms occurring - h after exposure; occurrence of diffuse parenchymal lung disease by lung function and hrct; bal abnormalities with lymphocytic alveolitis and increased cd + t cells. medication, drug, radiation and tobacco exposure drugs used in inflammatory or cancer pediatric diseases can cause ild. they include anti-inflammatory agents (e.g. aspirin, etanercept), immunosuppressive and chemotherapeutic agents (e.g. azathioprine, methotrexate, cyclophosphamide), antibiotics, cardiovascular agents, and, for teenagers, illicit drugs [ , ] . there are no distinct clinical, radiographic or pathologic patterns, and the diagnosis is usually made when a patient is exposed to medication known to result in lung disease, with a timing of exposure appropriate for disease development and elimination of other causes of ild. treatment relies on avoidance of further exposure and corticosteroids in markedly impaired patients. exposure to therapeutic radiation in the management of pediatric cancer may also results in ild. patients presenting within months of therapy generally have radiographic abnormalities with ground glass patterns in both radiation-exposed and unexposed tissue [ ] . the association between tobacco use and ild is less well appreciated than the relation with chronic obstructive pulmonary disease (copd). in addition, pediatric patients do not usually have a significant smoking history to develop respiratory disorders [ ] . connective tissues disorders (ctd) are a heterogeneous group of immunologically mediated inflammatory diseases. their origins are multifactorial with genetic, constitutional and environmental elements contributing to their development. ctd refers to any disease that has the connective tissues of the body as a primary target of pathology. the connectives tissues are composed of two major structural proteins, elastin and collagen, with different types of collagen proteins in each tissue [ ] . many ctd feature abnormal immune system activity associated with inflammation. pulmonary manifestations of ctd may include both vascular and interstitial components. from recent reports, the incidence of ild in the context of ctd appears to be higher than previously appreciated [ , ] . importantly, ild may precede the development of clinically obvious ctd, sometimes by months or years. table provides information on suggestive clinical and serological features in selected conditions. the main disorders to be considered in childhood are rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. the other include sjögren syndrome, dermatomyositis and polymyositis, ankylosing spondylitis, and mixed connective tissue disease. rheumatoid arthritis rheumatoid arthritis (ra) is an inflammatory disorder defined by its characteristic diarthroidal joint involvement. it is the most common ctd in children, but pulmonary involvement is less frequent than in adults. genetic and environmental factors seem to be important contributors of disease progression, with influence of sex (more frequent in male), presence of two copies of the hla-drb "shared epitope" (hla-dr se) and anticyclic citrullinated peptide antibody (anti-ccp), and possibly tobacco exposure [ , ] .almost % of patients with ra have specific serologic abnormalities several years before the onset of joint symptoms, and the findings of elevated serum levels of igm rheumatoid factor or anti-ccp is associated with a high risk for the development of ra [ ] . systemic sclerosis systemic sclerosis (ssc) is characterized by a progressive dermatologic abnormality [ ] . its etiology remains unknown; it is believed to be a complex disease in which interactions between environmental, auto-immune, and genetic factors result in various disease phenotypes [ ] . although it is a rare disease in childhood, the diagnosis is based on skin disease. cardiopulmonary complications are common and have been associated with death in young patients. almost all patients with ssc have serum antinuclear antibodies. the other autoantibody markers are listed in table . recently, the presence of anti-dna topoisomerase ii autoantibody has been reported to be a key factor in the development of ild, in association with class ii mhc status (hla-dr , hla-dpbi) [ ] . systemic lupus erythematosus systemic lupus erythematosus (sle) is an auto-immune disorder characterized by the involvement and dysfunction of multiple organ systems. the mechanisms of tissue injury involve autoantibody production and immunocomplex formation leading to an inflammatory process. diverse clinical phenotypes are observed, including a variety of mucocutaneous lesions, non erosive arthropathy, renal disease (glomerulonephritis and interstitial nephritis), lung disease, pericarditis, and a spectrum of neurologic disorders. laboratory abnormalities are characterized by the presence of antibodies reactive to nuclear (ana) and cytoplasmic antigens. pulmonary vasculitis are observed in vasculitic syndromes that preferentially affect small vessels (arterioles, venules, and capillaries). they include the anti-neutrophil cytoplasmic antibody (anca)-associated vasculitis (wegener's granulomatosis, churg-strauss syndrome, and microscopic polyangitis) that share histologic similarities without immune deposits; anti-glomerular basement membrane (gbm) disease; henoch-schönlein purpura and cryoglobulinemia vasculitis. vasculitic syndromes that affect large/medium vessels (such as kawasaki's disease, polyarteritis nodosa) only occasionally affect the lung [ ] . wegener's granulomatosis wegener's granulomatosis (wg) is a rare disease of uncertain cause. it seems to affect children as much as adults with an increasing reported incidence around . cases/million/year, mostly in teenagers with a reported median age of . years ( - years) [ , ] . it is characterized by inflammation in a variety of tissues including blood vessels (vasculitis). wg primarily affects the upper respiratory tract, lung, and kidneys. the diagnosis is based on the combination of symptoms and a biopsy of affected tissue with necrotising granulomatous vasculitis in the absence of an infectious etiology. the diagnosis is further supported by positive blood tests for cytoplasmic-staining (c)-anca pr type [ ] . churg-strauss syndrome churg-strauss syndrome (css) is a granulomatous small-vessel vasculitis. the cause of this allergic angiitis and granulomatosis is not known, but autoimmunity is evident with the presence of hypergammaglobulinemia, increased levels of immunoglobulin e (ige), and perinuclear-staining (p)-anca. the diagnosis relies on biopsy evidence for vasculitis and at least criteria among the following: moderate to severe asthma, blood eosinophilia (at least %), and nonfixed pulmonary infiltrates with extravascular eosinophils on biopsy [ ] . twenty-nine pediatric cases have been reported so far in the literature, with lung involvement in % of [ ] . anti-glomerular basement membrane disease goodpasture syndrome is a rare disease that involves rapidly progressive kidney failure along with lung disease and is characterized by the deposition of anti-gbm antibodies. several cases have been reported in the pediatric literature. the autoantibodies mediate tissue injury by binding to their reactive epitopes in the basement membranes. this binding can be visualized as the linear deposition of immunoglobulin along the glomerular basement membrane. the principle component of the basement membrane is type iv collagen which can be expressed as different chains, from alpha to alpha . the goodpasture antigen has been localized to the carboxyl terminus of the noncollagenous domain of the alpha chain of type iv collagen. the anti-gbm antibody can usually be found in serum [ ] . strong evidence exists that genetics play an important role. patients with goodpasture disease have an increased incidence of hla-drb compared to control populations [ ] . granulomatous disorders are characterized by the presence of granulomas defined as a focal, compact collection of inflammatory cells in which mononuclear cells predominate. granulomas form as a result of tissue injury by a wide variety of agents including microorganisms, antigens, chemical, drugs and other irritants. in other situations including sarcoidosis, the etiologic factors remain to be determined. sarcoidosis sarcoidosis is a chronic inflammatory disease in which granulomatous lesions can develop in many organs, mainly the lung. its cause remains obscure, and most likely involves environmental and host factors [ ] . the current concept is that a still unknown stimulus activates quiescent t cells and macrophages leading to recruitment and activation of mononuclear cells, with, as a consequence, granuloma formation, alveolitis, and in some cases interstitial lung fibrosis [ ] . sarcoidosis is relatively uncommon among children. its diagnosis is based on a combination of suggestive clinical features, with histologically-documented noncaseating granuloma, in the absence of other known causes of granuloma formation [ ] . the incidence and prevalence of sarcoidosis are reported to be influenced by age, race and geographic localization [ ] . although the youngest patients reported were infants and -months old, most of the cases in children occur in preadolescents and adolescents. from the national patient registry on patients with sarcoidosis in denmark during the period - , patients with a confirmed diagnosis were ≤ years of age [ ] . the calculated incidence was . per . person-years. in children ≤ years of age, the incidence was . ; it increased gradually to . in children aged - years. marked racial differences in the incidence and prevalence of sarcoidosis have been reported by many authors [ ] . various reports in the literature also indicate that race and ethnicity affect both the patterns of organ involvement and disease severity. in a follow-up study we have conducted in children with pulmonary sarcoidosis, children were black [ ] . also the number of organs involved was higher in the black than in the caucasian children. clinical manifestations in sarcoidosis are the consequences of local tissue infiltration with sarcoid granuloma. therefore, disease expression depends on the organ or system involved and a variety of symptoms and physical findings can be observed [ ] . the modes of presentation include non-specific constitutional symptoms, alone or associated with symptoms related to specific organ involvement. in the report of children with sarcoidosis in denmark, the most common non specific symptoms were asthenia, weight loss, and fever [ ] . clinical findings mainly include respiratory manifestations, lymphadenopathy, skin lesions, ocular and central nervous system abnormalities. the most common radiographic findings are hilar lymph node enlargements, with or without lung changes. lung function abnormalities are frequently observed in children with restrictive pulmonary pattern and abnormal diffusing capacity [ ] . other investigations such as bal documenting a lymphocytic alveolitis with increased cd /cd ratio, and elevated serum angiotensin-converting enzyme may provide additional evidence of sarcoidosis [ ] . other granulomatous disorders in children a number of pathological situations are associated with granulomatous disorders defined by the presence of non-caseating granuloma in biopsied tissues. infections are the main causes of other granulomatous diseases, and are in some cases related to disorders of neutrophil function such as chronic granulomatous disease (cgd) [ ] . most children with cgd present with recurrent bacterial and fungal infections. the most frequently encountered pathogens are staphylococcus aureus, aspergillus, burkholderia cepacia, and enteric gram negative bacteria [ ] . the most prominent pulmonary lesions include an extensive infiltration of the lung parenchyma and hilar adenopathy. in some situations, a homogeneous distribution of small granulomatous lesions can occur, with a radiological appearance of miliary tuberculosis. the other granulomatous diseases can be seen in other described diseases, such as immune disorders (including crohn's disease and histiocytosis x), hs pneumonitis, vasculitis disorders or neoplasms. lysosomal diseases gaucher's disease is an autosomal recessive disease and the most common of the lysosomal storage diseases. it is caused by a genetic deficency of the enzyme lysosomal gluco-cerebrosidase that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. the consequence is an accumulation of glucocerebroside in reticuloendothelial cells, leading to excessive deposition of fatty material in the spleen, liver, kidneys, lung, brain and bone marrow. pulmonary expression is mainly characterized by physiologic involvement (reduction in lung the diffusion capacity and the functional residual volume). lung imaging may show interstitial changes [ ] . niemann-pick diseases are genetic diseases primarily due to deficiency of sphingomyelinase resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte system, mainly the brain, spleen, liver, lung, and bone marrow. histology demonstrates lipid laden macrophages in the marrow, as well as "sea-blue histiocytes" on pathology. the infantile form with a dominant neurologic expression is rapidly fatal. in older patients, cases of ild have been reported [ ] . hermansky-pudlak syndrome is a heterogeneous group of autosomal recessive disorders associated with accumulation of a ceroid-like substance in lysosomes of a variety of tissues. it is characterized by albinism, bleeding tendency associated to poor platelet aggregation and systemic complications associated to lysosomal dysfunction. a chronic inflammatory process may explain the progressive development of ild and fibrosis [ ] . familial hypercalcemia with hypocalciuria familial hypercalcemia with hypocalciuria is caused by autosomal dominant loss-of-function mutations in the gene encoding the calcium-sensing receptor (casr), a g-protein coupled membrane receptor expressed in many tissues [ ] . loss-of-function mutations in casr impair the feedback inhibition of parathyroid hormone secretion in response to a rise in the blood calcium concentration. the result is hypercalcemia associated with inappropriately normal or mildly elevated levels of parathyroid hormone. in the kidneys, mutations in casr prevent the feedback inhibition of calcium reabsorption in situation of hypercalcemia, leading to relative hypocalciuria. respiratory symptoms are usually mild and associated with reduction in the lung diffusion capacity. lung histology indicates the presence of foreign body giant cells and mononuclear cells infiltrating the alveolar interstitium, without circumscribed granulomas. langerhans'-cell histiocytosis is part of the histiocytosis syndromes, which are characterized by an abnormal proliferation of langerhans' cells [ ] . the langerhans cells are differentiated cells of monocyte-macrophage lineage that function as antigen-presenting cells. the origin of the expanded population of langerhans' cells is unknown; in adults, the only consistent epidemiologic association is with cigarette smoking. these cells may form tumors, which may affect various parts of the body. most cases of pediatric langerhans'-cell histiocytosis are observed in children between ages and years, with usually bone involvement ( %) including the skull. the tumors produce a punched-out appearance on bone x-ray, and can cause fracture without apparent traumatism. langerhans'-cell histiocytosis can also affects various organs including the lung [ ] . children with pulmonary langerhans'-cell histiocytosis present in a variety of ways. they can be asymptomatic or present common symptoms such as nonproductive cough and dyspnea. hrct of the chest is a useful and sensitive tool for the diagnosis. indeed, the combination of diffuse, irregularly shaped cystic spaces with small peribronchiolar nodular opacities, predominantly in the middle and upper lobe, is highly suggestive of pulmonary langerhans'-cell histiocytosis [ ] . other abnormalities include ground-glass attenuation. the presence of increased numbers of langerhans' cells in bal fluid (identified by staining with antibodies against cd a) with a proportion greater than percent is also strongly suggestive of pulmonary langerhans'-cell histiocytosis. histologically, the cellular lesions forms nodules containing a mixed population of cells with variable numbers of langerhans' cells, eosinophils, lymphocytes, plasma cells, fibroblasts, and pigmented alveolar macrophages. several forms of ild have been reported to occur with inflammatory bowel diseases (crohn's disease) and celiac disease [ ] . primary biliary cirrhosis and chronic hepatitis have also been reported to be associated with parenchymal lung dysfunction [ , ] . in addition, there are reports on ild in association with neurocutaneous disorders (tuberous sclerosis, neurofibromatosis, ataxia-telangiectasia) and amyloidosis [ ] . depending on the causes, the components of the alveolar structure (the epithelium and the alveolar space, the interstitium, and the pulmonary capillary endothelium) can be involved differently and can serve as primary targets of the underlying pathological processes. based on history, clinical presentation, bal data, and, most important, on information from lung tissue studies, the disorders can be gathered in groups according to predominant structural targets (figure ). the disorders affecting primarily the alveolar epithelium and the alveolar space share common histopathological description, with preserved pulmonary architecture, hyperplasia of type aec, interstitial infiltrates composed of immuno/inflammatory cells and scattered myofibroblasts, and the alveolar space filled with either immuno/inflammatory cells, desquamated materials, or components derived from surfactant lipid and protein complex. in the coming years, it is likely that the list of disorders will expand rapidly with the availability of specific tissue markers. currently, the following grouping can be proposed: infections, surfactant disorders, and eosinophilic lung diseases. infections the role of infection, mainly viral, in the development and progression of ild is sustained by a number of human and experimental reports. from recent knowledge, it is strongly suggested that latent viral infections may be involved in the pathogenesis of ild, through targeting of the alveolar epithelium. the main virus implicated include adenovirus, members of human herpes virus family (epstein-barrr virus and cytomegalovirus), and respiratory syncitial virus [ ] . number of other viruses can also be involved such as influenza a, hepatitis c, or even human immunodeficiency virus (hiv) in immunocompetent children [ ] [ ] [ ] [ ] . human adenovirus being predominantly respiratory pathogens, adenovirus infections can cause a variety of pulmonary symptoms and can persist for long periods of time. several studies in adult patients have indicated that the adenovirus gene product e a could be detected figure alveolar structure disorder-associated ild. depending on the causes, the alveolar structure components can be involved differently and serve as primary targets of the underlying pathological processes. based on history, clinical presentation, bal and lung tissue information, the disorders can be gathered in groups according to the predominant alveolar targets: epithelium, vascular or interstitial components. in lung tissues by in situ hybridization in up to % of cases of idiopathic pulmonary fibrosis. the causative role of the virus in the initiation of the disease remains uncertain, but it may be an important factor in its progression as treatment with corticosteroids may make patients more susceptible to adenovirus infection or reactivation from latency. e a has been shown to increase the production of tgf-β and to induce lung epithelial cells to express mesenchymal markers, thereby contributing to remodeling of the alveolar structure [ ] . isolation of the virus from the throat and serologic studies are diagnostic supportive, but the diagnosis is confirmed by the detection of the virus in lung tissues. epstein-barrr virus (ebv) and cytomegalovirus (cmv) are widespread pathogens that share the characteristic ability of herpesviruses to remain latent within the body over long periods. in mice, the control of herpesviruses replication have also been reported to be associated with the arrest of lung fibrosis [ ] . ebv is present in all populations, infecting more than % of individuals within the first decades of life. infection by cmv is reported in % of individuals aged and older and more than % of aged individuals have antibodies against cmv. in addition, cmv is also the virus most frequently transmitted to a developing fetus. most healthy people who are infected by ebv and cmv after birth have no symptoms, but infection is important to certain high-risk groups of infants and immunocompromised individuals. several studies in the adult literature have reported an increased incidence of ebv and cmv infection in patients with pulmonary fibrosis, associated with virus dna-positive lung tissue biopsies in several cases [ ] . however, so far, no evidence of causal relationship between viruses and pulmonary fibrosis has been provided. respiratory syncytial virus (rsv) is the most common cause of viral lower respiratory tract infection. it affects people of all ages, and can cause severe disease in infants, in older immunodeficient children and the elderly. an intriguing feature of rsv infection is the susceptibility of previously infected individuals to reinfection with antigenically closely related viruses or the identical virus strain. recently, increased interest has been focused on the contribution of persistent rsv in several chronic lung diseases including chronic obstructive pulmonary disease [ ] . the role of rsv in the physiopathology of theses disorders as well as and the mechanisms of its persistence remain to be elucidated [ ] . interestingly, in a recent work on the histopathology of untreated human rsv infection, the presence of the virus in aec has been documented [ ] . from these various data, a role of rsv in the development of ild needs to be investigated. immunostaining with rsv-specific antibodies of tissues from lung biopsy should be proposed. among the other pathogens, chlamydophila pneumoniae and mycoplasma pneumoniae are currently drawing increasing consideration. they are frequent causes of community acquired pneumonia in children. before the age of years, almost % of children have had chlamydophila pneumoniae infection based on serological studies [ ] . these pathogens are intracellular organisms that primarily infect respiratory epithelial cells and alveolar macrophages and have the propensity to persist within several cell types such as macrophages. they are well known to cause a wide variety of respiratory manifestations, with possible progression towards diffuse parenchymal diseases associated with interstitial infiltrates on chest imaging and reduction in the lung diffusion capacity [ ] . regarding legionella pneumophilia infection, progression towards ild has been infrequently reported in adult patients. results from recent studies provided evidence that viruses can infect the alveolar epithelium and may be documented in lung tissues from patients using virus dna detection and immunohistochemistry. a number of specific antibodies are currently available and should prompt to investigate the presence of the above cited viruses in the lung tissues from children with ild. surfactant disorders surfactant disorders include mainly genetic surfactant protein disorders and pulmonary alveolar proteinosis the deficiency in sp-b is a rare autosomal recessive condition known to be responsible for lethal neonatal respiratory distress. rare survivals have been described in partial deficiencies [ , ] . the sftpc mutation i t (c. t > c) is the more prevalent mutation. others are described in only one family. the phenotype associated with sftpc mutations is extremely heterogeneous leading from neonatal fatal respiratory failure to children and adults chronic respiratory disease with ild [ ] . recessive mutations in the abca gene were first attributed to fatal respiratory failure in term neonates but are increasingly being recognized as a cause of ild in older children and young adults. over abca mutations have been identified in neonates with respiratory failure and in older children with ild [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . mutations in the ttf- gene are associated with "brainlung-thyroid syndrome" which combines congenital hypothyroidism, neurological symptoms (hypotonia, chorea), and ild of variable intensity [ ] [ ] [ ] [ ] [ ] [ ] [ ] . so far, few mutations have been reported, mostly in exon [ , ] . pulmonary alveolar proteinosis (pap) is a rare lung disorder characterized by alveolar filling with floccular material derived from surfactant phospholipids and protein components. pap is described as primary or secondary to lung infections, hematologic malignancies, and inhalation of mineral dusts. recently, the importance of granulocyte/macrophage colony-stimulating factor (gm-csf) in the pathogenesis of pap has been documented in experimental models and in humans. gm-csf signaling is required for pulmonary alveolar macrophage catabolism of surfactant. in pap, disruption of gm-csf signaling has been shown, and is usually caused by neutralizing autoantibodies to gm-csf. therefore, the emerging concept is that pap is an autoimmune disorder resulting in macrophage and neutrophil dysfunction. in a recent report, it has been reported that gm-csf autoantibodies are normally present in healthy individuals, but at lower levels than in pap patients [ ] . in addition, in vitro experiments indicated that these autoantibodies reduce gm-csp signaling similarly in healthy individuals and in pap patients. at levels above a critical threshold, gm-csf autoantibodies are associated with multiple impaired gm-csf dependent myeloid function [ ] . several cases of genetic defects in the common beta chain for the gm-csf receptor have been documented [ ] . eosinophilic lung diseases eosinophilic lung diseases constitute a diverse group of disorders of various origins. the diagnosis is suggested by the presence of pulmonary infiltrates on chest imaging and peripheral eosinophilia. it is confirmed by the presence of increased amounts of eosinophils in bal and/or lung tissue eosinophilia. in this section, eosinophilic vasculitis will not be discussed (see chapter . . ). the search for an etiology includes a combination of clinical and laboratory investigations. eosinophilic lung diseases of known cause in children include mainly allergic bronchopulmonary aspergillosis, parasitic infections and drug reactions. eosinophilic lung diseases of unknown cause comprise loeffler syndrome (characterized by migrating pulmonary opacities), acute eosinophilic pneumonia, and chronic eosinophilic pneumonia [ , ] . the idiopathic hyper-eosinophilic syndrome is a rare disorder observed mainly in adults; it is characterized by prolonged eosinophilia and a multiorgan system dysfunction due to eosinophil infiltration with pulmonary involvement documented in almost half of the patients [ , ] . alveolar capillary dysplasia and pulmonary capillary hemangiomatosis the pulmonary capillaries form a dense sheet-like meshwork composed of short interconnected capillary segments. the capillary meshes are wrapped over the alveoli, with only a single sheet of capillaries between adjacent alveoli on the same alveolar duct. impaired development of this vascular network can be caused by genetic defects, prematurity or injury. aberrant angiogenesis documented in pediatric patients include mainly alveolar capillary dysplasia, and pulmonary capillary hemangiomatosis [ ] . alveolar capillary dysplasia is a rare disorder, presenting with persistent pulmonary hypertension of the newborn [ ] . the strongest diagnostic features are poor capillary apposition and density, allied with medial arterial hypertrophy and misalignment of pulmonary vessels [ ] . pulmonary capillary hemangiomatosis is also a rare disease that is characterized by proliferation of capillary-sized vessels within the alveolar walls of the lung [ ] . intimal thickening and medial hypertrophy of the small muscular pulmonary arteries are present resulting in elevated pulmonary vascular resistance. most cases appear sporadic. chest imaging shows nodular pulmonary infiltrates and septal lines. a definitive diagnosis can be made only by histologic examination. interestingly, capillary proliferation in the alveolar wall has been reported in hereditary haemorrhagic telangiectasia [ ] . lymphatic disorders alveolar structure formation is characterized by refinement of the gas exchange unit and functional adaptation of endothelial cells into vessels including pulmonary lymphatics. the pulmonary lymphatic network promotes efficient gas exchange through maintaining interstitial fluid balance. lymphatic disorders can be classified as primary or secondary. congenital errors of lymphatic development can lead to primary pulmonary lymphatic disorders that include lymphangiomas and lymphangiomatosis, lymphangiectasis, and lymphatic dysplasia syndrome [ , ] . lymphangiomas are focal proliferations of well differentiated lymphatic tissue, and lymphangiomatosis describes the presence of multiple lymphangiomas. most of these disorders are discovered in fetuses or during the early postnatal period. lymphangiectasis is characterized by pathologic dilation of lymphatics. the term "lymphatic dysplasia syndrome" includes congenital chylothorax, and the yellow nail syndrome (a triad of idiopathic pleural effusions, lymphedema, and dystrophic nails) [ ] . secondary forms of lymphatic disorders result from a variety of processes such as chronic airway inflammation that impair lymph drainage and increase lymph production [ ] . diffuse alveolar hemorrhage syndromes diffuse alveolar hemorrhage (dah) syndromes are caused by the disruption of alveolar-capillary basement membrane as a consequence of injury to the alveolar septal capillaries, and less commonly to the arterioles and veinules. the hallmarks are intra-alveolar accumulation of red blood cells, fibrin, and hemosiderin-laden macrophages. it is important to point out that approximately one third of patients with dah do not manifest hemoptysis, and bal can be extremely helpful if this entity is suspected by showing the presence of siderophages or red blood cells within the alveoli. dah can be observed in association with systemic findings or without evidence of associated diseases. in children, situations of dah in the context of other disorders are reported in several forms of vasculitis discussed above. other disorders that can also be accompanied by dah include pulmonary hypertension and congenital heart diseases, pulmonary veino-occlusive disease, arteriovenous malformations and hereditary haemorrhagic telangiectasia, coagulation disorders, and celiac disease [ ] . in the absence of systemic findings, isolated pulmonary capillaritis should be discussed with the search for positivity of the antiglomerular basement membrane antibody with linear deposits in the lung tissue biopsy as well as suggestive serologic features such as p-anca antibodies [ ] . idiopathic pulmonary hemosiderosis is a diagnosis of exclusion based on patient presentation with acute, subacute, or recurrent dah, on the results of lung biopsy showing evidence of 'bland' pulmonary hemorrhage (ie, without capillaritis or vasculitis), and after exclusion of the conditions listed above [ ] . in this situation, red blood cells leak into the alveolar space without evidence of damage and/or inflammation of the alveolar capillaries. in addition, the diagnosis of idiopathic pulmonary hemosiderosis can only be considered after exclusion of diseases induced by environmental factors such as pesticide and cow's milk (heiner's syndrome) [ ] . this syndrome is a hypersensitivity disease that affects primarily infants, and is caused by antibodies to cow's milk proteins. the diagnosis is supported by positive milk precipitin test and rapid improvement of symptoms and pulmonary infiltrates on chest imaging after exclusion of milk proteins. in the resolution phase of tissue injury, elimination of mesenchymal cells and recruited inflammatory cells is essential for restoration of normal cellular homeostasis. dysregulated repair process in ild is associated with accumulation and dysfunction of interstitial fibroblasts [ ] . in the coming years, it is likely that progress in the understanding of the mechanisms involved in the impaired myofibroblast apoptosis as well as evasion of these cells from immune surveillance will open new areas of investigations and will provide support for the characterization of disorders that affect primarily the alveolar interstitial components in pediatric ild. indeed, recently, distinct intrinsic differences in gene expression pathways has been reported between control and lung fibrosis myofibroblasts which suggests that ild myofibroblasts are pathological cells with fundamental changes [ ] . in the context of ild, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia, and chronic pneumonitis in infancy have been reported to be exclusively observed in very young children [ ] . pulmonary interstitial glycogenosis (pig) is a non lethal disease, reported in neonates with respiratory distress syndrome developed shortly after birth [ , ] . very few cases are described so far but it seems to have a male preponderance [ ] . the histological hallmark of pulmonary interstitial glycogenosis is the accumulation of monoparticulate glycogen in the interstitial cells on lung biopsy. it is thought to represent a maturation defect of interstitial cells that leads them to accumulate glycogen within their cytoplasm [ , ] . it is discussed that pig could meet "chronic pneumonitis in infancy" as this remains a generalized term [ ] . as well, pig could be considered as a premature lung disease, but more than half of published cases were in term infants [ , , ] . the long term consequences in these infants need to be ascertained. neuroendocrine cell hyperplasia of infancy (nchi) is also a non lethal disease characterized by tachypnea without respiratory failure. the human airway epithelium contains highly specialized pulmonary neuroendocrine cells (pnec) system. it's function remains unknown but is hypothysed to act in modulation of fetal lung growth and in post-natal stem cell condition [ ] . the pnec system permits synthesis and release of serotonin and neuropeptides such as bombesin [ ] . as normal bombesin levels decrease after mid-gestation, its overexpression in nchi could be attributed to a nonregression of neuroendocrine cells [ ] . clinical presentation is typically a respiratory distress in post-natal young infant (mean age . months in a large serie, but cases in older children have been reported [ ] . hrct shows patchy centrally ground-glass opacifications and air trapping [ ] . on lung biopsy, the histological abnormality is hyperplasia of neuroendocrine cells within bronchioles documented by bombesin immunohistochemistry. the follow-up reveals in some cases the persistence of tachypnea and oxygen requirement for several months. usually, there is a good prognosis [ , , , ] . chronic pneumonitis in infancy was first described by katzenstein et al. [ ] . the clinical and radiologic features are similar to those observed in other forms of ild. specific histologic abnormalities include diffuse thickening alveolar septa, hyperplasia of type aec, and presence of primitive mesenchymal cells within the alveolar septa. in some cases, foci of pulmonary proteinosis-like material have been observed in air spaces. the prognosis has been reported to be poor with a high mortality rate. other disorders associated with pulmonary development and growth abnormalities encompass a broader spectrum of respiratory manifestations and are more adequately integrated in the classification of diffuse lung diseases [ ] . management of children with ild includes administration of oxygen for chronic hypoxaemia, and maintenance of nutrition with an adequate energy intake, immunization with influenza vaccine on an annual basis is recommended along with other routine immunizations against major respiratory pathogens [ ] . in addition, aggressive treatment of intercurrent infections and strict avoidance of tobacco smoke and other air pollutants are strongly recommended. a very few children do not require any treatment and recover spontaneously. in the majority of cases, treatment with immunosuppressive, anti-inflammatory, or anti-fibrotic drugs is required for weeks, months or even years [ , , ] . various drugs discussed below can be used, but no guidelines for treatment of ild in children have been proposed so far. the major reason is the very limited number of pediatric patients available for a prospective clinical trial. in addition, controlled studies with a placebo arm are unacceptable because of the poor prognosis of untreated cases and the reported efficacy of anti-inflammatory therapies in a number of pediatric ild. at the present time, the main therapeutic strategy is based on the concept that suppressing inflammation may most likely prevent progression to fibrosis. among the anti-inflammatory agents used in pediatric ild, steroids are the preferred choice, administered orally and/or intravenously. this has been well illustrated by the results of the ers task force on pediatric ild [ ] . oral prednisolone is most commonly administered at a dose of - mg/kg/day [ ] . children with significant disease are best treated with pulsed methylprednisolone at least initially [ , ] . this is usually given at a dose of - mg/kg/day for days consecutively at monthly intervals. the minimum number of cycles recommended is but treatment may need to be continued for a longer period of months or more depending on response. when the disease is under control, the dosage of methylprednisolone can be reduced or the time between cycles can be spaced out. the disease may then be controlled with oral prednisolone preferably given as an alternate day regime. in few cases oral prednisolone is used from the beginning simultaneously with intravenous methylprednisolone but this is only recommended in those with very severe disease. methylprednisolone may be effective when other forms of steroids administration fail without significant side effects. an alternative to steroids is hydroxychloroquine with a recommended dose of - mg/kg/day. individual case reports have described a response to hydroxychloroquine even in the presence of steroid resistance [ , , ] . some groups have proposed to base the decision as to which agent to use on the lung biopsy findings, with a preference for steroids in case of large amount of desquamation and inflammation and for hydroxychloroquine if increased amounts of collagen representing pre-fibrotic change are found. however, as documented in the ers task force on pediatric ild, the preferred choice between steroids or hydroxychoroquine in children is highly dependent on the expertise of the center in charge of the patient, and does not seem to be oriented by the histopathological pattern [ ] . in case of severe disease, steroids and hydroxychloroquine may be associated. in situations of inefficiency of steroids and hydroxychloroquine, other immunosuppressive or cytotoxic agents such as azathioprine, cyclophosphamide, cyclosporine, or methotrexate may be used. these treatments have been used mainly in situation of autoimmune disorders. promising therapeutic options include macrolides. indeed, these antibiotics have been shown to display a number of anti-inflammatory and immunomodulatory actions. although the mechanisms and cellular targets specific to macrolide activity remain to be elucidated, beneficial effects in several chronic lung diseases including chronic obstructive pulmonary diseases (copd) and cystic fibrosis have been reported [ , ] . of interest is the ability of macrolides to accumulate in host cells including epithelial cells and phagocytes. in a recent report, a favorable response to treatment with clarithromycine has been described in an adult patient with dip [ ] . other new therapeutic strategies currently proposed in adult patients target fibrogenic cytokines. the th cytokine interferon-γ has an antifibrotic potential through suppression of th fibrogenic functions. antagonists to tgf-β include pirfenidone and decorin. the use of molecules directed against tnf-α such as the soluble tnf-α receptor agent etanercept is also under investigation. to date, there are no reports on the use of these novel therapies in pediatric ild. finally, in the coming years, it is likely that an expanding number of molecules aimed at favoring alveolar surface regeneration and repair through activation and proliferation of tissue-resident (progenitor) cells will come out. depending on the underlying diseases, several specific treatment strategies needs to be considered. these include whole lung lavage for pulmonary alveolar proteinosis, which has been reported to be effective by removing the material from the alveolar space [ ] . gm-csf has also been shown of interest in this disease [ ] . other strategies such as interferon-α for pulmonary haemangiomatosis are effective [ ] . in recent years, lung transplantation has emerged as a viable option in children of all ages, even in young infants, and lung or heart-lung transplantation may be offered as an ultimate therapy for end-stage ild [ ] . the outcome and survival do not seem to be different from those reported in conditions others than ild, although comparisons are difficult to establish due to the limited number of reported cases. response to treatment and outcome can be evaluated in children based on several criteria such as decrease in cough and dyspnea, increase in oxygenation at rest and sleep, and changes in pulmonary function tests [ , ] . improvement on thoracic hrct may also be seen, but tends to occur over a much longer period of time. reports in pediatric ild have not shown a good correlation between histological findings and outcome. some children with relatively severe fibrosis on lung biopsy make good progress, whereas others with mild desquamation have a poor outcome. this is probably due to the variable severity of the disease in different parts of the lung especially in relation to the particular area biopsied, despite hrct guidance. overall a favorable response to corticosteroid therapy can be expected in - % of cases, although significant sequelae such as limited exercise tolerance or the need for long-term oxygen therapy are often observed. reported mortality rates are around %. the outcome for infants is more variable [ , ] . pediatric ild comprises a large spectrum of disorders, with compelling evidence that some of these disorders are observed more frequently in infants, while others are more specific to older children. ongoing basic research will provide new insights into the molecular basis of ild pathogenesis (including genetic factors causing familial disease) in children, and is expected to identify important preclinical markers of disease, pathways of disease regulation, and novel potential targets for therapeutic intervention. for the future, there is a strong need for international collaboration which will allow collecting sufficiently large cohorts of patients with specific entities in order to perform proper therapeutic trials. as a prerequisite, however, a clear and standardised classification of the histopathology of the underlying conditions is critical. such multicenter trials will help to reduce the still considerable morbidity and mortality in children with ild. abbreviations (ards): acute respiratory distress syndrome; (aec): alveolar epithelial cells ankylosing spondylitis; (ab): antibodie; (anti-ccp): anticyclic citrullinated peptide; (anti-gbm): antiglomerular basement membrane anca): anti-neutrophil cytoplasmic antibody; (ana): antinuclear antibodies u -rnp): anti-u -ribonucleoprotein; (sao ): arterial oxygen saturation binding immunoglobulin protein; (bal): bronchoalveolar lavage; (casr): calciumsensing receptor; (cgd): chronic granulomatous disease; (copd): chronic obstructive pulmonary disease; (css): churg-strauss syndrome; (ctd): connective tissue disorders; (cmv): cytomegalovirus; (c): cytoplasmicstaining; (dip): desquamative interstitial pneumonia; (dad): diffuse alveolar damage; (dah): diffuse alveolar hemorrhage; (dlco): diffusing capacity of the lung for carbon monoxide functional residual capacity; (sftpb): gene coding for sp-b; (sftpc): gene coding for sp-c; (gm-csf): granulocyte/ macrophage colony-stimulating factor human immunodeficiency virus; (hp): hypersensitivity pneumonitis; (ig): immunoglobulin; (ild): interstitial lung disease lymphocytic interstitial pneumonia; (mmp): metalloproteinases; (mpa): microscopic polyangiitis; (mctd): mixed connective tissue disease; (nchi): neuroendocrine cell hyperplasia of infancy; (nsip): non-specific interstitial pneumonia pulmonary function testing; (pig): pulmonary interstitial glycogenosis pulmonary neuroendocrine cells; (rv): residual volume; (rsv): respiratory syncitial virus; (ra): rheumatoid arthritis; (rnp): ribonucleoprotein; (srp): signal recognition particle systemic lupus erythematosus; (ssc): systemic sclerosis; (ttf- ): thyroid transcription factor ; (tlc): total lung capacity; (tlco): transfer factor of the lung for carbon monoxide; (tgf): transforming growth factor; (uip): usual interstitial pneumonia idiopathic interstitial pneumonitis in children: a national survey in the united kingdom and ireland factors influencing survival in children with chronic interstitial lung disease diffuse parenchymal lung disease. cape town: karger idiopathic pulmonary fibrosis: clinical relevance of pathologic classification european respiratory society international multidisciplinary consensus. classification of the idiopathic interstitial pneumonias pediatric interstitial lung disease: children are not small adults paediatric interstitial lung disease diffuse lung disease in young children: application of a novel classification scheme task force on chronic interstitial lung 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pulmonary neuroendocrine cell system in pediatric lung disease-recent advances gastrin-releasing peptide gene expression in developing, hyperplastic, and neoplastic human thyroid c-cells persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia neuroendocrine cell hyperplasia of infancy (nehi) chronic interstitial lung disease in children: response to high-dose intravenous methylprednisolone pulses chloroquine treatment of interstitial lung disease in children familial interstitial lung disease in children: response to chloroquine treatment in one sibling with desquamative interstitial pneumonitis role of macrolide therapy in chronic obstructive pulmonary disease effects of prolonged use of azithromycin in patients with cystic fibrosis: a meta-analysis beneficial response to macrolide antibiotic in a patient with desquamative interstitial pneumonia refractory to corticosteroid therapy pulmonary alveolar proteinosis in children diffuse neonatal haemangiomatosis interstitial lung diseases in children this work was supported by inserm, université pierre et marie curie-paris , paris, assistance publique-hopitaux de paris, ministère de la santé (centre de référence des maladies respiratoires rares), and comité de soutien de belleherbe. the authors would like to especially thank malika malhoul, delphine michon, alexandra blondel, aurore coulomb and hubert ducou le pointe for all of their effort towards the creation of the reference center for rare lung diseases. authors' contributions ac and nn contributed equally to this work and should be considered as joint first authors. ac, nn and hc drafted the review. re and bf have been involved in revising critically the review. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -xenq xj authors: chen, hsing i title: acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations date: - - journal: j geriatr cardiol doi: . /sp.j. . . sha: doc_id: cord_uid: xenq xj acute lung injury (ali) or acute respiratory distress syndrome (ards) can be associated with various disorders. recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ali or ards caused by various disorders. this literature review includes a brief historical retrospective of ali/ards, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of no, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ali/ards. acute lung injury (ali) or acute respiratory distress syndrome (ards) is a serious clinical problem with high mortality. [ ] in animals and humans, ali can be induced by various causes such as brain injury, [ ] [ ] [ ] [ ] enterovirus, [ , ] japanese b encephalitis, [ ] and coronavirus. [ , ] the risk factors for ards included septicemia, acid aspiration, infection, traumatic injury, fat embolism, ischemia/ reperfusion, and other caused. [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] our cardiopulmonary laboratory has carried out experimental studies and clinical investigations on ali and ards since . [ ] [ ] [ ] , , ] the purposes of this review article are: ( ) to describe in brief the historical perspective of ards and ali; ( ) to draw attention of an important clinical issue of neurogenic ali; ( ) to present the experimental studies and clinical investigations from our laboratory from to ; ( ) to elucidate the functional role of nitric oxide (no) and other mediators involved in the pathogenesis of ards/ali; ( ) to define the risk factors for ards and ali; and ( ) to discuss the pathogenetic mechanisms and therapeutic regimen for ards/ali. ali or pulmonary embolism (pe) has been reported in humans and animals with intracranial disorders such as head trauma, brain tumor, intracranial hypertension or cerebral compression. early studies in our laboratory demonstrated that acute pe of hemorrhagic and fulminant type occurred accompanying severe hypertension and bradycardia (cushing responses) in rats following cerebral compression (cc) or intracranial hypertension (ich). the lung pathology was characterized by intravascular congestion and disruption of pulmonary large and small vessels leading to severe alveolar hemorrhage (alveolar flooding). these changes was prevented by spinal transection, sympathectomy and sympathoadrenergic blocking agents, but was not affected by decerebration, adrenalectomy, vagotomy and atropine. these results suggest that sympathetic nervous system is pivotal in the neurogenic pe. brain areas above the medulla oblongata and parasympathetic nervous system play little role. [ ] a series of studies was carried out to elucidate the hemodynamic events involved in the neurogenic pe. in anesthetized rats, we measured the aortic and pulmonary blood flow and used techniques of right and left heart bypass. the imbalance in the right and left ventricular output was characterized by a rapid and dramatic decline in aortic flow accompanying a gradual decrease in pulmonary arterial flow. in rats with a right heart bypass, ich produced severe pulmonary hypertension and pe. in the left heart-bypassed rats, ich induced systemic hypertension, http://www.jgc .com; jgc@mail.sciencep.com | journal of geriatric cardiology whereas no significant changes occurred in the lungs. [ ] in anesthetized dogs with a total heart bypass preparation, ich produced constriction of the systemic and pulmonary resistance and capacitance vessels. [ ] [ ] [ ] [ ] the implications of these findings are: ( ) central sympathetic activation elicits increase in the systemic and pulmonary vascular resistance associated with decreases in vascular capacity in both circulations; ( ) the major cause of volume and pressure loading in the pulmonary circulation is acute left ventricular failure resulting in a marked decrease in aortic flow; and ( ) systemic venous constriction causes a shift of blood from the systemic to the pulmonary circulation ( figure ) . a schematic representation summarizes the neural and hemodynamic consequence caused by cerebral compression (figure ). spectral analysis of the aortic flow and pressure wave was employed to evaluate the hemodynamics of steady and pulsatile components. in anesthetized dogs, ich caused significant increases in characteristic impedance, pulse wave reflection and total peripheral resistance with decrease in arterial compliance and cardiac output. the ventricular work was elevated. [ ] clinical study in patients with head injury of various severities, analysis of the heart rate variability with frequency analysis revealed increased low frequency percentage, and low to high frequency ratio with decrease in high frequency. the findings indicate augmented sympathetic and attenuated parasympathetic drive. these autonomic functional changes were related to the severity of brain-stem damage. [ ] these two studies further support the contention that central sympathetic activation is involved in the cushing pressor response and consequent hemodynamic and autonomic alterations. in s, my associates and i were interested in the study of chest disorders. we developed an isolated perfused rat's lung in situ preparation ( figure ). previous method involved removing the isolated lungs from the body and placing the organ on a force-displacement transducer to record the changes in lung weight and these procedures were rather complicated and unstable. our in situ preparation does not require removing the lungs. instead, the isolated lungs were left in situ. the whole rat was placed in a scale platform to measure the change in body weight (bw). since the lungs are completely isolated from the body, the changes in bw reflect the lung weight (lw) changes. the preparation can be accomplished in min. we used a digital-analogue converter to transfer the weight change from the scale platform to a recorder. the lw thus could be continuously monitored during the experiment. in this model, we can obtain the lung weight gain, lw/bw ratio, the changes in pulmonary arterial, capillary and venous pressures, the microvascular permeability (capillary filtration coefficient, k fc ), protein concentration in bronchoalveolar lavage (pcbal), dye leakage, and exhaled nitric oxide (no). the concentration of nitrate/nitrite, methyl guanidine (an index for hydroxyl radical), proinflammatory cytokines [tumor necrosis factor α (tnf α ) and interleukin- β (il- β )] and other factors in the lung perfusate can also be detected. early animal experimentations investigated the pathogenesis, modulators and mediators involved in the ali induced by phorphol, air embolism, platelets, hypoxia, ischemia/reperfusion, endotoxin [lipopolysaccharide (lps)]. the major finding is that cyclooxygenase products of arachidonic acid, thromboxane a in particular is involved in the ali and pulmonary hypertension caused by phorbol, platelets and air embolism. [ , ] furthermore, we found that l-arginine and inhaled no enhanced the lung injury caused by air embolism, while blockade of no synthase (nos) with n ω -nitro-l-arginine methyl ester (l-name) attenuated the ali. [ ] the result suggests that no is also involved. during the summers from  , we encountered a total of children suffering from hand, foot, and mouth figure . isolated and perfused lung in situ preparation. the system consists of a perfusion pump with heat exchanger and a venous reservoir. the rat is artificially ventilated. pulmonary arterial pressure (pap) and venous pressure (pvp) are monitored with transducers. the whole rat is placed on a balance platform to record the body weight change. since the lung is isolated from the whole body, the change in body weight reflects the lung weight change. disease. [ ] chest radiography on admission revealed clear lung. however, out of cases developed severe dyspnea, hyperglycemia, leukocytosis, and decreased blood oxygen tension. arterial pressure (ap) and heart rate (hr) fluctuation ensued. spectral analysis of the ap and hr variabilities showed elevation in sympathetic activity at the onset of respiratory stress. thereafter, parasympathetic drive increased with declines in ap and hr. these children died within h after the onset of ards. before death, chest radiography revealed severe lung infiltration. similar to japanese b encephalitis, destruction of the medullary depressor area caused initial sympathetic activation. reversetranscriptase polymerase chain reaction (rt-pcr) found marked inos mrna expression in the lung parenchyma, suggesting inos may also be involved in the pathogenesis of ards in patients with enterovirus infection. furthermore, we have reported ards in patients with leptospirosis. [ ] in leptospirosis-induced ards, histochemical stain demonstrated spirochetes bacteria in the alveolar space. the pathology included alveolar hemorrhage, myocarditis, portal inflammation and interstitial nephritis. antigen retrieval immunohistochemical stain disclosed inos expression in the alveolar type cells, myocardium, hepatocytes and renal tubules. spectral analysis of ap and hr variabilities indicated decreased sympathetic drive with increased parasympathetic activity. the changes in autonomic functions led to severe hypotension and bradycardia. biochemical determinations suggested multiple organ damage. the pathogenesis of lung and other organ injury might also involve inos and no production. [ , ] in subjects with scrub typhus, orientia tsutsugamushi infection caused alveolar injury. marked inos expression was found in the alveolar macrophages with increase in plasma nitrate/nitrite, suggesting that no production from the alveolar macrophages accounts for the ali. [ ] the victim from rabies was a woman bitten by a wild dog. in addition to sign of hydrophobia, hypoxia, hypercapnia, hyperglycemia and increased plasma nitrate/nitrite were observed. the woman died of alveolar hemorrhage shortly after admission. [ ] recently, we encountered five cases with long-term malignancy. these subjects displayed signs of respiratory distress following an episode of hypercalcemia. two cases died of ards after the plasma calcium was increased above mmol/l. search of literatures revealed that holmes et al. [ ] reported a patient who died of ards following a hypercalcemia crisis caused by a parathyroid adenoma. we conducted animal experiments in whole rodent and isolated perfused rat's lungs. our results indicated that hypercalcemia (calcium concentration > mmol/l) caused severe ali in conscious rats and isolated lungs. immunohistochemical staining showed inos activity in the alveolar macrophages and epithelial cells. reversetranscriptase polymerase chain reaction (rt-pcr) found marked increase in inos mrna expression in lung parenchyma. hypercalcemia also increased nitrate/nitrite, methyl guanidine, proinflammatory cytokines and procalcitonin. pretreatment with calcitonin or l-n ( iminoethyl)-lysine (l-nil, an inos inhibitor) attenuated the hypercalcemia-induced changes. we proposed that hypercalcemia produced a sepsis-like syndrome. the ali caused by hypercalcemia may involve no and inos. [ , ] in addition to the aforementioned animal experimentations and clinical observations that no production through the inos may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (lps, endotoxin) provoked systemic hypotension, endothelial damage and ali accompanied by increased plasma nitrate/nitrite and expression of inos mrna, tnf α and il- β . the lps-induced changes were abolished by nonspecific and specific inos inhibitors such as n ω -monomethyl-l-arginine (l-nmma), l-name, aminoguanine and dexamethosone. [ ] this study suggested that no/inos, tnf α and il- β were involved in the endotoxemia-induced ali. generation of no from the activated neutrophil caused alveolar injury from smoke inhalation. [ ] experiments in many laboratories using specific inos inhibitors and/or inos-knockout animals have supported the contention that no/inos is responsible for the oxidative stress and endothelial damage in the ards/ali caused by endotoxin, ozone exposure, carrageenan treatment, hypoxia, acute hyperoxia, bleomaycin administration, acid aspiration and other causes. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] our laboratory further provided evidence to suggest that the no/inos system is involved in the pathogenesis of ali caused by air embolism, [ ] fat embolism, [ ] [ ] [ ] ischemia/ reperfusion, [ ] [ ] [ ] oleic acid [ ] and phorbol myristate acetate. [ ] in these recent studies, various insults caused increase in nitrate/nitrite in plasma or lung perfusate, upregulation of inos mrna in lung parenchyma accompanied with elevation of proinflammatory cytokines such as tnf α , il- β and il- . lin et al. [ ] have suggested that an increase in inos mrna triggers the release of proinflammatory cytokines in septic and conscious rats. the inflammatory responses results in multiple organ damage including ali. inhibition of inos with s-methylisothiourea (smt) or l-nil attenuated the inflammatory changes, release of no and cytokines and prevented the organ dysfunction and ali. [ ] in animal experiments and clinical investigations, the risk factors causing ali/ards include head injury, intracranial hypertension, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] sepsis, [ , , , , , , , [ ] [ ] [ ] [ ] and infections. [ ] [ ] [ ] [ ] [ ] [ ] , , [ ] [ ] [ ] ] pulmonary embolic disorders journal of geriatric cardiology | jgc@mail.sciencep.com; http://www.jgc .com such as fat and air embolism are less common causes. [ , , , , [ ] [ ] [ ] ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as pulmonary artery thromboendarterectomy, thrombolysis after pulmonary embolism and lung transplantation. [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] gastric aspiration occurs frequently in surgical patients under anesthesia and other causes such as blunt thoracic trauma, impaired glottis competency, and pregnancy. [ , , ] it is one of the major causes of acute respiratory syndrome (ards). [ , ] intratracheal instillation of hydrochloric acid (hci) or gastric particles has been employed as experimental model of acute lung injury (ali). [ , [ ] [ ] [ ] in addition, amphetamine, phorbal myristate acetate, oleic acid have been employed for the induction of ali. [ ] [ ] [ ] [ ] [ ] phorbol myristate acetate (pma, -o-tetradecanoyl-phorbol- -acetate), an ester derivative from croton oil has been used to induce ali. [ , , , ] experiments in vivo and in vitro have demonstrated that pma is a strong neutrophil activator. [ ] [ ] [ ] [ ] activation and recruitment of neutrophil that lead to release of neutrophil elastase and other mediators may play an initial role in the pathogenesis of ali. [ , ] the oleic acid-induced ali has several clinical implications. first, the blood level of oleic acid was significantly elevated in patients with ards. [ , ] second, the proportion of oleic acid incorporated into surfactant phospholipids was also increased in patients with ards and sepsis. [ , ] these observations have provided evidence to suggest that serum level of oleic acid as a prediction or prognostic factor for ards. [ , ] early studies focused on the potential toxic effects of high oxygen fractions on inspired air. [ ] ventilator-induced ali was attributed to the deleterious effects on capillary stress due to alveolar overdistension. cyclic opening and closing of atelectatic alveoli during mechanical ventilation might cause lung injury and enhance the injured alveoli. recent evidence indicated that over distension coupled with repeated collapse and reopening of alveoli initiated an inflammatory cascade of proinflammatory cytokines release. [ , [ ] [ ] [ ] in spite of the risk factors and causes, the pathophysiology of ards/ali has generally considered to be initiated by formation of alveolar edema (even hemorrhage) that is enriched with protein, inflammatory cells or red blood cells. after damage of alveolar-capillary barrier, impairment of gas exchange occurs, with decrease in lung compliance and increases in dispersion of ventilation and perfusion and intrapulmonary shunt. hypoxia, reduction in arterial oxygen partial pressure to fraction of oxygen in inspired air pao /fio , hypercapnia ensued despite ventilation with high oxygen. [ , , , , , ] in addition to the potential toxic effects of no and free radicals, certain chemokines, cytokines, neutrophil elastase, myeloperoxidase and malondialdehyde have been shown to be associated with several types of ards/ali. [ , , , , [ ] [ ] [ ] the balance between proinflammatory and anti-inflammatory mediators is regulated by transcriptional factors mainly nuclear factor-Κ b (nf-Κ b). [ ] pulmonary fluid clearance and ion transport are important factors to determine the extent of lung edema. regulator factors include cystic fibrosis transmembrane conductance regulators, sodium-and potassium-activated adenosine triphophatase (na + -k + -atpase), protein kinases, aclenylate cyclase, and cyclic adenosine monophosphate (camp). [ , , , ] the treatment of ards/ali is difficult and complex. several review articles and monographs have addressed the issue of possible therapeutic regimen. the modalities include extracorporeal membrane oxygenation, prone position, mechanical ventilation with appropriate tidal volume and respiratory pressure, fluid and hemodynamic management and permissive hypercapnic acidosis. [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] other pharmacological treatments are anti-inflammatory and/or antimicrobial agents to control infection and to abrogate sepsis, adequate nutrition, surfactant therapy, inhalation of no and other vasodilators, glucocorticoids and other nonsteroid anti-inflammatory drugs, agents that accelerate lung water resolution and ion transports. [ , , [ ] [ ] [ ] [ ] [ ] although most animal experimentations on these pharmacological options showed favorable results, the effectiveness and outcomes in clinical studies or trials were conflicting. beta agonists to facilitate water removal and ion transport have been shown to be promising. these agents may also stimulate secretion of surfactant and have no serious side effects. there were several reports on the pharmacological and molecular actions of beta agonists, surfactant and vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme (ace). [ , , ] in addition to the experimental studies and clinical investigations on the pathogenesis of ali/ards, our laboratory has carried out several experimentations on the therapeutic regimen for this serious disorder. in conscious rats, regular exercise training attenuates septic responses such as systemic hypotension, increases in plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, creatinine, amylase, lipase, asparate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactic dehydrogenase, tnf α, and il β . exercise training also abrogates the cardiac, hepatic and pulmonary injuries caused by endotoxemia. [ ] insulin exerts anti-inflammatory effects on the ali and associated biochemical changes following intravenous administration of lipopolysaccharide (lps). [ ] propofol ( , -diisopropylphenol) has been commonly used for sedation in critically ill patients. [ ] this anesthetic has rapid onset, short duration and rapid elimination. [ ] propofol protects the anesthetized rats from ali caused by endotoxin. [ ] in conscious rats, oleic acid results in sepsis-like responses including ali, inflammatory reactions and increased in neutrophil-derived factors (neutrophil elastase, myeloperoxidase and malondialdehyde), nitrate/nitrite, methyl guanidine, inflammatory cytokines. it depresses the sodium-and potassium-activated atpase, but upregulates the inos mrna expression. pretreatment and posttreatment with propofol alleviates or reverses the oleic acid-induced lung pathology and associated biochemical changes. [ ] pentobarbital, an anesthetic agent commonly used in experimental studies and a hypnotic for patients improves the pulmonary and other organ functions following lps administration. it also increases the survival rate. [ ] a later study by yang et al. [ ] further revealed that pentobarbital suppressed the expression of tumor necrosis factor α , which might result from decrease in the activities of nuclear factor-κβ and activator protein and reduction in expression of p mitogen-activated protein kinase. in vivo examination of cytotoxic effects of lps disclosed that lps caused multiple organ dysfunctions. these changes were attenuated by pentobarbital. pentobarbital also reduced the cell aptosis caused by deforoxamine-induced hypoxia. nicotinamide or niacinamide (compound of soluble b complex) abrogates the ali caused by ischemic/reperfusion or endotoxin by mechanism through inhibition on poly (adp-ribose) synthase or permerase cytoxic enzyme and subsequent suppression of inos, no, free radicals and proinflammatory cytokines with restoration of adenosine triphosphate atp. [ , ] n-acetylcysteine, an antioxidant and cytoprotective agent with scavenging action on reactive oxygen species and inhibitory effects on proinflammatory cytokines ameliorated organ dysfunctions due to sepsis in conscious rats. [ , ] in a similar endotoxin-induced ali model, we found that n-acetylcysteine improved the lps-induced systemic hypotension and leukocytopenia. it also reduced the extent of ali, as evidenced by reductions in lung weight changes, exhaled no and lung pathology. in addition, n-acetylcysteine diminished the lps-induced increases in nitrate/nitrite, tnf α , and il β [ ] in isolated lungs, n-acetylcysteine attenuated the ali caused by phorbol myristate acetate. [ ] in a recent study, we reported that posttreatment with n-acetylcysteine prevented the ali caused by fat embolism. [ ] our series of experimental studies provided results in favor of n-acetylcysteine. the conflicting results and practice guidelines from clinical studies in the recommendation of n-acetylcysteine in critically ill patients [ , ] were commented and analyzed by molnár. [ ] the clinical application of results from animal studies requires further investigations. ards or ali is a serious clinical problem with high mortality. the risk factors leading to ali/ards include head injury, intracranial disorders, sepsis and infections. pulmonary embolic disorders such as fat and air embolism are less common causes. ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as lung transplantation. gastric aspiration occurs frequently in several conditions such as anesthesia, trauma and pregnancy. the ventilator-induced ali has been attributed to the deleterious effects on capillary stress due to alveolar overdistension. in experimental studies, phorbol myristate acetate and oleic acid have been employed to induce ali. the pathogenesis of ards/ali is complex. experimental studies and clinical investigations from our and other laboratories have indicated the detrimental role of nitric no through inducible no synthase (inos). activation and recruitment of neutrophils that lead to release of neutrophil elastase, myeloperoxidase, malondialdehyde and proinflammatory cytokines may play an initial role in the pathogenesis of ali/ards. the possible therapeutic regimen for ali/ards include extracorporeal membrane oxygenation, prone position, fluid and hemodynamic management and permissive hypercapnic acidosis etc. other pharmacological treatments are antiinflammatory and/or antimicrobial agents, inhalation of no, glucocorticoids, surfactant therapy and agents that facilitate lung water resolution and ion transports. adrenergic beta agonists are able to accelerate lung fluid and ion removal and to stimulate surfactant secretion. there are reports on the actions of vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme. our laboratory has reported experimental studies on the effectiveness of several regimen for ali/ards. in conscious rats, regular exercise training 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response syndrome n-acetylcysteine as the magic bullet: too good to be true experimental studies and clinical investigations were supported in part by grants from the "national science council". the grant no. this fiscal year is nsc - -b- - -my . the author is grateful to ms. s. y. huang for the assistance in typing an editing. i appreciate the long-term coworkers involved this and other studies in my laboratory. key: cord- -tcobane authors: bartels, matthew n.; prince, david z. title: acute medical conditions: cardiopulmonary disease, medical frailty, and renal failure date: - - journal: braddom's physical medicine and rehabilitation doi: . /b - - - - . - sha: doc_id: cord_uid: tcobane cardiopulmonary rehabilitation includes essential interventions that help patients maximize functional potential due to progressive deconditioning or acute decompensation following an acute medical event. the population of patients who benefit from both cardiac and pulmonary rehabilitation is increasing as the population ages and heart disease remains a leading cause of global morbidity and mortality. the principles of exercise physiology when applied to this population can reverse deconditioning, build cardiopulmonary reserve, and ultimately reduce morbidity and mortality in these populations. the physically disabled also benefit from exercise conditioning. the model of cardiac rehabilitation can also be applied to improve functional status of stroke patients, and this is an emerging area of interest supported by the shared pathophysiology and risk factors of cardiovascular conditions. the benefits of supervised exercise can also be extended to patients with clinically recognized frailty and post-transplant decline in function. frailty is a complex diagnosis with multiple tools and approaches used to describe this syndrome. medical rehabilitation medicine needs to encompass the needs of patients with cardiopulmonary disorders as well as patients with debility and renal dysfunction. there are ever greater numbers of patients who are now presenting with these issues, especially as the population ages. cardiac disease is still the number one cause of mortality and disability in the united states, with chronic obstructive pulmonary disease (copd) currently being the third leading cause of mortality. even if it is not primary rehabilitation for patients with these diseases, many patients with other disabilities will have cardiac, pulmonary, and renal disabilities, and a common theme among all of these conditions is a degree of frailty. this issue of frailty underlies a great number of the common features of disability in these underlying conditions and will be discussed in the section on frailty, later. key areas that will be addressed include sarcopenia, acute and chronic deconditioning, and the role of exercise as medicine to improve patients with all of these conditions. important contributors to the prevalence of all of these conditions are the aging of the population and the effects of combinations of these conditions on the ability to rehabilitate patients. the overall approaches to exercise treatment in these patients will be discussed as well as how to approach these conditions in the acute, rehabilitation, and outpatient settings. it must be remembered that there are two types of cardiopulmonary patients, those with primary cardiac and pulmonary disease who need cardiac/pulmonary rehabilitation and those patients with other disabilities who have a cardiac or pulmonary secondary disability. patients with respiratory failure and patients who have need for ventilatory support are also in this group but are beyond the scope of this chapter. dual disability patients are more prevalent than ever in rehabilitation because more patients are currently older and have multiple comorbidities. many patients with stroke, vascular disease, or other conditions can be included in active cardiac and pulmonary rehabilitation programs or benefit from the application of cardiopulmonary rehabilitation principles to their rehabilitation. remember also that cardiopulmonary rehabilitation is one of the most underused yet most effective treatments for patients with cardiopulmonary disease. because we work with frail older adults and other compromised populations, it is important for rehabilitation specialists to know how to provide cardiopulmonary rehabilitation in patients with either primary or secondary cardiopulmonary disability. to use cardiac and pulmonary rehabilitation principles for patients with cardiopulmonary disease, whether it is a primary or secondary disability, it is necessary to review some of the basic principles of cardiac and pulmonary physiology and learn how to apply these principles to improve the exercise capacity of these patients. it is also essential to have an understanding of normal exercise physiology to appreciate the issues of patients with abnormal cardiopulmonary physiology. a complete cardiopulmonary history and physical examination are essential parts of the evaluation of patients with cardiopulmonary disease who participate in rehabilitation. key parts of the history include both verbal and nonverbal cues and will allow the establishment of goals and improve patient compliance with the treatment program. the history should include emotional state, concurrent illnesses, other disabilities, functional history, occupational history, social history, personal habits, family dynamics, and the effect of disability and cardiopulmonary illness on the patient in the community. both rest and activity symptoms are reviewed with particular emphasis on the following. dyspnea. shortness of breath is usually the prime complaint for patients with cardiopulmonary disease. the history of dyspnea helps to differentiate the role of cardiac or pulmonary disease in the patient's symptoms. cardiac dyspnea can be from ischemic heart disease, congestive heart failure, valvular heart disease, and arrhythmias. pulmonary dyspnea can come from pulmonary vascular disease, restrictive lung disease, and obstructive lung disease. in some patients both cardiac and pulmonary issues may be present, and in all cases physical conditioning needs to be assessed. because psychological factors are also important, patients also should be screened for anxiety and depression. finally, an assessment for hypoxemia should be done. see table . for a list of common causes of dyspnea. chest pain. chest pain and tightness is not only a mark of coronary insufficiency but can also be seen with valvular heart disease or arrhythmia. assessing the duration, quality, provocation, location of the pain, and any ameliorating factors can help to assess functional limitations and help to design the appropriate therapy program. in addition, lung conditions can cause chest pressure in both obstructive and restrictive lung disease and is very common in pulmonary vascular disease. palpitations. symptoms of palpitations can be indicative of serious arrhythmias. syncope. cardiac syncope is usually abrupt with no warning or only a brief warning (with the patient feeling as if he or she were about to pass out) and can be caused by aortic stenosis, idiopathic hypertrophic subaortic stenosis, primary pulmonary hypertension, hypercarbia, hypoxemia, ventricular arrhythmias, reentrant arrhythmias, high-degree atrioventricular block, or sick sinus syndrome. pulmonary syncope is often gradual in onset and can be caused by hypercarbia, hypoxemia, or pulmonary vascular disease. orthostatic syncope can be caused by autonomic dysfunction, neurologic disease, vagal stimuli, or psychological stimuli. edema. peripheral edema may be an indication of heart failure and may indicate the onset of right ventricular failure in pulmonary vascular disease. fatigue. fatigue is likely to be the most common complaint in cardiopulmonary disease and may be worsened by the presence of depression, physical exhaustion, medication side effects, and deconditioning. cough. cough can be from both cardiac and pulmonary diseases. "cardiac" cough is often nocturnal and postural, with little to no sputum production and relieved by assuming an upright position. cough is common in both restrictive and interstitial lung disease, with or without sputum production. a description of the complete and detailed physical examination of the patient with cardiopulmonary disease is beyond the scope of this chapter (see chapter ) . still, some important elements of the examination include a general survey of the patient for exophthalmos (possible thyrotoxicosis), xanthelasma (hypercholesterolemia), acrocyanosis (chronic hypoxemia), clubbing (chronic hypoxemia), ankylosis (aortic valve disease and conduction defects), down syndrome (cardiac abnormalities), myasthenia gravis, or neuromuscular disease (cardiomyopathy, conduction disease, and ventilatory failure). a good cardiopulmonary examination and history can help to prevent complications in a cardiopulmonary rehabilitation site of pathology pathophysiology program and should be done as a part of the physiatrist's initial history and physical examination. a few key cardiopulmonary examination findings are highlighted here. cardiac auscultation can indicate an atrial septal defect, a midsystolic click may indicate mitral valve prolapse, and a murmur may indicate valvular heart disease. pulmonary hypertension typically produces a heightened second heart sound, a noncompliant ventricle can be detected via an atrial gallop at the cardiac apex, and a left ventricular gallop may reveal heart failure. the pulse contour, split heart sounds, and the quality of the murmur can help to differentiate aortic sclerosis from aortic stenosis. in younger patients, pulmonary stenosis or valvular heart disease needs to be differentiated from idiopathic hypertrophic subaortic stenosis. diastolic murmurs may be mitral stenosis or pulmonary hypertension with pulmonary valve regurgitation, and continuous murmurs may be from ventricular septal or atrial septal defects. new findings or changes in findings are important as they may indicate the need for further evaluation or alterations in the program of cardiopulmonary rehabilitation. lung physical examination may have decreased breath sounds and/or barrel chest in obstructive disease, whereas interstitial lung disease may have diffuse or basilar crackles. inspiratory stridor may indicate upper airway obstruction, whereas expiratory wheezing and rhonchi can be seen with obstruction or secretions. it is also important to assess symmetry of breathing, accessory muscle use, and possible compromise to diaphragmatic function. to supervise cardiac rehabilitation, it is essential to be familiar with the normal distribution of the major arteries of the heart, the anatomy of the heart valves, and the distribution of ischemia or infarction from the coronary arteries. the heart has paired atria and ventricles, with deoxygenated venous blood entering the right atrium, traversing the right ventricle through the tricuspid valve, and entering the pulmonary artery through the pulmonic valve. oxygenated blood enters the left atrium, goes to the left ventricle through the mitral valve, and is ejected into the aorta through the aortic valve. the cardiac valves ensure unidirectional unobstructed flow of blood, with atrial contraction adding up to % to % to the total cardiac output (co). atrial contribution to blood flow is greater with increased heart rate and in conditions with decreased ventricular compliance. atrial fibrillation can cause a loss of this atrial "kick" and may contribute to cardiac dysfunction. the cardiac conduction system allows coordinated contraction of the atria and ventricles at a controlled rate. the normal heartbeat is initiated at the sinoatrial node and then travels through three atrial internodal pathways to the atrioventricular node, where conduction is delayed to cause sequential atrial and ventricular contraction. below the atrioventricular node, the signal passes into the bundle of his and divides into left and right bundles. all cardiac fibers then end in terminal branches, which excite the myocytes and cause contraction. the conduction system can be injured by myocardial infarction (mi), aging, and other conditions and can cause heart block or sick sinus syndrome. accessory pathways that bypass the atrioventricular node can be seen in wolff-parkinson-white syndrome. there are three main distributions of coronary circulation. normally the left main coronary artery divides into the left anterior descending and the circumflex arteries, whereas the right coronary artery continues on as a single vessel. right dominant circulation is seen in % of individuals, whereas left dominant circulation with the posterior descending artery arising from the left circumflex is seen in % to % of individuals. the remaining % of individuals have balanced circulation with the posterior descending artery coming from the left circumflex and right coronary arteries. cardiac myocytes extract nearly % of oxygen from the blood at all levels of activity (compared with % for brain and % for the rest of the body). cardiac myocytes prefer carbohydrates as an energy source ( %), with fatty acids making up most of the remaining %. with high oxygen extraction and coronary blood flow only during diastole, the heart is at high risk of ischemic injury, especially in the endocardium. coronary vasodilation with exercise is normally done via nitric oxide-mediated pathways and increases blood flow with exertion. the goal of most medical and surgical therapies for ischemia is to restore or preserve myocardial perfusion through vasodilation, bypass, or endovascular procedures. exercise can increase cardiac collateral circulation and improve arteriolar vasodilation and has long been known to be a primary therapy for cardiac ischemia. , , , another important issue to manage with patients with cardiac disease is fluid volume. appropriate venous return can maintain appropriate cardiac "preload," whereas fluid overload can lead to too much venous return and exacerbate heart failure. in cases of mechanical cardiac constriction, surgery can restore co, and in dilated heart failure, medical treatment aims to decrease the size of the ventricles to increase co. in refractory or end-stage disease, left ventricular assist devices (lvads) and cardiac transplantation are options. important pulmonary anatomy includes the upper and lower airways (the oropharynx, larynx, trachea, main stem bronchi, and smaller bronchi), the lung parenchyma, the chest wall, and musculature (diaphragm, accessory muscles of breathing, rib cage, and pleura). pulmonary limitations can come from abnormalities in any of these structures. the lungs also have a dual circulation with pulmonary arteries and veins, which deliver deoxygenated blood to the lungs and deliver oxygenated blood to the left atrium and intrinsic pulmonary artery circulation delivering oxygenated blood to the respiratory tree. stridor can result from upper airway obstruction from vocal cord paralysis or tumor, whereas asthma, bronchitis, or reactive airway disease may cause dyspnea from lower airway obstruction. emphysema is a result of parenchymal lung disease with a loss of alveoli leading to decreased intrinsic recoil of the lung and subsequent hyperinflation and dyspnea. in interstitial lung disease and pulmonary fibrosis, there is interstitial scarring with increased recoil and decreased ability to diffuse oxygen through the lung tissues. in some patients, both restrictive and obstructive diseases can be present with one predominant over another (cystic fibrosis and sarcoidosis). in these cases, it is important to evaluate the lung parenchyma with imaging or physiologic testing (pulmonary function tests) to assess which condition may predominate. normal breathing is regulated in the medulla oblongata by the respiratory center. respiratory signals are carried by the phrenic and other somatic nerves to the diaphragm and secondary inspiratory muscles (intercostals, sternocleidomastoids, and pectorals) and cause rhythmic breathing by generating negative pressure in the chest wall. normal exhalation is passive, resulting from the elastic recoil of the chest wall and the lung parenchyma. copd and emphysema can create the need for active exhalation, markedly increasing the work of breathing. interstitial lung disease with scarring decreases compliance of lung tissue so severely that lung volumes decrease and hypoventilation can result. any disease affecting the brain, spine, phrenic nerves, respiratory muscles, or changing the mechanical properties of the chest wall or diaphragm can affect normal respiration. , pulmonary vascular disease can result in either primary or secondary pulmonary hypertension. primary pulmonary hypertension can be idiopathic or can result from vasculitis, thromboembolic disease, or intrinsic parenchymal disease. secondary pulmonary hypertension is from vascular congestion, often a result of left heart failure. secondary pulmonary hypertension can lead to intrinsic vascular compromise if the condition is chronic. chronic hypoxemia may also create pulmonary hypertension in individuals with obesity, obstructive sleep apnea, or high-altitude exposure through a mechanism of pulmonary vascular constriction. chronic hypoxemia can lead to vascular intimal hypertrophy with resultant fixed pulmonary vascular resistance and pulmonary hypertension. aerobic capacity (vo max ) is the measure of the work capacity of an individual and is expressed as the oxygen consumed by the individual (liters of oxygen per minute or milliliters of oxygen per kilogram per minute). oxygen consumption (vo ) increases linearly with workload, up to the vo max , where it reaches a plateau. maximal exercise capacity assessment can assist in rating disability and planning exercise and recovery programs. heart rate is a useful guide for exercise as a result of having a linear relationship to vo . maximum heart rate is best determined by testing and decreases with age. it can be estimated either by the karvonen equation or by the equation heart rate = − age. physical conditioning can alter the slope of the relationship of heart rate and vo with improved conditioning lowering the slope (less heart rate increase for a given vo ). a limitation to using heart rate can be the alteration of heart rate response in the setting of medications that alter vagal and sympathetic tone. stroke volume (sv) is the volume of blood ejected with a left ventricular contraction. maximal sv can be increased with exercise and is sensitive to postural changes (least increases in supine), with the greatest increase during early exercise. normally sv increases in a curvilinear manner, achieving maximum at approximately % of vo max . sv declines with advancing age, with decreased cardiac compliance, after mi, and in heart failure. co is the product of the heart rate and sv. it has a linear relationship with work and is the primary determinant of vo max . at maximum exercise, left ventricular ejection fraction (lvef), and thus co, is greater in the upright position compared with the supine position. , myocardial oxygen consumption (mvo ) is the vo of the heart muscle increasing in proportion to workload. when the mvo exceeds the maximum coronary artery oxygen delivery, an individual will have myocardial ischemia and angina. the rate pressure product (rpp) = [heart rate × systolic blood pressure (sbp)]/ and has a direct relationship to the mvo . another consideration is that arm exercise, isometric exercise, and exertion in the cold, extreme heat, after eating, and after smoking all have a higher mvo for a given mvo . supine exercises have a higher mvo at low intensity and a lower mvo at high intensity compared with erect exercises. basic static lung volumes and dynamic responses to exercise are helpful in the assessment of exercise capacity in individuals with lung disease. although complete pulmonary function evaluation is beyond the scope of this chapter, some important values include: total lung capacity (tlc): volume of air in the lungs at full inspiration vital capacity (vc): volume of air between full inspiration and full expiration the best evaluation of the capacity to exercise in cardiac and pulmonary conditions is with a cardiopulmonary exercise test (cpet). the cpet yields diagnostic, prognostic, and exercise prescription guidance in patients with cardiopulmonary disease. the interpretation of pulmonary exercise testing in a number of conditions is shown in table . . physical exercise that increases the cardiopulmonary capacity (vo max ) allows for aerobic training. all aerobic training prescriptions must include four components: intensity, duration, frequency, and specificity. intensity. how hard an exercise is. it can be prescribed by a target heart rate, metabolic (met) level, or intensity (wattage). usual intensity target for cardiac primary prevention is a heart rate of % to % of the predicted maximum heart rate/peak heart rate from the exercise tolerance test (ett). for secondary prevention in patients with known cardiopulmonary disease, exercise should be at a safe level at % or more of the maximum heart rate to achieve a training effect. duration. how long a given bout of exercise is. usual cardiopulmonary conditioning requires -to -minute sessions and should have a -to -minute warm-up and cool-down period. the lower the intensity of an exercise, the longer the duration will need to be to achieve a similar training effect. frequency. how often exercise is performed over a fixed time period (usually a week). moderate-intensity training programs should be done at least three times per week, and low-intensity programs should be done five times per week. specificity. the activity to be done in exercise. training benefits are specifically related to the activities performed. thus elliptical exercise is not as beneficial for walking as treadmill training. specificity in prescription should be altered to adapt to the needs of each patient. for a patient with spinal cord injury, upper arm ergometry would be more functional, and for a patient with severe leg arthritis, cycle ergometry would be better than a treadmill. the law of specificity of conditioning should be remembered when designing a cardiopulmonary conditioning program. the benefits of aerobic training include the following: aerobic capacity: maximum capacity increases with training. resting vo is stable as is the vo at a given workload. the changes are specific to the trained muscles. cardiac output: maximum co increases, whereas resting co is stable. resting sv increases with a corresponding decrease in resting heart rate. heart rate: heart rate is lower at rest and at any given workload, whereas maximum heart rate is unchanged. the lower heart rate at rest and submaximal exercise causes a lower mvo with normal activity. stroke volume: sv increases at rest and at all levels of exercise. co is thus maintained at a lower heart rate and causes a lower rpp for a given level of exertion. myocardial oxygen capacity: after training, maximum mvo does not usually change but is less at a given workload. this reduces episodes of angina and increases safety for moderate activity. mvo can also increase after pharmacologic treatments or revascularization procedures. peripheral resistance: exercise training decreases peripheral vascular resistance (pvr) by reducing "afterload" through lowering arterial and arteriolar tone. the reduction in pvr results in a lower rpp and a lower mvo at a given workload and at rest. minute ventilation: with improved conditioning, individuals will require a lower vo and thus a lower minute ventilation for a given activity. for patients with pulmonary and cardiac disease, this can lead to a large reduction in dyspnea. tidal volume: exercise can lead to a higher tv on exertion, with a subsequent decrease in respiratory rate and decreased dyspnea. respiratory rate: as tv is improved, respiratory rate will be lower for a given minute ventilation, decreasing dyspnea. the application of basic physiologic principles to the design of cardiopulmonary rehabilitation programs can improve function, decrease symptoms, and improve outcomes for patients with cardiopulmonary disease. the prime effect of cardiac conditioning is in reduction of cardiac risk and improved cardiac conditioning. reduction of cardiac risk has been well established since , when pooled data from randomized studies of exercise in patients following acute mi demonstrated a % to % reduction in all-cause mortality, fatal mi, and cardiac mortality in a -year follow-up study. these benefits of cardiac rehabilitation apply across populations, including older adults, women, and patients after bypass. similar benefits have also been shown for pulmonary rehabilitation in copd with decreased hospitalizations, improved function, and improved quality of life, , , , and new studies are showing that interstitial disease and pulmonary vascular disease can also benefit from exercise. , , , , pulmonary rehabilitation patients with pulmonary disease demonstrate three main impairments: ( ) obstructive lung disease, ( ) restrictive lung disease, and ( ) pulmonary vascular disease. often more than one type of limitation may be present in a given patient and will increase the complexity of their condition. understanding the underlying physiology can assist in the design of a specific exercise program for an individual patient. for primary pulmonary disease, it is essential to know if the patient has primarily an obstructive or restrictive condition. obstructive lung disease is marked by an inability to exhale resulting from either upper airway or large airway disease (sleep apnea, tracheomalacia, vocal cord disease, asthma, and bronchitis) or as a result of lower airway disease from either secretions or lung parenchymal disease (emphysema and bronchiectasis). obstruction can also be exacerbated by a component of acute obstruction (asthma) combined with a chronic condition (copd). the hallmark of severe copd is carbon dioxide retention and active exhalation. medical treatments are limited for copd, with steroids and bronchodilators offering incomplete relief. lung reduction surgery is appropriate only in selected individuals, and transplant is only for end-stage disease. for all levels of obstructive disease, pulmonary rehabilitation is appropriate, and in the "gold" recommendations for treatment of copd, pulmonary rehabilitation is recommended for all patients with moderate to severe disease. , in restrictive lung disease, the primary limitations are low tvs from an inability to expand the chest wall (extrinsic restriction) or from very noncompliant lung tissue (intrinsic restriction). in extrinsic restrictive disease (neuromuscular disease, paralysis, and kyphoscoliosis), the parenchyma of the lung is normal and gas exchange is preserved, meaning that treatment is usually respiratory muscle training and mechanical ventilatory support as needed. with intrinsic restrictive lung diseases (pulmonary fibrosis, sarcoidosis, etc.), there may be a profound associated hypoxemia from severely decreased diffusion capacity of scarred lung tissue. patients with parenchymal restrictive disease classically have severe hypoxemia and may need highflow supplemental oxygen. patients with end-stage intrinsic restrictive disease can have ventilatory failure with hypercarbia and hypoxemia and may be refractory to ventilatory support, and lung transplantation is then often the only remaining treatment option. table . shows some of the lung pathologies and effects on inspiratory reserve and rv (obstructive diseases) and the effects of various conditions on lung compliance (restrictive diseases). finally, patients with pulmonary vascular disease have a similar presentation in many ways to patients with heart failure, and in the end stages of the disease, right ventricular heart failure is a major part of the condition and leads to excess mortality and morbidity. rehabilitation is focused on a program that resembles exercise for patients with heart failure, with the addition of close monitoring of oxygen saturation and the use of appropriate levels of supplemental oxygen to prevent hypoxemia. for patients with either intrinsic restrictive or obstructive disease, pulmonary rehabilitation is an important treatment to consider and should be offered for patients whether or not they have their pulmonary condition as a primary or a secondary disability. a brief overview of pulmonary rehabilitation programs for primary pulmonary disease is shown in table . . an understanding of abnormal cardiac physiology in disease is necessary for appropriate cardiac rehabilitation. in general, cardiac limitation is caused by either decreased co, or ischemic disease, or a combination of these. ischemia causes the myocardium to have lower contractility and lower compliance reducing sv. valvular heart disease lowers maximum co through stenotic valves (e.g., aortic or mitral stenosis) or valvular regurgitation (e.g., aortic or mitral insufficiency). finally, heart failure is a state of low co, often as a result of low sv, and is associated with a reduction of vo max , increased resting heart rate, and often a greater mvo for a given vo . arrhythmias decrease co by lowering sv and increasing heart rates. for atrial arrhythmias, the mechanism can be by a loss of atrial ventricular filling (atrial "kick") during atrial fibrillation or supraventricular tachycardias, or from high heart rates without atrial coordination as in ventricular tachycardias and ventricular bigeminy. surgical treatments for heart disease either restore coronary circulation (e.g., bypass and intravascular procedures) or restore normal anatomy (e.g., valve replacement). surgical treatment for heart failure can include lvads or transplantation. , medical treatment for heart disease either aims to improve coronary circulation for ischemia or works to improve blood flow and restore co for heart failure by lowering afterload, reducing fluid overload, and increasing inotropy. although medical treatment of ventricular arrhythmias has been limited, implantable defibrillators and pacemakers have been very successful. severe end-stage heart disease of all types may require cardiac transplantation or an lvad. in all of these conditions and treatments, cardiac rehabilitation has an important role to play. some basic concepts to remember include that patients before transplantation are similar to patients with heart failure, whereas patients after transplantation have several physiologic changes that are unique, including high resting heart rate, limited increase in sv, and peak heart rate with exercise. the basic principles of cardiac rehabilitation are discussed as follows. cardiac rehabilitation is either primary prevention, which includes risk factor modification and education before a cardiac event, or secondary prevention, which is cardiac rehabilitation after the onset of cardiac disease including both exercise and risk factor modification. primary prevention is usually performed in primary care settings rather than a rehabilitation setting. the focus is on the reduction of cardiac risk factors with a combination of education and exercise for patients in the community. primary prevention can have a profound effect on the rate of cardiac disease with a decrease in obesity, blood pressure, and lipid profiles. , , ideally, behavior modification should begin in childhood with the establishment of healthy behavior and then maintained throughout life. because populations who are disabled are generally sedentary and may have other risk factors, primary prevention should be an important component of the care of the disabled and should include management of hypertension and lipids along with encouraging exercise and consideration of antiplatelet agents. these are all cost-effective approaches and can decrease mortality and morbidity on a population-based scale, in addition to the individual benefits. , , after an episode of cardiac disease, it is essential to have secondary risk factor modification, which includes all of the features of primary prevention programs discussed earlier. in addition, disease-specific education and formal exercise is a part of the secondary prevention program. in both cardiac and pulmonary disease, smoking cessation is crucial as part of both primary and secondary prevention programs. , , rehabilitation programs for patients with pulmonary disease are similar to cardiac rehabilitation programs. after severe acute exacerbations, some patients can benefit from a short acute inpatient rehabilitation, but the majority of pulmonary rehabilitation is done in an outpatient setting. for patients who are in an intensive care setting, early mobilization programs are now being used to limit debility in these vulnerable patients. , , outpatient pulmonary rehabilitation programs also have primary prevention for pulmonary disease with smoking prevention and cessation, occupational safety, and prevention of exposure to environmental and infectious agents. secondary pulmonary prevention involves medication adherence and education, smoking cessation, supplemental oxygen use and education, and environmental modification for known environmental triggers. , for patients with ventilatory failure that cannot be supported with noninvasive ventilation, lung transplant may become necessary. rehabilitation before transplantation is focused on both the underlying condition and transplant-specific education, whereas rehabilitation after transplantation includes education and restoration of muscle strength, which is impaired from the medical regimen for patients after transplantation. the standard model for cardiac rehabilitation after mi was first described by wenger et al. in . because revascularization is currently common and infarcts are smaller than in the past, there loss of inspiratory reserve have been modifications to the classical program with a reduction to three phases, eliminating the classical stage recovery phase. a modern acute phase mobilization program is illustrated in table . . the exception to bypassing the recovery phase for cardiac rehabilitation comes for surgical patients with sternotomy who may require recovery from their surgery before starting the training phase of rehabilitation. in summary, phase rehabilitation is the acute phase in hospital immediately following a cardiac event and ends at discharge. phase is an outpatient training phase, with secondary prevention, intense education, and aerobic conditioning. phase is the most difficult, the maintenance phase in which patients seek to achieve continued aerobic exercise and maintenance of lifestyle modifications. risk factor modification is performed at all phases. this model is similar for patients with pulmonary disease. for patients with cardiopulmonary disease who are not hospitalized, the goal is essentially phase and phase for all patients at the time of diagnosis. a more detailed description of each of the phases follows. the basics of the phase program are illustrated in table . . education about cardiopulmonary risk factor modification is introduced at the time of acute hospitalization. for patients with cardiac disease, all acute mobilizations should be done with cardiac monitoring with appropriate supervision by trained therapists or nurses. a post-mi heart rate increase with activity should be kept to within beats/min of baseline and sbp kept within mm hg of baseline. a decrease of mm hg or more is indicative of further medical issues, and exercise should be halted. the target intensity at the end of the phase i program exercise is to a level of four mets, covering most of the daily activities patients may perform at home after discharge. for patients with pulmonary disease, similar phase goals exist and there is new emphasis on early mobilization in the intensive care unit (icu) to prevent frailty and deconditioning. patients are aggressively mobilized, some while still on the ventilator. innovations, including extracorporeal membrane oxygenation, are also now allowing more aggressive mobilization of patients because sedation is less, and patients may maintain better nutritional status. these patients with pulmonary disease should be enrolled in outpatient pulmonary programs to maintain their early gains and complete a full program of education and exercise. to distinguish between patients who have a rapid recovery after their cardiopulmonary event (pure phase ) and those patients who require either acute or subacute rehabilitation treatment before discharge home, the designation of phase b rehabilitation has been established. with advanced age or substantial comorbidities or other disabilities that make mobilization more difficult, many rehabilitation specialists will care for these patients in phase b. the guidelines for exercise are the same as they are for patients in phase but with a longer recovery period extending their hospitalized care to an acute or subacute rehabilitation setting before discharge. classically, phase cardiopulmonary rehabilitation starts after a symptom limited full-level ett for patients with cardiac disease or a cpet for patients with complex pulmonary disease. this allows for setting target heart rates and target exercise intensity from the exercise. a target heart rate of % of the maximum heart rate on an ett or a cpet is generally regarded as safe for patients at low risk. exercise intensity targets are lower for patients at higher risk or those with underlying conditions. in patients with life-threatening arrhythmias or chest pain, target heart rates are chosen that are below notable end points. because hypoxemia can add risk and limits participation with exercise, it is important to provide supplemental oxygen as needed (up to a rate of l/ min as needed) to maintain saturation greater than % for safe exercise. a target heart rate of % to % of maximum is safe and effective in a regular exercise program for patients at higher risk and, with target rates as low as %, still provides a training benefit. monitoring also needs to be customized to accommodate the underlying risk profile. classically, a cardiopulmonary training program is three sessions per week for to weeks. cardiac rehabilitation is covered by most insurance plans, but the major limitation is a lack of referral and/or a lack of facilities in many areas. creative and innovative care delivery programs have been developed to increase access and include home programs (patients at low risk), telemedicine programs, and community-based programs in nonmedical facilities. because training continues after the -to -week period, it is important for patient self-efficacy that they learn to perform self-monitoring following the guidelines presented in standard references. , patients need to learn to begin exercise with a stretching session, then a warm-up session, a period of training exercise at designated intensity, followed by a cool-down period. the principles of specificity of training need to be remembered because training benefits generally are seen in the specific muscles exercised. although the maintenance phase of cardiopulmonary rehabilitation is the most important part of the program, it often receives the least attention. the benefits of a phase program can be lost in as little time as a few weeks if a patient ceases to exercise. because of this, patient education of the importance of making exercise a part of their new health habits has to be emphasized and the patient needs to integrate exercise as a part of a healthy lifestyle. to maintain capacity, patients should perform moderate exercise at the target intensity learned in their rehabilitation program for at least minutes three times a week. with low-level exercise, the frequency has to be increased to five times a week for maintenance of gains. although telemetry monitoring is usually not used with patients with cardiac disease, patients with pulmonary disease can benefit from the use of home pulse oximetry and should be taught to adjust their supplemental oxygen as needed with exercise to maintain adequate oxygenation. cardiac rehabilitation for angina aims to lower heart rate at rest and with given levels of activity to decrease angina by improving fitness. exercise benefits for patients with angina include improved peripheral efficiency and improved coronary artery collateralization. cardiac rehabilitation after coronary artery bypass grafting (cabg) emphasizes secondary prevention aims to improve conditioning and fitness. for patients with low ejection fractions and heart failure, closer telemetry monitoring should be done. if a patient had a sternotomy, arm exercises will have to be limited until sternal healing occurs, usually at approximately weeks after surgery. patients who have had percutaneous interventions usually pursue the program immediately and it is similar to the program after cabg. because most patients after cardiac transplantation have severe heart failure and debility before transplantation, involvement in a heart failure pretransplant program can help to limit deconditioning and help to treat depression and anxiety. heart transplantation usually improves cardiac function; therefore a posttransplant program can focus on conditioning, education, and secondary prevention. an added feature is that many patients after transplantation may have vascular and neurologic complications, which may mean a phase b program is needed before starting the phase outpatient program. this is often done in either acute or subacute rehabilitation settings. remembering the alterations of cardiac physiology in the patients after transplantation is important. transplanted hearts are denervated and have no direct sympathetic or vagal central regulation. in many patients, the loss of vagal inhibition creates a resting tachycardia of to beats/min. by contrast, because there is a loss sympathetic innervation, the chronotropic response to exercise is in response to circulating catecholamines, leading to a delayed and blunted heart rate response to exercise. posttransplant, peak heart rates are usually % to % lower than in matched controls. other cardiovascular effects that are seen include resting hypertension from the renal effects of calcineurin inhibitors (e.g., cyclosporine and tacrolimus) and prednisone, along with diastolic dysfunction in some patients. combined, these effects usually reduce maximum work output and maximum oxygen by approximately one-third compared with age-matched individuals. of interest, despite no denervation of the heart, similar decreases in exercise capacity are also seen in patients after lung transplantation. with exercise, patients after transplantation have a lower work capacity, reduced co, lower peak heart rate, and lower oxygen uptake and a higher resting heart rate and sbp than normal individuals. in addition, resting and exertional diastolic blood pressures are usually higher for patients after heart transplantation. , the net effect of these alterations in exercise response is higher than normal perceived exertion, minute ventilation, and ventilatory equivalent for oxygen at submaximal exercise levels. the focus of a cardiopulmonary rehabilitation program after transplantation is on conditioning and education. target intensity for aerobic exercise is usually approximately % to % of peak effort for to minutes three to five times weekly. intensity can be regulated with rating of perceived exertion target at to on the borg scale, approximately to on the modified borg scale, with the goal being to consistently increase the level of activity. education focuses on learning the complicated medical regimen and vocational and psychological needs. for patients after cardiac transplantation, a program of rehabilitation can help to assist them to improve work output and exercise tolerance, with some patients able to participate in competitive athletics. , , cardiomyopathy fortunately, cardiac rehabilitation for heart failure is currently covered by insurance plans, since medicare regulations started to cover rehabilitation for heart failure in march of ( c.f.r. § . (b) ( )(vii)). an important consideration for heart failure rehabilitation is the increased risk of complications such as sudden death, depression, and chronic cardiac disability. closer monitoring of telemetry and vital signs is also needed because some patients with heart failure have inconsistent responses to exercise with increased fatigue, possible exertional hypotension, and syncope. most patients also exhibit low endurance and chronic fatigue as a result of their low-exercise capacity. however, a positive effect can be realized in their fatigue and function with even a small improvement in vo . these changes in capacity can lead to a marked improvement in quality of life and may help patients with heart failure to continue to live independently. because of the increased risk for complications in patients with heart failure, a graded ett is helpful before starting a cardiac rehabilitation program. long warm-up and cool-down periods with gentle exercise at a limited workload helps to compensate for an impaired ability to generate a dynamic exercise response, and dynamic exercise is preferred to isometric exercise because isometric exercise can lead to an increase in diastolic pressure and cardiac afterload. heart rate targets are usually set beats/min less than any notable end point found with cardiopulmonary exercise testing. cardiac rehabilitation begins with cardiac monitoring especially when severe left ventricular dysfunction is present. once the patient has demonstrated stability with an exercise program and has learned how to self-monitor, the patient should be taught a self-monitored program. education of patients with heart failure also includes doing a daily body weight (to observe for fluid accumulation) and monitoring their blood pressure and heart rate responses to exercise. patients who are on pharmacologic inotropic support or left ventricular mechanical support for end-stage heart failure can also exercise in a cardiac rehabilitation program with similar precautions to other patients with congestive heart failure. rehabilitation after an lvad usually follows a classical postsurgical course and may include phase and phase b rehabilitation followed by phase and phase programs. patients with an lvad seen in acute and subacute units require staff training, close cooperation with the lvad team, and familiarity with the devices that are used locally. because an lvad often restores a reasonable co, exercise tolerance is often only limited by the peak flow of the device. in addition to normal secondary prevention education, lvad-specific family and patient education are also essential parts of post-lvad rehabilitation. cardiac rehabilitation for valvular heart disease resembles the program for cardiac heart failure. postsurgical considerations are the same as for cabg, with the added consideration of anticoagulation for patients with mechanical valves. because anticoagulation increases the risk of hemarthrosis and bruising, patients need to avoid impact exercises and need education regarding injury avoidance. the overall training program is similar to that discussed for the patient post-cabg. an essential consideration for patients with cardiac arrhythmias is the need for telemetry monitoring with increases in intensity of exercise and new exercises. patients at high risk can benefit from an automatic implantable cardiac defibrillator (aicd), which may offer protection form ventricular arrhythmias. cardiac rehabilitation for patients with aicd needs to be done at intensities that avoid the heart rates at which the device is set to respond to ventricular tachyarrhythmias. an exercise stress test can help to set appropriate target heart rates for an exercise program. in addition to secondary prevention and education, aicd-specific education and emotional support are important to include in the rehabilitation program. an emerging area of scientific exploration is using the cardiac rehabilitation model for stroke recovery and prevention. , this is a logical extension of the effectiveness of the cardiac rehabilitation model in reducing known coronary artery disease risk factors in regular participants. because the risk factors for coronary artery disease are the same as the risk factors for stroke, it is logical to apply the same group exercise-based behavior modification model to a similar at-risk population. participants must be screened carefully for balance impairments and muscle strength asymmetry that could increase the risk of falling in a group exercise setting. asymmetric muscle fatigue must be scrupulously monitored and can contribute to degradation of gait or exercise form as exercise progresses. subtle cognitive deficits may require close observation until it is determined that the stroke patient care set machine intensity levels accurately and independently. meticulous blood pressure control must be maintained and may require more frequent measurements than regularly collected in cardiac patients. any questions regarding safe blood pressure range should be directed to the referring neurologist. this is analogous to target heart-rate range directed by referring cardiologist when indicated. a new and exciting area of emerging research is the conditioning of cardiac patients with high-intensity interval training (hiit). , following appropriate screening and evaluation, patients are enrolled in a traditional cardiac rehabilitation program. once they are familiar with the execution of exercise intervals, an accurate setup of exercise machines trials of hiit can be introduced. patients are instructed to exercise at high intensity (> % of vo max ) for short or ultra-short intervals followed by low-intensity or rest intervals. it is recommended to start hiit training on seated machines to reduce likelihood of falls on standing machines due to loss of balance, distraction during interval initiation or termination, and dizziness from blood pressure fluctuations. meticulous blood pressure and telemetry monitoring should take place until the practitioner is confident they have established an individualized baseline response for each patient. additional considerations are the potential for exercise-induced hypoglycemia-an expected and physiologically beneficial outcome. symptomatic hypoglycemia can be quickly treated with any source of oral glucose. it is important to reassure cardiac patients that hypoglycemic symptoms are not the onset of cardiac ischemia to reduce negative associations with exercise. hiit has been shown to provide significant conditioning benefits in the cardiac rehabilitation population with medically supervised selection of candidates. demand for cardiac rehabilitation services is unable to keep up with the current and projected future supply throughout the world leading to innovative approaches to delivery included home-based and "hybrid" programs. , , numerous innovative models are emerging in both cardiac and pulmonary rehabilitation. all models are initiated with an in-person evaluation and followed by various technology driven follow-up contacts. the telerehabilitation approach allows one-on-one live supervised sessions or weekly coaching via video link. a less technology-driven approach includes weekly phone calls and reviews of self-kept activity logs that may also include additional communication via text message. hybrid programs begin as a traditional facility-based, telemetry-monitored exercise program followed by rapid transition to home-based continuation. most hybrid programs do not extend telemetry monitoring into the home setting, although with technologic advances this has been demonstrated in at least two foreign studies. , in addition, current technology allows physiologic data to be collected and relayed to the provider via wearable technology and app-or web-based interfaces. , , regular follow-up appointments, whether in person or via video link or phone call, are recommended to ensure continuity of care. it has been demonstrated that homebased programs are not inferior to facility-based programs, but the medical literature is still developing regarding conclusions of superiority. home-based cardiac rehabilitation is an emerging and exciting trend. there is a wide variety of solutions being explored throughout the international cardiac rehabilitation community. exercise has been repeatedly demonstrated to be safe for patients in the cardiac rehabilitation population-extrapolation from this well-accepted practice is leading to new delivery methods to an everexpanding population. , , , rehabilitation for patients with copd is the standard for pulmonary rehabilitation. goals of a pulmonary rehabilitation program include improving disease management and exercise capacity. because pulmonary rehabilitation does not improve lung function, the goal of the rehabilitation program is to improve peripheral efficiency and decrease dyspnea. energy conservation education (how to do a given activity at a lower level of exertion), anxiety reduction, and improved endurance all contribute to improved function and decreased dyspnea. longer-duration exercise of moderate intensity is often used rather than high-intensity exercise. investigations have started to evaluate a possible role for hiit for patients with copd, but this has not yet been proven to be more effective than the standard training program. because isometric exercises increase intrathoracic pressures, they should be avoided in patients with copd. appropriate supplemental oxygen should be given to maintain saturation greater than %, with education to lower supplemental oxygen after exercise back to baseline levels to prevent resting hypercarbia. patients with copd generally have relatively modest oxygen needs and can often maintain their oxygen saturation levels with to l of oxygen via a nasal cannula. bilevel ventilation may have a role for patients with sleep apnea or ventilatory failure, and education for these patients should include the proper use of this modality. for patients being considered for lung volume reduction surgery, pulmonary rehabilitation is considered essential both to qualify for the surgery and after surgery to ensure adequate outcomes. airway clearance and chest physical therapy has a role in the pulmonary rehabilitation of patients with substantial secretions. a combination of external percussion devices, vibration devices, and inhaled saline in combination with cough training and huffing may help to mobilize secretions. it is also important to include family training and education about inhaled medications, supplemental oxygen use, and management of equipment. the basics of a program of pulmonary rehabilitation for interstitial lung disease are the same as for copd. an essential issue for patients with interstitial lung disease is often profound hypoxemia that requires high-flow oxygen with exercise to maintain adequate saturation for activity. it is essential in this group of patients to avoid chronic hypoxemia to prevent secondary pulmonary hypertension because the coexistence of interstitial lung disease and pulmonary hypertension can lead to a markedly decreased life expectancy. exercise intensity is often limited in patients with interstitial lung disease by oxygenation rather than dyspnea, and airway secretions are usually not an important issue. for some individuals with severe end-stage disease, there may be ventilatory failure with hypercarbia, but in those patients, rehabilitation may no longer be possible. because interstitial lung disease is often progressive, transplant evaluation and education or end-of-life planning may be needed to permit as many patient goals as possible to be achieved. patients with pulmonary hypertension have similar limitations as patients with heart failure and share many similar precautions. effective medical treatment for pulmonary hypertension has made a once-fatal condition into a chronic disease for many patients. patients with pulmonary hypertension currently have a much longer life expectancy, and improved functional status is essential for maintaining an active life. major concerns for pulmonary rehabilitation are preventing debility and improving dyspnea. because hypoxemia can worsen pulmonary hypertension, it is important to maintain oxygen saturation with exercise, and cardiac monitoring may be needed for patients with a history of arrhythmias and right ventricular failure. education for this group of patients should include a review of their vasodilating medications and supplemental oxygen use. intravenous and continuous subcutaneous vasodilator infusion is appropriate for a pulmonary rehabilitation program, but, similar to patients with heart failure, there may need to be long warm-up and cool-down periods. for patients with severe pulmonary vascular disease, the program should start with moderate-to low-level exercise. definitive research of the efficacy and safety of pulmonary rehabilitation for patients with pulmonary hypertension is still ongoing. for alert patients on either invasive or noninvasive ventilation for ventilatory failure, a program of pulmonary rehabilitation can help to increase mobility and prevent complications. exercise programs for patients on nocturnal or intermittent ventilatory support aim to improve efficiency and decrease fatigue while off the ventilator. the details of ventilatory support for patients requiring noninvasive ventilation is beyond the scope of this chapter. as the population ages and more patients survive a disabling condition, there is an increase in patients with both physical disability and cardiopulmonary disease. an issue for cardiac rehabilitation for patients with dual disability is the impaired mobility that can impair both evaluation and participation in a rehabilitation program. individuals who are disabled tend to have lower activity levels, which puts them at increased risk of cardiac and pulmonary disease and may present obstacles for a standard rehabilitation program for a person who is newly disabled and who has preexisting cardiopulmonary limitations. for new-onset cardiac or pulmonary disease, cardiopulmonary rehabilitation is just as important and needs to be considered. cardiopulmonary primary and secondary prevention also overlaps with the education needed for stroke and peripheral vascular disease and is especially important for patients with physical disabilities because they are often more sedentary with a higher prevalence of obesity and deconditioning. finally, because mobility in individuals who are disabled requires greater energy expenditure, compromised work capacity from cardiopulmonary disease may impose an even greater degree of disability on an individual who is disabled than an individual who is able bodied. cardiopulmonary exercise prescription for individuals who are disabled has to be adapted for the individual disabilities that the patient has. individuals who have a lower extremity impairment resulting from neurologic or orthopedic conditions can perform upper extremity ergometry or use modified lower extremity exercise equipment, whereas an adapted bicycle ergometer or airdyne may be helpful for a patient with hemiplegia. the higher mvo requirements for upper extremity exercise compared with lower limb exercise should be considered to adapt the cardiac rehabilitation program for patients who are disabled. patients who are disabled also need to focus on task-specific activities while increasing their aerobic conditioning and endurance, with a goal of lowering the mvo for any given task. because of the expertise in dealing with physical disabilities and understanding the mechanics of motion, physiatrists are particularly well positioned to lead cardiopulmonary rehabilitation programs for the disabled. it is especially important when many traditional cardiac rehabilitation program teams are hesitant to work with patients who are physically disabled because of their lack of experience with physical disability. , cardiopulmonary rehabilitation is an area where physiatry is uniquely positioned to help manage the patient who is multidisabled, and the multidisciplinary approach is well suited to address the education and team management needed for successful cardiopulmonary rehabilitation. a goal for cardiopulmonary rehabilitation is to increase the access to cardiopulmonary rehabilitation to a greater number of patients, including populations who are underserved in rural and urban areas, women and minority groups, and patients with dual disabilities as they become a larger proportion of the patients seen with cardiopulmonary disease. movement is an essential part of human life and is important for the preservation of function throughout the entire life cycle. since the beginning of human history, a high degree of physical activity has been required to maintain a livable environment and to secure adequate nutrition to ensure survival. it is only following industrialization, a relatively recent event from an evolutionary point of view, that the diseases and conditions associated with inactivity and immobility began to manifest themselves throughout human societies. obesity and the resultant conditions of diabetes, hyperlipidemia, and decreased cardiopulmonary reserve have increased steadily throughout the past century. much attention is focused on the "westernization" of diet, although less attention is focused on the "westernization of physical activity levels." as physicians concerned with function, physiatrists intuitively understand the dangers of activity reduction in all settings from all causes, both medical and environmental. in fact, often physiatrists are the only physicians who have familiarity with the maintenance of function via physical activity using therapists, nurses, and family members. the knowledge of how to modify physical and social environments to maximize functional movement and overall function for their patients allows physiatrists to improve and maintain function in their patients. the physiatric focus on activities of daily living (adls) is an effort to return functional movements to an individual who is disabled, allowing them to maintain their baseline degree of physical activity required for autonomy and independent movement. the link between physical activity and cardiovascular disease has been well described since the s, , when the relationship between workplace activity levels were directly related to higher rates of cardiovascular events. it is no surprise that less physically active daytime behavior (e.g., mail sorters vs. mail deliverers) affected the development of cardiovascular disease. a more interesting finding is the strength of this association; primarily seated workers developed almost twice the rate of cardiovascular disease. more research investigating and elucidating the cellular biology of inactivity needs to be done until this area of physiology is as well understood as exercise physiology. currently, the global workforce is becoming more sedentary in numerous sectors as desk-based work responsibilities dominate the work day and after-hours couch-based recreational activities, including home theaters, media centers, and ubiquitous social media, create prolonged voluntary immobilization after work. in the united states the amount of daytime sedentary hours is high, as revealed by data from the national health and nutrition examination survey (nhanes) database, which showed that . % of waking hours in the population studied was spent during sedentary activities, with late adolescents and older individuals being the most sedentary. rising "sedentarism" is not only an american phenomenon. in australia a large population-based study found that sedentary behavior (television viewing time) was positively associated with abnormal glucose metabolism and metabolic syndrome. , more concerning is that these associations were preserved even when controlling for what would be considered active individuals who participated in sustained and moderate-intensity recreational activities. prolonged physical inactivity appears to be a unique risk factor for maladaptive energy metabolism. in the future it is possible that number of hours spent sitting will be recognized as a risk factor for the development of cardiovascular disease. in the context of this discussion, these observational data support the hypothesis that the physiology of inactivity is a risk factor for poor health outcomes in numerous settings. this supports the idea that there should be a paradigm shift in how all physicians view physical inactivity in their patients, especially in the hospital setting where the physiatrist is in a key position to increase patient mobility. in addition to increased cardiovascular risk, there are numerous associations between inactivity and poor health outcomes, including the metabolic syndrome, deep vein thrombosis, obesity, and serum insulin levels. although there have not been studies to elucidate the molecular biology linking prolonged sitting to metabolic syndrome, epidemiologic data are compelling. the metabolic syndrome is the presence of three out of five of the following findings: central obesity, elevated blood pressure, low serum high-density lipoprotein cholesterol, high triglycerides, and elevated fasting glucose. patients with this constellation of findings are at increased risk for the development of cardiovascular disease and diabetes. in recent years, the recognition of the metabolic syndrome and its prevention has produced a rich literature specific to this syndrome. prolonged inactivity (sitting) more than doubles the risk for development of metabolic syndrome. development of the metabolic syndrome has been shown to increase with each additional hour of sedentary television viewing, as opposed to having television in the background during other household activities. the correlation with prolonged sitting and development of deep vein thrombosis has been well described. this can occur even in active individuals who are immobile for prolonged periods of time. case reports from varied settings have reported seated individuals who developed deep vein thrombosis since the s. these have included observations from air raid shelters, sitting in theater, sitting on extended airplane flights, and even prolonged sitting during video game playing. , presumed causes include rheologic changes and hemoconcentration. , obesity the relationship between physical activity and body mass index is supported by the medical and epidemiologic literature. in varied populations, pediatric, adult, or older adult individuals who have a lower level of baseline physical activity generally have a higher rate of obesity. sedentary behavior is a reversible cause of obesity in all populations, , , and improvement of physical activity levels should begin with school-aged children. , this is especially true because there is evidence that an obese child has a significantly greater likelihood of continuing life as an obese adult. , even high levels of physical activity in athletic adults may not be able to compensate for the deleterious effects of sedentary behavior. insulin resistance is a component of the metabolic syndrome, and thus it is reasonable to assume that an association would exist between amount of insulin present and sedentary behavior. reduced leisure time physical activity levels are associated with higher levels of insulin at baseline. numerous studies have demonstrated the relationship between prolonged sitting, obesity, and the development of type diabetes, an insulin resistance state. more interestingly, however, is the suggestion that insulin levels are elevated in individuals who have prolonged sitting, even in the presence of regular exercise. the frailty syndrome is a recognized syndrome of decreased ability to adapt to stressors accompanied by reduced physiologic reserves and reduced energy metabolism. the frailty syndrome has been reported to vary widely depending on the population studied, ranging from % to %. the frailty syndrome is clearly associated with advanced age and becomes more prevalent in older groups studied; however, it is considered to be a separate syndrome and not a variant of normal aging. if it were considered the end result of normal aging, it would be reasonable to expect all individuals to acquire the frailty syndrome if they lived long enough, which they do not. the potential for confusion exists when the descriptor "frail" is confused with the frailty syndrome. a universally accepted definition or set of variables to diagnose the frailty syndrome has not yet been agreed upon; however, the conversation in the medical literature is ongoing and evolving. substantial opportunities exist for physiatric contribution to this discussion because the frailty syndrome is defined in most tools as having a strong functional component. a true consensus on the definition of the frailty syndrome has yet to be agreed upon internationally; however, the following findings are discussed in the medical literature as possible variables in evaluating individuals thought to be at risk for the frailty syndrome: there are numerous frailty screening tools being used in a variety of settings. two of the most commonly cited tools in the medical literature include the fried frailty phenotype and the "rockwood indices" from the canadian study of health. these measurement tools can be of use to physiatrists depending on the practice setting in which they are used. fried and colleagues at johns hopkins university developed a screening tool that identifies frailty based on a positive score in three out of five possible domains: weight loss, exhaustion, low physical activity, slow walking speed, and reduced grip strength. a positive response was assigned a score of or for each category. a positive value of was assigned when participants responded "yes" to the following question, "in the last year, have you lost more than pounds unintentionally?" because there is considerable room for self-reported bias, follow-up measurements to confirm weight loss are recommended to confirm the initial findings. two questions extracted from the center for epidemiologic studies short depression scale (ces-d ) were used as indicators of exhaustion: "i felt that everything i did was an effort" and "i could not get going." scoring was based on the strength of participants' agreement with these statements. a positive score was assigned a value of . kilocalories per week expended were calculated with a self-reported description of voluntary activities adapted from the minnesota leisure time activity questionnaire. this included questions about walking, chores, outdoor gardening, and numerous types of exercise. interpretation of the answers should be clarified to ensure that negative answers are not based on different settings (urban vs. suburban) or culture. a positive value of was assigned for participants with the lowest % of activity. measurement was the time in seconds required to walk feet. stratification by gender and height took place. the slowest % of the population studied was defined as receiving a positive score and a value of . results were stratified based on gender and body mass index with values recorded in kilograms with a standard dynamometer. participants who scored in the lowest % after adjustment for gender and body mass index were assigned a positive value of . after scores are totaled, individuals who score are considered "robust." the presence of one to two of the criteria listed earlier are considered to be "prefrail," and three or more positive criteria are considered "frail." this phenotypic description has been correlated with notable clinical outcomes that are recognized as important in the geriatric population including falls, hospitalizations, and mortality. this clinical applicability and relevance to important measurable outcomes has made the fried frailty measure a popular tool in clinical research. there are no laboratory tests or psychosocial components taken into account when determining a score with this scale. using these criteria, fried identified individuals who met the criteria for the frailty syndrome in % of the participants included in the cardiovascular health study, % of the participants older than years of age, and % of the women's health and aging studies. the "rockwood index," also known as the canadian study of health and aging (csha) frailty index, and the clinical frailty scale were both derived from the csha dataset, a prospective cohort of more than , participants. both of these scales have been widely used in medical studies. the -item csha frailty index is driven by clinical judgment. this is a detailed tool in which clinical deficits are scored based on a -item index. the items include self-reported functional activities, mood, and motor symptoms, as well as signs and symptoms derived from medical history and physical examination. each deficit is assigned a value between and . to give a total score, which is then divided by . some examples of variables collected are listed in table . , with division into categories provided as a conceptual framework. this index determines clinical deficits and allows scoring based on evaluating participants for accumulation of impairments. the clinical frailty index was developed as an attempt to integrate clinician judgment into a formal and universally applicable model to evaluate frailty. the authors recognized that simply evaluating frailty based on a limited number of phenotypic variables may correlate with mortality but does not give considerably more information across all populations. although it is of benefit to identify participants at risk for increased overall mortality, it does not guide the physician to develop interventions that can address specific and more importantly correctable impairments. the frailty index gives structure to an intensive review of deficit accumulation that can serve as a starting point for interventions. these same authors recognized the utility for a shorter more clinically oriented scale that could be used by clinicians across numerous specialties. in , they developed and validated the csha clinical frailty scale. this is a descriptive scale with seven categories from "very fit" to "severely frail." it has been demonstrated to be an effective measure of frailty and offers predictive information about probability of survival and likelihood of institutionalization. this is a judgment-based scale that would be more applicable in the physiatric setting, whereas the more timeintensive frailty index would give more specific information to a primary care provider or geriatrician. both tools are validated instruments of benefit in the research setting (table . ). in addition to the functional, psychological, and musculoskeletal changes, there are also altered organ system and homeostatic responses in the frailty syndrome. these include a reduced capacity to maintain homeostasis and an increased vulnerability to stressors caused by lower energy metabolism, sarcopenia, altered hormonal activity, and decreased immune function. changes in the endocrine axis, specifically the growth hormone/insulin-like growth factor (gh/igf- ) axis, affect numerous metabolic systems. hepatic igf- production is controlled by pituitary growth hormone secretion and is essential for normal metabolic processes in adults. because growth hormone secretion declines with normal aging, igf- levels also decline; this is often referred to as the "somatopause," which accounts for the normal age-related decline in endocrine function. decreasing circulating levels of endocrine hormones contribute in part to osteoporosis, alteration in muscle/fat ratio, and cognitive decline in addition to sarcopenia. there is an association between the frailty syndrome and abnormally low igf- levels. routine testing of igf- levels is not recommended because it is neither diagnostic nor cost effective. however, appreciating the metabolic setting in which the frailty syndrome is more likely to occur provides a framework for understanding this complex syndrome. in the women's health and aging study, participants who had disabilities in mobility and disabilities in adls were more likely to have an increase in the proinflammatory cytokine interleukin- (il- ). the combination of decreased igf- and increased il- could contribute to a theoretical shift from the normal slowly decreasing anabolic state of aging to a rapidly increasing catabolic state seen in the frailty syndrome. as the population ages, the incidence of the frailty syndrome will also increase. this complex syndrome will continue to be elucidated as advances in the molecular biology of normal aging progress. for the physiatrist, early recognition of the frailty syndrome may allow multidisciplinary intervention with the intended goal of preserving function as long as possible for these patients. traditional hospital practices (bed rest, sedation, and immobilization). there has been a long-standing culture of bed rest in hospital culture. the concept of "convalescence" is that an ill person's strength returns gradually and is enhanced through greater than normal rest. this word is believed to have entered regular use in the late th century at a time when patients who were ill had few medical options other than rest. the deeply held belief that hospitals are places to "rest" influences sedation practices and encourages the overuse of bed rest despite there being a clear understanding of the dangers of immobility. this is especially true in the traditional critical care setting. long-standing provider beliefs include the idea that undersedation during mechanical ventilation is painful, traumatic, and panic-inducing despite ample data to the contrary. , in a recently published study that explored nurse sedation practices in the icu, % of nurses surveyed believed that sedation is necessary for patient comfort and % of the nurses surveyed would want sedation if they were ventilated themselves. although some degree of sedation is usually required, % of the nurses surveyed believed that patients who are "spontaneously moving hands and feet" are undersedated. although overuse of sedation is associated with an increase in posttraumatic stress disorder (ptsd) and prolonged mechanical ventilation with the accompanying complications of total immobility, it is still a widely held belief in many institutions that "rest is best." these practices lead to accelerated and iatrogenic deconditioning resulting from immobilization. iatrogenic immobilization and deconditioning. the dangers of immobilization have been understood for a long time (table . ). the often-cited % to % loss of muscle strength for each week of bed rest was derived from studies that involved young healthy test individuals without underlying disease or musculoskeletal conditions. it is likely that the rate of deconditioning is even faster in older adult patients with multiple comorbidities, because ambulatory function and ability to perform basic adls have been shown to decline in one-third of hospitalized patients older than the age of years. some of the complications of immobility include orthostatic intolerance, skeletal muscle changes, joint contractures, pulmonary atelectasis, urinary stasis, glucose intolerance, and pressure ulcers. traditionally, physiatrists have served as advocates for increased patient activity in the hospital setting because they evaluate and identify patients who can benefit from physical and occupational therapy. rationale. the importance of early mobilization is well accepted as a "best clinical practice" in every hospital setting, not just the icu. as the complications of immobilization became more widely understood, the importance of early mobilization throughout hospital organizations becomes a logical institutional goal, ideally approached through the quality improvement methodology. less universally agreed is how to design and implement a multidisciplinary early mobilization program and how to effect the accompanying culture change that is required for success. the physiatrist, working closely with colleagues in nursing, critical care, physical therapy, and occupational therapy is ideally suited to take a major role in the effort to bring mobilization to all patients who are hospitalized. the icu is an ideal setting in which to initiate such a program because of the increased staffing to patient ratios, extended length of stay, and awareness within the critical care community as to the important role of physical medicine and rehabilitation in these programs. culture of immobility. to successfully mobilize patients who are hospitalized, one must understand the many reasons that patients are ordered to bed rest and immobilization. only then can the root causes of reduced patient activity be addressed. the concept of therapeutic bed rest can be a difficult idea to challenge. therapeutic bed rest has been recommended for almost every medical problem at some point in medical history, including a variety of cardiac and pulmonary conditions in both the pediatric and adult populations. , , in the intensive care setting, longheld beliefs that the experience of mechanical ventilation was traumatic and frightening for patients gave rise to a culture of complete sedation and resultant immobility. the idea that patients who were unconscious would recover faster, "fight the vent" less, and be spared psychological suffering was essentially unchallenged. similar to the experience of patients with cardiac disease before unit-based cardiac rehabilitation efforts began in the s, survivors of critical illness were profoundly weak with substantial disabilities resulting from their prolonged immobilization. this was often interpreted as proof of how tenuous their conditions were at the time of presentation, rather than the side effects of immobilization and oversedation. culture of mobility. the first step to increase patient activity is gaining the trust and "buy-in" of colleagues in medicine and nursing. the importance of having evidence-based discussions with colleagues cannot be overstated. the common ground of all healthcare providers is commitment to patient care and improved functional outcomes. there is currently a developing medical literature on the benefits of early mobilization. , , journal clubs, consultative rounds, and a strong inpatient presence contribute to an understanding of the physiatric approach and will provide an appropriate venue for discussions about early mobilization. physiatric involvement. as a physician who understands the important role of physical, occupational, and speech therapy, the physiatrist is ideally suited to emphasize the vital role that these services play in the hospital setting. because of hospital-bundled payments, physical therapy expenditures have traditionally been seen as cost centers and not profit centers by hospital administrators. to address this perception, the physiatrist should be well aware of the importance and robust discussion taking place in the medical literature about the cost-effectiveness as well as clinical use of early mobilization programs in a variety of medical settings. , , , familiarity with the current literature demonstrating the multiple savings to an institution is key in acquiring the resources needed to implement an early mobilization program. having a physiatrist as part of the implementation team is optimal to represent the interests and contributions of the entire spectrum of physical medicine and rehabilitation providers. ambulatory devices. hospitalized patients who use assistive devices normally are generally unsafe to ambulate without their usual devices while in the hospital. because of staffing ratios and constant surveillance, ambulation in the icu would not take place unassisted; however, in a noncritical unit a mobilization program would need accommodation for patients who can ambulate independently as well as with assistance. a recently developed fall prevention tool kit includes bedside signs identifying risks and required assistive devices if they are determined to be necessary for safe ambulation. in one study, % of falls were related to attempts by patients to reach the bathroom. it is logical that removing assistive devices from ambulatory patients entering the hospital will result in increased falls when patients attempt to ambulate independently. training. coordinated interdisciplinary training before implementation is essential for any mobilization program. although early mobilization is often focused on physiatric oversight and physical therapy services, without appropriate coordination by all disciplines involved, successful early mobilization cannot take place. multidisciplinary simulation training with case-based scenarios should take place in the unit where mobilization is planned. all members of the healthcare team should have clearly defined roles before simulation training to experience the difference between standard multidisciplinary care and interdisciplinary coordination of care, which is at the heart of early mobilization. unit-based simulation training, ideally with an actor as the patient, is optimal when possible. cases provided should address medical emergencies and the challenges of physical coordination of care. allocating time following simulation training for team members to discuss their experiences further facilitates the team-building experience. patients hospitalized in critical care units almost universally have hemodynamic instability. the systemic inflammatory response syndrome causes peripheral vasodilation, cardiac dysfunction, capillary leak, and circulatory shunting leading to hypovolemia. a constantly changing cardiovascular environment makes daily evaluation essential. as a result of vasodilation, patients who are critically ill may be unable to tolerate bed elevation, let alone seated positioning. observing hemodynamic response to simple turning is a bedside test of hemodynamic tone that is easily carried out by a single provider. patients who cannot tolerate trunk elevation can be treated in a supine position with range of motion and progressive resistance. it is important for treating therapists to continually observe blood pressure response to intervention. it is strongly recommended that treating therapists consult with nursing providers to discuss any changes since last treatment resulting from rapid changes in physiologic state. with constant surveillance and gradual progression, mobilization of the patient who is critically ill is unlikely to produce any unexpected events. hypoxemic failure causes numerous pathophysiologic effects culminating in requirement for ventilator support. these include hypoxemic failure caused by ventilation/perfusion (v/q) mismatch, shunting, and altered oxygen exchange properties. hypercapnic failure causes decreased minute ventilation relative to physiologic demand, especially in the setting of critical illness complicated by increased dead space ventilation. coordination of therapy in conjunction with ventilator management should take place between physical medicine and rehabilitation and respiratory therapy. in some cases, therapists may be given parameters by the primary team as to titration of oxygen during treatment sessions. oxygen titration should always take place in coordination with respiratory therapy or nursing. similar to hemodynamic monitoring, ventilator status and oxygen saturation can vary quickly in response to activity and should be monitored at all times. during active ambulation, a respiratory therapist is essential to monitor oxygenation and the position of an endotracheal tube. icu-acquired weakness is common following hospitalization in the intensive care setting. approximately % of patients with prolonged mechanical ventilation, sepsis, or organ failure have some degree of neuromuscular dysfunction. the presence of icu-acquired weakness can cause abnormalities at any point in the gait cycle. endurance is reduced in all patients following prolonged bed rest with or without paralytics. ambulation trials should begin with standing at bedside and progress only out of the patient room once the entire team is assembled. this will ensure patient safety and continuous monitoring in the face of global weakness. early and aggressive physical therapy intervention has been shown to improve recovery of muscle strength in patients in the icu. , psychology of the patient in the intensive care unit survivors of critical illness often have symptoms of ptsd. in a recently published study, % of icu survivors following admission for acute lung injury reported ptsd symptoms during the -year period following critical care admission. symptoms of ptsd can be persistent, given that % of patients who reported symptoms confirmed their persistence at months. of these, % had taken psychiatric medications and % had seen a psychiatrist since hospital discharge. clearly, the complications following an episode of critical illness are multifactorial. although it is too early to definitively state that early mobilization programs reduce symptoms of ptsd, it is likely that the benefits of such a program include reduced psychiatric complications. delirium in the intensive care setting frequently complicates patients' hospital courses with resulting negative health outcomes. it is important that all providers in the intensive care setting recognize delirium and understand how it can impact on early mobilization programs. by definition, delirium is a change in cognitive function hallmarked by a fluctuating course over a short period of time (hours to days). in the critical care setting, delirium is not just a descriptive term; it is a measurable medical syndrome associated with poor outcomes. the confusion assessment method (cam) and cam-s (short form) are measurement tools that have been validated for use in this setting. it is important for therapists to understand that the interventions the provider has been shown reduce delirium and improve functional outcomes. recent critical care practice guidelines state, "we recommend performing early mobilization of adult icu patients whenever feasible to reduce the incidence and duration of delirium." for the rehabilitation provider, even though the fluctuating nature of delirium has the potential to interfere with physical and occupational therapy, it is essential that therapy intervention be provided whenever possible. this often necessitates frequent reevaluations throughout the day until an appropriate window of intervention can be found. the importance of care transitions is receiving greater attention in both the medical literature and the administrative realm of hospital management. an appreciation for the impact of poorly structured systems to transition care from one medical setting to another has become an area of intense focus across the healthcare spectrum. transitional care programs have been studied using different combinations of licensed providers including social workers, pharmacists, nurses, and physicians with most of these programs showing some degree of benefit. , , the use and feasibility of transitional care programs has been studied in varied environments where the transition begins including icu, hospital, nursing home, emergency department, and rural care centers. , , , , the effect of early mobilization programs on care transition has not been studied, but the current interest in ensuring continuity of communication emphasizes the importance in developing and studying systems to ensure transition of physical and occupational therapy. without attention to appropriate transition of care of rehabilitation services, the benefits gained during early mobilization are rapidly lost following transfer. this is an area of emerging interest that justifies research efforts on the part of all disciplines involved in early mobilization programs. although the importance of early mobilization in the critical care setting has received substantial attention, the principles of early mobilization are applicable throughout the healthcare continuum. evaluating patients at risk for immobility or reduced mobility followed by appropriate referral to trained providers can increase patient activity levels throughout a medical system. the type of provider selected is determined by the degree of assistance required for a patient to safely increase their activity level. in the hospital setting, "bed rest" orders should be replaced by systemized evaluations regarding safe patient activity levels. allowing patients who are hospitalized to use bedside commodes and assistive devices where appropriate is an economical way to increase patient activity without skilled intervention. providing assistive devices to appropriate and carefully selected patients who are hospitalized can increase mobility and reduce incidence of falls in the context of a structured fall-prevention program. healthy people . the us department of health and human services has initiated five "healthy people" initiatives since . these are comprehensive public health programs designed to provide structure and guidance to achieve more than objectives to improve the health of all americans. each health objective has a reliable data source, baseline measurement, and target for specific improvements to be achieved by the year (table . ). the healthy people website is a rich resource that includes leading health indicators, tips and tools for implementation of programs, and a consortium of organizations and agencies committed to achieving the healthy people goals. community mobilization programs can play a role in achieving targets for some of the most important leading health indicators listed as follows. wellness centers. chronic diseases and their cost are responsible for approximately % of us healthcare costs. the prevention and public health fund was established by the patient protection and affordable care act of to administer the community transformation grant program. more than grantees have been funded to support americans in adopting healthier lifestyles including healthy eating, active living, and tobacco-free living. funding opportunities exist within this new structure to explore evidence-based community wellness initiatives. although the causes of preventable chronic diseases in the united states are clear (cigarette use, lack of physical activity, calorie-dense/nutrient-poor dietary patterns), the solutions are as varied as the communities throughout the country. there are many unique and innovative programs that intervene at different stages of the disease process. preventative programs are some of the most appealing as long as the cost-benefit ratio strongly supports ongoing investment. some programs may involve disease-specific secondary prevention, such as a traditional cardiac rehabilitation program. others may be more broadly based and focus on increasing fitness in the context of a community. although wellness programs with general physical activity goals may be common in senior centers, some of the most innovative approaches to the overarching problem of obesity in the united states are taking place in community centers with a focus on modifying heath behavior in the context of community-based family education and counseling. the growing right onto wellness (grow) program in nashville, tennessee, represents an innovative program with a population of parent-child pairs who received educational interventions from to with a goal of preventing childhood obesity from developing in children. wellness centers can be freestanding but with community resources (community centers, houses of worship, schools, and employers) because locations for population-specific wellness programs are an efficient way to improve health outcomes. regardless of the population being targeted, all wellness programs can be developed based on a standard approach, listed as follows: step : organize advocates and advisors wellness programs are multidisciplinary in nature. identifying a group of committed and interested leaders and creating a working group is a logical first step. having the input and involvement of advocate community members at an early stage can improve awareness and uptake in later stages. step : determine the target population the most common wellness programs are either community or workplace based in scope. a work-based program will by definition be multidisciplinary. a physiatrist would be ideally suited to spearhead this type of intervention within a medical center based on their understanding of function, occupational health concerns, and expertise in multidisciplinary work. surveying the target population by questionnaire will yield the most accurate and direct information regarding what types of conditions a population is at risk for. this in turn will guide the development of appropriate interventions. in the community setting, an open forum or informal sampling of health concerns and interests can serve the same purpose. a needs assessment survey is also an opportunity to determine the preferences and interests of the target community. for example, there are numerous ways to increase physical activity levels. early identification of prevailing interests will guide the working group to direct its efforts where they will yield the greatest participation. information from health risk appraisals will direct the priorities for each organization or community. some examples include: exercise/physical fitness, tobacco reduction, stress management, back care, nutrition, weight control, and mental health. there is no way to predict what topics will be of importance to a population without sampling opinion. in a study that queried medical students regarding priorities for a health promotion program, % were interested in financial planning initiatives and only % were interested in alcohol and drug abuse programming. targeted polling will inform where resources should be directed for maximum impact. human behavior is driven by reinforcement. creating sustainable incentives (e.g., t-shirts vs. weekend getaways) will contribute to success over time. newsletters, parties, recognition meals, snacks, and gift cards are all popular workplace incentives that have the added value of increasing visibility of a new program for nonparticipants. workplace competition can be a healthy way to promote a program, especially if a substantial incentive is being offered as reward to the winning team. geographic competitions, departmental teams, and intradisciplinary teams can all contribute to employee "buy-in" and team building. step : implementation before implementation, additional community members, division heads, or other leaders should be included as part of the implementation team. it is just as challenging to develop programs with too many members as it is to implement a program launch with too few members on the launch team. leaving some choices to be decided by the entire implementation team will improve participation and sense of involvement for all team members, leading to better enthusiasm and community participation following deployment. spearheading or participating in implementation of an employee wellness program can be a gratifying and worthwhile way to improve function on a population level rather than at the individual level. highlighting the importance of the unique physiatric approach in the healthcare setting, as well as educating communities as to the important role physiatrists can play in keeping their community members healthy and active, are additional benefits to involvement in these types of programs. scientific advances have expanded our understanding of what constitutes renal failure. once thought to be solely attributable to volume overload, urea buildup, and hypocalcemia, it is currently known that uremia is a complex syndrome caused by the accumulation of organic waste products, some of which have yet to be identified. hemodialysis cannot fully duplicate the complex actions of the nephron, which filters blood, reabsorbs water and solutes, secretes toxic substances, and excretes essential hormones. chronic kidney damage leading to kidney failure has numerous causes; however, the most common causes are uncontrolled hypertension, poorly controlled diabetes, and glomerulonephritis. uncontrolled hypertension leads to nephrosclerosis, or localized damage to the glomeruli. there are two proposed mechanisms of hypertensive nephrosclerosis, the first glomerular ischemia and the second hypertension-induced damage and resultant hyperfiltration. diabetic glomerulopathy has excessive extracellular matrix as the most important pathologic feature. glomerulonephritis can be primary or secondary, each of which has many causes, a full discussion of which is beyond the scope of this chapter. infections, immune diseases, and vasculitides can all cause primary glomerulonephritis with resulting scarring of the nephrons. secondary causes include diabetes, hypertension, and lupus, among others. alternatively, chronic kidney disease can be classified based on the anatomic part of the nephron that is affected. glomerular, interstitial, tubulointerstitial, vascular, and obstructive are all anatomic classification examples that are listed in table . . fluid overload with hypertension can occur when the glomerular filtration rate falls below ml/min. the ability to maintain normal potassium levels is preserved until the glomerular filtration rate reaches approximately % of normal. although patients with chronic kidney failure can secrete potassium until an advanced stage of renal failure, the rate of excretion is reduced, causing prolonged elevations in potassium following ingestion. caution must be used when a patient is noted to be receiving spironolactone. spironolactone is an aldosterone agonist that can result in dangerous hyperkalemia if not monitored closely. sodium metabolism is maintained until renal failure becomes advanced. as renal failure progresses, the ability to conserve sodium is compromised, resulting in hyponatremia. uremia literally means "urine in the blood." it is a general term that began to be used before the understanding that end-stage kidney disease was more complex than just the inability to filter urea from the blood. as nephrons die, the remaining units increase their capacity in a process known as compensatory hyperfiltration. increased glomerular permeability is another adaptation to the reduced number of functioning nephrons. metabolic acidosis is caused by the reduced ability of the failing kidney to excrete acid. this is exacerbated by decreased ability to resorb bicarbonate. bicarbonate serves as the main ph buffer in the body and is derived from bone stores. hypocalcemia. hypocalcemia is loss of calcitriol and leads to decreased calcium absorption and stimulation of parathyroid hormone release. hyperphosphatemia. hyperphosphatemia is caused by impaired excretion. in the face of abnormal bone metabolism, soft tissues became the phosphate reservoir, causing increased vascular calcification. this leads to increasing pulse pressure in advanced disease. anemia of chronic disease resulting from decreased erythropoietin and iron deficiency contributes to fatigue and weakness. supplementation with erythropoietin is recommended and overseen by the primary nephrologist. studies have shown that a glomerular filtration rate of less than ml/min is associated with reduced well-being and overall function. , patients who are dependent on dialysis have multiple possible sources of debility depending on the type of dialysis they receive. peritoneal dialysis using the peritoneum as a membranous filter typically takes place in the patient's home, causing less functional impact than hemodialysis, a facility-based intervention. both methods of dialysis have potential for infection resulting from indwelling catheters, but peritoneal dialysis is more likely to be complicated by subacute bacterial peritonitis as opposed to bacteremia in hemodialysis. sbp is more likely to result in hospitalization, whereas hemodynamically stable bacteremia will be treated on an outpatient basis with antibiotics and with less likelihood of iatrogenic complications during hospitalization. patients who are hemodialysis dependent often report substantial fatigue following dialysis sessions; this impacts on their ability to participate not only with adls but also with rehabilitation efforts. the term "residual syndrome" has been applied to the syndrome of partially treated uremia, because dialysis cannot fully replace all renal functions. electrolyte imbalances and the resultant acid-base abnormalities are responsible in part for the uremic symptoms that are seen in patients who are dialysis dependent. uremic sarcopenia has been described in chronic kidney disease. , the presence of uremia causes changes in skeletal muscle fibers including mitochondrial depletion and atrophy of both slow-and fast-twitch muscle fibers. , , this in turn contributes to the overall sense of fatigue and weakness reported by these patients. the role of exercise in maintaining health-related quality of life and exercise capacity has been described, and patients should be enrolled in an exercise program whenever possible to preserve skeletal muscle function as soon as possible following the diagnosis of renal insufficiency. , patients with chronic renal insufficiency are often candidates for rehabilitation in both the hospital as well as outpatient settings. chronic deconditioning resulting from uremic sarcopenia, a predisposition to chronic pain and gait abnormalities, represents areas for substantial rehabilitative intervention. , , patients on dialysis should be instructed in a regular stretching program because of the potential for hip and knee contractures from prolonged sitting. patients on hemodialysis are at risk for a substantial degree of sedentary behavior as a result of extended immobility during hemodialysis sessions and postdialysis fatigue following dialysis sessions. three hours of dialysis followed by hours of resting while watching television constitutes up to hours of additional sedentary time a week. early referral to a rehabilitation professional for institution of a home exercise program before dialysis is warranted for all patients with uremia. it has been shown to be beneficial for patients on hemodialysis to exercise during dialysis sessions, although this is rarely standard practice. similar to cardiac transplantation, patients following renal transplantation are substantially disabled as a result of a long-standing chronic medical condition: uremia instead of congestive heart failure. although a patient on hemodialysis is typically more functional than a patient with end-stage heart failure, the principles of preprocedure rehabilitation or "prehab," posttransplant evaluation, and coordination of rehabilitative care are the same. following transplantation, reduced mobility, prescribed corticosteroids, and a sedentary lifestyle during recovery can greatly accelerate debility even in the face of a normally functioning kidney. unlike cardiac transplantation, there is no expected increase in co to boost energy metabolism. it is essential that all patients be evaluated following renal transplantation for potential rehabilitation intervention whether it be for aggressive mobilization and extended monitoring or for discharge to acute or subacute facilities. patients following renal transplantation have complex rehabilitative needs similar to patients who are critically ill in the medical intensive care setting. both populations have multisystem organ damage, distributive shock, hemodynamic instability, and severe deconditioning and are at risk for functional decline. unlike the medical icu where a comprehensive early mobilization program may be implemented previously, the patient following renal transplantation may be more reliant on physiatric consultation and coordination of care to receive required services. applying the early mobilization model to this population would necessitate evaluation for participation with physical medicine and rehabilitation on postoperative day . patients requiring ventilator support can receive physical and occupational therapy if sedation is interrupted long enough to participate with the treating therapist. physical therapy is often automatically ordered for all appropriate patients postoperatively and coordination with the primary team should take place in the morning with an agreed upon time for treatment should an interruption in sedation be needed. daily physiatric consultation and review of treatment session notes can guide expectations for the following treatment session. it is crucial to ensure uninterrupted therapy at least three times a week because posttransplant physical reserve is reduced and potential for accelerated deconditioning in the presence of an immunosuppressive regimen that includes corticosteroids is substantial. outpatient rehabilitation programs following renal transplantation should focus on controlled conditioning and education regarding the importance of exercise in maintaining exercise capacity and lifelong function. the same target heart ranges can be used for patients following both cardiac and renal transplantation: % to % of peak effort for to minutes three to five times weekly. rate of perceived exertion as described in the borg scale is a validated method to regulate intensity. it is important to provide consistent encouragement because patients following transplantation can be extremely debilitated and depressed. advising transplant survivors that functional improvement may not be seen for weeks or more following initiation of conditioning will help to maintain participation. a comprehensive rehabilitative program will offer numerous benefits following renal transplant. physical therapy can be focused on achieving a baseline improvement to facilitate participation in activities that the patient following transplantation may have forgone in the face of declining function. perhaps more than any other solid organ transplant, successful candidates for renal transplantation can hope to achieve maximum function with optimal rehabilitation. the coronavirus disease (covid- ) pandemic caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) has been the most significant public health crisis in years, and it has affected all aspects of healthcare, including every area of rehabilitation medicine. at the time of publication, covid- is still increasing worldwide, and with the high number of survivors who have suffered a severe acute respiratory distress syndrome (ards) with prolonged intubations or severe pneumonia, the need for rehabilitation interventions has never been higher. a even though recent evidence has suggested that most patients hospitalized with covid pneumonia can be successfully treated without mechanical ventilation, there are severe pulmonary implications for many patients. all hospitalized patients should be discharged with clear recommended guidelines for safe and progressive conditioning at home as standard of care is now to provide medical oversight and guidance for patients at home whenever possible. a, a this has led to a rapid expansion of telehealth services across the medical continuum that includes all disciplines within physical medicine and rehabilitation even as the medical complexity of patients admitted to acute rehabilitation has increased. a the common admitting diagnoses to acute rehabilitation units during the pandemic has been deconditioning following acute hypoxic respiratory failure secondary to covid pneumonia. a key principle guiding care of covid- patients is the maintenance of adequate oxygenation at all times. for hospitalized patients the principles of early mobilization should be utilized whenever possible to prevent rapid deconditioning and further need for already limited rehabilitation services. a oxygen saturation should be maintained above % with liberal use of supplemental oxygen. continuous oximetry monitoring may be indicated for patients whose oxygenation level declines with trial mobilization on room air. covid- patients have also been found to be at higher risk for venous thromboembolic events (vtes), and baseline laboratory studies for all patients admitted to a rehabilitation unit should 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scientific statement from the council on clinical cardiology subcommittee on exercise, cardiac rehabilitation, and prevention effect of individualized exercise during maintenance haemodialysis on exercise capacity and healthrelated quality of life in patients with uraemia the full reference list for this chapter is available online. key: cord- -s ecvk authors: thota, sai manohar; balan, venkatesh; sivaramakrishnan, venketesh title: natural products as home‐based prophylactic and symptom management agents in the setting of covid‐ date: - - journal: phytother res doi: . /ptr. sha: doc_id: cord_uid: s ecvk coronavirus disease (covid‐ ) caused by the novel coronavirus (sars‐cov‐ ) has rapidly spread across the globe affecting countries or territories with greater than six million confirmed cases and about . million deaths, with world health organization categorizing it as a pandemic. infected patients present with fever, cough, shortness of breath, and critical cases show acute respiratory infection and multiple organ failure. likelihood of these severe indications is further enhanced by age as well as underlying comorbidities such as diabetes, cardiovascular, or thoracic problems, as well as due to an immunocompromised state. currently, curative drugs or vaccines are lacking, and the standard of care is limited to symptom management. natural products like ginger, turmeric, garlic, onion, cinnamon, lemon, neem, basil, and black pepper have been scientifically proven to have therapeutic benefits against acute respiratory tract infections including pulmonary fibrosis, diffuse alveolar damage, pneumonia, and acute respiratory distress syndrome, as well as associated septic shock, lung and kidney injury, all of which are symptoms associated with covid‐ infection. this review highlights the potential of these natural products to serve as home‐based, inexpensive, easily accessible, prophylactic agents against covid‐ . . mers emerged in saudi arabia in and spread mostly to the middle east with a few cases in europe, asia and north america (hemida, ) . it accounted for around , cases with a higher mortality rate of . % (who, ). since , there have been a few active sporadic outbreaks of mers (ramadan & shaib, ) . the symptoms of sars and mers are similar and include fever, cough, shortness of breath, myalgia or fatigue (muscle pain), and diarrhea. in severe cases, both these infections result in pneumonia, severe respiratory infection, acute respiratory distress syndrome (ards), sepsis, and multiple organ failure (al hajjar, memish, & mcintosh, ; peiris, yuen, osterhaus, & stöhr, ) . there is an increased risk of progression associated with age and comorbid conditions such as diabetes, hypertension, cardio, pulmonary, and renal diseases. pathological analysis of sars and mers reveals diffused alveolar damage (dad), edema, elevated levels of collagen, fibrin and inflammatory cells in alveoli leading to decline in lung function and acute lung injury (alsaad et al., ; franks et al., ) . bats were reported to be the natural hosts for sars and mers coronaviruses which were transmitted to intermediate hosts, and finally to humans (omrani, al-tawfiq, & memish, ; salata et al., ) . the transmission of sars and mers was by direct contact or through droplets of coughs and sneezes from the infected patients (killerby, biggs, midgley, gerber, & watson, ; peiris et al., ) . treatment for sars and mers involved administration of antiviral drugs in combination with corticosteroids and interferon-α (ifn-α), however, the treatment had minimal benefits to patients and severe adverse effects (al ghamdi et al., ; tai, ) . covid- first emerged in december in china causing acute respiratory tract infections (guo et al., ) . this new virus is highly contagious and has spread rapidly across the globe. who declared the outbreak as "public health emergency of international concern" (who, b) . by the end of may , the virus had spread to countries or territories with greater than six million confirmed cases and about . million deaths. furthermore, during this period, there was a steep rise in the number of reported cases and associated mortality (who, d) . although the overall fatality rate for covid- -infected patients is lower ( . %) compared with sarsand mers-infected subjects, the spread of the disease has been exceptionally rapid, causing a global pandemic. figure shows the covid- global pandemic curve with the total number of confirmed cases and deaths. the current statistics on the extent of infections globally could be a significant underestimate given the lack of enough testing kits and a large number of asymptomatic carriers. covid- has very close similarities to the sars virus and hence is named sars-cov- . bats are believed to be the primary source of the virus and although the exact mechanism of transmission to humans is unclear, it is considered to have resulted f i g u r e structure of sars-cov- virus showing the single-stranded rna and nucleocapsid (n) along with spike (s), envelope (e), and membrane (m) proteins. schematic representation shows viral entry through the respiratory tract causing lung infection by damaging bronchioles and alveoli. this is associated with edema or swelling and elevated levels of fibrin, collagen, and inflammatory cells leading to pulmonary fibrosis. the spike (s) protein of sars-cov- binds to ace on the human bronchial and alveolar epithelial cells and activates fibrosis, oxidative stress, and inflammatory responses leading to acute lung infection. ace , angiotensin-converting enzyme ; sars-cov- , severe acute respiratory syndrome coronavirus [colour figure can be viewed at wileyonlinelibrary.com] either from direct contact, consumption of meat or through intermediate hosts (guo et al., ) . patients with mild infection show fever, fatigue, dry cough, slight nasal congestion, and muscle pain. in severe cases, shortness of breath (dyspnea) associated with dry cough or sputum/ phlegm production (expectoration), along with signs of pneumonia are observed (guan et al., ) . in critical cases, patients show ards associated with complete respiratory failure, sepsis, septic shock, and multiple organ dysfunction including heart, liver, and kidney. these patients need ventilators in the intensive care unit (cascella, rajnik, cuomo, dulebohn, & di napoli, ) . elderly patients with chronic comorbidities like diabetes, hypertension, cardiovascular, and cerebrovascular diseases are at greater risk of contracting covid- (lai et al., ) . laboratory studies show low blood levels of lymphocytes and white blood cells, and high levels of c-reactive protein and lactate dehydrogenase in covid- -infected patients (tian et al., ; wang, hu, et al., , p. ). post-mortem lung sections from covid- -infected patients revealed dad with thickening of alveolar walls, edema, fibrin, and proteinaceous exudates in alveolar spaces, vascular congestion, and pneumocyte hyperplasia with viral inclusions and multinucleate giant cells (tian et al., ; . the chest computed tomography (ct) of covid- patients shows bilateral multifocal ground-glass opacity indicative of alveolar exudate and transudate, as well as pleural thickening (guan et al., ; wang, hu, et al., ) . the transmission of covid- virus occurs with close, prolonged, and unprotected contact with symptomatic or patients who test positive for the virus (person-to-person), (ghinai et al., ) , as well as via respiratory droplets (cascella et al., ) . figure shows the schematic representation of sars-cov- viral entry through the respiratory tract of a healthy individual leading to acute lung infection. it is thought that short distance aerosol transmission could also be a possible mode of transmission, although the evidence in support of this is not strong. furthermore, the transmission of the infection from asymptomatic individuals has been reported leading to the fear of community transmission (mizumoto, kagaya, zarebski, & chowell, ; rothe et al., ) . a retrospective study conducted in china examined a total of patients including individuals who recovered from covid- infection and patients who succumbed to the infection. in this study, individuals who recovered had a median age of years, whereas those who died were older with a median age of years. furthermore, the prevalence of comorbidities was significantly higher among the patients who failed to recover versus those who recovered. this included hypertension ( . vs. . %), prior history of lung disease ( . vs. . %), diabetes ( . vs. . %), and heart disease ( . vs. . %). interestingly, the common symptoms associated with the infection like fever, muscle pain, fatigue, and cough were found to f i g u r e covid- pandemic curve showing the total number of confirmed cases (orange bars) and the total number of deaths globally (blue bars). in-set highlights the increasing number of deaths (who, d) [colour figure can be viewed at wileyonlinelibrary.com] the same extent in both the patient groups with the exceptions of shortness of breath ( . vs. %) and expectoration ( . vs. . %). furthermore, patients who died had a higher incidence of ards ( . vs. . %), acute cardiac injury ( . vs. . %), acute kidney injury ( . vs. %), septic shock ( . vs. %) compared with individuals who showed complete recovery (deng et al., ) . another study described % of infected individuals to exhibit generic symptoms, with only about % showing dyspnea with rapid and shallow breathing, pneumonia, and disturbed pulmonary gas exchange. included within this group of individuals showing progressive symptoms was a smaller subset ( %) who developed acute symptoms of lung infection, sepsis, and organ failure requiring icu admission. importantly, the course of progression of this viral infection is relatively slow spanning an incubation period of - days from the time of exposure to onset of symptoms. in individuals who progress to a more severe state, this usually happens by around day after appearance of the initial symptoms (thomas-rüddel et al., ). preventive measures to control the spread of covid- pandemic are crucial and should be followed strictly. coronaviruses are inactivated by ethanol, chlorine-containing disinfectants, and lipid solvents. washing hands regularly with soap and sanitizers containing % ethanol/isopropanol to prevent the spread of viral infection is the recommended standard (kampf & kramer, ) . environmental surfaces have to be cleaned regularly with detergent or bleach such as sodium hypochlorite (naocl) solution. close contact with symptomatic individuals has to be avoided, while also avoiding touching eyes, nose, and mouth. individuals with a prior history of respiratory distress should wear masks and cover their coughs or sneezes. health care workers (hcws) should follow appropriate safety measures during the diagnosis, hospitalization, and isolation of covid- positive patients (who, c). during sample collection, precautions should be taken to prevent direct contact or exposure to airborne droplets. it is very essential to quarantine symptomatic individuals prior to diagnostic testing with appropriate safety guidelines (adhikari et al., ) . hcws caring for covid- patients should self-monitor body temperature and respiratory symptoms. strict hygiene protocols should be implemented in hospitals. immunocompromised individuals should avoid public/private gatherings (cascella et al., ) . social distancing or physical space between two individuals should be maintained to prevent the spread of the covid- pandemic. when symptomatic or asymptomatic covid- -infected person coughs or sneezes, the respiratory droplets (> - μm size) (atkinson et al., ) containing the sars-cov- virus are released into the air, which can infect a healthy individual within m radius. the virus can enter into the subject through the mouth (oral), nose (mucosal), or eyes (conjunctiva). given this, social distancing requires maintaining at least m or ft distance between individuals to avoid respiratory droplet transmission (yu & yang, ) . it requires avoiding crowded places and public gatherings and implements staying at home and limiting the number of visitors. respiratory hygiene should be followed by covering mouth and nose with a tissue or bent elbow while coughing and sneezing. in addition to the above, indirect transmission of the virus by contacting contaminated environmental surfaces has been described. hence, touching eyes, nose or mouth should be avoided. quarantining refers to keeping an asymptomatic individual who has been exposed to covid- , in isolation (sharma et al., ) . quarantine can be implemented at home (self-quarantine) or the individual can be secluded in a specially designed facility. importantly, quarantined individuals should be monitored for sign of fever, cough, and any other respiratory symptoms for up to days. isolation refers to segregating confirmed covid- patients away from healthy individuals to avoid the spread of the infection. this can be implemented either at home or in a hospital/isolation facility (wilder-smith & freedman, ; tang et al., ) . infected patients are monitored and administered care to manage their symptoms. to date, treatment is symptomatic and supportive, with oxygen therapy and mechanical ventilation for ards and hypoxemia; fluid bolus therapy, vasopressors, and antibiotics for septic shock, as well as treatment to mitigate co-infections (who, a). there are no potentially effective drugs or vaccines available for the treatment of covid- and this has resulted in an explosion in research aimed at developing specific drugs. in parallel, existing drugs are being repurposed to test their efficacy against the sars-cov- virus. for example, broad-spectrum antiviral drugs (remdesivir, ribavirin, and ifn-α) (dong, hu, & gao, ) , antimalarial drugs (chloroquine and hydroxychloroquine) (gautret et al., ) , and combination of retroviral drugs (ritonavir/lopinavir) are being evaluated in covid- patients. early results suggest that patients treated with these repurposed drugs show no improvement in the mortality rate, while the viral rna load seems to show a slight decrease. however, in most patients, increased adverse events have been observed , which in more pronounced in individuals with underlying comorbidities (srinivasa, tosounidou, & gordon, ) . given the lack of targeted drugs to treat covid- , different approaches to mitigate covid- -associated complications are being evaluated. in this context, this review highlights the potential beneficial effects of natural products that are actively used in alternative/ traditional medicines to treat many of the acute pulmonary infections, routinely seen in covid- patients. these natural products can also boost immunity which is key to resist covid- infection. medicinal plants are the biggest age-old source of therapeutically beneficial phytochemicals used for maintaining good health, and to prevent and treat many diseases. these include plants and herbs that are both used in ayurveda, a traditional and alternative medicinal therapy based on holistic body healing, which originated in the indian subcontinent. a huge body of research is currently focused on understanding the therapeutic efficacy and mechanism of action of these phytochemical agents. the following sections describe dietary supplements and home-based remedies that have shown value as preventive agents for acute respiratory infections, pulmonary fibrosis, pneumonia, sepsis, and multiple organ failure; all of which are characteristic manifestations of severe covid- infection. in addition, many of these agents boost the immune system and imbues protection against infective agents. figure summarizes the beneficial properties of natural products against viral or chemically induced fibrosis, oxidative stress, inflammatory response, and associated acute lung injury in the setting of covid- . mechanistically, the available knowledge base shows that oxidative stress and dysfunctional immune system, in addition to existing comorbidities, contribute to many of the complications associated with covid- infection. for example, oxidative stress is an important factor resulting in pathogen-induced pulmonary fibrosis (cheresh, kim, tulasiram, & kamp, ) . along the same lines, an effective immune system is essential for surveying pathogens and neutralizing them in an efficient and timely manner to protect the individual from the infection. the medicinal plants described here contain diverse phytochemicals that have antiviral, antifibrotic, antioxidant, antiinflammatory, and immunomodulatory properties. these, when used in combination, could have a synergistic effect as prophylactic or supportive agents to minimize certain clinical symptoms observed in covid- -infected patients. in addition, certain species of bacteria, algae, and fungi also exert therapeutic effects against pulmonary fibrosis and acute lung injury. table summarizes the evidence in the literature supporting the therapeutic value of specific species of bacteria, algae, and fungi, as well as plants. the detailed summary of the therapeutic properties for each of the key natural products discussed in this review is provided in table s . among these, we have identified ginger, turmeric, garlic, onion, cinnamon, lemon, neem, basil, and pepper as well as mushrooms as readily available home-based remedies that have shown efficacy against pulmonary symptoms associated with covid- infections in various pre-clinical and clinical trials. ginger (zingiber officinale) has therapeutic properties against pulmonary fibrosis, pneumonia, ards, sepsis, and acute kidney injury. in addition, ginger along with its phytochemicals has antiviral, antifibrotic, antioxidant, antiinflammatory, and hepatoprotective properties (chang, wang, yeh, shieh, & chiang, ; mao et al., ; rahmani, shabrmi, & aly, ) . f i g u r e schematic illustration summarizing the beneficial properties of natural products and their impact on oxidative stress, inflammatory response, pulmonary fibrosis, and acute lung injury [colour figure can be viewed at wileyonlinelibrary.com] t a b l e literature-based evidence supporting the therapeutic value of various species of bacteria, algae, fungi, and plants ginger has significantly reduced pulmonary fibrosis and mitigated oxidative stress and inflammatory response in chemically induced pulmonary fibrosis in animal models. for example, bleomycin, a cytotoxic antibiotic used in cancer treatment, has idiopathic pulmonary fibrosis (ipf) as a side effect. in bleomycin-treated rats, zingerone, a bioactive compound in ginger has significantly reduced fibrosis score in histopathological sections of lungs, reduced levels of fibrosis marker, hydroxyproline and oxidative stress marker, and malondialdehyde (mda). in addition, it increased levels of antioxidant markers like reduced glutathione (gsh), superoxide dismutase (sod), and glutathione peroxidase (gsh-px) in the lungs . similarly, in ethanol-treated rats that exhibit symptoms of diffuse alveolar damage and acute lung injury leading to ards, extracts of ginger mitigated abnormalities in alveolar air space, wall thickening, infiltration of multinucleated cells and pneumocytes, lung cell proliferation, and fibrosis in the ethanol-treated rats. in addition, ginger significantly reduced the oxidative stress markers namely -hydroxy- -deoxyguanosine ( -ohdg), oxidized low-density lipoprotein (ox-ldl), and nadh oxidase levels. (shirpoor, gharalari, rasmi, & heshmati, ) . in a separate clinical study on ards patients, mg of ginger extract was shown to increase the tolerance of enteral feeding, significantly reduced nosocomial pneumonia and increased the icufree and ventilator-free days compared with the placebo group (shariatpanahi, taleban, mokhtari, & shahbazi, ) . ginger with its bioactive compounds has also ameliorated sepsis and acute kidney injury (aki) induced by cecal ligation and puncture (clp) in rats. specifically, in this study, the authors demonstrated that -gingerol and -gingerol significantly reduced pathological levels of aki markers, oliguria, blood urea nitrogen, urinary protein, serum creatinine levels, urinary sodium, and osmolarity in these rats. both compounds have also reduced the levels of oxidative stress markers, mda and nitrite, as well as increased the levels of antioxidants, gsh and sod. in addition, they also reduced levels of inflammatory markers such as tumor necrosis factor-α (tnf-α), interleukin (il)- β, and kidney injury marker, turmeric (curcuma longa) has potential therapeutic effects on pulmonary fibrosis, severe respiratory disorders, lung infections, liver abnormalities. curcumin, the bioactive compound in turmeric has been shown to have antifibrotic, antioxidant, antiinflammatory, and immunomodulatory activities (jurenka, ; menon & sudheer, ; srivastava, singh, dubey, misra, & khar, ) . in bleomycin-induced pulmonary fibrosis rats, curcumin increased the expression of cathepsins (catk, catl) which degrade collagen, and inhibited lung fibroblast proliferation by blocking transforming growth factor (tgf)-β (smith et al., ; zhang et al., ) . in these rats, curcumin also suppressed the inflammatory cytokine tnf-α released by alveolar macrophages ameliorating pulmonary fibrosis (punithavathi, venkatesan, & babu, ) . paraquat is a toxic herbicide that leads to pulmonary fibrosis, edema, acute lung injury, and respiratory failure. in the paraquatinduced pulmonary fibrosis rat model, curcumin reduced the deposition of collagen fiber and inhibited fibrosis. in parallel, it also improved the tidal volume (volume of air taken during normal breath) and arterial partial pressure of oxygen (pao ) in the lungs (chen, yang, et al., ) . in these rats, at the molecular level, curcumin decreased the levels of fibrosis marker hydroxyproline, as well as oxidative stress markers, and inhibited lung fibrosis (hosseini et al., ) . in addition, it is well documented that impaired immune system with imbalances in inflammatory cells and cytokines can aggravate lung fibrosis (hügle, ) . in this context, it is important to note that curcumin is a potent immunomodulator and can regulate the function of dendritic cells, natural killer (nk) cells, neutrophils, macrophages, t cells, and b cells, as well as inflammatory cytokines (gautam, gao, & dulchavsky, ) . all the above pre-clinical findings strongly implicate turmeric as an agent that can improve lung function, and protect against acute lung injury and associated dad, pulmonary fibrosis, and ards, all of which are observed in covid- patients. garlic (allium sativum) has potential therapeutic effects against respira- garlic is also a potent immunomodulator (ishikawa et al., ) . in a clinical study on humans, dietary consumption of g of garlic every - days, boosted the basal plasma ifn-α levels which are known to be protective against viral infections and prevent viral replication (bhattacharyya, girish, karmohapatra, samad, & sinha, ) . importantly, these pre-clinical studies highlight the efficacy of garlic in mitigating pulmonary fibrosis, lung injury, and sepsis-associated organ failure, all of which are symptoms observed in patients with advanced covid- infection. onion (allium cepa) has potential therapeutic benefits against acute respiratory tract infection and lung injury caused by collagen deposition, inflammatory cell infiltration, and pulmonary fibrosis. onion along with its bioactive compounds, quercetin, apigenin, and selenium is known to exert antiviral, antifibrotic antioxidant, antiinflammatory, antiasthmatic and hepatoprotective properties (kumar & pandey, ; marefati et al., ; suleria, butt, anjum, saeed, & khalid, ) . onion has been shown to significantly alleviate pulmonary fibrosis tnf-α, ifn-γ, and il- a (farazuddin et al., ) . in a separate clinical study, lower selenium levels were observed in patients with respiratory disorders admitted to the icus that correlated with decreased lymphocytes and increased c-reactive protein levels (lee et al., ) . in other studies, conducted on hospitalized patients with pneumonia and bronchiolitis, mg of sodium selenite was found to reduce signs of respiratory infection and improve the recovery time. at the molecular levels, it increased the levels of antioxidant glutathione peroxidase as well as the leukocyte count (hu, liu, yin, & xu, ; liu, yin, & li, ) . together, these pre-clinical and clinical studies highlight the potency of onion in ameliorating pulmonary fibrosis, acute respiratory tract infections, and lung injury which are the critical symptoms of covid- patients. cinnamon (cinnamomum verum or c. zeylanicum) along with its major bioactive compounds, cinnamaldehyde, eugenol, and linalool, has potent antiviral, antioxidant, antiinflammatory, and hepatoprotective properties (jayaprakasha & rao, ; kawatra & rajagopalan, ; rao & gan, ) . in ccl and lps-stimulated rat and mice, cinnamon extracts reduced mda and increased levels of antioxidant markers catalase and sod. it also reduced antiinflammatory markers tnf-α/il- , reduced phosphorylation of mapks (jnk, p and erk / ), and interfered with nf-κb activation by inhibiting the degradation of iκbα. it has also reduced necrosis and infiltration of lymphocytes in the liver of rats with hepatic injury (hong et al., ; moselhy & ali, ) . overall, these studies implicate promising therapeutic roles of cinnamon against the sars-cov- infection in covid- . lemon (citrus limon) has potential therapeutic benefits against pulmonary fibrosis, pneumonia, ards, sepsis, acute lung, kidney, and liver injury. lemons contain vitamin-c (vit-c) or ascorbic acid (aa), which is an antifibrotic, antioxidant, antidiabetic, as well as an immunomodula tor. it is also documented to be protective against respiratory infections (ashbel' & arziaeva, ; chambial, dwivedi, shukla, john, & sharma, ; hong, lee, lee, & kim, ) . consistent with this, individuals with lower ascorbic acid levels are prone to severe infections and other acute diseases (bakaev & duntau, ) . in a case study involving a patient with dyspnoea, hypoxemia, and ards, placed on ventilator support, vitamin-c ( mg/kg body weight every hr) administered intravenously improved bilateral lung opacities as seen by chest x-ray, attenuated sepsis-associated ards, and was extubated (bharara et al., ) . in an independent clinical study containing critically ill surgical patients from icus, patients receiving antioxidant therapy (aa and α-tocopherol) had a relatively lower risk of pulmonary morbidity (a measure of ards and pneumonia), multiple organ failure and mortality compared with the standard of care patients. importantly, patients on antioxidant therapy required mechanical ventilation and icu admission for a shorter period of time (nathens et al., ) . in a separate clinical study, elderly patients hospitalized for bronchitis and pneumonia were administered oral vitamin-c ( mg/day) and compared with the placebo arm. vitamin-c levels in the treated group were higher in the plasma and leukocytes, and these patients were showed pulmonary complications (hunt, chakravorty, annan, habibzadeh, & schorah, ) . in a pre-clinical study comparing the effect of sepsis in mice lacking the capacity to synthesize vitamin-c (l-gulono-γ-lactone oxidase deficient, −gulo) versus wild-type controls (+gulo), lack of vitamin-c resulted in multiple organ failure, pulmonary edema, and proinflammatory response, all of which were attenuated by intraperitoneal infusion of vitamin-c (fisher et al., ) . similar results were obtained in independent studies using sepsis and acute lung injury models treated with or without vitamin-c ( mg/kg) (fisher et al., (fisher et al., , . along the same lines, in paraquat-induced pulmonary fibrosis mice model, vitamin-c has blocked infiltration of lymphocytes, neutrophils, macrophages, and attenuates pulmonary fibrosis. it also significantly decreased collagen deposition and reduced levels of pro-inflammatory markers, tgf-β, il- , il- , and enhanced antioxidant markers namely catalase and sod . vitamin-c also has significant immunomodulatory properties. it gets accumulated in neutrophils and enhances phagocytosis, nk cell activity, and lymphocyte proliferation (carr & maggini, ; wintergerst, maggini, & hornig, ) . taken together, preclinical and clinical studies suggest that vitamin-c could have promising therapeutic benefits in individuals with pulmonary fibrosis, pneumonia, ards, sepsis, acute lung injury, and multiple organ dysfunction all of which are observed in advanced covid- patients. neem (azadirachta indica) has potential therapeutic benefits against pulmonary fibrosis pulmonary inflammation, acute lung injury, and alveolar damage. the bioactive compounds in neem are azadirachtin, nimbolinin, nimbolide, quercetin, and β-sitosterol. these are known to exhibit antiviral, antioxidant, and antiinflammatory (alzohairy, ; subapriya & nagini, ; tiwari, darmani, yue, & shukla, ) properties. in a bleomycin-induced pulmonary fibrosis mice model, nimbolide has been shown to significantly reduce pulmonary fibrosis by decreas- basil a.k.a. tulsi (ocimum sanctum) along with its bioactive compounds, quercetin, eugenol, and apigenin has been shown to exhibit antiviral, antioxidant, antiinflammatory, antiasthmatic, and immunomodulatory properties (mahajan et al., ; mediratta, sharma, & singh, ; pattanayak et al., ; saini, sharma, & chhibber, ). in healthy humans, weeks oral administration of ethanol extracts of tulsi significantly increased the levels of ifn-γ, il- , t-helper cells, and nk-cells (mondal et al., ). black pepper (piper nigrum), known as "king of spices", has antiviral, antioxidant, and antiinflammatory properties (butt et al., ; vijayakumar et al., ) . the bioactive compound piperine is known to enhance the bioavailability of many drugs and phytochemicals by increasing their absorption from the gastrointestinal tract (pattanaik, hota, prabhakar, & pandhi, ) . for example, mg black pepper when taken along with g turmeric was shown to increase the bioavailability of the latter by -fold (shoba et al., ) . in light of this, one would envision that the bioavailability of the supplements discussed above could be enhanced by combining them with black pepper. medicinal mushrooms are an untapped resource which show potential antiviral, antiinflammatory, and immunomodulatory properties against various viruses like hsv, ebv hepatitis c virus, (hcv), human immunodeficiency virus (hiv), h n strain of flu, and influenza (ellan et al., ; linnakoski et al., ; muszy nska, grzywacz-kisielewska, kała, & gdula-argasi nska, ) . the secondary metabolites from these mushrooms such as alkaloids, non-ribosomal peptides, polyketides, and terpenoids have shown protease inhibitory activities against hiv- and hepatitis c virus (el-fakharany, haroun, ng, & redwan, ; sato et al., ; sillapachaiyaporn et al., ) . papaya (carica papaya) along with its bioactive compounds show antiviral, antioxidant, and antiinflammatory properties (joseph, sankarganesh, ichiyama, & yamamoto, ; panzarini, dwikat, mariano, vergallo, & dini, ) . thrombocytopenia or low blood platelet count could be another risk factor correlating with both, severity and higher mortality in covid- patients (lippi, plebani, & henry, ) . similarly, low platelet count is also associated with ipf, multiple organ failure and acute kidney injury (nguyen, cruz, & carcillo, ; steiropoulos et al., ) . thrombocytopenia is a common clinical manifestation in dengue patients and studies suggest that activation of platelets leads to prothrombotic state in these patients (jayashree, manasa, pallavi, & manjunath, ; ojha et al., but was inactivated at temperatures greater than c (rabenau et al., ) . similarly, uv radiation for -min was also shown to inactivate the virus (duan et al., ) . in turn, these findings highlight the importance of boiling water before drinking. in addition, inhaling steam generated from water containing turmeric and tulsi is effective against respiratory tract infections (saleem, rani, & daniel, ; shuman, raju, & jogdeo, ; singh, singhi, & walia, ). furthermore, fumigating living rooms with medicated smoke from burnt neem leaves has also been shown to be effective in combating the virus (khedekar, goel, & ojha, ) . taken together, the prophylactic measures to protect against coronaviruses could include avoiding cold beverages, boiling/or uv-based sterilization of drinking water. the spike protein (s-protein) of sars-cov- virus recognizes and binds to the angiotensin-converting enzyme (ace , figure ) on bronchial and alveolar epithelial cells and vascular endothelial cells (zhang, penninger, li, zhong, & slutsky, ) . the viral membrane fuses with the host membrane, and the viral rna along with nucleocapsid proteins is released and replicated further in the host cells. the viral infection triggers apoptosis of epithelial and endothelial cells leading to secretion of inflammatory cytokines, il- β, il- , il- , tnf-α, and ifn-γ, that destroy the host cells (fu, cheng, & wu, ) . sars cov papain-like protease (plpro) upregulates the expression of tgf-β , a profibrotic cytokine (li et al., ) . the activation of tgf-β by proteolytic cleavage of its latent complex form is carried out by mmp- and mmp- (kobayashi et al., ; wang et al., ) . interestingly, as shown in figure , the bioactive compounds inhibit tgf-β activation by suppressing these mmps kumar, kumar, saravanan, & singh, ) . tgf-β induces proliferation of fibroblasts and their differentiation into myofibroblasts that secrete extracellular matrix (ecm) leading to fibrosis michalik et al., ) . in the canonical pathway, tgf-β phosphorylates the downstream effector proteins smad and smad that further activate the expression of pro-fibrotic proteins namely fibronectin, collagen type i/iii, α-sma, and vimentin (malmström et al., ) . the bioactive compounds inhibit the phosphorylated smad and smad , and enhance the expression of smad (a tgf-beta antagonist), leading to downstream suppression of fibroblast proliferation and their differentiation into myofibroblasts, as well as inhibition of pro-fibrotic gene expression (nie et al., ; smith et al., ) . in the non-canonical pathway, tgf-β activates p mitogenactivated protein kinase (mapk) that induces epithelial to mesenchymal transition (emt) zhang, (huang, ; park, kim, & lee, ). the non-structural proteins (nsp , nsp a, and nsp a) and spike proteins of sars-cov activates nf-κb, resulting in the inflammatory response and ros, which further drives the pathogenesis (liao et al., ) . s protein also degrades iκb-α, resulting in activation of nf-κb, that further upregulates tnf-α and il- (dediego et al., ; wang et al., ) . bioactive compounds inhibit expression of tnf-α and enhance iκb-α expression, together leading to suppression of nf-κb-mediated expression of inflammatory cytokines and chemokines. these compounds also have direct inhibitory effect on ros and inflammatory cytokines and enhance the expression of antioxidants. it has also been shown that the sars-cov virus downregulates the ace expression, and this could further trigger acute lung injury (glowacka et al., ; kuba et al., ) . covid- causes acute respiratory tract infections, pulmonary fibrosis, sepsis, and multiple organ failure, all of which could result in mortality. study on the severity and progression of covid- suggests that, among the patients who died, % had shortness of breath and % had expectoration. this implies that underlying pathogenesis like the initiation of fibrosis and alveolar damage might begin early during the - days of incubation period after exposure to the virus. natural products taken during these initial stages of viral infection could prevent further progression of the infection and stabilize the initial symptoms. furthermore, among the patients who died, around % had ards, suggesting that the major cause of mortality was the acute lung infection, pulmonary fibrosis and pneumonia. natural products that are effective against these pulmonary conditions could be beneficial supplements to promote the recovery of patients showing these advanced covid- -related symptoms. considering the widespread global outbreak of covid- , controlled clinical trials might not be feasible. in some clinical settings, antimalarial, retroviral drugs, and corticosteroids are being repurposed and are showing adverse side effects. in this context, given the therapeutic efficacy of many of the natural products, these could be administered in combination with the clinical standard of care to mitigate treatment-related side effects. importantly, unlike chemotherapeutic supplements, natural products have no adverse effects. in summary, natural products have shown therapeutic efficacy against multiple symptoms observed in advanced covid- patients. they are highly tolerated with no side effects and can be used in combination with existing clinical standard of care. in this setting, natural products have the potential to serve as prophylactic agents in populations that are at risk to develop covid- infection. these include elderly individuals as well as those who have underlying comorbid conditions. in addition, in symptomatic patients, natural product supplementation can halt the progression of the infection. in the case of patients who have progressed to an advanced stage, natural products can mitigate many of the complications and reduce mortality. importantly, natural product supplementation constitutes homebased remedies that are inexpensive and can be easily implemented on a community-wide scale. the authors declare no conflicts of interest. sai manohar thota conceptualized, designed, searched databases/ articles, and wrote the manuscript. venkatesh balan and venketesh sivaramakrishnan contributed to manuscript writing and provided scientific guidance. dedicated to india and her traditional medicine system-ayurveda. sai manohar thota https://orcid.org/ - - - venkatesh balan https://orcid.org/ - - - venketesh sivaramakrishnan https://orcid.org/ - - - epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid- ) during the early outbreak period: a scoping review treatment outcomes for patients with middle eastern respiratory syndrome coronavirus (mers cov) infection 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against bleomycin-induced pulmonary fibrosis by inhibiting tgf-β /smad pathways and overexpression of nox antifibrotic effects of curcumin are associated with overexpression of cathepsins k and l in bleomycin treated mice and human fibroblasts angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target histopathologic changes and sars-cov- immunostaining in the lung of a patient with covid- preventive effects of rhodiola rosea l. on bleomycin-induced pulmonary fibrosis in rats quercetin ameliorates pulmonary fibrosis by inhibiting sphk /s p signaling non-smad pathways in tgf-β signaling gastrodin protects against lps-induced acute lung injury by activating nrf signaling pathway neferine, a bisbenzylisoquinline alkaloid attenuates bleomycininduced pulmonary fibrosis effects of andrographolide on the concentration of cytokines in balf and the expressions of type i and iii collagen mrna in lung tissue in bleomycin-induced rat pulmonary fibrosis protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice procyanidins and butanol extract of cinnamomi cortex inhibit sars-cov infection natural products as home-based prophylactic and symptom management agents in the setting of covid- the authors thank prof. arun sreekumar, baylor college of medicine, houston, texas, usa, for careful and insightful review of the manuscript. mr. thota and dr. sivaramakrishnan thank central research key: cord- -ralxw ad authors: oishi, peter; fineman, jeffrey r. title: diseases of the pulmonary vascular system date: - - journal: the respiratory tract in pediatric critical illness and injury doi: . / - - - - _ sha: doc_id: cord_uid: ralxw ad nan although historically considered the lesser circulation, pathology of the pulmonary circulation is a great source of pediatric morbidity and mortality. this is most commonly displayed in neonates with persistent pulmonary hypertension; neonates, infants, and children with congenital heart disease; and adolescents and young adults with primary pulmonary hypertension. recent evidence indicates that normal pulmonary vascular tone is regulated by a complex interaction of vasoactive substances that are locally produced by the vascular endothelium [ ] [ ] [ ] [ ] [ ] [ ] . these substances, such as nitric oxide (no) and endothelin- (et- ), are capable of producing vascular relaxation and/or constriction, modulating the propensity of blood to clot, and inducing and/or inhibiting smooth muscle cell migration and replication [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in fact, mounting data implicate endothelial injury and the subsequent aberration in the endogenous production of these substances in the pathophysiology of pulmonary hypertensive disorders [ ] [ ] [ ] [ ] [ ] . this chapter discusses the normal regulation of the fetal, transitional, and postnatal pulmonary circulations, the pathophysiology of pediatric pulmonary hypertensive disorders, and new therapeutic and preventative strategies for pulmonary hypertension. particular emphasis is placed on the role of the pulmonary vascular endothelium in these processes and treatment modalities. fl ow and decreases pulmonary vascular resistance but not to newborn values [ ] . a proportion of this decrease relates to alterations in the physical architecture of the alveoli and small pulmonary vessels that occur with mechanical distention [ ] . in addition, physical expansion of the lung results in the release of vasoactive substances, such as pgi , which increases pulmonary blood fl ow and decreases pulmonary vascular resistance in the fetal goat and lamb independent of the changes in oxygen tension [ ] [ ] [ ] [ ] [ ] [ ] . when ventilation is accompanied by changes in oxygen tension (i.e., ventilation with ambient air or supplemental oxygen), fetal pulmonary blood fl ow increases and pulmonary vascular resistance falls to newborn values. the exact mechanisms of this oxygen-induced pulmonary vasodilation remain unclear. alveolar and/or arterial oxygen may directly dilate pulmonary resistance vessels or may trigger the release of vasoactive substances, such as pgi or no. in fact, data indicate that no, in particular, participates in the decrease in pulmonary vascular resistance that accompanies increases in alveolar and arterial oxygen tension [ , ] however, despite its important role, inhibition of no does not impair the immediate fall in pulmonary vascular resistance seen after birth, further suggesting that multiple mechanisms are involved in this transitional physiology. in fact, recent data implicate fl uid shear forces across endothelial cells, which result in the production of both no and pgi , as an additional mechanism by which vasodilation occurs after birth [ ] . it is possible that this particular mechanism acts to maintain pulmonary vasodilation once it has been established by the mechanisms described earlier. in general, the dramatic increase in pulmonary blood fl ow with the initiation of ventilation and oxygenation at birth refl ects a shift from active pulmonary vasoconstriction in the fetus to active pulmonary vasodilatation in the newborn. failure to undergo this normal transition contributes substantially to the pathophysiology of many neonatal pulmonary hypertensive disorders, including bronchopulmonary dysplasia, persistent pulmonary hypertension of the newborn, chronic lung disease, and congenital heart disease [ , . the successful transition from the fetal to the postnatal pulmonary circulation is marked by the maintenance of the pulmonary vasculature in a dilated, low-resistance state [ ] . recent evidence suggests that basal no release, and the subsequent increase in smooth muscle cell cyclic guanosine monophosphate (cgmp) concentrations, in part mediate the low resting pulmonary vascular resistance of the newborn [ ] . other vasoactive substances, including histamine, -hydroxytryptamine, bradykinin, and metabolites of arachidonic acid by the cyclooxygenase and lipoxygenase pathways, have also been implicated in mediating postnatal pulmonary vascular tone; however, their roles are not well elucidated. two of the most important factors affecting pulmonary vascular resistance in the postnatal period are oxygen concentration and ph. decreasing oxygen tension and decreases in ph elicit pulmonary vasoconstriction [ ] . alveolar hypoxia constricts pulmonary arterioles, diverting blood fl ow away from hypoxic lung segments, toward well-oxygenated segments, thus enhancing ventilationperfusion matching [ ] . this response to hypoxia, unique to the pulmonary vasculature, is greater in the younger animal than in the adult [ ] . indeed, in most vascular beds (e.g., cerebral vasculature), hypoxia is a potent vasodilator. the exact mechanism of hypoxic pulmonary vasoconstriction remains incompletely under-stood but likely involves changes in the local concentration of reactive oxygen species that in turn regulate voltage-gated potassium channels and calcium channels [ , ] . acidosis potentiates hypoxic pulmonary vasoconstriction, whereas alkalosis reduces it [ ] . the exact mechanism of ph-mediated pulmonary vascular reactivity also remains incompletely understood but appears to be independent of paco [ ] . recent data suggest that potassium channels play an important role in mediating these responses as well [ ] . manipulating alveolar oxygen tension and systemic arterial ph are fundamental approaches to changing pulmonary vascular tone in the critical care setting. alveolar hyperoxia and alkalosis are often used to decrease pulmonary vascular tone because they generally relieve pulmonary vasoconstriction with little effect on the systemic circulation as a whole. however, severe alkalosis is generally avoided because of the detrimental effects of severe hypocarbia or alkalosis on cerebral and myocardial blood fl ow (see general treatment approach, later) [ , ] . despite extensive innervation of the lung, neural input is not a major determinant of basal pulmonary vascular tone. however, pulmonary neurohumoral receptors are sensitive to α-adrenergic, β-adrenergic, and dopaminergic agonists [ , ] . therefore, vasoactive agents that stimulate these receptors will affect the vascular tone of both the pulmonary and systemic circulations. alterations in vascular tone, in response to a given agent, are dependent on the relative tone of the vascular bed at a given time. therefore, the response of these agents is diffi cult to predict in an individual critically ill patient. pulmonary vascular resistance changes throughout gestation and after birth. the resistance of the pulmonary circulation at any one time is related to several factors and can be estimated by applying the resistance equation and the poiseuille-hagen relationship [ ] . the resistance equation (the hydraulic equivalent of ohm's law) states that the resistance to fl ow between two points along a tube equals the decrease in pressure between the two points divided by the fl ow [ , ] . for the pulmonary vascular bed, where rp is pulmonary vascular resistance and qp is pulmonary blood fl ow, the decrease in mean pressure is from the pulmonary artery (ppa) to the pulmonary vein (ppv) or left atrium, where la is mean left atrial pressure: rp = [ppa − ppv or la (mean)]/qp therefore, the calculated pulmonary vascular resistance increases when pulmonary arterial pressure increases or when pulmonary blood fl ow decreases. changes in pulmonary venous pressure or mean left atrial pressure are somewhat more complicated. in isolation, increases in pulmonary venous pressure and left atrial pressure would decrease the calculated pulmonary vascular resistance. however, increases in pulmonary venous pressure are generally accompanied by a greater increase in pulmonary arterial pressure (which maintains driving pressure), resulting in an increase in the calculated resistance across the pulmonary vascular bed. furthermore, changes in left atrial pressure, which occur independent of alterations in pulmonary vascular resistance, must be considered. for example, large intracardiac shunts (e.g., ventricular septal defect) may result in congestive heart failure with an elevation in left atrial pressure. closure of the ventricular septal defect may acutely decrease left atrial pressure, resulting in an elevation in the calculated pulmonary vascular resistance (provided that pulmonary arterial pressure does not decrease to the same extent), when in fact no change in pulmonary vascular tone has occurred [ ] . other factors that affect pulmonary vascular resistance can be defi ned by applying a modifi cation of the poiseuille-hagen relationship, which describes the resistance (r) to fl ow of a newtonian fl uid through a system of round, straight glass tubes of constant cross sectional area: where l is length of the system of vessels, n is vessel number, r is the internal radius of the system of vessels, and η is the viscosity of the fl uid. according to this relationship, increasing the viscosity of blood perfusing the lungs or decreasing the radius or crosssectional area (πr ) of the pulmonary vascular bed increases pulmonary vascular resistance. because the above equations describe steady, laminar fl ow of a newtonian fl uid in rigid, glass tubes, differences between physical and biologic systems should be considered. first, blood is not a newtonian fl uid. however, this is probably of little importance at normal hematocrit levels [ ] . the viscosity of blood is related to red cell number, fi brinogen concentration, and red cell deformability. an increased hematocrit (secondary to fetal hypoxemia, twin-to-twin transfusion, maternal-to-fetal transfusion, or delayed clamping of the umbilical cord) will increase viscosity [ , ] as pulmonary vascular resistance increases logarithmically when the hematocrit increases. second, pulmonary vessels are not rigid tubes. their walls are deformable, and their size and shape are infl uenced by transmural pressure. for example, as pulmonary blood fl ow or left atrial pressure increases, vessel diameter may change, and/or the recruitment of additional pulmonary vessels may occur. therefore, the fall in calculated pulmonary vascular resistance with increases in pulmonary blood fl ow is nonlinear [ , , ] . third, blood fl ow through the pulmonary circulation is pulsatile, not laminar, and the small pulmonary arteries are branched, curved, and tapered, not smooth [ ] . in addition, the small pulmonary arteries are in parallel, and the radii of these arteries may differ in different lung zones. despite these differences from physical models, the general effects of changes in physical factors, such as viscosity and radius, do apply [ ] [ ] [ ] . in fact, a change in luminal radius is the major factor responsible for maintaining a high pulmonary vascular resistance in the fetus. consideration of these factors, particularly viscosity and cross-sectional area of the vascular bed, is important in evaluating the pathophysiology of pulmonary hypertensive disorders. finally, it is important to note the overall relationship between lung volume and pulmonary vascular resistance, which has been described by several investigators [ , ] . these studies have shown that this relationship to be u-shaped (figure . ) with minimal pulmonary vascular resistance noted at functional residual capacity. using an open-chest model, pulmonary vascular resistance decreased as lungs were infl ated from a collapsed state and then progressively increased at higher lung volumes, which was thought to be related to infl ation pressure on the alveolar vessels. these observations support the concept that lung infl ation may have a variable effect on the distribution of pulmonary blood fl ow. when pressure is expressed in mm of hg and fl ow in l/min, units of resistance are derived as mm of hg/l/min (wood unit, u). however, comparisons among patients of differing weight and age are problematic. therefore, resistance is more commonly expressed in relation to body surface area, as u·m . multiplying u by converts to dynes/sec/cm − , a common form utilized to express resistance in other settings. pulmonary vascular resistance may be as high as - u·m immediately after birth and then, under normal conditions, falls as previously described to adult levels of - u·m by to weeks of life [ , ] . pulmonary hypertensive disorders are a signifi cant source of morbidity and mortality in the pediatric population. pulmonary hypertension is defi ned as a mean pulmonary artery pressure of greater than mm of hg at rest or greater than mm of hg during exercise. in addition, a calculated pulmonary vascular resistance of greater than u is generally considered abnormal. in neonates, the most common etiology results from a failure to undergo the normal fall in pulmonary vascular resistance at birth termed persistent pulmonary hypertension of the newborn (pphn) that has an incidence of ∼ per , live births. however, other pulmonary abnormalities, such as congenital diaphragmatic hernia, respiratory distress syndrome, and bronchopulmonary dysplasia, may also result in neonatal pulmonary hypertension. beyond the neonatal period, the majority of pediatric pulmonary hypertensive disorders are associated with congenital heart defects. other, less common causes of pediatric pulmonary vascular disease include primary (idiopathic) pulmonary hypertension, hypoxiainduced pulmonary vascular disease, rheumatologic disorders, sickle cell disease, portal hypertension, chronic thromboembolic disease, human immunodefi ciency virus disease, and drug-toxin induced disease. a number of clinical classifi cation systems for vascular endothelial cells are capable of producing a variety of vasoactive substances that participate in the regulation of normal vascular tone. a schematic of some of these endothelial factors is shown in figure . . these substances, such as no, et- , and prostacyclin are capable of producing vascular relaxation and/or constriction, modulating the propensity of the blood to clot, and inducing and/or inhibiting smooth muscle cell migration and replication [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . nitric oxide is a labile humoral factor produced by nitric oxide synthase (nos) from l-arginine in the vascular endothelial cell [ ] [ ] [ ] . nitric oxide diffuses into the smooth muscle cell and produces vascular relaxation by increasing concentrations of guanosine ′ ′-monophosphate (cgmp) via the activation of soluble guanylate cyclase [ , ] . nitric oxide is released in response to a variety of factors, including shear stress (fl ow) and the binding of certain endothelium-dependent vasodilators (such as acetylcholine, adenosine triphosphate [atp], and bradykinin) to receptors on the endothelial cell [ , ] . basal no release is an important mediator of both resting pulmonary and systemic vascular tone in the fetus, newborn, and adult, as well as a mediator of the normal fall in pulmonary vascular resistance that occurs immediately after birth , , ] . in addition, aberrant no-cgmp signaling is integral to the pathophysiology of pulmonary hypertension, as well as a number of other biologic vascular disorders [ , , , , , , , ] . endothelin- is a amino acid polypeptide also produced by vascular endothelial cells [ ] . the vasoactive properties of et- are complex, and studies have shown varying hemodynamic effects on different vascular beds [ ] [ ] [ ] [ ] [ ] . however, its most striking property is its sustained hypertensive action. in fact, et- is the most potent vasoconstricting agent discovered, with a potency times that of angiotensin ii. the hemodynamic effects of et- are mediated by at least two distinct receptor populations, et a and et b [ , ] . the et a receptors are located on vascular smooth muscle cells and mediate vasoconstriction, whereas the et b receptors are located on endothelial cells and smooth muscle cells and thus may mediate both vasodilation and vasoconstriction, respectively. individual endothelins occur in low levels in the plasma, generally below their vasoactive thresholds. this suggests that they are primarily effective at the local site of release. even at these levels, they may potentiate the effects of other vasoconstrictors, such as norepinephrine and serotonin [ ] . the role of endogenous et- in the regulation of normal vascular tone is unclear at present [ ] . nevertheless, alterations in et- have been implicated in the pathophysiology of a number of disease states, including pulmonary hypertensive disorders, and has been implicated in the so-called rebound effect of inhaled no [ , , , , ] . endothelial-derived hyperpolarizing factor (edhf), a diffusible substance that causes vascular relaxation by hyperpolarizing the smooth muscle cell, is another important endothelial factor. endothelial-derived hyperpolarizing factor has not yet been identifi ed, but current evidence suggests that its action is dependent on k + channels [ ] . activation of potassium channels in the vascular smooth muscle results in cell membrane hyperpolarization, closure of voltage-dependent calcium channels, and ultimately vasodilation. potassium channels are also present in endothelial cells. activation within the endothelium results in changes in calcium fl ux and may be important in the release of no, prostacyclin, and edhf. potassium channel subtypes include atp-sensitive k + channels, ca + -dependent k + channels, voltage-dependent k + channels, and inward-rectifi er k + channels [ ] . the breakdown of phospholipids within vascular endothelial cells results in the production of the important byproducts of arachidonic acid, including prostacyclin (pgi ) and thromboxane (txa ). prostacyclin activates adenylate cyclase, resulting in increased camp production and subsequent vasodilation, whereas txa results in vasoconstriction via phospholipase c signaling. other prostaglandins and leukotrienes also have potent vasoactive properties. increasing evidence suggests that endothelial injury and the resulting alteration in the balance of these and other vasoactive substances has a signifi cant role in the development of pulmonary hypertension and increased vascular reactivity [ , , ] . support for this hypothesis is strengthened by observations that endothelial injury precedes pulmonary hypertension and its associated vascular remodeling in several animal models of pulmonary hypertension [ , ] . in humans, endothelial dysfunction, including histologic abnormalities of the endothelium, impairment of endothelium-dependent pulmonary vasodilation, and increased plasma et- concentrations have been described in children with congenital heart defects and pulmonary hypertension before the development of signifi cant vascular remodeling [ , , ] . in addition, neonates with pphn and adults with advanced pulmonary vascular disease have evidence of endothelial dysfunction, impairment of endothelium-dependent pulmonary vasodilation, increased plasma et- concentrations, and decreased prostacyclin production [ , , , ] . the mechanism of injury to the vascular endothelium is unclear but is likely multifactorial and in part dependent on the etiology of the pulmonary hypertension. for example, in children with congenital heart disease and increased pulmonary blood fl ow, the initiating endothelial injury is likely mediated by increased shear stress. however, once pulmonary arterial pressure is elevated, shear stress-mediated endothelial injury appears to promote the progression of the disease, independent of the underlying etiology. finally, a genetic disposition appears to be important in some subtypes of pulmonary vascular disease and remains an area of active research. for example, up to % of patients with familial idiopathic pulmonary hypertension have mutations resulting in the loss of function of bone morphogenetic protein receptor ii [ ] [ ] [ ] [ ] . following an initial endothelial injury, smooth muscle proliferation and progressive structural remodeling occurs. the progression of anatomic changes is best characterized in congenital heart disease (see later discussion) [ ] [ ] [ ] [ ] . however, regardless of the etiology, advanced disease is characterized by medial hypertrophy, intimal hyperplasia, angiomatoid formation, in situ thrombi, and eventual vascular obliteration. if the underlying stress remains untreated (e.g., delayed repair of cardiac shunt), these structural changes can progress to the point of becoming functionally "fi xed" or irreversible. an important goal of therapy is to halt this progression and reverse the early vascular remodeling if possible. regardless of the underlying etiology, the general treatment approach is similar and can be subdivided into four major goals: ( ) prevent and acutely treat active pulmonary vasoconstriction, ( ) support the failing right ventricle, ( ) treat the underlying etiology, and ( ) chronically promote, if possible, the regression of pulmonary vascular remodeling. in the intensive care setting, the prevention and treatment of active pulmonary vasoconstriction is a primary focus for the care of patients with underlying pulmonary vascular disease. it is well appreciated that these patients have augmented pulmonary vasoconstriction in response to such stimuli as hypoxia, acidosis, the catecholamine-mediated α -adrenergic stimulation associated with pain and agitation, and increases in intrathoracic pressure [ ] [ ] [ ] . in fact, acute increases in pulmonary vascular resistance can lead to signifi cant cardiopulmonary compromise (i.e., a pulmonary hypertensive crisis). the pathophysiology of such a crisis in outlined in figure . . following an acute increase in pulmonary arterial pressure, there is an acute increase in right ventricular afterload, producing right ventricular ischemia and, ultimately, failure [ , ] . the resulting increase in right ventricular end diastolic volume shifts the intraventricular septum to the left, decreasing left ventricular volume and cardiac output. decreased cardiac output results in decreased systemic perfusion and metabolic acidosis. increased pulmonary vascular resistance and right ventricular failure also decrease pulmonary blood fl ow, increasing dead space ventilation. distention of the pulmonary arteries and perivascular edema produce large and small airways obstruction, respectively, which impairs ventilation-perfusion matching and decreases lung compliance. in fact, the decrease in lung compliance can be so dramatic that chest wall movement is impaired, even with manual ventilation. the ensuing hypoxemia, hypercapnia, and acidosis (metabolic and/or respiratory) further increase pulmonary vascular resistance and perpetuate this cascade. prevention of pulmonary hypertensive crises may be accomplished by avoiding stimuli known to increase pulmonary vascular resistance, including hypoxia, acidosis, agitation, pulmonary overdistention, and polycythemia [ ] . various regimens have been utilized for this purpose, including the judicious use of supplemental oxygen, analgesics, sedatives, and muscle relaxants (especially before noxious stimuli, such as suctioning); the maintenance of an alkalotic ph with the use of controlled ventilation and buffer; aggressive evacuation of pneumothoraces and pleural effusions; the utilization of low lung volume ventilator strategies; the minimization of positive end-expiratory pressures; and the maintenance of the hematocrit below % [ , ] . in addition, data suggest that the use of pulmonary vasodilator therapy may decrease the incidence of pulmonary hypertensive crises [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . treatment of active pulmonary vasoconstriction is accomplished with the use of pulmonary vasodilator therapy. the mainstay of acute pulmonary vasodilator therapy remains supplemental oxygen and moderate alkalosis, as these therapies have minimal effects on the systemic vasculature. interestingly, the dose-dependent response of the pulmonary vasculature to these agents has not been well established. studies in newborn lambs demonstrate dosedependent pulmonary vasodilation in response to increasing ph from . to . , and a dose-dependent response to increasing inspired oxygen concentrations from . to . , with minimal effects at higher concentrations [ ] . several intravenous agents have been utilized to promote pulmonary vasodilation, including tolazoline, sodium nitroprusside, nitroglycerin, prostacyclin, prostaglandin e , nifedipine, and α-adrenergic antagonists, such as phenoxybenzamine [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the effi cacies of these agents are variable, at least in part because of their effects on the systemic vasculature. systemic afterload reduction can be advantageous in the setting of left ventricular dysfunction; however, signifi cant reductions in pulmonary arterial pressure without unacceptable systemic hypotension are often not possible [ ] [ ] [ ] . in addition, intravenous vasodilators can override intrinsic hypoxic pulmonary vasoconstriction, resulting in an increase in dead space ventilation, which may not be tolerated in some critically ill patients [ ] [ ] [ ] [ ] [ ] . more recent treatment modalities, most notably inhaled no, deliver short-acting vasodilators to the pulmonary vasculature via an inhalational route [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . when administered to the lung in its natural gaseous form, no diffuses through the alveolar wall to reach small pulmonary arteries. it then enters vascular smooth muscle cells, initiating a cascade that results in pulmonary vasodilation via increases in cgmp. after entering the blood vessel lumen, no is rapidly inactivated by hemoglobin, which confi nes its effects to the pulmonary vasculature. because of these properties, inhaled no has several advantages over other vasodilators, including ( ) selective pulmonary vasodilation caused by rapid inactivation by hemoglobin, ( ) rapid onset and elimination, and ( ) an improvement in ventilation-perfusion matching because of the limitation of delivery to well-ventilated lung regions. accordingly, inhaled no has become a mainstay of treatment for acute pulmonary hypertensive disorders and the assessment of pulmonary vascular reactivity. inhaled prostacyclin has similar pulmonary selectivity, secondary to rapid inactivation by hemoglobin. its vasodilating effects are secondary to increasing camp concentrations. currently, studies on the use of inhaled prostacyclin for pediatric pulmonary hypertension are sparse, and comparison studies between inhaled no and inhaled prostacyclin are lacking [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . inhibitors of phosphodiesterases (pdes), a family of enzymes that hydrolyze the cyclic nucleotides camp and cgmp, are a relatively new class of agents that have potent vasodilating and inotropic effects [ ] . milrinone is a pde inhibitor that increases camp concentrations. animal and human data demonstrate pulmonary vasodilation in response to milrinone that can be in excess of its systemic effects if the pulmonary vasculature is constricted [ ] [ ] [ ] [ ] . in addition, a large, randomized study demonstrates that its use decreases the incidence of low cardiac output syndrome following surgery for congenital heart disease [ ] . given these properties, milrinone is increasingly utilized in the postoperative management of patients with congenital heart disease and pulmonary hypertension. sildenafi l, a pde inhibitor, which increases cgmp concentrations, also has potent pulmonary vasodilating effects [ ] . the oral formulation is currently being investigated for chronic pulmonary hypertensive therapy, and recent short-term studies demonstrate benefi cial effects in children with advanced pulmonary vascular disease [ ] . the intravenous formulation is currently being investigated for acute pediatric pulmonary hypertensive disorders (pphn and perioperative pulmonary hypertension) [ , ] . increasing data implicate alterations in et- in the pathophysiology of pulmonary hypertension (see earlier) and suggest that et-receptor antagonism may be a useful therapeutic strategy [ , , , , ] . in fact, bosentan, an oral combined et a and et b receptor antagonist, has demonstrated effi cacy as a chronic therapy for advanced pulmonary vascular disease [ , ] . to date, there have been no large studies on the use of et receptor antagonists for acute pulmonary hypertensive disorders. in addition, the use of selective et receptor antagonism is under investigation but has not yet reached clinical trials. a signifi cant component of the pathophysiology of both acute and chronic pulmonary hypertension is the development of right ventricular dysfunction, which often requires pharmacologic support. maintenance of adequate preload is necessary to optimize cardiac output in patients with pulmonary hypertension. continuous central venous pressure monitoring may be helpful to guide volume therapy, keeping in mind that patients with a poorly compliant right ventricle or increased right ventricular afterload may require elevated central venous pressures to maintain an adequate cardiac output. frequent clinical assessment of liver size can be helpful, particularly in infants. despite adequate preload, cardiac output may be compromised secondary to elevated right ventricular afterload and/or biventricular myocardial dysfunction after cardiac surgery and cardiopulmonary bypass, necessitating the use of inotropic agents [ , ] . these agents increase stroke volume at a given preload and afterload by stimulating ß -adrenergic receptors [ , ] . however, some of these agents also stimulate ß -or α -adrenergic receptors, which are found on the smooth muscle cells of both the pulmonary and systemic arteries. agents that stimulate ß -adrenergic receptors decrease both pulmonary and systemic vascular resistance and improve right and left ventricular function [ , ] . agents that stimulate α -adrenergic receptors may increase both systemic and pulmonary vascular resistance. therefore, a rational approach to using inotropic agents in the setting of pulmonary hypertension is to utilize agents with ß -receptor selectivity and minimal α -adrenergic stimulation (i.e., dobutamine). although animal studies have shown that high doses of dopamine increase pulmonary vascular resistance, human studies have shown increased cardiac output with minimal effects on pulmonary vascular resistance [ , ] . milrinone is also a useful therapy for patients with pulmonary hypertension and myocardial dysfunction, given its vasodilatory and inotropic properties [ ] . in the setting of pulmonary hypertension secondary to congenital heart defects, an atrial communication can be benefi cial in that it allows the failing right ventricle to decompress when right atrial pressure rises [ ] . accordingly, atrial septal defects can be left unclosed (i.e., patent foramen ovale) or created at the time of surgery. the existence of an atrial level communication decreases the risk of right ventricular failure and maintains left-sided cardiac output. the resulting right-to-left shunt is generally well tolerated, particularly if high hemoglobin concentrations are maintained. as right ventricular function improves, right-to-left shunting decreases and oxygenation improves. atrial septostomy as a part of management for chronic pulmonary hypertension (e.g., primary pulmonary hypertension) has been advocated but must be considered carefully on an individual basis [ ] [ ] [ ] [ ] [ ] . in patients with refractory pulmonary hypertension, short-term postoperative extracorporeal support has been useful during the postoperative period of extreme vasoreactivity. however, its use should be limited to support those patients in which the underlying pulmonary vascular disease is deemed reversible. whenever possible, treatment of the underlying disorder must coincide with symptomatic treatment for pulmonary hypertension if attenuation and/ reversal of the disease are to be successful. for example, in neonates, this may involve correction of underlying metabolic disturbances, antibiotics for infectious etiologies, and exchange transfusions for polycythemia. for patients with congenital heart disease, repair of the underlying defect, after determining that the pulmonary vascular disease is reversible (see later), is mandatory. for hypoxia-induced disease, tonsillectomy and adenoidectomy may be required for sleep apnea, and a descent to sea level may be needed for high-altitude-related disease. finally, for rheumatologic disease, immunosuppression may be required. the mainstay of chronic therapy has been aimed at decreasing pulmonary vascular resistance, thereby assisting right ventricular function and perhaps attenuating the progression of vascular remodeling by decreasing the pressure to which the vasculature is exposed. the continuous infusion of prostacyclin (epoprostin) has been the most successful therapy to date in this regard [ ] [ ] [ ] [ ] [ ] . in fact, several studies in humans with advanced pulmonary vascular disease demonstrate improved -year survival and improved exercise tolerance. interestingly, even those patients without an initial vasodilating response to the infusion show signifi cant longterm benefi t, suggesting that effects beyond vasodilation, such as antiplatelet effects, camp-mediated inhibition of smooth muscle cell growth, or other unknown mechanisms may be responsible for the treatment effect [ ] . despite the impressive results, several factors limit its utilization, including the need for chronic intravascular assess with the associated infectious and thrombotic risks, and many other untoward effects, including headache, fl ushing, and acute cardiopulmonary compromise with disruption of the infusion [ ] . with the increasing appreciation for the role of et- in the pathophysiology of pulmonary vascular disease, et receptor antagonists have been developed as a potential treatment modality. to date, bosentan, a combined et a and et b receptor antagonist, is the most widely studied agent and is the only receptor antagonist approved for the treatment of pulmonary hypertension [ , ] . recent studies in adults with primary pulmonary hypertension demonstrate similar improvements in survival and exercise tolerance as those demonstrated with epoprostenol [ ] . the use of et receptor antagonists for pediatric pulmonary hypertensive disorders is currently under investigation. defi ciencies in the no-cgmp cascade in pulmonary vascular disease are well documented. in addition, the vasodilating effects, antiplatelet effects, and antiproliferative effects of augmenting this cascade are well appreciated. therefore, new chronic therapies that augment no-cgmp signaling, which include chronic inhaled no delivered by nasal cannula and sildenafi l, are currently under investigation [ ] . in fact, the short-term benefi t of sildenafi l in children with advanced pulmonary hypertension has recently been reported [ ] . data indicate that several of these new oral therapies, such as bosentan and sildenafi l, may offer additional benefi t by virtue of their ability to inhibit vascular smooth muscle growth and fi brosis [ ] . a number of other treatment strategies, including combination drug therapies, are currently under investigation. to date they have been used predominantly in advanced pulmonary vascular disease, but, due to these favorable characteristics, several potential applications warrant investigation. this includes their use in lung hypoplastic syndromes, in hypoxia-associated disease, and in congenital heart disease in order to improve the operability of patients with modest vascular changes [ ] . in a number of clinical conditions, pulmonary vascular resistance does not decrease normally at birth. as a result, pulmonary blood fl ow remains reduced and pulmonary arterial pressure remains high. the pathophysiologic effects are hypoxemia, myocardial dysfunction, and a resulting reduction in systemic oxygen delivery. the hypoxemia is most often secondary to extrapulmonary rightto-left shunting of blood at the atrial and/or ductal levels but may also be secondary to intrapulmonary right-to-left shunting of blood when associated with parenchymal lung disease. the pathophysiologic mechanisms preventing the normal pulmonary vasodilatation at birth remain unclear and are most likely multifactorial in etiology. within this defi nition of pphn, three major subgroups are often characterized: those with underdevelopment of the lung, those with maladaptation of the lung, and those with maldevelopment of the lung [ ] . these subgroups represent a spectrum of etiologies and pathophysiology. for example, underdevelopment of the lung represents disorders of vascular hypoplasia, which are usually associated with varying degrees of lung hypoplasia. within this subgroup, patients with congenital diaphragmatic hernia have been most thoroughly investigated. although the structural abnormalities are greatest on the side of the hernia, both of the lungs of these patients are smaller and have fewer alveoli than do lungs from a normal control population [ ] [ ] [ ] . their lungs also have fewer vessels per unit of lung [ ] . thus, the total cross-sectional area of the vascular bed is markedly decreased. furthermore, the existing pulmonary arteries have increased muscle mass with medial hypertrophy in normally muscularized arteries and an abnormal extension of muscle into the intra-acinar arteries. the increased muscularization may explain the labile, right-to-left extrapulmonary shunting of blood seen in such patients [ , ] . the response to therapy and long-term outcome is dictated by the degree of hypoplasia of the underlying vasculature. following acute therapies, which often include surgical repair, mechanical ventilation with inhaled no, and extracorporeal support, subacute and chronic pulmonary hypertension has been increasingly recognized as a major outcome variable in these patients. because ultimately lung and vascular growth are necessary to reverse the disease process, aggressive long-term support with agents that inhibit vascular remodeling (i.e., et receptor antagonists and pde inhibitors) is an emerging treatment approach to support these infants as they grow. maladaptation of the lung represents a stress event at the time of delivery that does not allow the normal dilating stimuli, such as increases in systemic arterial ph and oxygen tension, to occur. this may occur in the setting of apnea, pneumonia, sepsis, and aspiration of meconium or amniotic fl uid [ ] [ ] [ ] . the underlying pulmonary vasculature is often normal, and, thus, these neonates are likely to respond to vasodilator therapy and the correction of contributory metabolic abnormalities. maldevelopment of the lung represents a group of conditions in which the vasculature is thickened and abnormally distributed. for example, some newborns who die from persistent pulmonary hypertension have abnormally muscular pulmonary vascular beds, even when they die on the fi rst day of life. in particular, they have thickened muscular coats in the normally muscular preacinar arteries, and extension of muscle into the normally nonmuscular intra-acinar arteries [ , ] . because vascular remodeling takes time to develop, it has been hypothesized that this increased muscularization is caused by a chronic intrauterine stress. in animal models, this pathophysiology can be mimicked by chronic placental insuffi ciency, fetal hypoxemia, chronic constriction of the ductus arteriosus, and chronic no inhibition [ , , [ ] [ ] [ ] [ ] [ ] [ ] . interestingly, pphn has been associated with maternal indomethacin use, which causes constriction of the ductus arteriosus [ , ] . the response to therapy in neonates with maldevelopment of the lung is variable and may be related to the extent and type of underlying structural vascular pathology. the primary therapeutic approach is to decrease pulmonary vascular resistance and support myocardial function. the specifi c treatment modality depends on the underlying etiology. if the cause is perinatal asphyxia, correcting alveolar hypoxia, hypercarbia, and metabolic acidosis by ventilation with % oxygen, and by administration of buffer, should decrease pulmonary vascular tone toward normal levels. if parenchymal disease (i.e., respiratory distress syndrome, meconium aspiration, or pneumonia) is causing pulmonary vasospasm due to alveolar hypoxia and hypercarbia, then infl ation of the alveoli with positive end-expiratory pressure, surfactant administration, and mechanical ventilation may reverse the pulmonary hypertension [ ] [ ] [ ] . the near-term child can exert substantial intrathoracic pressure opposing mechanical ventilation; thus, sedation and occasionally muscle paralysis may be necessary to obtain stable mechanical ventilation [ ] . when treatment of the underlying pulmonary parenchymal, infectious, or infl ammatory disease is ineffective, or if there is no such underlying disease, therapy is directed at reversing abnormal pulmonary vasoconstriction. this is generally accomplished with sedation, mechanical ventilation with % oxygen, and alkalinization. when further pulmonary vasodilation is needed, inhaled no is utilized with or without high-frequency ventilation. in fact, several multicentered, randomized trials have demonstrated that inhaled no improves oxygenation and decreases the need for extracorporeal life support in newborns with persistent pulmonary hypertension [ , , ) , although no differences in mortality were noted. the use of extracorporeal membrane oxygenation has substantially decreased overall mortality for most subsets of pphn. however, overall mortality rates remain substantial at %- % [ ] [ ] [ ] [ ] . the development of pulmonary hypertension and increased pulmonary vascular reactivity is associated with two major types of congenital heart disease: ( ) those with increased pulmonary blood fl ow and pulmonary arterial pressure and ( ) those with increased pulmonary venous pressure [ ] [ ] [ ] ] . after birth, large communications at the level of the ventricles or great vessels result in increased pulmonary blood fl ow and pulmonary arterial pressure, which produces progressive structural and functional abnormalities of the pulmonary vasculature [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . similarly, elevated pulmonary venous pressure results in progressive increases in pulmonary venous and arterial pressure, which produces structural abnormalities of the pulmonary vasculature. heath and edwards fi rst described the progression of these pulmonary vascular changes in [ ] . in their classifi cation, changes progress from medial hypertrophy (grade i) to intimal hyperplasia (grade ii), lumen occlusion (grade iii), arterial dilatation (grade iv), angiomatoid formation (grade v) and fi brinoid necrosis (grade vi). in addition, morphometric analysis shows progression of disturbed arterial growth and remodeling of the pulmonary vascular bed, which correlates with the aberrant hemodynamic state of the pulmonary circulation [ , , [ ] [ ] [ ] . these changes are characterized by ( ) abnormal extension of vascular smooth muscle into small peripheral pulmonary arteries and mild medial hypertrophy of normally muscular arteries (grade a), ( ) severe medial hypertrophy of normally muscular arteries (grade b), and ( ) decreased pulmonary arterial number (grade c). uncorrected, these vascular changes result in decreased cross-sectional area and obliteration of the pulmonary vascular bed and death secondary to severe cyanosis or myocardial failure. different congenital heart defects vary considerably in the frequency and severity of pulmonary hypertension. the risks and frequencies of developing advanced pulmonary vascular disease (pvd) for particular heart defects are summarized in table . . importantly, children with trisomy and congenital heart defects often have an accelerated development of advanced pulmonary vascular disease [ ] . this may be secondary to confounding factors such as airway obstruction or another unidentifi ed predisposition. after surgical correction, early vascular changes (grades i-iii, grades a, b) are reversible; however, more severe changes are irreversible and progressive. therefore, the pathophysiologic state of the pulmonary circulation is the main determinant of the clinical course and the success of surgical treatment, and it explains the trend toward early repair of congenital heart defects [ ] . although early surgical repair of congenital heart defects has decreased the incidence of irreversible pulmonary vascular disease, even those children with reversible vascular changes suffer morbidity and mortality in the perioperative period secondary to chronic and/or acute elevations in pulmonary vascular resistance ] . chronic elevations are related to the structural changes that decrease the cross-sectional area of the pulmonary vascular bed. these alterations may take several months to normalize following surgical repair. acute elevations in pulmonary vascular resistance are often seen immediately following surgery with cardiopulmonary bypass, when there is often a period of enhanced pulmonary vascular reactivity [ , , ] . this period may last up to - days and is most likely a manifestation of preexisting aberrant endothelial cell-smooth muscle cell interactions that are exacerbated at the time of surgery. during cardiopulmonary bypass, several factors including the disruption of pulmonary blood fl ow, complement activation, and neutrophil activation induce pulmonary vascular endothelial dysfunction. this results in an increase in the production and/or release of endothelial factors that promote vasoconstriction, such et- and txa , and a decrease in endothelial relaxing factors, most importantly no [ ] . this period of extreme reactivity may produce severe hypoxemia, acidosis, low cardiac output, and death if not treated immediately. classically, a preoperative determination of pulmonary vascular reactivity is made in the cardiac catheterization laboratory in order to assess the operability of a given patient, that is, the degree to which the pulmonary vascular disease is reversible, as well as the postoperative risk. this testing involves measuring pulmonary arterial pressure and calculating pulmonary vascular resistance under varying conditions. the vascular resistance following acute maximal vasodilator therapy (e.g., oxygen and no) represents the degree of structural pulmonary vascular disease that is present. despite the frequent utilization of such testing, there is no absolute pulmonary vascular resistance that is universally considered inoperable. in general, a larger reduction in resistance in response to vasodilator therapy correlates with an increased chance of reversibility and a lower risk of perioperative morbidity from pulmonary hypertension. recent studies suggest that the combination of % oxygen and inhaled no produces maximal pulmonary vasodilation and has some perioperative predictive value [ , ] . in fact, a % decrease in the ratio of the pulmonary-to-systemic vascular resistance with vasodilator therapy, and a nadir in this ratio of less than %, was % sensitive and % accurate in predicting a good surgical outcome. therefore, the combination of oxygen and inhaled no is now most commonly used for pulmonary vascular reactivity testing. reactivity testing may also be helpful in the intensive care unit in the setting of a persistent postoperative elevation of pulmonary arterial pressure in order to differentiate between residual anatomic defects and prolonged periods of increased tone [ ] . the optimal treatment for perioperative pulmonary hypertensive morbidity is prevention with early surgical repair. it is increasingly clear that the longer the pulmonary vasculature is exposed to the abnormal forces associated with increased blood fl ow and/or pressure, the greater the risk of perioperative pulmonary vascular reactivity. following surgery, the goal of perioperative management is to minimize active pulmonary vasoconstriction during the period of exaggerated reactivity and support the right ventricle. to this end, avoidance of those stimuli that increase pulmonary vascular resistance (hypoxia, acidosis, pain, agitation, increased intrathoracic pressure) is critical. continuous pulmonary arterial and right atrial pressure monitoring is often helpful by allowing prompt recognition of pulmonary hypertensive crises and evaluation of the response to therapeutic maneuvers. monitoring systemic arterial pressure and systemic arterial oxygen saturation is essential in that it allows changes in pulmonary arterial pressure to be interpreted in the context of the total cardiopulmonary response. for example, if systemic and pulmonary arterial pressures increase in response to pain and agitation, but right atrial pressure does not increase, and systemic perfusion and oxygen saturation remain adequate, then specifi c treatment directed at the pulmonary vasculature is not necessary. conversely, increases in pulmonary arterial pressure that are associated with increased right atrial pressure, decreased systemic pressure, and/or decreased systemic saturation might herald imminent collapse. the objective of vasodilator therapy is to decrease right ventricular afterload and prevent acute increases in pulmonary arterial pressure. inhaled no, in combination with oxygen, has been increasingly utilized because of its potent vasodilating effects, pulmonary selectivity, and rapid onset and elimination (see earlier). several studies demonstrate its potent vasodilating effects in this population [ ] [ ] [ ] [ ] ; however, large, randomized trails are lacking. one randomized trial did demonstrate that inhaled no decreased postoperative pulmonary vascular resistance, the incidence of pulmonary hypertensive crises, and the days of mechanical ventilation compared with placebo [ ] . in patients with a history of pulmonary venous hypertension (total anomalous pulmonary venous return, mitral valve disease), aggressive diuresis may be helpful because interstitial pulmonary edema may contribute signifi cantly to elevations in pulmonary vascular resistance. therapies that maintain an adequate cardiac output in this patient population are not dissimilar to therapies utilized in other patient populations, with the exception of the particular emphasis placed on right ventricular afterload reduction and support. it is noteworthy that patients with a poorly compliant right ventricle or with increased right ventricular afterload may require elevated central venous pressures to maintain an adequate preload. in addition, the use of inotropic agents with signifi cant α -adrenergic effect should be minimized to avoid the associated pulmonary vasoconstriction. agents such as dobutamine, milrinone, and dopamine are routinely utilized. the use of high levels of positive end-expiratory pressure (peep) is somewhat controversial. mechanical hyperventilation with high peep increases intrathoracic pressure and pulmonary vascular resistance [ , ] . this therapy should be avoided if adequate systemic arterial saturation can be achieved by other means. however, at low lung volumes, the use of peep may increase lung volume until very recently, pulmonary arterial hypertension of unknown etiology was termed primary pulmonary hypertension. however, recent evidence indicates a genetic disposition in a subset of patients with primary pulmonary hypertension, and a number of diseases that lead to pulmonary arterial hypertension with similar histological and pathophysiologic features have been uncovered [ ] [ ] [ ] [ ] . thus, at the third world symposium on pulmonary arterial hypertension, a new classifi cation was proposed to further classify primary pulmonary hypertension into the following subgroups: ( ) idiopathic pulmonary arterial hypertension (ipah), ( ) familial pulmonary arterial hypertension (fpah), and ( ) pulmonary arterial hypertension related to risk factors or associated conditions (apah) [ ] . unfortunately, mortality from primary pulmonary hypertension remains high and may be higher for children than adults. in fact, the primary pulmonary hypertension national institutes of health registry reports a median survival of only months for pediatric patients [ ] . however, recent data suggest that pediatric patients may respond differently than adults to new therapies and that these differences may portend a better outcome in younger patients [ , ] . the frequency of primary pulmonary hypertension in pediatric patients is not known, but it appears that the number of confi rmed cases is increasing. the incidence is slightly increased in females [ ] . the most common causes of death in children with primary pulmonary hypertension are right ventricular failure and sudden death, which may be related to malignant cardiac arrhythmias, pulmonary emboli, or acute right ventricular ischemia [ ] . physicians caring for children in an intensive care unit setting must be cognizant of this disorder, albeit rare, because relatively benign disease processes, such as pneumonia, can be life threatening for children with primary pulmonary hypertension, which may not have been previously identifi ed. as opposed to adults with primary pulmonary hypertension, who often have severe plexiform lesions resulting in relatively fi xed vascular changes, children display greater medial hypertrophy with less intimal fi brosis and fewer plexiform lesions [ , ] . in addition, pediatric patients have a decreased pulmonary arterial number and increased pulmonary vascular reactivity compared with adult patients. the molecular mechanisms underlying primary pulmonary hypertension remain speculative; however, studies suggest an integral role for endothelial dysfunction, resulting in an increase in factors that favor both vasoconstriction and mitogenesis, such as et- and txa , and a decrease in factors that promote vasodilation and smooth muscle antiproliferation, such as no and prostacyclin [ , , , [ ] [ ] [ ] [ ] . other mechanisms have been investigated including, altered gene expression, coagulation abnormalities (resulting in intravascular thrombosis), and defects of pulmonary vascular smooth muscle cell potassium channels [ ] [ ] [ ] . recent advances in the understanding of pulmonary hypertension have established an association with a number of disease processes and toxins. thus, it is now known that pulmonary hypertension can be related to collagen vascular disease, portal hypertension, human immunodefi ciency virus infection, chronic obstructive pulmonary disease, interstitial lung disease, sleepdisordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitudes, thromboembolic disease, sickle cell disease, schistosomiasis, sarcoidosis, thyroid disorders, glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, myeloproliferative disorders, and pulmonary capillary hemangiomatosis. in addition, drugs or toxins, most notably anorexigens, have been associated with the development of pulmonary hypertension [ , ] . in general the diagnostic work-up includes history and physical examination, electrocardiography, chest radiography, echocardiography, and cardiac catheterization. serologic evaluation in order to exclude secondary causes is required, and v/q scanning to evaluate for pulmonary emboli may be necessary. treatment strategies for pediatric pulmonary arterial hypertension are evolving. when the disease is associated with a known disorder, treatment must include specifi c therapy aimed at the underlying condition. however, general treatments include the approach reviewed above, with oxygen, calcium channel blockers, anticoagulation, et receptor antagonists, prostacyclin analogues, acute and chronic inhaled no, pde type inhibitors, atrial septostomy, and lung or heart-lung transplant considerations as indicated [ ] . patients with pulmonary arterial hypertension have histologic evidence of in situ pulmonary vascular thrombosis, which is the rationale for anticoagulation therapy. although several adult studies have demonstrated its effi cacy, pediatric studies are lacking [ , ] . currently, warfarin is the treatment of choice for adult patients and in large pediatric centers with signifi cant experience with pediatric pulmonary arterial hypertension. low-molecularweight heparin is another alternative [ ] ; aspirin does not have any demonstrated effi cacy. chronic calcium channel blockade is effi cacious for a subset of adults and children with pulmonary arterial hypertension. in fact, whereas less than % of adults respond to calcium channel blockers, up to % of children are positive responders [ , ] . it is worth noting that calcium channel blockers are not utilized in the management of other common causes of pediatric pulmonary hypertension, such as pphn and congenital heart disease. indeed, calcium channel blockade should be avoided in neonates and after congenital heart surgery. however, studies indicate that long-acting calcium channel blockers, such as nifedipine and amlodipine, are well tolerated in children with primary pulmonary hypertension. an important caveat is that a positive response to calcium channel blockers (i.e., an acute reduction in pulmonary arterial pressure) must be demonstrated as a part of acute vasodilator reactivity testing. children without a positive acute response do not benefi t from chronic treatment. prostaglandins are a mainstay of therapy for patients with pulmonary arterial hypertension. in general, prostacyclin (epoprostenol) is administered as a continuous infusion, necessitating a permanent indwelling central catheter, with its associated risks [ ] [ ] [ ] [ ] [ ] . however, various other formulations including oral, inhaled, and subcutaneous prostacyclin analogues have been developed and are in various stages of clinical investigation [ ] [ ] [ ] [ ] . supplemental oxygen, cardiac glycosides, antiarrhythmic therapy, and inotropic agents are also variably utilized in certain patients [ , ] . diuretic therapy is also often benefi cial, keeping in mind that these patients may require elevated right ventricular preload. based on an expanding understanding of the disease process, future therapies might include elastase inhibitors and gene therapy [ , ] . as noted previously, atrial septostomy may have a role in the management of a select group of patients [ ] . however, atrial septostomy in the setting of an acute exacerbation of chronic pulmonary hypertension may lead to unacceptable hypoxemia because of excess right-to-left atrial shunting. finally, heart-lung, single-lung, or bilateral lung transplantation has been successful in pediatric patients with terminal pulmonary hypertension [ , ] . the international society for heart and lung transplantation reports survival of approximately % at years in pediatric patients [ ] . consensus is lacking as to the best type of transplant. increases in pulmonary arterial pressure in response to hypoxia are well described. clinical and experimental evidence suggests that prolonged exposure or chronic intermittent exposure to hypoxia can result in functional and structural derangements of the pulmonary vasculature, leading to pulmonary hypertension [ ] [ ] [ ] . fortunately, elevations in pulmonary arterial pressure that occur in response to acute hypoxia (such as an acute ascent in altitude) are rapidly reversible. interestingly, there is great clinical variability in the response to hypoxia. for example, increased susceptibility to high-altitude pulmonary edema, which is associated with increased pulmonary arterial pressure, has been linked to certain major histocompatibility complexes [ , ] . the mechanisms of hypoxia-induced pulmonary hypertension continue to be an area of intense investigation. to date the precise mechanisms remain unclear, but it is known that a number of endothelial derived factors, such as no, et- , leukotrienes, and potassium channels, participate [ , [ ] [ ] [ ] [ ] . furthermore, additional genetic polymorphisms are also under investigation. pediatricians must consider this physiology in patients with conditions such as upper airway obstruction, central hypoventilation, and neuromuscular disorders that affect ventilation. in fact, many of these patients do develop evidence of pulmonary hypertension, with right ventricular enlargement. in most cases, addressing the underlying pathology is curative, but it can take some time to fully reverse the structural changes that have occurred. the pathophysiology of acute lung injury involves damage to both the alveolar epithelium and pulmonary vascular endothelium. vascular endothelial injury accounts for key features of acute lung injury, including intravascular thrombosis and capillary permeability that increases alveolar fl uid [ ] . in fact, pulmonary vascular injury, in the setting of acute lung injury, can lead to pulmonary arterial hypertension, resulting in increased intrapulmonary shunting, hypoxia, pulmonary edema, and right ventricular dysfunction [ ] [ ] [ ] [ ] . in children with acute lung injury, persistently elevated pulmonary arterial pressures have been associated with worse outcomes [ ] ; therefore, vasodilators have been utilized in the management of these patients. however, intravenous vasodila-tors that dilate both the systemic and pulmonary vasculature have signifi cant problems, including systemic hypotension, right ventricular ischemia, increased intrapulmonary shunting (i.e., increased v/q mismatch), and increased hypoxemia [ ] [ ] [ ] [ ] [ ] . consequently, selective pulmonary vasodilation with inhaled no has been utilized, as it improves v/q matching and oxygenation without untoward systemic effects [ , ] . unfortunately, improvements in oxygenation associated with inhaled no are transient, and large randomized trials have failed to demonstrate an improvement in mortality with its use [ , , ] . the routine use of inhaled no in patients with acute lung injury, therefore, cannot be justifi ed; however, it may be indicated in individual patients, particularly those with an acute hemodynamic compromise and refractory hypoxemia caused by elevated pulmonary arterial pressures. clearly, physicians caring for pediatric patients with acute lung injury must include an awareness of the pulmonary vascular aberrations associated with the disease in their management considerations. historically, diseases of the pulmonary vasculature, although not uncommon, have been underrecognized. this was caused, in part, by the paucity of effective treatments as well as an incomplete understanding of the vascular biologic mechanisms. in fact, over the past decade, the therapeutic gold standard has been the continuous infusion of prostacyclin. although certainly extending and improving the lives of many patients, intravenous prostacyclin administration has been predominantly limited to patients with irreversible disease, given the inconvenience and morbidity associated with its delivery. fortunately, an expanded understanding of the vascular endothelium, vascular smooth muscle cells, and the role of their interactions in the pathophysiology of pulmonary vascular disease have resulted in new effective treatments, with additional potential therapies evolving rapidly. oral agents such as bosentan and sildenafi l are two examples with great promise. in addition, accumulated experience and focused research have uncovered a multitude of disease processes that contribute directly or indirectly to the development of pulmonary hypertension. physicians caring for critically ill children must be aware of these illnesses, the pathophysiology of pulmonary hypertension, and the available treatment options in order to translate these advances into improved outcomes for patients. cultured endothelial cells synthesize both platelet-activating factor and prostacyclin in response to histamine, bradykinin, and adenosine triphosphate a novel potent vasoconstrictor peptide produced by vascular endothelial cells vascular endothelial cells synthesize nitric oxide from l-arginine flow-induced release of endothelium-derived relaxing factor molecular mechanisms of endothelium-mediated vasodilation the l-arginine-nitric oxide pathway n omega-nitro-l-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs endothelial modulation 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vandevenne, jan; thillai, muhunthan; lavon, ben r.; lanclus, maarten; bonte, stijn; godon, rik; kendall, irvin; de backer, jan; de backer, wilfried title: assessment of small pulmonary blood vessels in covid- patients using hrct date: - - journal: acad radiol doi: . /j.acra. . . sha: doc_id: cord_uid: nq f gmu background: mounting evidence supports the role of pulmonary hemodynamic alternations in the pathogenesis of covid- . previous studies have demonstrated that changes in pulmonary blood volumes measured on ct are associated with histopathological markers of pulmonary vascular pruning, suggesting that quantitative ct analysis may eventually be useful in the assessment pulmonary vascular dysfunction more broadly. methods: building upon previous work, automated quantitative ct measures of small blood vessel volume and pulmonary vascular density were developed. scans from covid- patients and healthy volunteers were analyzed and their results compared, with comparisons made both on lobar and global levels. results: compared to healthy volunteers, covid- patients showed significant reduction in bv (pulmonary blood volume contained in blood vessels of < mm( )) expressed as bv /(total pulmonary blood volume) (p< . ), and significant increases in bv - and bv (pulmonary blood volumes contained in vessels between and mm( ) and above mm( ), respectively) (p< . ). these changes were consistent across lobes. conclusions: covid- patients display striking anomalies in the distribution of blood volume within the pulmonary vascular tree, consistent with increased pulmonary vasculature resistance in the pulmonary vessels below the resolution of ct. mounting evidence supports the role of pulmonary hemodynamic alternations in the pathogenesis of covid- . previous studies have demonstrated that changes in pulmonary blood volumes measured on ct are associated with histopathological markers of pulmonary vascular pruning, suggesting that quantitative ct analysis may eventually be useful in the assessment pulmonary vascular dysfunction more broadly. building upon previous work, automated quantitative ct measures of small blood vessel volume and pulmonary vascular density were developed. scans from covid- patients and healthy volunteers were analyzed and their results compared, with comparisons made both on lobar and global levels. compared to healthy volunteers, covid- patients showed significant reduction in bv (pulmonary blood volume contained in blood vessels of < mm ) expressed as bv /(total pulmonary blood volume) (p< . ), and significant increases in bv - and bv (pulmonary blood volumes contained in vessels between and mm and above mm , respectively) (p< . ). these changes were consistent across lobes. in december a novel beta coronavirus, since dubbed sars-cov , emerged as the cause of an outbreak of respiratory disease beginning in wuhan, china, before eventually spreading widely across the globe. the resulting disease, named covid- by the world health organization, remains mild or asymptomatic in the majority of those infected, but causes severe or potentially life-threatening disease in a minority, most of whom are thought to have preexisting comorbidities. initially it was believed that severe refractory hypoxia and death in covid- patients was the result of viral pneumonia progressing to acute lung injury and, in severe cases, acute respiratory distress syndrome (ards). as the pandemic progressed, a distinct clinical picture began to emerge of patients with progressive hypoxia but relatively wellpreserved lung function and compliance which is inconsistent with conventional understandings of ards [ ] . alongside emerging understanding of the role of the ace pathway, the entry receptor for the virus, in the pathogenic process, it has become clear that at least some covid- patients exhibit significant pulmonary vascular involvement [ , ] . while the nature of this involvement remains unclear, widespread coagulopathy, microthrombi, and dysregulated hypoxic pulmonary vasoconstriction (hpv) have all been implicated [ , ] . in previous work examining pulmonary vascular remodeling in smokers, significant correlations have been drawn between histopathological markers of microvascular pruning and ct-derived markers of pulmonary blood loss in the smallest caliber vessels that may be resolved on scans [ ] . these results suggest that while the pathological changes to the pulmonary vasculature implicated in pulmonary vascular disease (pvd), collectively termed "pulmonary vascular remodeling", occur primarily below the resolution of ct scans, those processes do have a measurable effect on larger, more proximal vessels. while the clinical significance of these quantities is not yet clear, they hold promise as potential noninvasive measures of pulmonary hemodynamics that may be valuable in the development of more effective diagnosis and treatment of pvd. in this study we assessed the use of novel ct-derived measures of pulmonary blood volume and pulmonary vascular density in patients with covid- . we hypothesized that the so-called "silent hypoxia" noted in hospitalized patients may be due impaired gas exchange resulting from abnormalities in the distribution of pulmonary blood volumes, and moreover that ct may offer clues as to the processes occurring in pulmonary arterioles and capillaries. hospitalized covid- patients were retrospectively selected based on the availability of ct scans of the lungs with slice thickness . mm or less, as well as pcr-confirmed sars-cov infection. thin-sliced ct scans were provided by the respective hospitals where they were acquired. institutional review board approval was granted by the respective local committees, and written informed consent was obtained. scans came from belgium ( from az sint-maarten (mechelen), from ziekenhuis oost-limburg (genk)), from the uk (royal papworth hospital) and from china (wenzhou medical university). inspiratory scans from healthy patients were acquired from the copdgene cohort (nct ). because the patient scans were acquired in the course of clinical care and without a standardized protocol, slice thickness varied between . mm and . mm. the demographics for these cohorts are shown below in (table ) . d reconstructions of the lungs and pulmonary vasculature were created. an automated blood vessel segmentation algorithm performs an eigenvalue analysis of the hessian matrix to enhance and identify tubular structures, by returning the probability of each voxel belonging to tubular structure based on shape analysis [ ] . next, hounsfield unit (hu) thresholds are used to limit the vessels. the hu thresholds are based on the vessels size and are defined by an automated adaptive iterative threshold method. in the preprocessing, a gradient anisotropic diffusion filter is applied, and a region of interest is defined to remove some false positives. subsequently, the smaller non-connected parts are removed. to account for the effects of slice thickness on results, sensitivity analysis was performed. volumes were then computed from the cross-sectional area of each vessel. following the convention established by rahaghi et al., the volume of blood contained in vessels below mm cross sectional area (down to a cutoff of . mm ) was termed "bv ". we additionally defined bv - as the volume of blood contained in vessels with cross-sectional area between and mm , and bv as the volume contained in vessels with cross-sectional area above mm . we refer collectively to these quantities as bvx. to account for variation in lung volume, we chose to normalize bvx by total pulmonary blood volume. this permits for the computation of a "bv spectrum", a curve representing the percent of total pulmonary blood volume contained within vessels of a given caliber as a function of cross-sectional area ( figure ). it had previously been observed in analysis of scans from healthy volunteers that this yielded values with very low variance over all scales (figure ) covid- patients often present with various opacities on ct. because these regions are more dense than surrounding tissue, they may be confused for blood by our segmentation algorithm (and vice versa). in an effort to control for this and to understand the scope of its impact on our results, a fully convolutional deep learning model was trained on a set of manually labeled axial volumetric ct scans ( axial slices) to detect and segment ground glass opacities, consolidation, and pleural effusion, and estimate the combined volume of tissue with any of the three labels. the trained model was then evaluated on annotated slices, achieving a mean dice similarity coefficient of . %. training and test data were obtained from the open-source covid- ct segmentation dataset (http://medicalsegmentation.com/covid /) two-sample t-tests were used to assess significance (p < . ). all analyses were performed using the open-source statistical environment r version . . or higher (the r foundation for statistical computing, vienna, austria). the results of bvx analysis can be seen in figure , below. compared with healthy volunteers, patients from the covid- cohort have markedly reduced bv (p<. ), with corresponding increases in bv - (p< . ) and bv (p< . ), figure shows the bv spectra for the covid- and healthy cohorts overlaid and allows for a qualitative grasp of this redistribution. the covid- curve dips below the healthy curve at approximately mm , with a flatter-than-usual peak to the right of the healthy patients at just below . mm and remaining elevated until ~ mm before normalizing. this represents a sharp drop in the amount of blood contained in small vessels with a more gradual renormalization over the medium and larger sized vessels. these changes can be seen quite strikingly in figure , which compares d reconstructions of the pulmonary vasculature of a representative healthy and covid- patient. segments are color-coded according to size, and the relative and marked absence of small vessels (colored red) is notable, as is the marked "proliferation" of medium-sized yellow vessels. figure shows the results of a mixed effect model of the relationship between bvx and the opacity score on a lobar level. bv shows a significant but modestly inverse relationship with increasing opacities (p< . , r = . ). bv - was likewise inversely related, but the effect size was even smaller (p= . , r = . ), and bv shows a direct relation with opacity (p< . , r = . ). while it remains unclear how sars-cov infection leads to the constellation of clinical and imaging signs associated with covid- , certain elements are well established. the virus has been discovered to enter cells by way of the angiotensin-converting enzyme (ace ) receptor, and further to downregulate its expression [ ] . because ace interfaces with the vasoactive renin-angiotensin-aldosterone system (raas), this pathway has been implicated as the cause of vascular anomalies observed in covid- patients [ ] . because total pulmonary blood volumes as measured on ct does not vary significantly between groups (figure ), this loss of blood volume in small vessels and increase of blood volumes in medium and large vessels can be interpreted as a "redistribution" of blood throughout the pulmonary vasculature, in particular from smaller vessels to larger vessels. the precise mechanism leading to this redistribution remains unknown, but these results may point towards a better understanding of the pathophysiology involved. the observed effects could be explained by increased pulmonary vascular resistance (pvr) downstream which, given constant cardiac output and left atrial pressure, is concomitant with increased pulmonary arterial pressure. this could result from dysregulated vasoconstriction leading to increased tone in the pulmonary arteries, or by occlusion due to microthrombi or tissue damage. this would be consistent with the observed pattern of hypoxia in the context of preserved lung compliance, with sar -cov infection leading to an infectious mimic of idiopathic pulmonary hypertension, which is associated with both coagulopathy and increased muscularization of pulmonary arteries [ ] . future studies could elucidate these mechanisms further by way of more careful analysis of changes in bvx, additional hemodynamic data from covid- patients, or potentially through pathological examination of lung tissue. it should be noted that in most anatomical studies of human pulmonary vasculature the "muscularized" pulmonary arteries, which are thought to be primarily (but not exclusively) responsible the hypoxic pulmonary vasoconstriction, have diameters in the range of - µm [ ] [ ] [ ] [ ] . this range corresponds to cross-sectional areas of ~. -. mm , somewhat below the resolution of current ct technology. we quantify vessels as small as . mm ; vessels this size and larger are characterized are by the amount of elastic tissue contained within their walls, which allows them to both actively vasoconstrict and to change caliber elastically in response to fluctuations in pressure [ , ] . the pulmonary vascular system is highly dynamic, with many "moving parts" capable of active and passive responses to changes elsewhere in the system. these measurements of blood volume distribution may offer a powerful means of understanding hemodynamic processes more completely and lead to more effective treatments for pvd. the study has several limitations. all data was collected in the course of clinical practice during a pandemic, and was retrospective, with the result that acquisition protocols varied between centers. the characteristics of the patient were not always available, such that age, gender, and a height could not be well controlled for. normalization of bvx by total pulmonary blood volume mitigates this somewhat, as previous samplings have shown these measures to vary little across healthy populations. as noted, areas of opacification confound these algorithms. in most past studies of imaging of pulmonary blood volumes, these opacities have been grounds for excluding scans from analysis. this was neither possible nor desirable in this context given the ubiquity of these findings and their hypothesized role in the pathogenesis of covid- [ ] [ ] [ ] . bvx is normalized for total segmented blood volume, which limits the magnitude of error introduced. notable is the presence of lobes with minimal opacity but markedly reduced bv compared to healthy subjects. in combination with the small effect sizes observed in the mixed effect model ( figure ), this suggests that the detected opacities likely introduce modest error, specifically loss of bv and gain of bv , but are not the singular or even primary driver of these anomalies. we speculate that observed anomalies in vascular volumes are a result of the pathogenic process of the sars-cov virus itself and possibly the resulting immune response. to the extent that total pulmonary blood volumes are slightly larger in covid- patients than in healthy patients (as was observed in cohorts from belgium and china), this is accounted for in part, we believe, by the mistaken segmentation of opacities as blood. future research will be needed to either better segment areas of opacification or else more completely account for their effect on measurements of pulmonary vascular density. this includes the possibility that, apart from whatever confounding effect they may have, the observed opacities are themselves caused by the same processes that drive bvx anomalies as some researchers have suggested [ ] . in its current iteration, the algorithm used to quantify opacities is not validated specifically on scans drawn from the study cohort, but rather on covid- patients from other centers. in the future, additional training and testing of the algorithm on labeled scans from different sites and scanners and in different patient population will allow for further validation of its use more broadly. this understanding is of particular importance in facilitating the use of bvx and bv spectra in research on pvd secondary to chronic lung disease. additional research will seek to improve the accuracy of these methodologies in acquiring the desired measurements in the target populations, as well as to make comparisons with a wealth of clinical data to better understand the part that these hemodynamic redistributions play in the presentation and progression of pvd generally and covid- specifically. while beyond the scope of this report, comparisons with past outbreaks of novel coronavirus strains could be useful for understanding the pathogenic properties of similar viruses which may emerge in the future. such analysis may be limited by the availability of sufficiently thin-sliced ct data from those outbreaks. covid- does not lead to a "typical" acute respiratory distress syndrome renin-angiotensin-aldosterone system inhibitors in patients with covid- covid- and its implications for thrombosis and anticoagulation pulmonary vascular density: comparison of findings on computed tomography imaging with histology improved hessian multiscale enhancement filter. bio-medical materials and engineering pulmonary vascular remodeling in pulmonary hypertension structure and composition of pulmonary arteries, capillaries, and veins interpretation of the appearances of the small pulmonary blood vessels in animals comparative morphologic features of the pulmonary vasculature in mammals hypoxic pulmonary vasoconstriction in humans radiology perspective of coronavirus disease (covid- ): lessons from severe acute respiratory syndrome and middle east respiratory syndrome chest ct severity score: an imaging tool for assessing severe covid- relation between chest ct findings and clinical conditions of coronavirus disease (covid- ) pneumonia: a multicenter study diagnosis, prevention, and treatment of thromboembolic complications in covid- : report of the national institute for public health of the netherlands the authors declare that this report does not contain any personal information that could lead to the identification of the patient(s). the authors declare that they obtained a written informed consent from the patients and/or volunteers included in the article. the authors also confirm that the personal details of the patients and/or volunteers have been removed. key: cord- -j m wno authors: d’ortho, marie-pia title: mmps, inflammation and pulmonary arterial hypertension date: journal: matrix metalloproteinases in tissue remodelling and inflammation doi: . / - - - - _ sha: doc_id: cord_uid: j m wno pulmonary arterial hypertension (pah) is characterised by remodelling of small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure [ ]. pah can be idiopathic, familial, or associated with a number of conditions or diseases, such as connective tissue disease. its prognosis is poor, less than yr from diagnosis. the aetiology of severe unexplained pulmonary hypertension remained largely unknown until a few years ago. the gene underlying familial pah was identified in , the bmpr- gene. however its mutations are not always present, and it probably does not explained the full scope of the disease. pah is associated with structural alterations in pulmonary arteries including intimal fibrosis, medial hypertrophy and adventitial changes, pointing towards extracellular matrix remodelling which have raised the question of involvement of the matrix degrading enzymes. among them, serine proteases, such as plasmina and endogenous vascular elastase (eve), and matrix metalloproteases have been studied. in experimental models, the three of them are increased. accordingly, their inhibition has preventing and in some cases therapeutic effects. however it should be stressed that opposite consequence of protease inhibition on pah can be observed depending on the experimental model, either chronic hypoxia-induced pah (deleterious) or toxic moncrotalin-induced pah (positive). in humans, only sparse reports exist, that found increase in the mmp inhibitor, timp- , and mmp- expression and decreased collagenase (mmp- ). inflammation is part of the pah, and accordingly, protease production is a well known part of the inflammatory response. answering the question whether protease inhibition might represent a therapeutic option in human pah is however certainly too early. pulmonary arterial hypertension (pah) is characterised by remodelling of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure [ ] . pah can be idiopathic, familial, or associated with a number of conditions or diseases, such as connective tissue disease, congenital heart disease, portal hypertension, hiv infection, and exposure to toxins and drugs, including appetite suppressants [ , ] . severe unexplained idiopathic pulmonary arterial hypertension (ipah), previously known as primary pulmonary hypertension, is a rare condition with an estimated incidence of - per million per year [ ] . its prognosis is poor, less than yr from diagnosis before the advent of modern therapies. more recently, targeted therapy with endothelin receptor antagonists, phosphodiesterase inhibition, and prostanoids have been reported to improve symptoms of breathlessness and, in the case of epoprostenol, survival [ ] . in most patients, the condition is believed to evolve over several years, with an initial asymptomatic increase in pulmonary arteriolar reactivity and remodelling. signs and symptoms appear when the mean pulmonary artery pressure is in the range of - mmhg at rest (normal is < mmhg). gradual clinical deterioration occurs when the mean pulmonary artery pressure plateaus - mmhg and cardiac output progressively declines. the aetiology of severe unexplained pulmonary hypertension remained largely unknown until a few years ago. reports of a causal association between appetitesuppressant drugs [ ] and the occurrence of severe pulmonary hypertension provided some insight into its pathogenesis. however, the identification of the gene underlying familial pah (fpah) in provided a firm basis for mechanistic studies [ ] [ ] [ ] . after localisation of the disease gene to the long arm of chromosome ( q ) [ ] , two independent groups identified heterozygous germline mutations in the bone morphogenetic protein (bmp) type ii receptor (bmpr-ii), a receptor for the transforming growth factor (tgf)-superfamily [ , ] . mutations in the bmpr gene have been found in approximately % of families [ ] . in addition, up to % of patients with apparently sporadic ipah have been found to harbour similar mutations [ ] . pah that occurs in association with collagen vascular disease or congenital left-to-right shunting and may be triggered by appetite suppressants (mainly fenfluramines and aminorex), human immunodeficiency virus (hiv) infection or portal hypertension, is indistinguishable from primary pah, with regard to clinical course, histopathology and response to treatment. therefore, a recent world health organization-sponsored consensus conference has suggested that the concept of primary pah be extended to include these conditions and be renamed 'pulmonary arterial hypertension' (pah). at present, it remains unknown whether this concept of 'pah' corresponds to a common pathogenic mechanism. although understanding of the pathobiological mechanisms underlying ipah has progressed rapidly over the past few years, it is still unfeasible to classify patients on a pathogenic basis and to define therapeutic approaches accordingly. current treatments, including continuous infusion of prostaglandin (pg)i and oral endothelin receptor antagonists, probably address downstream manifestations of the disease rather than the central pathogenic mechanisms. the identification of the fpah gene, bone morphogenetic protein (bmp) receptor (bmpr)-ii, and the recognition of central pathobiological abnormalities associated with ipah, now provide a unique opportunity to develop a more robust understanding of the disease. in the near future, this should serve to assess new treatments aimed at correcting selective pulmonary vascular remodelling processes, and, simultaneously, to validate the pathophysiological concepts. identification of these molecular pathways might also provide insight into the understanding of secondary forms of pah, including pah secondary to chronic obstructive lung disease and left heart failure. in these conditions, as well as in persistent pah in neonates, a genetic predisposition has been suggested. the severity of hypoxia-induced pah also varies in intensity among individuals. variations in expression and/or function of candidate genes involved in the process of pulmonary vascular remodelling might therefore improve understanding of secondary forms of pah and also help to define susceptibility to pah of various origins. pulmonary hypertension is associated with structural alterations in pulmonary arteries including intimal fibrosis, medial hypertrophy and adventitial changes [ ] . intimal lesions account for a great part of the reduction of luminal area of small arteries and potentially largely influence the overall pulmonary vascular resistance. intimal lesions consist of eccentric intima thickening and fibrotic plexiform concentric and angiomatoid lesions. more advanced lesions acquire a fibrotic pattern, with interspersed myofibroblasts and marked accumulation of mucopolysaccharides. these lesions are widely present in explanted lungs of patients with severe pah, both ipah or pah associated with crest syndrome [ ] . variable degree of eccentric thickening can be seen also in cigarette smoker's lungs [ ] . the increase in media thickness occurs by a combination of hypertrophy and hyperplasia of smooth muscle cells together with accumulation of extracellular matrix, including thicker but fragmented elastic laminae. fragmentation of elastic laminae was initially described in pah accompanying heart congenital defects [ ] but is now recognised in all forms of pah. in experimental pah induced by the toxin monocrotaline, changes in elastin and collagen synthesis in the pulmonary artery walls, assessed both biochemically and ultrastructurally, were related to the development of progressive pulmonary hypertension with an increase in both insoluble elastin synthesis and total insoluble elastin content and an increase in collagen synthesis and total collagen content [ ] . these changes have also been observed in other models of pah, such as progressive pulmonary venous obstruction [ ] . noteworthy, the extracellular matrix is both a component of the thickened pulmonary vascular media and a regulator of smooth muscle cell growth. tenascin, a glycoprotein involved in lung and vascular morphogenesis, which is strongly expressed in remodelled intima and medial layers of human hypertensive pulmonary arteries [ ] , is a potent regulator of smooth muscle cell proliferation [ ] [ ] [ ] . fibronectin changes smooth muscle cell phenotype from contractile to migratory. the adventitia is mostly composed of fibroblasts. there is growing evidence that, rather than just a structural support to pulmonary vessels, the adventitia may also play a role in the regulation of pulmonary vascular function from the 'outside-in' (as comprehensively reviewed in [ ] ). the normal adventitia represents approximately % of the external diameter of pulmonary arteries larger than m in diameter. in ipah arteries, the adventitial thickness increases to % of artery diameter, predominantly due to collagen deposition [ ] . it also contains a perivascular cuff of inflammatory cells, which might modulate the growth of or transdifferentiate themselves into vascular structural cells in the pulmonary vascular wall. altogether these data show that extracellular matrix remodelling is a key component of pah pathophysiology. matrix deposition is the result of increased matrix degradation insufficient to counterbalance excessive matrix synthesis [ , ] . the normally tightly regulated degradation of extracellular matrix results from the activity of several proteases that are active at neutral ph and act in concert. based on their active sites, two main classes of neutral proteases are the focus of interest: the serine-proteases, including the endogenous vascular elastase (eve) and the plasminogen activator/plasmin system on one hand and the matrix metalloproteases (mmps) also called the matrixins on the other hand. early studies, analysing the ultrastructure of pulmonary arteries on lung biopsy from patients with pah, showed that the internal elastic lamina, which normally separates endothelial from smooth muscle cells in muscular arteries, is fragmented [ ] . this suggested that an elastinolytic enzyme might be involved in the pathophysiology of the disease. this was further explored in experimental pah induced in rats by the toxin monocrotalin, in which an increased number of breaks in the internal elastic lamina was associated with the initiation of vascular structural changes as early as days after the toxin injection [ ] . subsequently, early increase in elastinolytic activity that precedes vascular changes and a later increase associated with progressive disease were confirmed, and the inhibition profile of enzymatic activity showed that it was attributable to a serine protease [ ]. this increased elastinolysis was also shown in chronic hypoxia-induced experimental pah [ ] . jacob et al. [ ] and hornebeck et al. [ ] showed that a serine elastase was produced by aortic smooth muscle cells and associated with atherosclerosis, which was further characterised by zhu et al. in pulmonary artery smooth muscle cells as the endogenous vascular elastase (eve) [ ] . this elastase, like the polymorphonuclear neutrophil serine elastase, is inhibited by -antitrypsin/ -proteinase inhibitor ( -pi), -macroglobulin, elafin and by some synthetic inhibitors [ ] , the most relevant inhibitor in vascular biology being elafin. eve is a powerful enzyme that, by virtue of its ability to degrade elastin, will also degrade proteoglycans that serve as storage sites for growth factors, such as basic fibroblast growth factor (fgf- ) and transforming growth factor. a study from rabinovitch's group has shown that eve releases fgf- in a biologically active form that stimulates smooth muscle cell proliferation [ ] . elastase activity either directly or via activation of matrix metalloproteinases (see below) can induce production of the matrix glycoprotein tenascin (tn), which optimises the mitogenic response to fgf- and is, in fact, a prerequisite for the response to epidermal growth factor (egf) in cultured smooth muscle cells [ , ] . the process of smooth muscle cell migration also appears to depend, at least in experimental animals, on the continued activity of elastase. obviously, elastin peptides stimulate the production of the matrix glycoprotein fibronectin, which changes smooth muscle cells from a contractile to a migratory phenotype [ , ]. although these findings emphasise the important role of elastase in the pathogenesis of pah, the question remains open regarding the role of other proteases specialised in extracellular matrix degradation, namely plasminogen activators/plasmin system and mmps. several observations point to an additional role of the plasminogen system in pulmonary hypertension and to enhanced plasmin proteolysis that contributes to pulmonary vascular remodelling. the central reaction of the plasminogen activator (pa) system is the conversion of plasminogen to plasmin by plasminogen activators (pas), the tissue plasminogen, tpa, and urokinase plasminogen activator, upa [ ] . the serine protease plasmin degrades fibrin to fibrin-degradation products. however, plasmin has several substrates other than fibrin, including blood coagulation factors, cell surface receptors, some matrix metalloproteinases, that plasmin activates, and structural components of the extracellular matrix such as fibronectin or laminin. while plasminogen resides primarily within the plasma, with the liver representing the primary site of plasminogen synthesis, plasminogen mrna is present in several tissues, including adrenal, kidney, brain, testis, heart, lung, uterus, spleen, thymus, and gut, supporting a broadly distributed functional role of the pa system [ ] . tissue-type pa and u-pa activate plasminogen by cleaving a specific arg-val peptide bond located within the protease domain. the activation of plasminogen by t-pa is highly dependent on the presence of cofactors, such as fibrin, that bind and alter the conformation of plasminogen [ ] . the activation of plasminogen by u-pa is tightly regulated at the cell surface, due to anchorage of u-pa to cell surface via a specific receptor, the upa-r. plasmin formation is intensely regulated by pa inhibitors, which inhibit t-pa and u-pa, most notably pa inhibitor- (pai- ) [ ] . plasmin is directly inhibited by -antiplasmin, which circulates in plasma. in addition to functioning within the vascular lumen to control fibrinolysis, the pa system is active within the blood vessel wall, where it plays an important role in controlling vascular remodelling. the development of intimal hyperplasia after vascular injury is diminished in plasminogen-deficient mice, supporting the concept that plasmin associated with vascular smooth muscle cells enhances cell migration by fostering extracellular matrix degradation, either directly or indirectly by activating matrix metalloproteinases [ ] . vascular smooth muscle cells express u-pa and its receptor. urokinase (u-pa) deficiency and pharmacological inhibition of u-pa receptor, but not t-pa deficiency, inhibit neointima formation in mice, suggesting that u-pa-triggered plasmin formation drives vascular smooth muscle cell migration [ ] [ ] [ ] . regarding pulmonary vascular system and pulmonary hypertension, hypoxia increases expression of u-par, enhances plasma fibrinolytic activity, and upregulates expression of plasminogen activators during ventricular hypertrophy in response to hypoxia or overloading [ ] [ ] [ ] . interestingly, and also similar to elastase, plasmin could also participate in smooth muscle cell proliferation indirectly as it has been shown to induce the release of fgf- from the extracellular matrix [ ] . the matrixins form a family of > members known in humans, initially identified based on their ability to degrade extracellular matrix proteins (e.g., collagenases degrade fibrillar collagens, metallo-elastase, elastin, etc.), and are known to have many other roles [ ] . one of the striking features of the matrixins is that many of those genes are 'inducible'. the effectors include growth factors, cytokines, chemical agents (e.g., phorbol esters, actin stress fibre-disrupting drugs), physical stress and oncogenic cellular transformation. mmp gene expression may be downregulated by suppressive factors (e.g., transforming growth factor, retinoic acids, glucocorticoids). their proteolytic activities are precisely controlled during activation from their precursors and inhibition by endogenous inhibitors, -macroglobulins and tissue inhibitors of metalloproteinases (timps). all matrixins are synthesised as pre-pro-enzymes, the loss of the 'pre' peptide is a signal of secretion. apart from a few members activated intracellularly by furin, most are secreted from the cell as inactive zymogens. secreted promatrixins are activated in vitro by proteinases, such as plamin, and by nonproteolytic agents, such as in vivo reactive oxygen species and in vitro, thiol-reactive agents, mercurial compounds, and denaturants. in all cases, activation requires the disruption of the cys-zn + (cystein switch) interaction between the zinc of the active site and the cystein present within the 'pro'-domain. subsequently, the removal of the propeptide proceeds often in a step-wise manner [ ] . in vivo, most promatrixins are likely to be activated by tissue or plasma proteinases, such as neutrophil elastase [ ] or plasmin, or opportunistic bacterial proteinases. using transgenic mice deficient in upa, carmeliet et al. have shown that the upa/plasmin system is, in vivo, a pathophysiologically significant activator of promatrixins [ ] . by contrast, no data exist regarding activation of promatrixin by eve. other activation cascades are known; for example, the activation of pro-mmp- takes place primarily on the cell surface and results from the action of membrane-anchored mmps, the 'membrane-type mmps' (mt-mmps). studies have shown that this activation process requires both active mt -mmp and the timp- -bound mt -mmp [ ] . timps ( - kda) are the major endogenous inhibitors of mmp activities in tissue, and four homologous timps (timps - ) have been identified to date [ ] . timps exhibit additional biological functions. as detailed above, timp- plays a role in mmp- activation. timp- and timp- have mitogenic activities on a number of cell types, whereas overexpression of these inhibitors reduces tumour cell growth, and timp- , but not timp- , inhibits fgf- induced human endothelial cell growth. these biological activities of timps are independent of mmp-inhibitory activities [ ] . mmps, particularly gelatinase a/mmp- , which degrade the type iv collagen of basement membranes, are increased in the pulmonary vascular bed, during both toxin-and hypoxia-induced experimental pah [ ] . increases in interstitial collagenase (mmp- ), stromelysin- (mmp- ) and gelatinases a (mmp- ) and b (mmp- ) have also been described following return to normoxia [ , ] . interestingly, inhibition of mmps by either a synthetic inhibitor, doxycycline, or adenovirusmediated human timp- gene transfer during chronic hypoxia is associated with exacerbation of pah and vascular remodelling. either of two mmp-inhibiting treatments increased muscularisation and collagen accumulation in small pulmonary arteries [ ] , providing strong support for the argument that mmps play a crucial protective role in hypoxic pah. in keeping with these results is the demonstration that deficiency of upa-mediated plasmin generation impairs vascular remodelling in hypoxic pah [ ] . mmps and plasmin probably protect against pah by limiting matrix deposition. another important hypothesis concerns angiogenesis, which represents an important protective mechanism, as demonstrated by increase in lung vascular endothelial growth factor (vegf) during hypoxic pah, improvement of pah after vegf gene transfer and worsening of pah following angiostatin gene transfer [ , ] . in contrast to hypoxic pah, inhibition of mmps in an ex vivo model of organ culture of pulmonary artery rings obtained from rats treated by monocrotalin, showed regression of medial thickness to control levels [ ] . similar results in this study, obtained by either serine-protease inhibitors or metalloprotease inhibitors, come from tight interactions between the two proteolytic systems, as elastase can activate some pro-mmps [ ] and degrade the mmp-inhibitor, timp- [ ] . in contrast, most mmps degrade the major elastase inbihitor, -pi [ ] . in keeping with the ex vivo results, in vivo experiments in toxic monocrotaline-induced pah have shown that inhibition of mmps by adenovirus-mediated human timp- gene transfer in the lung leads to less severe pah with decreased muscularisation and increased lung-cell apoptosis, as compared to controls [ ] . the effect of timp- on pah is consistent with an ability of mmp inhibition to prevent monocrotalineinduced pulmonary vascular remodelling and pah, in part by reducing smooth muscle cell migration and proliferation. all together, these data support a synergistic and deleterious role for serine-and metalloproteases in toxic pah and indicate that mmps may have opposite effects in different pah models. bmps are the largest group of cytokines within the tgf-superfamily and were originally identified as molecules regulating growth and differentiation of bone and cartilage [ ] . bmps regulate growth, differentiation, and apoptosis in a diverse number of cell lines, including mesenchymal and epithelial cells, acting as instructive signals during embryogenesis and contributing to the maintenance and repair of adult tissues [ , ] . tgf-superfamily type ii receptors are constitutively active serine-threonine kinases and form homodimers that exist constitutively or are recruited to receptor complexes on ligand stimulation. bmpr-ii is distinguished from other tgf-superfamily type ii receptors by a long carboxyl-terminal sequence following the intracellular kinase domain [ ] . bmpr-ii initiates intracellular signalling in response to specific ligands: bmp , bmp , bmp , bmp , growth and differentiation factor- (gdf ), and gdf [ ] . mutations of bmpr-ii have been found in fpah [ ] . approximately % of mutations are missense mutations occurring in highly conserved amino acids with predictable effects on receptor function. for example, many of these involve the serine-threonine kinase domain of bmpr-ii or the extracellular ligand binding domain. however, the majority (~ %) of bmpr coding mutations are frameshift and nonsense mutations, many of which would be expected to produce a transcript susceptible to nonsense-mediated mrna decay. thus, haploinsufficiency for bmpr-ii represents the predominant molecular mechanism underlying inherited predisposition to fpah. further genetic analysis is revealing an increasing number of families in which bmpr-ii mutation is implicated, including the identification of gene deletions and rearrangements. interestingly, bmpr-ii alterations are also involved in experimental pah, either induced by chronic hypoxia [ ] or by the toxic model, monocrotalin-induced [ ] . clearly, one major mechanism by which bmpr-ii plays a role in fpah is smooth muscle proliferation. however, interference with extracellular matrix remodelling can be hypothesised. very recently, induction of upa upon bmp stimulation of bmpr-ii has been reported in tumoral cell line [ ] . this report is the only one to date that has explored induction of protease(s) after engagement of the bmpr-ii receptor but is certainly a promising direction. very few studies are available in the human disease, regarding mmps. based on studies using cultured human smooth muscle cells isolated from elastic pulmonary arteries from ipah patients obtained surgically, we reported mmp/timp production by smooth muscle cells in vitro. we also performed immunolocalisation in whole medium-sized pulmonary arteries. in vitro, timp- was overexpressed and mmp- underexpressed by ipah cells, whereas mmp- expression was similar in the two groups. total mmp- overexpression was also found, with a greater amount of the active form in ipah cells as compared with controls. in situ studies showed gelatinolytic activity in tissue sections and strong mmp- immunostaining along the inner elastic lamina up to the lamina break. timp- immunostaining was found in both control and ipah arteries, whereas mmp- staining was detected only in the media of a few control specimens [ ] . it is unclear whether a similar pattern is present in distally remodelled pulmonary arteries; however, endothelial cells express moderate/intense immunohistochemical expression of mmp- , while myofibroblasts display low levels of this extracellular protease [ ] . membrane type- -mmp was also expressed in endothelial and myofibroblastic cells of concentric and plexiform lesions. demonstration of a timp- -mmp imbalance conducive to extracellular matrix accumulation does not rule out a role for active mmp- in ipah. proteolysis may be effective in limited areas even when timp levels are high in the extracellular milieu, because mmp- tethering and activation at the cell surface focuses the catalytic activity on limited targets on the cell membrane. this hypothesis is supported by immunohistology and in situ zymography data, which clearly show that gelatinolytic activity colocalised with mmp- immunostaining in arteries from ipah patients [ ] . this pattern of mmp and timp expression, characterised by increased timp- levels coexisting with evidence of extracellular matrix degradation, has been found in other fibrotic diseases, such as adult respiratory distress syndrome (ards). in bronchoalveolar lavage (bal) fluid from ards patients, timp- levels were significantly higher than in healthy controls. despite the high timp- levels, extracellular matrix degradation by mmps is suggested by the presence of active mmp- in epithelial lining fluid [ ] and of basement membrane disruption markers in bal fluid of ards patients [ ] . altogether, these data suggest that a timp- -mmp imbalance promoting extracellular matrix accumulation within the interstitial tissue may coexist with the presence of active mmp- confined to the cell surface. in ipah, disruption of the internal elastic lamina, extracellular matrix disorganisation and smooth muscle cell migration are strong arguments supporting a direct role for active mmp- . this enzyme not only degrades nonfibrillar collagen, but also cleaves elastin. moreover, latent-mmp- may both bind to elastin and undergo auto-activation, subsequently degrading elastin [ ] . these results on mmp- expression in pah are consistent with previous data, as in situ zymography and mmp- immunolocalisation showed colocalisation of gelatinolytic activities and mmp- along elastic fibres. also, active mmp- may contribute not only to extracellular matrix remodelling but also to important processes in ipah, such as smooth muscle cell migration and proliferation [ ] . there is compelling evidence of global immunological alterations in ipah patients [ ] and pah occurs in the setting of profound immune deregulation underlying hiv infection and collagen vascular diseases. the recognition of an inflammatory component in pah [ ] supports the investigation of expression of cytokines that might potentially drive perivascular inflammation and thus contribute to the disease. remodelled pulmonary arteries express il- , il- , and pdgf in infiltrating inflammatory cells [ , ] , the chemokine rantes (acronym for regulated upon activation, normal t cell expressed and secreted), an important chemoattractant for monocytes and t cells, and the macrophage inflammatory protein- (mip- ). lungs of ipah patients have increased expression of fraktaline, a chemokine involved in t cell trafficking and monocyte recruitment, and their circulating cd and cd t cells have higher levels of the fraktaline receptor cx cr when compared with controls or samples of patients with thromboembolic pah. inflammatory cells infiltrating remodelled pulmonary arteries may include subpopulations of vascular precursor or early-progenitor cells, also potential contributors to pulmonary vascular remodelling in pah. pulmonary arteries in pah caused by chronic hypoxia contain an infiltrating subpopulation of fibrocytes, identified by the expression mononuclear cell markers cd , cd b, cd , and the fibroblast marker -procollagen. about % and % of these cells also undergo proliferation and express smooth muscle -actin, respectively [ , ] . these studies also document that depletion of circulating monocytic cells alleviates pulmonary vascular remodelling caused by chronic hypoxia. endothelial cell precursors may play a beneficial role in pah since their administration to monocrotaline-treated rats has dramatic healing effects in remodelled pulmonary arteries, notably when transfected with the endothelial nitric oxide synthase gene [ ] . pulmonary vascular inflammation has also been documented in chronic obstructive pulmonary disease with or without coexisting pah [ , [ ] [ ] [ ] [ ] , and vascular progenitor cells identified in lung vessels [ ] . within the scope of the present review, it should be stressed that protease production is part of the inflammatory response. sources of protease are circulating cells, leukocytes [ , ] and platelets [ , ] , together with resident endothelial [ ] and smooth muscle cells [ ] . in experimental models, protease inhibition, especially elastase inhibition has clearly proven its efficacy, both at preventing and curing pah induced by monocrotalin [ , ] . accordingly, overexpression of the eve inhibitor elafin protects partially transgenic mice from hypoxic pah [ ] . however, conflicting results have been obtained regarding metalloprotase inhibition, depending on the considered model: worsening hypoxic pah [ ] and preventing toxic monocrotalin-induced pah [ ] . it is certainly worth asking the question "should we expect an improvement in pah when using protease inhibitors?". it seems quite clear-cut when thinking of elastic lamina fragmentation, but not so obvious when taking into account the large increase in extracellular matrix deposition observed in pulmonary vascular beds and regarding all other roles for these proteases in different cellular processes, such as angiogenesis, cell migration and cell differentiation. all these considerations leave the question of their beneficial or deleterious role open. the tight interplay between the three proteolytic systems further complicates the answer. pulmonary arterial hypertension clinical classification of pulmonary hypertension primary pulmonary hypertension new treatments for pulmonary arterial hypertension appetite-suppressant drugs and the 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invasion of hct cells smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension immunohistochemical study of endothelin- and matrix metalloproteinases in plexogenic pulmonary arteriopathy gelatinase in epithelial lining fluid of patients with adult respiratory distress syndrome s collagen in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome binding of kda and kda progelatinases to insoluble elastin modulates their proteolytic activation the role of protein-tyrosine phosphorylation and gelatinase production in the migration and proliferation of smooth muscle cells inflammation in pulmonary arterial hypertension hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage circulating mononuclear cells with a dual, macrophage-fibroblast phenotype contribute robustly to hypoxia-induced pulmonary adventitial remodeling rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and enos gene therapy in established disease pulmonary hypertension in chronic obstructive pulmonary disease inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease identification of vascular progenitor cells in pulmonary arteries of patients with chronic obstructive pulmonary disease enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease elastolytic metalloproteinases produced by human mononuclear phagocytes. potential roles in destructive lung disease collagenolytic metalloenzymes of the human neutrophil: characteristics, regulation and potential function in vivo platelet release of trimolecular complex components mt -mmp/timp /mmp : involvement in mmp activation and platelet aggregation release of gelatinase a during platelet activation mediates aggregation proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase- : implication for angiogenesis in fibrin matrices smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension key: cord- - gsq l authors: li, hongjun title: hiv/aids related respiratory diseases date: - - journal: radiology of hiv/aids doi: . / - - - - _ sha: doc_id: cord_uid: gsq l lungs are the most commonly involved organ by hiv/aids related diseases, and pulmonary infections are the main reasons for the increasing death rate from aids. pathogens of hiv related pulmonary infections include parasites, fungi, mycobacteria, viruses, bacteria and toxoplasma gondii. according to international reports, pathogens have different geographical distribution, which is also closely related to the socioeconomic status of the region to produce varied aids related diseases spectra. for instance, in the united states, pneumocystis carnii pneumonia (pcp), tuberculosis and recurrent bacterial pneumonia (at least twice within year) occur frequently in hiv infected patients. an international report published years ago indicated that pcp is the most common and serious pulmonary opportunistic infections in hiv infected patients. now its incidence has dropped with the application of antiretroviral treatment and preventive measures. pcp will continue to occur initially in patients who are aware of their hiv infection. in addition, hiv related viral and parasitic infections have been reported both domestically and internationally. in this section, the clinical manifestations and imaging findings of hiv related pulmonary infections are analyzed and discussed, which provide effective diagnosis basis, so as to reduce the incidence of hiv-related pulmonary infections. lungs are the most commonly involved organ by hiv/aids related diseases, and pulmonary infections are the main reasons for the increasing death rate from aids. pathogens of hiv related pulmonary infections include parasites, fungi, mycobacteria, viruses, bacteria and toxoplasma gondii. according to international reports, pathogens have different geographical distribution, which is also closely related to the socioeconomic status of the region to produce varied aids related diseases spectra. for instance, in the united states, pneumocystis carnii pneumonia (pcp), tuberculosis and recurrent bacterial pneumonia (at least twice within year) occur frequently in hiv infected patients. an international report published years ago indicated that pcp is the most common and serious pulmonary opportunistic infections in hiv infected patients. now its incidence has dropped with the application of antiretroviral treatment and preventive measures. pcp will continue to occur initially in patients who are aware of their hiv infection. in addition, hiv related viral and parasitic infections have been reported both domestically and internationally. in this section, the clinical manifestations and imaging fi ndings of hiv related pulmonary infections are analyzed and discussed, which provide effective diagnosis basis, so as to reduce the incidence of hiv-related pulmonary infections. pneumocystis has been believed to be a kind of protozoon. recently, based on its ultrastructure and ribosomal rna phylogenetic analysis, pneumocystis is now believed to be a kind of fungus, with high affi nity to the lung tissues. due to the compromised immunity, % aids patients sustain different types of pulmonary infections, of which pcp is the most common life-threatening opportunistic infection with an incidence rate of about - %. about - % patients suffering from aids complicated by pcp are adolescents and adults with their cd t cell counts being less than / μl. clinical manifestations of typical pcp are fever, cough (dry cough without phlegm), dyspnea, chest distress and shortness of breath. dyspnea is shown as progressive difficulty in breathing, which initially occurs after physical activities and develops into diffi culty breathing even in resting state. pcp is commonly accompanied by weight loss, fatigue, anemia, general upset and lymphadenectasis. all these symptoms are non-specifi c, but patients often report subjective feelings of severe symptoms while physical signs are mild. by auscultation, the lungs are normal or with slightly dry, moist rales. these are the clinical fi ndings characteristic to aids complicated by pcp. in most patients with pcp, the serum ldh level increases but it is non-specifi c. in cases of aids complicated by pcp, the blood po reduces, commonly being lower than mmhg in patients in the middle and advanced stages. the diagnostic imaging for pcp includes chest x-ray and ct scanning. due to the low resolution of chest x-ray, its demonstrations are negative for pcp patients in the early stage or only include thickened pulmonary markings and decreased pulmonary transparency. however, ct scanning demonstrates tiny lesions or more detailed changes in lungs. especially with the application of hrct, the detection rate of pcp lesions has been greatly improved. it has been internationally reported that nearly % of pcp patients show negative fi ndings by the chest x-ray but with abnormal fi ndings by hrct. due to the rapid progression of pcp as well as its complex pathological changes, ct scanning demonstrations are diverse with specifi city. according to different pulmonary ct scanning demonstrations in different stages of the illness, pcp is divided into early stage (exudative and infi ltrative stage), middle stage (fusion and parenchymal stage) and advanced stage (absorption or fi brosis stage). the early typical manifestations include intrapulmonary multiple miliary nodules, mainly distributed in both middle and lower lung fi elds. it may be accompanied by enlarged hilar shadow, which should be differentiated from acute miliary tuberculosis. the middle stage is a period of infi ltration. as the disease progresses, miliary and patchy shadows fuse and expand into a dense infi ltrative shadow with even density, showing a diffuse ground glass liked change. the typical manifestations include bilaterally symmetric foci with the hilus as the center. the foci infi ltrates from the hilus to bilateral pulmonary interstitium, progressing from the both middle lungs to both lower lungs. hrct can more clearly demonstrate the foci, showing a map liked or gravel road liked appearance, with clearly demonstration of gas containing bronchus penetrating the foci. the pulmonary apex is involved later. the exterior stripe of the lung fi eld has increased transparency, showing typical willow leaf sign or moon bow sign which is the manifestation of compensatory pulmonary emphysema. during the late compensatory repair period, the intrapulmonary lesions are mainly parenchymal changes and fi brosis, with large fl aky high density shadows as well as cords liked and reticular changes. pneumothorax, mediastinal emphysema, pneumatocele, pleural effusion and other complications may occur, with an incidence of pneumatocele in about - % patients. the autopsy grossly demonstrates swelling of the lung tissue, and the alveoli are fi lled with large quantity foamy liquid. the pathological changes mainly manifested as interstitial pneumonia, with early manifestations of increased permeability of the capillary wall basement membrane in the alveolar walls, which leads to fl uid exudation. the pneumocystis carinii proliferate in large quantity and adhere to cause degeneration of the type i alveolar epithelial cells and shedding of the basement membrane. vascular congestion, edema as well as infi ltration of lymphocytes, plasma cells and mononuclear cells can be found in the pulmonary interstitium. due to the extensive existence of aspergillus in natural world, sputum smear positive often fails to defi ne its invasive infection. in the cases with aspergillus infection, hyphae can be found in the sputum. fungal infections often occur in patients with cd t cell count below /μl, of which the most common pulmonary infection is aspergillus infection, followed by penicillium marneffei infection. pulmonary infections caused by candida albicans and histoplasma are rarely found. the incidence of cryptococcal pulmonary infection is still in a disagreement, which is increasing recently. there are also some common endemic fungal infections, such as the most commonly found fungal infections of aids complicated by penicillium infections in guangxi zhuang autonomous region and hong kong, china. aspergillus has an extensive existence in the natural world. aids complicated by aspergillus infection is related to the application of corticosteroid hormone or broad-spectrum antibiotics, which occurs commonly in the advanced/critical stage of aids. the cases of pulmonary fungal infections, with fi ndings of hyphae (aspergillus or candida) or yeast in cytoplasm (histoplasma capsulatum) in tissue sections and simultaneous fi ndings of histiocytic reactions including the infi ltration of neutrophilic granulocyte and the necrosis of histocytes, can be diagnosed as having invasive fungal infection. candida albicans is yeast liked fungus, which is widespread in the natural world. it can parasitize in the mocous of skin, oral cavity, intestinal tract and vagina of the human being. candida albicans cannot cause disease in immunocompetent people but is pathogenic in immunocompromised population. after its invasion into the tissues, it turns into mycelia and multiplies in large quantity with great toxicity. it also has the ability to fi ght against phagocytosis. clinically, its infection is characterized by a chronic onset and clinical symptoms of low and moderate grade fever but rarely high fever, cough, shortness of breath, cyanosis, irritation or dysphoria. the pulmonary signs include weakened breathing sounds by auscultation and obvious moist rales of lungs. the serious cases may have symptoms of systemic poisoning. the illness is prolonged and repeated during its whole progression. by diagnostic imaging demonstrations, it can be divided into the following types: ( ) bronchitis type, with chest x-ray demonstrations of increased pulmonary markings in lower fi elds of both lungs; ( ) pneumonia type, commonly with accompanying extrapulmonary lesions. the lesions are mainly located in the middle and lower lung fi elds and lesions in the lower lung fi eld are more common. the apex is generally not involved. the lesions are recurring one after another. a small number of patients may sustain complications of exudative pleurisy. ( ) disseminated type, with miliary shadows, diffuse nodular shadows or multiple small abscesses. the lesions often involve the middle and lower lungs. chest x-ray demonstrates thickened pulmonary markings and accompanying spots, small fl akes and large fl akes of parenchyma shadows, in manifestations of bronchial pneumonia. in some serious cases, the foci may fuse together and enlarge to involve the entire lobe. ct scanning demonstrates pulmonary nodules and few have ground glass liked changes of the lungs. pathological changes include acute infl ammatory lesions in the lungs, alveolar exudation and infi ltration of monocytes, lymphocytes and neutrophils. acute disseminated lesions often cause multiple small abscesses, central caseous necrosis, spores and hyphae in and around the lesions. histoplasma capsulatum belongs to moniliales family, deuteromycetes class and fungal kingdom, whose growth requires organic nitrogen. it is often isolated from the soil with abundant contents of birds or bats faeces and spreads along with chickens, birds, dogs, cats, and mice. when the conidia and mycelial fragments of histoplasmosis are inhaled, most can be expelled by the defense mechanism of the human body. granulomas may form, but in immunocompromised patients, it may cause disseminated histoplasmosis. when the cd t cell count in aids patients is less than /μl, histoplasma capsulatum infection of lungs may occur. histoplasma capsulatum pneumonia has a higher incidence in south america, africa and india. in the slight cases, the clinical manifestations are similar to symptoms of the cold, with low-grade fever, cough, and general upset. in the serious cases, there are symptoms of infl uenza, including chills, high fever, cough, chest pain, dyspnea, fatigue and poor appetite. in the cases of acute cavity, thin-walled cavity may form within a month. complications may be pericarditis, arthritis, skin nodules, rash fi brous mediastinitis and mediastinal granuloma. diagnostic imaging demonstrations are non-specifi c, with scattering pulmonary acinus exudation, multiple nodules in a diameter of about mm with accompanying thickened septa, and formation of granulomas with accompanying calcifi cation. it should be differentiated from bacterial pneumonia, tuberculosis and other pulmonary fungal infections by laboratory tests to defi ne the diagnosis. the specifi city of the glycogen antigen detection of histoplasma capsulatum is up to %. mucor spreads through the respiratory tract. it commonly invades the blood vessels, especially arteries. it reproduces locally or causes thrombosis and embolism. clinical manifestations are high fever, cough, sputum, shortness of breath, chest distress, chest pain and hemoptysis (pulmonary artery involvement). the diagnostic imaging demonstrates fl akes infl ammatory foci, with manifestations of pulmonary cavity and pulmonary infarction. the pathological changes are hemorrhagic infarction of local tissue, pneumonia and exudation of neutrophils. hemorrhagic infarction of local tissue may be related to hyphae induced minor arteries lesions. it is estimated that one third of the world population was/is infected with tubercle bacillus and % of them are aids patients. the who reported that there are , newly infected patients of tb each year and . % of them are caused by aids. it is estimated that each year in , hiv infected patients, - sustain active tb, and there is a great risk of active tb progressed from the latent tuberculosis infection. hiv infected patients with tuberculosis are commonly young and middle aged adults, with more male patients than female patients. tuberculosis can occur at any stage of aids and at any level of cd t cell counts. it has been internationally reported that hiv infection complicated by tb has no specifi c imaging demonstrations. it has an acute onset, with an incidence of acute onset . times as high as that in non-hiv infected patients. the lesions are morphologically diverse, which are different from non-hiv infected patients with tb. hiv infection complicated by tb has commonly an acute onset, while tb in non-hiv infected patients is commonly secondary to other lesions, with cavities, fi brosis, pleural thickening and calcifi cation. a study conducted in china has demonstrated that for aids complicated by tb, the acute cases mainly have military and exudative lesions, with an incidence of and % respectively; while the incidence of chronic cases including cavity, fi brosis and calcifi cation is declining, being , and respectively. a later occurrence of tuberculosis in hiv infected patients indicates a more seriously immunocompromised immunity, with less typical clinical manifestations and imaging demonstrations. when the cd t cell count level is above - /μl, the systemic symptoms are fever, chills, night sweating, fatigue, poor appetite and weight loss. respiratory symptoms are cough, expectoration, hemoptysis, chest pain and dyspnea. it manifests as primary tuberculosis, with its foci distributing in the middle and lower lungs, involving multiple lobes and segments. when the cd t cell count decrease, the impact of tb increase including the occurrence of extrapulmonary tuberculosis and disseminated disease. when the cd t cell count drops below /μl, pulmonary tuberculosis manifests as acute onset (such as miliary tuberculosis) or extrapulmonary tuberculosis (such as ileocecal tuberculosis) and peripheral lymph nodes tuberculosis. its difference from the clinical manifestations of non-hiv infected patients is as the following: ( ) more common pulmonary infi ltration with multiple involvements and rare cavities; ( ) higher incidence of dissemination ( - %) commonly along with blood fl ow and higher incidence of extrapulmonary tuberculosis ( - %); ( ) more common lymph node tuberculosis, such as hilar, mediastinal and extrapleural lymphadenectasis; ( ) lower positive rate of tuberculin test (ppd); ( ) more patients with no expectoration, with sputum smear for acid-fast bacilli staining is negative; ( ) higher incidence of resistant strains, high recurrence rate, and higher mortality (table . ). foci in the cases with aids complicated by pulmonary tuberculosis are change quickly. after anti-tb treatment, the lesions are absorbed quickly. those receiving no anti-tb therapy, the foci tend to fuse together to form a mass or diffusely distribute. bacterial septicemia often occurs in aids patients. many opportunistic pathogens can cause respiratory infections, including bacterial bronchitis, pneumonia and pleuritis. the incidence rate of bacterial pneumonia (bp) is - %. bp has a larger range of impact on hiv infected patients than on non-hiv infected groups. repeated episode of bp is considered to be the fi rst manifestations of latent hiv infection. therefore, for those individuals who have recurrent pneumonia without other risk factors, they should be alert to hiv infection. the common pathogenic bacteria include streptococcus pneumoniae, staphylococcus aureus, rhodococcus equi, haemophilus and pseudomonas aeruginosa. as non-hiv infected patients, the most common pathogens of pneumonia are streptococcus pneumoniae and haemophilus infl uenzae. legionella and klebsiella are also common. many factors, such as the reduced t lymphocytes in hiv infected patients, manufacturing disorders of neutrophils, mononuclear cells and cytokines, and dysfunctional b lymphocytes, provide chances for opportunistic bacterial infections. in addition, the application of broad-spectrum antibiotics also increases the chance of opportunistic infections. bp can occur in any stage of hiv and at any level of cd t cell count. when the cd t cell count decreases, the incidence of bp also increases. the clinical manifestations of hiv infected patients are the same as non-hiv infected patients, with acute onset ( - days) , high fever ( - °c) , chills, chest pain, dyspnea, cough, purulent sputum (bloody or rusty). being different from non-hiv infection, pulmonary infection in hiv-infected patients is often recurrent. the imaging demonstrations of hiv/aids related bacterial pneumonia are similar to those in non-hiv infected patients. most cases of streptococcal pneumonia and haemophilus pneumonia have unilateral, confi ned and partially fused foci with accompanying pleural effusion. the imaging demonstrations include thickened and deranged pulmonary markings, alveolar fi lling of infl ammatory exudates with the progression of the illness, large fl aks infl ammatory infi ltration shadows or parenchymal shadows, bronchial gas fi lling phase in the parenchymal shadows. the lesions distribute along the pulmonary segments or lobes, rarely with accompanying pleural effusion. during the absorption period, the density of the parenchymal shadows gradually reduces and the scope narrows down. there may be cavities in some individual cases. but in most cases it is completely absent after poor effi cacy and more side effects favorable effi cacy and less side effects - weeks. lesions absorption are slow in elderly patients and recurrent patients, which is diffi cult to be completely absorbed and often develop into organic pneumonia. rhodococcus equi was initially discovered in and nominated as corynebacterium equi. after structure analysis of the cell wall, it was found to be different from corynebacterium, and therefore it is classifi ed into rhodococcus. rhodococcus equi is generally considered as the pathogens of horses, pigs and cattle. human rhodococcus equi infection is rare. but in recent years, due to an increase in patients with immunodefi ciency syndrome, reports of rhodococcus equi induced human respiratory infection and sepsis are increasing. rhodococcus equi is an intracellular facultative parasitic bacterium. its optimum temperature for growth is °c, and suitable temperature for its growth is - °c. the acid-fast staining for rhodococcus equi shows uncertain results. due to its various morphology, it is commonly mistaken as diphtheroids bacilli, bacillus or micrococcus. on sheep blood agar plate, the bacterium can have synergistic hemolysis with staphylococcus aureus, mononuclear listeria and corynebacterium pseudotuberculosis. toxicity mechanisms of rhodococcus equi has been recently discovered the existence of toxic plasmid, which provides a new idea for the full understanding of its pathogenesis. clinical symptoms are usually cough, orange red sputum, high fever and other symptoms. e marchiori et al. in studied fi ve cases of aids complicated by rhodococcus equi pulmonary infection. all the patients had a case history of cough and fever history for - months with accompanying shortness of breath and chest pain. li et al. in [ ] studied a group of cases. all patients had fever, with a body temperature being - °c, cough, orange red sputum. the typical clinical manifestations of the disease are fever, dyspnea and chest pain. other symptoms such as weight loss, diarrhea and joint pain are not representative. based on the course of the disease, the diagnostic imaging demonstrations of rhodococcus equi pulmonary infection can be divided into early stage, showing round liked fl aky blurry shadows surrounding unilateral hilum that has blurry boundary; middle stage (parenchymal change), showing central sphere liked high density shadow surrounding unilateral hilum, in parenchymal changes and with clear boundary; advanced stage (necrosis) showing secondary cavity of the pulmonary mass, possibly with hydropneumothorax and pleurisy. the imaging demonstrations are characteristic, but lack of specifi city. and it should be differentiated from pulmonary tumors. the pathological changes include the most commonly chronic suppurative bronchopneumonia and extensive pulmonary abscesses. the histopathology demonstrates massive bleeding in alveolar space, large quantity erythrocytes, intact cellular wall and large quantity epithelial cells. the predominant pathological changes may also be fi broblasts, with parenchymal changes of lung tissue and thickened alveolar septa. accumulating piles of strip liked purple rhodococcus equi can be found by pas staining. common pathogenic viruses of the opportunistic pulmonary infections in hiv infected patients are cytomegalovirus (cmv) and infl uenza virus. cmv is the most common pathogen of hiv/aids related pulmonary infection. by autopsy, - % patients with hiv/aids have cmv infection, only second to pneumocystis carinii pneumonia. moskowitz et al. [ ] reported that among the direct causes of death in aids patients, % is due to pulmonary cytomegalovirus infection. because of the lack of typical clinical manifestations and sensitive examinations for its early diagnosis, the defi nitive diagnosis rate of cytomegalovirus pneumonia is only - % before autopsy. the clinical manifestations of cmv infection are non-specifi c. the systemic symptoms are fever, soreness of joints and muscles. respiratory symptoms are paroxysmal dry cough, progressive shortness of breath, diffi culty in breathing during activities. pulmonary cmv infection may develop secondary fungal infection or be complicated by bacterial, fungal, and pneumocystis carinii infections. the cytomegalovirus can widely spread in the organs and tissues of the infected patients, and the infections can directly lead to the damage of infected host cells. in addition, the virus can also cause pathogenic effects via immune pathological mechanism. some scholars classifi ed cmv pneumonia into diffuse, miliary necrosis and cytomegalic. diffuse and cytomegalic cmv pneumonia are often accompanied by diffuse alveolar damage (dad), which is more common in the diffuse type of cmv pneumonia but less common in cytomegalic type of cmv pneumonia. the pathological basis of diffuse small nodules in lungs is hemorrhagic necrosis. sometimes cmv infection is concurrent with other infections in the lungs, and even co-infects one cell. pulmonary parenchymal changes indicate bacterial and fungal infections, such as fi ndings of inclusion bodies in the cells, commonly known as eagle's eye sign. the imaging demonstrations of cytomegalovirus pneumonia are diverse. some studies summarize that the lungs commonly have manifestations of diffuse interstitial infi ltration or alveolar infi ltration, with ground glass liked changes, pulmonary parenchymal changes, grid liked changes, thickend bronchial wall, bronchiectasis, pulmonary nodules or masses. the principal changes include the early lesions of ground glass liked changes and advanced lesions of pulmonary masses. lymphoid interstitial pneumonia is the abnormal hyperplasia of the pulmonary lymphoid tissue. its occurrence is related to autoimmune diseases, and is believed to be a direct response of the lungs to hiv. the clinical manifestations are recurrent infections, poor appetite, hepatomegaly and splenomegaly, and arrested development. the diagnostic imaging demonstrates no characteristic changes by ct scanning, with thickened bronchial wall, diffuse central lobular nodules or bronchiectasis, grid liked and cords liked shadows in uneven thickness. the pathological changes include accumulating lymphocytes and plasma cells that are mixed to infi ltrate the pulmonary interstitium and expand to surrounding areas of the bronchi. toxoplasma pneumonia is caused by the infection of the intracellular parasite, toxoplasma gondii. ludlam et al. in fi rstly proposed the concept of pulmonary toxoplasmosis, which was believed to cause atypical pneumonia [ ] . the clinical manifestations are cough and expectoration. in the serious cases, dyspnea and cyanosis can occur. in the chronic cases, there are long term low grade fever, cough, weight loss and enlarged lymph nodes. the diagnostic imaging demonstrates bronchopneumonia, interstitial pneumonia and pleurisy. ( ) bronchial pneumonia is also known as lobular pneumonia, with scattered patchy and blurry density shadows. ( ) interstitial pneumonia has typical manifestations of reticular and nodular shadows. ( ) pleurisy is rare, showing pleural effusion, limited diaphragmatic activity. the imaging demonstrations are non-specifi c, which can be defi ned in combination with the etiologic examinations. the pathological changes are congestion and edema of the surrounding connective tissue of the alveolar wall and bronchial walls, widened pulmonary interstitium, small quantity serous fi brin exudation from alveoli and pulmonary interstitium, and infi ltration of macrophages and lymphocytes. toxoplasma cysts and tachyzoites may be found in pulmonary interstitium and macrophages as well as alveolar epithelium. kaposi's sarcoma, a vascular tumor, was discovered in , and is also known as multiple hemorrhagic sarcomas, multiple vascular sarcomas, or multiple pigmented sarcomas. kaposi's sarcoma is believed to be the defi ning tumor of aids. outbreak of ks occurred in male homosexuals in europe and the united states. data show that in about % caucasian homosexuals, kaposi's sarcoma is a major complication of in hiv/aids patients. it has been confi rmed that, though kaposi's sarcoma has strong invasion, the disease itself has little impact on the mortality of aids. the cause of death in majority of the patients is still opportunistic infections. the clinical manifestations include face and neck lesions in dark red to purple red plaques. the plaques do not fade away when pressed, with surrounding brown ecchymosis. it commonly involves multiple organs including lungs, spleen, oral cavity, lymph nodes, gastrointestinal tract and liver. the lungs are the major target of invasion. the diagnostic imaging demonstrates hilar lymphadenectasis and its surrounding nodular infi ltration, bilateral interstitial changes, and pleural effusion that are its typical x-ray demonstration. early pathological changes are similar to those of common angioma; with gathering of capillaries into groups containing histocytes engulfed hemosiderin and orderly arranged vascular endothelial cells. it further progression see active proliferation of endothelial cells and fi broblasts, increased nuclear mitosis with anaplasia, and scattered lymphocytes and histocytes between blood vessels. in the advanced stage, occlusion and necrosis of the vascular lumen can be found. irregular lumen and fi ssures of the new capillaries can be commonly found in the tumor, fi lled with blood and common hemorrhage. in china, ks is relatively rare. its defi nitive diagnosis can be made by pathological examination. other hiv/aids related malignancies include burkitt's lymphoma, non-hodgkin's lymphoma, hodgkin's lymphoma and lung cancer. in summary, hiv/aids related pulmonary infections are important diseases in the disease spectrum of hiv/aids imaging. the diagnostic imaging is irreplaceable examinations for pulmonary infections. early prevention and correct diagnosis are the keys to improve the quality of life and prolong the lives of patients. the complexity and multiplicity of hiv/aids related pulmonary diseases present challenges for the clinicians. firstly, hiv/aids related diseases should be optimally classifi ed. each type should has a disease spectrum, which can be used for exclusion in combination with immunological indices to make the diagnosis and differential diagnosis. the diagnosis of hiv/ aids related pulmonary infections should be made in combination with case history and laboratory tests for targeting individualized diagnosis to serve clinical practice. carnii pneumonia (pcp) the pathogen is the trophozoites and cysts produced by pneumocystis carinii, principally living in the lungs. pneumocystis carinii was used to being categorized as as protozoon, but recently, it is believed to be belonged to fungus according to its ultrastructure and pneumocystis ribosomal rna phylogenetic analysis. the main infection route of pcp is airborne transmission and reactivation of in vivo latent pneumocystis carinii. infl ammatory and immune responses of the host include phagocytosis of pneumocystis carinii by the alveolar macrophages, infi ltration of lymphocytes in peribronchial and vascular area, proliferation of type ii alveolar cells, local and systemic increase of antibody. by naked eyes observation, there are extensive and diffuse invasion of lungs, which is soft like waterlogged sponge and in milky white with black spots. the fi lled foamy substance in the alveoli and bronchioles is a mixture of necrotic fungus and immunoglobulin. the alveolar septum has infi ltration of plasma cells and lymphocytes, resulting in thickened alveolar septa up to - times as the normal thickness that occupy / of the entire lung volume. the cysts are fi rstly located in the macrophage cytoplasm of the alveolar septa. subsequently, the alveolar cells containing cysts sheds off into the alveolar space. after the rupture of the cystic wall, sporozoite is discharged to turn into free trophozoites, which gains its access into the alveolar space. the alveolar exudates include plasma cells, lymphocytes and histocytes ( fig. . a-c ). the clinical symptoms include dry cough, shortness of breath and an indoor hypoxia. about % aids patients have multi-pathogens induced pulmonary infections. the most signifi cant laboratory abnormality in most pcp patients is hypoxemia. based on correlation between pcp and arterial oxygen partial difference, hypoxemia is divided into three degrees. the slight cases at indoor conditions have their pao being above mmhg, or alveolar-arterial oxygen pressure difference being less than mmhg, or both. the moderate and severe cases have their pao being usually less than mmhg, or alveolar-arterial oxygen pressure difference being above mmhg, or both. the most common manifestations of aids complicated by pcp are progressive subacute onset of dyspnea, fever, dry cough and chest distress, the symptoms aggravating in a few days or weeks. pulmonary examination is usually negative in slight cases. as the disease aggravates, the cases show shortness of breath, cyanosis, tachycardia, and diffuse dry rales. pneumocystis carinii infection accounts for - % of aids patients, which is one of the major causes of death in aids patients. the diagnostic imaging examinations include chest x-ray, ct scanning and nuclear medicine examination. ( ) chest x-ray is the conventional examination for screening. early lesions tend to be missed for the diagnosis due to the limited resolution or atypical lung lesions. ( ) ct scanning with high resolution is superior to chest x-ray. ( ) nuclear medicine examination demonstrates increased uptake of the isotope-labeled monoclonal antibodies in the lung tissues of the pcp patients. ( ) by tracheal suction or lung tissue biopsy, the detection rate of pneumocystis carinii is up to %. by tissue section staining, abundant protozoa can be found in intra-alveolar foamy eosinophil substance mass (by methenamine silver nitrate staining, the dark brown round or oval shaped cysts can be found in a diameter of - μm out of the cells). ( ) by elisa, pneumocystis igg antibody can be detected and by latex particle agglutination test, the protozoa antigen can be detected. ( ) molecular biology techniques, such as pcr can be applied for early diagnosis. the following examinations are non-specifi c, but can be used to assess the severity of pcp and its progression. ( ) by arterial blood gas analysis, the patients may show reduced blood oxygen saturation and respiratory alkalosis. ( ) by serum enzyme spectrum analysis, the patients may show increased ldh. ( ) it can be detected to have increased alveolar-arterial oxygen partial pressure difference. in the early stage (exudation period), alveolar fl uids exudate, with diffuse granular shadows in the bilateral lung fi elds extend from the hilum to the surrounding. in the middle stage (infi ltration and fusion period), the intrapulmonary lesions fuse, with ground glass liked or cloudy shadows that are bilaterally symmetric like butterfl y wings. in the middle and advanced stages (parenchymal changes period), the lung tissues show parenchymal changes, with high density shadows and accompanying air bronchogram. the lung periphery shows stripes of transparent shadows. in the advanced stage (pulmonary fi brosis period), the pulmonary interstitium is thickened in dense cords liked appearance, with interval irregular patchy shadows. the pulmonary ventilation improves and the lung periphery shows dense parenchymal shadows with emphysema, pneumomediastinum and pneumothorax. in the early stage (exudation period), the lesions radiatus develop from the hilum to lung fi eld. in the early stage, the diffuse exudative lesions distribute as pulmonary acinus, with changes similar to pulmonary interstitial changes. it was believed to be interstitial pneumonia. however, acute pcp is actually exudation of alveoli and spaces containing a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of dyspnea, cyanosis and wheezing for weeks, with obviously decreased oxygen saturation. his cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of dyspnea, cyanosis and wheezing for weeks, with obviously decreased oxygen saturation. her cd t cell count was / μl. patients with acquired immunodefi ciency. the early symptoms include fever, dry cough and shortness of breath. the advanced symptoms are serious dyspnea, cyanosis, progressive hypoxemia and respiratory failure. by pulmonary examinations, scattered dry and moist rales can be heard. trophozoites of pneumocystis cysts can be found by liquid giemsa staining. slight and moderate interstitial infl ammation responses mainly involve lymphocytes and alveolar macrophages. the detection of cysts containing sporozoites is the basis to defi ne the diagnosis. chest x-ray chest x-ray demonstrations of pcp can be classifi ed into four types. ( ) early pulmonary interstitial infi ltration and diffuse miliary alveolar exudation; ( ) in the middle stage, there are alveolar exudates, with fusion and parenchymal changes; ( ) in the middle-advanced stage, diffuse parenchymal changes; ( ) pulmonary interstitial fi brosis and lung cavity or lung bulla, as well as pneumothorax and emphysema. for the cases with negative or atypical fi ndings by chest x-ray, ct scanning with high resolution should be performed. ct scanning demonstrates early lesions of multiple symmetric diffuse miliary nodal shadows, which have clear boundaries. in the middle stage, there are thin cloudy shadows or ground glass liked density shadows. in the middleadvanced stage, the lung tissues show parenchymal shadows, with trachea-bronchial sign. in the outer strip of the lung, a transparent area in shape of willow leaf can be demonstrated. in the advanced stage, fi brous cords liked shadows are demonstrated some lung tissues with compensatory emphysema and even pulmonary pseudocysts. the intake of the isotope-labeled monoclonal antibody by lung tissues of pcp patients increases. hiv/aids related pcp should be differentiated from bacterial pneumonia, pulmonary tuberculosis, viral pneumonia, fungal pneumonia, ards, and lymphocytic interstitial pneumonia (lip). bacterial pneumonia has more focal lesions but less diffuse lesions. pulmonary mycobacterium tuberculosis infection has manifestations of military pulmonary tuberculosis by chest x-ray, which is diffi cult to be differentiated from early pcp. hiv/ aids related pcp shows miliary nodules, which further fuse into cloudy or ground glass liked shadows or parenchymal changes. the lesions are commonly symmetrical, with the hilus as the center. the clinical manifestations include fever, dry cough or accompanying diffi culty breathing, and even cyanosis. but in the cases of pulmonary mycobacterium tuberculosis infections, most show miliary nodules, which further fuse into large nodules or mass. after about weeks treatment in the early stage, the military nodules in both lungs can be absent, with common clinical symptom of high fever. correlation studies of miliary tuberculosis and peripheral blood cd t cell count have demonstrated that the general incidence of miliary tuberculosis is low, only - %, but it is the main manifestation of hiv/aids related pulmonary miliary tuberculosis. generally, when cd t cell count is below /μl, the incidence of cavity lesions is %, noncavity lesions %, complicated by pleural effusion % and lymphadenectasis %. when cd t cell count is between and /μl, the incidence of cavity lesions and non-cavity lesions each accounts for %, complicated pleural effusion % and lymphadenectasis %. when cd t cell count above /μl, the manifestation is commonly pneumonia type, in fl aky shadows or parenchymal shadows in just one pulmonary segment. the incidence of cavity lesions is %, non-cavity lesions %, complicated by pleural effusion % and no lymphadenectasis. chest x-ray demonstrates cytomegalovirus pneumonia negative in / patients. the foci are commonly bilateral, with reticular particles in % patients, alveolar foci in % patients, nodular foci in % patients, complicated by cavity in % patients, cysts in % patients, pleural effusion in % patients and lymphadenectasis in % patients. the incidence of diffuse foci in the cases of cryptococcus neoformans pneumonia is %, interstitial foci or mixed foci %, alveolar foci %, nodular foci %, lymphadenectasis % and pleural effusion %. hiv/aids related pcp is more likely to occur in children with aids, which presents diffi culty for its differentiation form lymphoid interstitial pneumonia. however, lymphoid interstitial pneumonia commonly has a chronic onset, with commonly manifestations of cough and dry rales. systemic lymphadenectasis and enlargement of salivary glands can also be found. by lung tissues biopsy, ebv-dna can be detected, which provides basis for their differentiation. pneumocystis, a unicellular organism, is the pathogen of pneumocystis carinii pneumonia. pneumocystis carinii pneumonia is one of common opportunistic infections in aids patients, which is also the leading cause of death in aids patients. in the initial episode of pcp, most patients have a cd t cell count of less than /μl. diagnostic imaging demonstrates bilaterally symmetrical ground glass liked shadows, which can be diffusely distributed and tend to mainly involve the periphery of the hilus or the middle and lower lung fi elds. hrct scanning is commonly applied to assess early pcp that is demonstrated negative by chest x-ray. hrct scanning demonstrates bilaterally symmetric patchy or fused ground glass liked shadows. the pathological basis of ground glass liked shadows and parenchymal areas refl ect that the acinus is fi lled by the foamy exudates, which are composed of surface active substances, cellulose and cell debris. all of the ground glass liked shadows, overlapping septa and the intralobular linear shadows are in gravel road liked manifestation. the septa and intralobular linear shadows demonstrate pulmonary interstitial edema or cellular infi ltration. in the middle-advanced stage of pcp, there are manifestations of small pulmonary nodules, pulmonary parenchymal changes, thickened interlobular septa, intralobular linear shadows, mass like lesions, pleural effusion, and lymphadenectasis. the cysts tend to mainly involve the upper lobes, which can be unilateral or bilateral pulmonary cysts, pneumothorax, mild or severe interstitial fi brosis and traction bronchiectasis. hrct scanning demonstrations of pcp are non-specifi c. its diagnosis should be in combination with hivph and etiological examinations. bacterial infections mycobacterium tuberculosis is still an important pathogen for pulmonary infection in hiv positive patients. since the mid- s, the main cause of the increasing incidence of tuberculosis is the prevalence of hiv infection. the incidence of tuberculosis in aids patients is - times higher than the general population. hiv infection is the most dangerous factor for progression of latent tuberculosis into active tuberculosis. tubercle bacillus belongs to mycobacterium family of mycobacterium genus, which is divided into types of human, bovine and murine. the main cause of human tuberculosis is human mycobacterium tuberculosis, which is known as acid-fast bacilli. tubercle bacillus wall is the complex containing high molecular weight fatty acids, lipids, proteins and polysaccharides, which are related to its pathogenicity and immune responses. lipid can cause the infi ltration of human monocytes, epithelial cells and lymphocytes to form tuberculous nodules. its protein contents can cause allergic reactions, and infi ltration of neutrophils and mononuclear cells. polysaccharides participate in certain immune responses (such as agglutination). these pathogenic factors lay the foundation for the occurrence of tuberculosis in aids patients. human immunity, allergic responses as well as the number and pathogenicity of tubercle bacilli are closely related to the quality, range, spreading rate and the progression of tuberculosis. its pathological changes are characterized by exudation, infi ltration, proliferation and hyperplasia, degenerative necrosis (caseous necrosis) and cavity formation. the manifestations include congestion, edema and infi ltration of leukocytes. the exudative lesions occur in early stage of tuberculosis infl ammation or when the lesions deteriorate. it can also be found in the serosa tuberculosis. there is neutrophilic granulocytes in the exudative lesions, which are gradually substituted by monocytes (phagocytes). the engulfed tubercle bacilli can be found in the large mononuclear cells. the exudative lesions are absorbed and dissipated through the phagocytosis of the mononuclear-phagocyte system, even with no scar. when large mononuclear cells engulf and digest tubercle bacilli, the phospholipid of the bacteria render the large mononuclear cells to enlarge and be fl at, similar to epithelial cells, which is known as epithelioid cells. these epithelioid cells gather into groups, with central langhans giant cells that pass the messages of the bacteria antigens to lymphocytes. surrounding the langhans giant cells, there are often many lymphocytes to form typical tuberculous nodules, which are characteristic lesions of tuberculosis. this is why it is called tuberculosis. in the tuberculous nodules, tubercule bacilli are usually undetectable. proliferation based lesions often occur in the cases with less bacteria invasion and when human cells mediated immunity is predominant. degeneration often occurs on the basis of the exudative or proliferative lesions. tubercle bacilli overcome macrophages and then continually proliferate in large quantity. after the cells become cloudy and swelling, the foci show fatty degeneration, dissolved into fragments, until the occurrence of necrosis. after the death of infl ammatory cells, proteolytic enzymes are released to dissolve the tissues that results in necrosis, which is coagulative necrosis. by naked eyes observation, they are yellowish gray, with loose and brittle quality like caseous. therefore it is known as caseous necrosis. microscopic examination demonstrates an area of solid and eosin staining red necrotic tissues with no tuberculosis. tubercle bacilli in the foci of caseous necrosis proliferate in large quantity to cause liquefaction, which is related to infi ltration of neutrophile granulocytes and large monocytes. part of liquefi ed caseous necrotic substances can be absorbed and part can be discharged by the bronchus to form cavities. otherwise, it may cause intrapulmonary spreading along with bronchi. the small caseous necrosis or proliferative lesions can be shrunk and absorbed after treatment, with only residues of slight fi brous scars. due to the compromised immunity in aids patients, the lesions rarely show fi ber tissues proliferation, but form cords liked scar. calcifi cation rarely occurs. if the necrotic lesions erode the blood vessels, tubercle bacilli can cause systemic miliary tuberculosis along with blood fl ow, including brain, bones and kidneys. large quantity sputum containing tubercle bacilli gains its access into the gastrointestinal tract. it can also cause intestinal tuberculosis and peritoneal tuberculosis. pulmonary tuberculosis can cause tuberculosis pleurisy via direct spreading to the pleura ( fig. . a-c ). clinically, it is a chronic progression, with rare acute onset. the clinical symptoms are commonly systemic, with fever and fatigue. the respiratory symptoms include cough and hemoptysis. pulmonary tb can be divided into primary and secondary, with the initial episode commonly being primary (type i). the residual bacteria after primary infection can cause secondary infection (type ii-iv) when the immunity is compromised via spreading along blood fl ow or direct spreading. it is common in hiv positive children. most cases are asymptomatic, sometimes with symptoms of low grade fever, mild cough, sweating, rapid heartbeat, and poor appetite. hiv/aids related miliary tuberculosis is one of the major manifestations of pulmonary tuberculosis, which is more common. the onset of acute miliary tuberculosis is rapid, with symptoms of chills and high fever with a body temperature up to °c, mostly remittent fever or continuous fever. there may be decreased leukocytes count and accelerated sedimentation rate. the progression of subacute and chronic hematogenous disseminated pulmonary tuberculosis is relatively slow. infi ltrative pulmonary tuberculosis in aids patients commonly occurs in both middle and lower lung fi elds, with fl aky and fl occulent foci or parenchymal changes in lobes or segments. caseous lesions are rare. the early stage of infi ltrative pulmonary tuberculosis is commonly asymptomatic, with later occurrence of fever, cough, night sweating, chest pain, weight loss, expectoration and hemoptysis. this type of pulmonary tb rarely occurs in aids patients. in non-aids patients, chest x-ray demonstrates three major changes, namely cavity, fi brosis, and bronchial dissemination. in the aids patients, the pulmonary manifestations include single or multiple nodular shadows with clear boundaries. tuberculous pleuritis is an exudative infl ammation caused by the direct invasion of tubercle bacillus from the primary lesion near the pleura into the pleura, or hematogenous dissemination via the lymphatic vessels to the pleura. the routes for occurrence of tuberculous pleurisy include: ( ) the bacteria in the hilar lymph tuberculosis counterfl ow to the pleura along lymph vessels. ( ) tb lesions adjacent to pleura rupture to cause direct access of the tubercle bacilli or products of tuberculosis infection into the pleural cavity. ( ) acute or subacute hematogenous disseminated tuberculosis causes pleuritis. ( ) due to the increased allergic responses, the pleura highly respond to tuberculosis toxins to cause exudation. ( ) thoracic tuberculosis and rib tuberculosis rupture into the pleural cavity. clinically, pleuritis can be divided into three types, dry pleuritis, exudative pleuritis and tuberculous empyema (rare). the common clinical manifestations are fever, cough with accompanying chest pain of the affected side and shortness of breath. ( ) sputum smear examination is simple to manipulate, with high accuracy rate. the fi ndings of the tubercle bacilli can defi ne the diagnosis. it still is the golden criteria for the diagnosis of pulmonary tuberculosis. ( ) sputum tubercle bacilli culture has high reliability. tubercle bacilli drug sensitivity test can be performed but requires - weeks to obtain the results. therefore, its application is limited. ( ) tuberculin purifi ed protein derivative (ppd) test is commonly used. its positive result is one of the evidence confi rming a past history of tb infection. ( ) bactec test can be performed to detect the metabolites of mycobacterium tuberculosis. generally, mycobacterium can be detected in weeks. the quantity of mycobacteria can affect the period required for test results. ( ) pcr has poor specifi city but high sensitivity of up to - %. both can be applied to observe the enlarged lymph nodes in the chest and mediastinum. in addition, they can be applied to obtain specimens for biopsy, which facilitates the diagnosis and differential diagnosis. diagnostic imaging examinations include chest x-ray and ct scanning. chest x-ray can demonstrate the location, quality and range of the lesions. it can also help to assess the therapeutic effi cacy. ct scanning can demonstrate small or hidden lesions, with a high resolution. primary pulmonary tuberculosis, also known as primary syndrome, is rare in adult aids patients. chest x-ray demonstrates intrapulmonary patchy or large fl aky parenchymal changes, hilar and mediastinal lymphadenectasis in connection to irregular cords liked shadows (located between intrapulmonary lesion and the hilum). lymph node tuberculosis is demonstrated to have mediastinal lymphadenectasis that sometimes fuse into mass. in aids patients, simple mediastinal lymph node tuberculosis is more common than primary syndrome. tuberculosis ( ) the acute cases are demonstrated to have diffused miliary nodules in both lungs with even distribution, even size and even density. ( ) the subacute and chronic cases are demonstrated to have nodules in both lungs, with uneven distribution, uneven size and uneven density. sometimes calcifi cation occurs in the nodules, with fi brous cords and thickened pleura. infi ltrative pulmonary tuberculosis are demonstrated to have patchy parenchymal changes in the middle and lower lung fi elds as well as parenchymal changes, cavities and fi brous cords liked foci in the segments and lobes. it can also occur in the upper lung fi elds, commonly with accompanying mediastinal and hilar lymph node tuberculosis. it commonly occurs in the advanced stage of aids,, with manifestations of pulmonary interstitial fi brosis and formation of cavities. this type of pulmonary tuberculosis is less common. it rarely occurs, mostly in the early stage of aids. it is rare in the middle and advanced stages of aids. dry pleuritis has manifestations of blunt costophrenic angle and limited diaphragm mobility. exudative pleuritis is manifested as small quantity pleural effusion and thickened pleura, commonly with encapsulated effusion of the lateral pleura. calcifi cation is rare. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of dull chest pain, dyspnea, fever, night sweating, fatigue and anorexia. his cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of dull chest pain, dyspnea, fever, night sweating and fatigue. her cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he was infected hiv via blood transfusion, with complaints of cervical lymph node tuberculosis, ascites and abdominal infection, fungal stomatitis, biliary stones with infection and severe anemia. his cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and night sweating. her cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she was hospitalized due to complaints of chest distress, cough and expectoration for months, with after noon low grade fever and weight loss. on admission, she was confi rmed hiv positive and a cd t cell count of /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and chest pain for months, with acid-fast bacilli positive in the pleural fl uid culture. her cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and chest pain for months, with acid-fast bacilli positive in the pleural fl uid culture. her cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and chest pain for months, with acid-fast bacilli positive in the pleural fl uid culture. her cd t cell count was /μl. cough expectoration, chest pain, dyspnea, fever, night sweating, fatigue, anorexia, lymphadenectasis and rapid progression of the conditions. ppd skin test with a resulted diameter of more than mm should be considered as tuberculosis infection. but its positive rate remains low. the culture of sputum and bronchoalveolar lavage fl uid can detect the pathogens. nucleic acid analysis or dna probe technique, pcr and chromatography can be applied to detect tubercle bacilli. the commonly used diagnostic imaging examinations include chest x-ray and ct scanning. the main demonstrations include ( ) intrapulmonary and extrapulmonary lymphadenectasis; ( ) miliary tuberculosis manifestations; ( ) infi ltrative (pneumonia type) pulmonary tuberculosis; ( ) pulmonary interstitial fi brosis, cavity, pulmonary emphysema, nodules, emphysema, and bronchiectasis with accompanying infections. in the cases with their cd t cell count being above /μl, the imaging demonstrations are similar to those of non-hiv/aids patients with pulmonary tuberculosis. in the cases with their cd t cell count being above /μl, the manifestations are intrapulmonary large fl aky parenchymal changes, surrounding satellite lesions as well as mediastinal and hilar lymphadenectasis. sometimes the manifestations may be only mediastinal lymphadenectasis and their fusion into mass. in the cases with cd t cell count being above /μl, there may be accompanying extrapulmonary tuberculosis, such as tuberculous peritonitis, bone tuberculosis, brain tuberculosis and splenic tuberculosis. in the cases with their cd t cell count being lower than /μl, the manifestations are mostly miliary tuberculosis. hiv/aids related tuberculosis should be principally differentiated from pneumocystis carinii pneumonia, fungal infections, other pneumonia and lung cancer. hiv/aids related tuberculosis should be differentiated from pcp. pcp is mainly manifested as multiple lesions with hilum as the center to extending symmetrically to outside of the lungs. in the advanced stage, pcp has main lesions of pulmonary interstitial fi brosis, with less accompanying mediastinal and hilar lymphadenectasis. the laboratory tests can facilitate to defi ne the diagnose. hiv/aids related tuberculosis should be differentiated from fungal infections. fungal infections are relatively less common than tuberculosis. the imaging fi ndings of hiv/aids related pulmonary fungal infections are diverse, with manifestations of miliary, fl aky fl occulent liked, parenchymal, mass, and interstitial changes. in general, the diffuse lesions are mainly interstitial changes, while confi rmed lesions, compared to tb lesions, are more likely to have thick walled cavities. satellite lesions of fungal infections are less than those of tuberculosis, with less accompanying mediastinal and hilar lymphadenectasis. sometimes laboratory tests are necessary to defi ne the diagnosis. hiv/aids related tuberculosis should be differentiated from non-tuberculosis mycobacteria pneumonia. their imaging fi ndings are similar to each other, which presents challenges for their differential diagnosis. molecular biology examinations play an important role in the differentiation. hiv/aids related tuberculosis should be differentiated from other pneumonia. non-bacterial pneumonia (mycoplasma, viral and allergic) often shows patchy shadows, which are similar to the manifestations of early infi ltrative pulmonary tuberculosis. when bacterial pneumonia shows lobar lesions, it may be confused with tuberculous caseous pneumonia, which should also be differentiated for the diagnosis. symptoms of mycoplasma pneumonia are mild, with imaging fi ndings being always inconsistency with the clinical symptoms, which usually subside within - weeks. in the cases of allergic pneumonia, eosinophils in the blood increase, with intrapulmonary mobile shadows, which are the basis for their differentiation. bacterial pneumonia can have acute onset, with chills, high fever, rust colored sputum, and streptococcus pneumoniae positive. recovery is rapid after antibiotic treatment and all these symptoms can subside within month. hiv/aids related tuberculosis should be differentiated from pulmonary abscesses. in the cases of infi ltrative pulmonary tuberculosis with cavities, it should be differentiated from pulmonary abscess. especially, tuberculosis with cavities in the apical segment of inferior lobe should be differentiated from acute pulmonary abscess. chronic fi brous cavity tuberculosis should be differentiated from chronic pulmonary abscess. the key points for the differentiation are tubercle bacilli positive by sputum culture in the cases of tb, while tubercle bacilli negative by sputum culture in the cases of abscesses. pulmonary abscess has an acute onset, with increased leukocytes and neutrophils as well as favorable therapeutic effi cacy of antibiotics. but sometimes tuberculosis with cavity may develop into bacterial infection, with undetectable tubercle bacillus by sputum culture. hiv/aids related tuberculosis should be differentiated from lung cancer. the central type of lung cancer has nodular shadow in the hilum or hilar and mediastinal lymph node metastasis, which should be differentiated from lymphatic tuberculosis. the peripheral type of lung cancer has small fl aky infi ltration and nodules in the periphery of the lungs, which should be differentiated from tuberculoma or tuberculosis infi ltrative lesions. lung cancers occur commonly in people aged above years. the central type mainly is squamous carcinoma and the cases often have a history of long term smoking, with symptoms of no fever but diffi culty breathing or chest distress as well as gradually increasing chest pain. there are also symptoms of irritated cough with blood phlegm and progressive weight loss. the cases with supraclavicular metastasis have palpable harden lymph nodes. the intrapulmonary nodules can lobulated with fi ne spikes, no satellite lesions, generally no calcifi cation and possible vacuole sign. the peripheral type of lung cancer shows pleura invagination sign. tuberculin test often shows negative in the cases of lung, positive or weakly positive in the cases with tb, and negative or weak positive in aids patients. hiv infection is known to be the main factor for the development of latent tuberculosis into active tuberculosis. immunosuppression are similar to those in the cases with primary tuberculosis, with characteristic abnormal manifestations of hilar and/or mediastinal lymphadenectasis and parenchymal changes of the air chambers. ct scanning demonstrates enlarged nodules with low density. enhanced scanning demonstrates marginal enhancement of the lymph nodes. the incidence of military tuberculosis in aids patients is increasing due to reduced thymic t lymphocytes in aids patients and the defects of delayed allergic responses, which result in the formation of granulomas and impaired functions to kill bacilli and confi ne the lesions. nontuberculous mycobacteria (ntm) refer to the mycobacteria except for mycobacterium tuberculosis complex (human, cattle, african and vole) and mycobacterium leprae. the most commonly known nomination is nontuberculous mycobacteria (ntm). more than kinds of ntm have been found so far. according to berger manual of systematic bacteriology, ntm is divided into two categories, rapid growth type and slow growth type. ntm are widely spread in nature, such as soil, dust, fl owing water and raw milk. under a microscope, ntm is morphologically similar to tubercle bacilli, with red stained fi ndings by acid-fast staining. according to the growth of ntm in solid medium, the runyon classifi cation divides ntm into the following four groups, light chromogenic bacteria; dark chromogenic bacteria that can cause cervical lymphnoditis in children, intrapulmonary or extrapulmonary infections and abrasive abscess; non-chromogenic bacteria including mycobacterium avium complex, intracellular mycobacteria that can cause pulmonary infections, lymphnoditis, arthritis and meningitis; rapid growth bacteria including mycobacterium fortuitum, mycobacterium, mycobacterium abscessus that can cause pulmonary diseases and skin infections. immunocompromised populations, such as hiv infected patients, patients with neoplasms, patients with long-term use adrenocortical hormone or immunosuppressive agents, are more susceptible to disseminated ntm infection. immunocompetent people may have mycobacterium kansasii and mycobacterium avium infections. it was reported in the united states that the occurrence of mycobacterium avium complex infection in hiv positive patients is up to more than %. the pathological changes of ntm infections are similar to those of tuberculosis. ntm lymphnoditis is pathologically characterized by granulomatous infl ammation. tuberculous nodules formed by epithelioid cells and langhans giant cells are rare, with no accompanying central caseous necrosis. due to the weak pathogenicity of ntm, the pathological changes are slight, but there is difference in the pathological changes of ntm infections in terms of location, type and host. cavities are common in the cases with pulmonary ntm infection, commonly being multiple or multilocular thin wall cavities. the pleuron is rarely involved, with non-specifi c pathological changes of infl ammation but with large quantity pathogens of ntm. patients often have a history of chronic obstructive pulmonary disease, tuberculosis, silicosis, pulmonary abscess, bronchiectasis, cystic fi brosis, diabetes, ulcer as well as use of hormone or immunosuppressive agents. its occurrence is more common in males than in females. the symptoms include cough, expectoration, hemoptysis, chest pain, diffi culty breathing, low grade fever, weight loss and fatigue. the symptoms are nonspecifi c and the conditions progress slowly. for patients with suspected diagnosis of pulmonary ntm infection, sputum smear for acid-fast staining, sputum culture and bronchial lavage specimen culture can be performed. the positive fi ndings should be identifi ed with two to three times repeated culture. the same fi nding of ntm can defi ne the diagnosis. pathological biopsy can be performed for the diagnosis of ntm lymphnoditis. using s- srdna gene spacer sequence (igs) of ntm for pcr-restriction fragment length polymorphism analysis (pcr-rflp), ntm species can be identifi ed, which is more accurate, faster and simpler than the conventional morphological and biochemical examinations. mycobacterium tuberculosis and ntm have common antigen. ppd skin test produces cross-reaction, but there are still differences between mycobacterium tuberculosis and ntm. ppd-t of the mycobacterium tuberculosis and ppd-ntm of ntm are simultaneously obtained for mantoux skin tests. the induration diameter of ppd-t in ntm patients is generally within mm. for the cases with the induration diameter of ppd-ntm skin test being mm larger or over % larger than that of ppd-t skin test, ntm infection can be confi rmed. both are the most commonly used imaging examinations. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of cough and chest distress for half a month, fever for days, day after cesarean section and fi nding of hiv positive for day. her cd t cell count was /μl, with treponema pallidum antibody negative and ppd test negative. imaging demonstrations include various lesions such as infi ltration, cavity, nodules, fi brous caseation and extensive fi ber contraction in unilateral or bilateral lungs. the incidence of cavity is up to %, being singular or multiple. cavities caused by intracellular mycobacterium are mostly found in the pleura, with thin wall and less surrounding exudates. the incidence of non-tuberculous mycobacterial infections in aids patients is high. mac infection is usually caused by the initial exposure rather than the reactivation of latent pathogens. in patients with complications of mac related lung diseases, most of the imaging fi ndings are normal. the most common manifestation is mediastinal or hilar lymphadenectasis. and the pulmonary symptoms are similar to those of tuberculosis. in the cases with multiple patchy parenchymal changes, cavities can be found, as well as nodules with blurry boundaries, pleural effusion and rarely found miliary nodules. sputum or bronchoalveolar lavage fl uid culture positive, clinical symptoms, imaging fi ndings, and response to treatment can defi ne the diagnosis. staphylococcus aureus is a gram positive coccus and is coagulase positive staphylococcus. the pathogenic substances of staphylococcus aureus mainly are toxins and enzymes, such as hemolytic toxins, leukocidin and enterotoxin, which play a role in hemolysis, necrosis, killing leukocytes and vascular spasm. the staphylococcus aureus coagulase is the main reason for suppurative infection. pneumonia caused by inhaled staphylococcus aureus through the respiratory tract often shows lesions in the large lobes or extensive fusion of bronchopneumonia lesions. bronchial and alveolar rupture allows gas to enter the pulmonary interstitium, which is communicated with the bronchi. in the cases of bronchiolar blockage by necrotic tissues or pus, the one-way valve effect is formed to cause tension pulmonary emphysema. in the cases with superfi cial pulmonary emphysema with excessively high tension, it ruptures to form pneumothorax or pyopneumothorax, as well as bronchooleural fi stula ( fig. . a, b ) . the symptoms include chills, persistent high fever, cough, expectoration, chest pain and other symptoms. there is no sign in the early period. symptoms are scattered moist rales in both lungs, being in consistency to severe toxic symptoms and respiratory symptoms. yellow purulent sputum is the typical characteristics of staphylococcus aureus pneumonia. in the cases with larger lesions or fusion of lesions, signs of parenchymal changes, pneumothorax or pyopneumothorax can be found. in the sputum or pleural fl uid smears examinations, the bacteria with a concentration being no less than cfa/ml is the pathogen, the bacteria with a concentration being - cfa/ml is the suspected pathogen, and the bacteria with a concentration being less than cfa/ml is the contaminated bacteria. there are increased wbc count and neutrophils, leftward migration of the nucleus and possibly no increase of wbc count in aids patients. immunofl uorescence, enzyme-linked immunosorbent assay and counter immunoelectrophoresis can be performed to detect serum antigen or antibody of the pathogenic bacteria, which can defi ne the diagnosis. polymerase chain reaction has certain signifi cance in pathogen detection. the protected bronchoscopic specimen (pbs) and bronchoalveolar lavage (bal) can be applied to collect the specimen, which has reduced chances of specimens contamination by oral bacteria. biphasic tv monitors guided pulmonary puncture and suction for pulmonary tissues examinations can be performed to detect the real pathogenic bacteria. both are the most commonly used imaging examinations. the diagnostic imaging demonstrates staphylococcus aureus pneumonia as lesions in the inner zone of both middle lower lungs. there are singular or multiple parenchymal changes in patchy or lobar distribution that may fuse into large fl akes. it may be complicated by cavity and pulmonary emphysema, with surrounding compensatory emphysema. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever with a body temperature of about °c and chest pain for months. his cd t cell count was /μl. chills, fever, cough, expectoration, chest pain and other symptoms commonly; hemoptysis and dyspnea rarely the patients may be found with fever appearance, rarely shortness of breath and cyanosis. in the serious cases, the body temperature can be as high as - °c and blood pressure decreases, with signs of shock. by chest examinations, decreased ipsilateral respiratory motion; increased or decreased fremitus, dull sound in percussion; bronchial breathing sounds or moist rales by auscultation; rarely pleural friction and weakened breathing sounds. increased wbc count and neutrophils, possible the nucleus left shift; no increase or even decrease of wbc count in aids patients; staphylococcus aureus positive by blood culture. sputum or pleural fl uid smears examinations for pathogenic bacteria culture is positive, and antibiotic sensitivity test is positive. by chest x-ray and ct scanning, the most common demonstrations are lesions of bronchial pneumonia. the fi ndings of pulmonary emphysema and cavities can facilitate the diagnose. the lesions should be differentiated from infi ltrative parenchymal bronchioloalveolar carcinoma. the smaller lesions should be differentiated from pulmonary infarction. the large lesions should be differentiated from obstructive pneumonia. it is diffi cult to identify the types of common bacterial pneumonia simply by chest x-ray and ct scanning. in combination to the laboratory tests, the diagnosis can be defi ned. the incidence of pyogenic bacterial infection is increasing in aids patients, which is caused by their weakened cellular and humoral immunity. the manifestations of these most common bacterial infections are similar to those of non-hiv infected patients by chest x-ray. bacterial pneumonia and purulent bronchitis are the most common causes of pulmonary infections in aids patients. particularly, they are frequently found in patients with a history of intravenous drug abuse and smokers. they are histologically characterized by infl ammations of the bronchi and bronchioles as well as infl ammatory exudates and mucus in the airway lumens. ct scans facilitates the diagnosis of bronchiolitis and early bronchial pneumonia. the demonstrations are characterized by ( ) small centrilobular nodular shadows, which is the cross sectional demonstration of bronchioles fi lled with infl ammatory substances and its surrounding infl ammations; rhodococcus equi infection is one of the zoonotic diseases, which commonly occurs in the grazing areas. patients with t lymphocyte immunodefi ciency caused by aids and other factors are especially susceptible to the infection. rhodococcus equi was fi rstly discovered in and was nominated as corynebacterium equi. after structure analysis of the cell wall, it was found that the bacterium is quite different from corynebacterium, and therefore classifi ed as rhodococcus. rhodococcus equi infection in human is rare. but in recent years, due to an increase of patients with immunodefi ciency syndrome, reports on rhodococcus equi caused human respiratory infections and sepsis are increasing. in the past, the toxicity mechanism of rhodococcus equi was mostly speculated. until recently, the damage process of toxic plasmid to human tissue is discovered, which presents a new way for the study of the pathogenesis of rhodococcus equi infections. rhodococcus equi is one of the facultative parasites in the cells and its optimum growth temperature is °c, with a suitable growth temperature of - °c. acid-fast staining of rhodococcus equi shows uncertain results. due to its morphological diversity, it is often mistaken as diphtheroid bacillus, bacillus or micrococcus. in sheep blood agar, rhodococcus equi can have synergistic hemolysis with staphylococcus aureus, listeria monocytogenes and corynebacterium pseudotuberculosis, which is a characteristic manifestation of rhodococcus equi. the most common pathological changes in rhodococcus equi infection are chronic purulent bronchitis and extensive lung abscess. imaging often demonstrates subacute pneumonia, commonly with cavities. the clinical manifestations are poor appetite, drowsiness, fever and shortness of breath. studies by e marchiori et al. [ ] in revealed that all the cases of aids complicated by rhodococcus equi pulmonary infection have cough and fever lasting for - months, with accompanying shortness of breath and chest pain. all the cases, studied by li et al. in [ ] , have fever with a body temperature up to - °c and cough. in addition, there are also expectoration with orange red sputum in cases, hemoptysis in cases, dyspnea in cases, moist rales of lungs in cases, emaciation in cases, poor appetite in cases, diarrhea in cases, joint pain in case, oral candidiasis infections in cases, oral herpes in cases, chest pain in cases, no obvious symptoms in case and hepatitis b in cases. typical clinical manifestations of this disease are fever, cough, dyspnea and chest pain, while others such as emaciation, diarrhea and joint pain are not representative symptoms. identifi cation of the bacteria various specimens were inoculated on blood plates at a temperature of °c for - culture, with bacteria growth of strains. they are biologically characterized by a diameter of about . mm, non-transparent and slight yellowish colonies. after - h, the colonies expand to - mm, which can be emulsifi ed in mucous fl uid liked state. most of the colonies produce orange and orange red pigments, which can be cultured in ordinary agar. histopathological fi ndings are typical for rhodococcus equi infection. h&e staining demonstrates mainly bleeding in the alveolar space, large quantity epithelial cells, possibly predominant fi broblasts, parenchymal changes of lung tissue and thickened alveolar septa. pas staining demonstrates scattered or clustered rhodococcus equi in pink or purplish red. both are the most commonly used imaging examinations. biphasic tv monitor guided lung puncture can be performed to suck lung tissues for biopsy, based on which the real pathogenic bacteria can be detected. the typical demonstrations include central hilar sphere liked shadow with increased density in unilateral lung, accounted for %. there are also manifestations of exudative infi ltration and large fl aky or spherical mass shadows in the right or left hilar area. the lesions are in patchy or fl aky appearance, radiating from the hilum to the lung fi eld with blurry boundaries. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of recurrent fever, cough and chest pain for days; and was found hiv positive for days. he was also a carrier of hepatitis c virus, with symptoms of fever with no known causes, cough, chest distress and weak limbs. by examinations, he was found to have complexion of chronic conditions; many moist and dry rales by cardiopulmonary auscultation. he had a past history of hiv positive for years, with drug abuse and extramarital affairs. the history of present illness includes fever, paroxysmal cough with a little whitish yellow thick sputum since may , . he also had subjective paroxysmal dull pain in the left chest, and hemoptysis once which was bright red with blood clot in a volume of about ml. his cd t cell count was /μl. by sputum culture, rhodococcus equi was found positive. after receiving antibiotic treatment, his conditions improved and he was discharged from the hospital. catalase test of the strain is positive, which is confi rmed as rhodococcus equi by api coryne system. examinations h&e staining demonstrates mainly bleeding in the alveolar space, large quantity epithelial cells or mainly fi broblasts, parenchymal changes of lung tissue and thickened alveolar septa. pas staining and masson staining demonstrate scattered or clustered distribution of rod rhodococcus equi in pink or purplish red. aids complicated by pulmonary rhodococcus equi infection shows subacute infl ammation. firstly, there are exudates in the surrounding area of unilateral hilum as well as sphere shaped mass shadows which is centrally dense and peripherally blurry, with its apex pointing to the hilum. the lesions can be complicated by cavities and fl uid level, with thick wall of the cavities. as the disease progresses, the abscess cavities have increased tension, with gradually thinner abscesss cavity walls and uneven wall thickness, even showing pleural effusion. these are its characteristic imaging fi ndings. it often needs to be differentiated from pneumocystis carinii pneumonia, tuberculosis, staphylococcus aureus pneumonia, central type lung cancer and other diseases. imaging fi ndings of pneumocystis carinii pneumonia usually are ground glass liked changes in the lung fi eld, with parenchymal changes and centrilobular nodules. tuberculosis often shows miliary tuberculosis, with lymphadenectasis, large tubercles and parenchymal changes. these characteristic pathological and imaging fi ndings of staphylococcus aureus pneumonia are similar to those of bronchial pneumonia (lobular pneumonia). the lesions are nodules with blurry boundaries in a diameter of - mm. the disease progresses rapidly, while pulmonary rhodococcus equi infection has a chronic progression. hrct scanning demonstrates staphylococcus aureus pneumonia as centrilobular nodules and branch linear shadows (tree buds sign), which can be found in % patients, with - % will develop into commonly singular pulmonary abscess. chest ct scanning demonstrates round liked abscess cavity with thick wall and liquid level in it. the inner wall of the abscess cavity is often irregular, with various changes within short period. the central type of lung cancer is commonly demonstrated as round liked shadow of unilateral hilum with rough boundary. lobulation or bronchial stenosis sometimes occurs. however, aids complicated by rhodococcus equi pneumonia is demonstrated as sphere liked mass in the hilum; mostly sphere liked increased density shadow with hilum as the center. the shadow is centrally dense and peripherally blurry, with no bronchial stenosis. rhodococcus equi was fi rstly discovered in and was nominated as corynebacterium equi. after structure analysis of the cell wall, it was found that the bacterium is quite different from corynebacterium, and therefore classifi ed as rhodococcus. rhodococcus equi is generally believed to be the pathogen for horses, pigs and cattle. [ ] showed a ct t cell count of lower than /μl. all the results are in consistency. in conclusion, aids complicated by pulmonary rhodococcus equi infection is mainly subacute infl ammation. there are exudation around the unilateral hilum as well as centrally dense and peripherally blurry sphere shaped mass shadows, with secondary cavities and parenchyma changes and even pleural effusion. all of these are characteristic imaging demonstrations. most cases of hiv positive complicated by respiratory or pulmonary diseases are caused by aspergillus fumigatus. aspergillus fumigatus belongs to filamentous fungi, which is a common opportunistic fungus and has a wide distribution in the nature. as conditional pathogenic bacteria, it can parasitize in the human skin and upper respiratory tract. human has certain resistance to aspergillus so it commonly fails to cause diseases. in immunocompromised aids patients, the pathogenic bacteria can pass through the defects in the skin and mucous membrane into the blood flow to infect the tissues and organs. aspergillus commonly violates bronchus and lung, with involvements of rhinal sinuses, external auditory canal, eye and skin. otherwise, it disseminates to organs of the body along with blood fl ow. the early lesions are diffuse infi ltrative and exudative changes. and advanced lesions are necrosis, pyogenesis or granuloma. large quantity hyphae can be found in the lesions. the hyphae penetrate the blood vessels to cause vasculitis, perivascular infl ammation and thrombosis. and thrombosis can cause ischemia and necrosis of the tissue. according to the pathological changes and imaging fi ndings, it can be divided into three major types: vascular invasion type, bronchopneumonia type and allergic bronchopulmonary aspergillosis type. ( ) the vascular invasion type is the result caused by toxins released in the process of aspergillus spreading extensively from the primary focus to the lungs. vascular infi ltration of the pulmonary parenchyma and coagulative necrosis are believed to be the cause of vascular occlusion and pulmonary infarction. ( ) bronchopneumonia type is acute bronchitis caused by inhalation of aspergillus spores. in the cases of hyphae invasion into the lung tissues, extensive infi ltrative pneumonia or focal granuloma are resulted in. it can also cause necrosis, pyogenesis and multiple small abscesses. spherical pulmonary aspergillosis is often secondary to bronchiectasis, tuberculosis, carcinous cavity and other lung diseases. mycelia multiply and gather in the cavities of the lungs to form a spherical mass with fi brin and mucosal cells, which are called aspergillar glomera, which do not invade the lung tissue. ( ) allergic bronchopulmonary aspergillosis type is the proliferation and germination of inhaled aspergillus spore in the airway, often showing obvious related mucosal lesions and eventually resulting in bronchiectasis ( fig. . a-c ) . the cases with acute onset have symptoms of high fever or irregular fever, cough, shortness of breath and green purulent sputum. the cases with a chronic onset have symptoms of repeated cough and hemoptysis, which are similar to those of tuberculosis. the pulmonary signs are not obvious, with occasional fi ndings of moist rales. most cases are asymptomatic and sometimes there are fever, cough, shortness of breath, and mucous purulent sputum. the main symptoms are persistent fever, cough and chest pain. in the serious cases, there is dyspnea. by microscopic examination of sputum, aspergillus hyphae can be found. the culture for aspergillus fumigatus is positive. serum ige is commonly above , μg/l. skin test for aspergillus antigen is positive. serum anti-aspergillus antigen igg antibody precipitin is positive. puncture of lungs and pleura for biopsy facilitates the diagnosis of pulmonary fungal infections. both are the most commonly used imaging examinations. hiv/aids related aspergillus bronchopneumonia is commonly demonstrated to have increased pulmonary markings, diffuse patchy blurry shadows and mass shadows in both lungs. spherical pulmonary aspergillosis is commonly demonstrated to have sphere liked aspergillar glomera suspending in the cavities to form a crescent shaped transparent area, in characteristic meniscus sign, rolling ball sign and fi ngertip sign. meniscus sign is nominated due to a meniscus liked space between the aspergillar glomera growing in the cavity and the cavity wall. rolling ball sign means that the aspergillar glomera moves along with the changes of posture. fingertip sign indicates that the substance formed by aspergillar glomera in dilated bronchi is in a fi nger shape, sometimes in v shape sign and y shape sign. invasive lesions refer to lesions invading or destroying lung structures, such as pneumonia, parenchymal changes and necrosis. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of cough and chest distress, with increased eosinophilic granulocytes. her cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever or irregular fever, cough and shortness of breath. his cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever or irregular fever, cough and shortness of breath. his cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he was hospitalized due to complaints of fever for week, chest distress and shortness of breath for day. on admission, he was confi rmed as hiv positive, with a cd t cell count of /μl. by physical examinations, he was in poor physical conditions, respiratory rate /min, lips cyanotic, coarse breathing sounds of both lungs with small quantity dry rales. his conditions progressed rapidly and death occurred due to respiratory failure after days. lung and pleura puncture for biopsy can detect the growth of aspergillus hyphae. sputum culture can detect aspergillus hyphae, with fi ndings of aspergillus fumigatus positive. in the cases with allergic bronchopulmonary aspergillosis, the serum ige is above , μg/l. skin test of aspergillus antigen is positive. the serum anti-aspergillus antigen igg antibody precipitin is positive. characteristic ct scanning demonstrations of hiv/aids related parasitic aspergillar glomera include pulmonary cavities or cavity lesions with spherical contents, smooth boundaries of the spherical contents with even density, lunate shaped or ring shaped transparent shadows between cavity or cavity walls and the contents, migration of the contents with the body postures. according to the pathological and imaging demonstrations, it can be divided into three major types: in the early stage, ct scanning demonstrates soft tissue density nodules or light ground glass liked halo sign around the mass, which is the evidence for the diagnosis of the invasion type pulmonary aspergillosis. air cresent sign refers to round pulmonary infi ltration with accompanying central necrosis and surrounding lunate or ring shaped cavity. other noncharacteristic ct scanning demonstrations include multiple lobular parenchyma lesion shadows or lobular fusion shadows, parenchyma lesion shadows in the lobes, segments and subsegments, nodular or mass shadows and thin/thick wall cavities or low density areas in the mass shadows. it is demonstrated to have parenchymal lesions around the airway or/and central small nodules in the lower lobes. the parenchymal lesions prove the occurrence of mycotic bronchopneumonia. the most common imaging fi nding is the thickened bronchial wall. central bronchiectasis is its characteristic demonstration. in the cases of dilated bronchi containing sputum bolt or mucus, it shows fi ngertip shaped or toothpaste shaped shadow, which should be considered as its characteristic demonstration. hiv/aids related pulmonary aspergillosis should be differentiated from congenital bronchial atresia. most cases of the congenital bronchial atresia are atresia at the proximal pulmonary segment of the bronchi, often with a clearly defi ned mass. in the typical cases, there are bronchial branches and more branches in fi ngertip shape, pointing to the pulmonary hilum. confi ned pulmonary air retention in the pulmonary lobe and segment of the atresic bronchi is the important evidence for the diagnosis of congenital bronchial atresia. hiv/aids related pulmonary aspergillosis should be differentiated from allergic bronchial-pulmonary aspergillosis. in the cases of allergic bronchial-pulmonary aspergillosis have no clearly defi ned mass, with demonstrations of v shaped, y shaped, grapes shaped or fi ngertip shaped shadows with clearly defi ned boundaries, which are characteristic in those patients with bronchial asthma or a case history of exposure to dusts containing fungi. there is also increased proportion of eosinophilic granulocytes in the peripheral blood. detection of aspergillus in phlegm can defi ne the diagnosis. hiv/aids related pulmonary aspergillosis should be differentiated from central lung cancer. central lung cancer also can cause mucus impaction of the distal bronchi, with manifestations of bronchial arctia and/or truncation, and the surrounding soft tissue mass shadows. hiv/aids related pulmonary aspergillosis should be differentiated from pulmonary cavities and abscesses induced by dissolved tuberculoma, secondary pulmonary tb, chronic lung abscess and peripheral lung cancer as well as cystic bronchiectasis. except aspergilloma, spheric morphology caused by other causes is commonly irregular. the cavity contents cannot migrate with body postures, which is the key point for the differential diagnosis. hiv/aids related pulmonary aspergillosis can be caused by many pathogenic bacteria and aspergillus fumigatus is the most common one. the infection is often caused by inhaled aspergillus fumigatus in the environment. vascular invasion type of pulmonary aspergillosis usually has multiple lesions and nodular changes. generally in pathology, the center of nodule presents typical pale color; commonly with fi brous ring surrounding the nodules resulted from hemorrhage and/or lung parenchymal changes. histologically, they are characterized by coagulative necrosis of the lung tissues, infi ltration of large quantity hyphae in the necrotic tissue, pulmonary vascular infi ltration, but usually without responses of vasculitis and thrombosis. the enzymes released by neutrophile granulocytes can cause the separation of necrotic tissue from its adjacent lung tissues to form necrotic mass in the cavities. airway invasion type of pulmonary aspergillosis, also called aspergillus bronchopneumonia, accounts for - % of invasive aspergillosis. the most common imaging fi ndings are unilateral/bilateral fl aky parenchymal changes, centrilobular small nodules and branches liked linear shadows (tree buds sign). histologically, it is characterized by necrosis and infi ltration of neutrophil granulocytes. the lesions surround the bronchiole and the bronchiole. the invasion of the pulmonary artery can cause bleeding of the adjacent pulmonary parenchyma. allergic bronchopulmonary aspergillosis rarely has lesions, with no unknown pathogenesis, which is generally believed to be related to type i and type ii allergic reactions. it usually shows obvious asthma related mucosal lesions. hyphae generated by aspergillus fumigatus can induce the production of mucus and additional mucosal lesions, eventually leading to bronchiectasis. dilatate bronchial lumen is fi lled with mucus or with absence of epithelium, which is replaced by a granulomatous infl ammatory infi ltration. the most common imaging manifestations are migratory fl occulent, branched y shaped and v shaped (fi ngertip sign) shadows in the pulmonary parenchyma, which are related to the infi ltration of eosinophils. pathologically, bronchial cystic dilatation in the pulmonary segment and sub-segment occurs, with large quantity eosinophils in the bronchial mucus and scattered broken aspergillus hyphae. in combination with the case history, the diagnosis can be defi ned. compromised immunity is an important cause of cryptococcosis, especially in patients with aids or abnormal lymphoproliferative diseases. cryptococcus neoformans, a single phase mould, exists widely in the natural world. the cryptococcus has a diameter of less than μm, which can be inhaled into the human body via respiratory tract. under the impact of a high concentration carbon dioxide, it forms a clearly defi ned protective layer composed of polysaccharide capsule to antagonize the defense mechanisms of the host. thus, lung infection occurs after its inhalation in immunocompetent people, which is commonly asymptomatic. of cryptococcus, inhalation of cryptococcus by aids patients can lead to hilar lymphadenopathy, as well as singular or multiple subpleural small nodules, being similar to those in the cases of mycobacterium tuberculosis infection. in the early stage of cryptococcal infection, only a mild infl ammatory reaction or diffuse infi ltrative exudative changes occur. but in the advanced stage, necrosis, suppuration or granuloma is formed. large quantity hyphae can be found in the focus. in the cases with hyphae penetrating the blood vessels, vasculitis, perivascular infl ammation and thrombosis occur. and thrombosis leads to ischemia and necrosis of the tissue (fig. . ). pulmonary cryptococcus infection in aids patients often is extensively disseminating, with symptoms of fever, cough, diffi culty breathing, expectoration, chest pain caused by pleuritis, and even acute respiratory distress syndrome (ards). hiv/aids related pulmonary cryptococcus infection has no characteristic imaging demonstrations. chest x-ray and ct scanning show multiple morphology of the lesions. in the slight cases, there are thickened pulmonary markings in both lower lungs or isolated nodular shadows, and occasionally cavities. in the cases of acute interstitial infl ammation, there are diffuse infi ltrative or miliary foci, with infi ltration, nodules or exudation in any lobe which is more common in bilateral middle and lower lungs, in unilateral lung or confi ned to one lobe. the foci may be isolated huge spherical or multiple nodular, without obvious surrounding infl ammatory responses, similar to those of tubercles or tumors. otherwise, they are diffuse miliary shadows or fl aky infi ltrative shadows. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he was hospitalized on - - due to headache and vomiting for more than days. in the csf, cryptococcus was found. by blood and sputum culture, cryptoccocus was detected. the diagnosis was cryptococcal meningitis, cryptococcal pneumonia and cryptococcal sepsis. after receiving amphotericin b antifungal treatment and dehydration, headache and vomitting were relieved. but chest ct scanning reexamination demonstrated increased pulmonary lesions, which was considered as tuberculosis. on - - , he was given herv anti-tuberculosis treatment. twenty days ago he sustained weakened lower limbs, which gradually aggravated and completely paralyzed in the recent week, his cd t cell count was /μl. hiv/aids related pulmonary cryptococcus infections should be differentiated from tuberculosis, primary or metastatic lung cancer. tuberculosis mostly is secondary tuberculosis, which is caused by repeated infections of tubercule bacillus. lesions show fl aky or fl occulent shadows in the two upper lungs, with blurry boundaries. the wrapped necrotic foci by fi bers develop into nodules. it can also show miliary shadows, mostly with mediastinal lymphadenectasis. it should also be differentiated from primary or metastatic lung cancer. cryptococcus is a relatively common pathogen of pulmonary fungal infection, and mostly develops in aids patients. usually, it is a disseminated disease, with common involvement of the central nervous system and the lungs. in immunocompetent patients, the nodular granuloma caused by the pathogen is similar to those of other pulmonary fungal infections. in patients with serious immunosuppression, wide tissue infi ltration of the pathogens may occur in the lungs. liked shadows, parenchymal changes of air cavity and miliary nodules. the pathogenic fungi can be found mainly in the pulmonary interstitium. imaging fi ndings include singular or multiple nodules or masses, parenchymal changes of lung lobes and lung segments with clear or unclear boundaries in size of - cm. there may be also miliary lesions, lymphadenectasis and cavity shadows. candida is an opportunistic pathogen, which widely exists in nature. candida albicans parasitize in the oral cavity, laryngopharynx, upper respiratory tracts, vaginal and intestinal mucosa of human being. pulmonary and bronchial moniliasis is commonly caused by candida albicans which has the strongest pathogenicity. after its invasion into the tissues, candida transforms into hyphae and multiplies in a large quantity, with strong toxicity and ability to fi ght against phagocytosis. aids patients may have disseminated pathological changes. only when the immunity is compromised, the pathogen invades into the bronchus or lungs to cause diseases. therefore, pulmonary candida infection is commonly secondary. candidosis can cause acute infl ammation in bronchus and lungs, mainly exudation of neutrophils, which can be divided into two types: bronchitis type and pneumonia type. the pathological changes in the early stage are acute suppurative infl ammation, accompanied with the formation of abscesses. by the naked eyes observation, they are large fl aky parenchymal changes, with central grayish white coagulative necrosis. under a microscope, the lesions are large fl aky caseous necrosis, accompanied with the formation of abscesses, and surrounding infi ltration of hyphae and phagocytes. in the advanced, there are caseous necrosis, formation of cavities, fi brosis and granuloma. symptoms in aids patients are mild, with frequent cough, with a small amount of white mucous phlegm or thick phlegm, no fever or low grade fever; scattered spots of white membranes in the mucosa of oral cavity, throat and bronchus. dry rales can be heard occasionally in both lungs. in aids patients, the manifestations are mostly acute pneumonia or sepsis, with chills, fever, cough, expectoration of white mucous jelly liked phlegm or thick phlegm often with blood or necrotic tissue. the thick sputum, candidal hyphae and shedding cell debris can be condensed into small colloid clumps, with yeast smell. other symptoms include even haemoptysis and diffi culty breathing. dry and moist rales can be heard in lungs. symptoms may be diffi culty breathing, rhinocnesmus, runny nose and sneezing. wheezing rales can be heard in both lungs. chest x-ray chest x-ray demonstrates nodular shadows and fl aky parenchyma changes in unilateral or bilateral lungs. sometimes there is miliary infection. ct scanning demonstrates most lesions in the middle and lower lung fi elds, with rare involvement of the apex. there are thickened lung markings or diffuse small fl aky/patchy shadows, some of which can fuse into large fl aky dense shadows, with blurry boundaries. nodules, due to bleeding around it, may be surrounded by ground glass liked shadows, which is necrotic bronchopneumonia, usually accompanied with a large quantity neutrophils. cough expectoration with white mucous phlegm or thick phlegm, hemoptysis and shortness of breath. examinations of the oral cavity and the throat demonstrate spots liked white membrane covering the surface, and dry and moist rales in the lungs. successive cultures of phlegm, lung tissue, pleural fl uid or cerebrospinal fl uid repeatedly demonstrate the same strain of candida, or direct microscopic fi ndings of large quantity pseudohyphae or hyphae and groups of spores can defi ne the diagnosis. it is demonstrated to have thickened and deranged lung markings in double lung, diffuse small fl aky/patchy shadows, fusion of some small shadows into large fl aky dense shadows, with blurry boundaries, enlarged hilum and blurry structures. the conditions progress rapidly, with repeated lesions occurrence. hiv/aids related pulmonary candida infection should be differentiated from bacterial pneumonia. bacterial pneumonia often has symptoms such as high fever, cough, expectoration, chest pain and shortness of breath. ct scanning demonstrates fl occulent infi ltrative shadows or parenchyma changes and cavities. the pathogen can be detected in the sputum or chest liquid. hiv/aids related pulmonary candida infection should be differentiated from virus pneumonia. viral pneumonia fi rstly causes upper respiratory tract infection, which spread downward to cause pulmonary infl ammation. the demonstrations a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever, cough, expectoration, chest pain and shortness of breath, with pulmonary parenchymal changes sign and moist rales. his cd t cell count was /μl. include ground glass liked changes in the lung fi elds or mass shadows. the defi nitive diagnosis should be based on throat swabs, virus isolation from the sputum and serum specifi c antibodies test. hiv/aids related pulmonary candida infection should be differentiated from pulmonary tuberculosis. in the early stage, the symptoms and signs include irritative dry cough, expectoration, hemoptysis and cavities in lungs. (detailed manifestations of tuberculosis see the section about tuberculosis in this chapter) its diagnosis mainly should be based on chest x-ray and fi ndings of tubercule bacillus in sputum or other specimens, or tuberculosis specifi c pathological changes. hiv/aids related pulmonary candida albicans is a widespread dimorphism bacteria. the oval shaped budding yeasts and hyphae both can be found in the tissues. candidiasis is a common disease in aids patients. chest x-ray demonstrates unilateral or bilateral patchy parenchymal changes of the air cavity and nodules with unclear boundaries. miliary lesions are common. hrct demonstrates multiple nodular shadows in both lungs, often accompanied with parenchymal changes. its defi nitive diagnosis should be based on the fi ndings of candida albicans in the tissues. penicillium marneffei (pm) is a newly found penicillium in , which is a special strain with a distribution in south east asia and southern china. rhizomys is its natural host. in , disalvo et al. [ ] reported the fi rst case of natural human pm infection. in , the fi rst case of human pm infection in china was reported in guangxi zhuang autonomous zone. pm is an opportunistic pathogen and immunocompromised people are susceptible to its infection. its spreading is along with soil contaminated by rhizomys feces to invade human body via the respiratory tract, the digestive tract and skin defects. pm infection is believed to be one of the most common opportunistic infections in aids patients in southeast asia, which has an increasing incidence. pm is the only dimorphic fungus in hyphomycetes penicillium, which is a special strain of penicillium. at different culture temperatures, it shows conversion of biphasic forms: fungal phase at °c and yeast phase at °c. the fungal phase is the hyphae of many cells, with certain biological morphology, such as penicillus, conidiophore, chain liked conidiospore and chains between spores. the yeast phase shows unicellular or bicellular form. in the growth process of pm, large quantity bright rosy or dark rosy pigments are produced, which is characteristically pm. the pigment of yeast phase is secondary metabolites of cells with strong hydrophobicity, which can promote the adhesion of conidiums in fungal phase and cells in yeast phase to the alveolar macrophages and other cells surface in the human body. the pigment monoclonal antibody (mab) can interrupt the pathological process of adhesion. in addition, this pigment can determine the expression of cluster-encoding genes mbr through diffusion and penetration of drugs to the cell membrane, thus preventing the penetration of hydrophilic antifungal drugs, such as fl uconazole. that is to say, it improves the natural antifungal resistance level of pm. the soluble components of the pigment in fungal phase can trigger the generation of anti-conidium antibody (only igg) in animals to prevent its spreading in the body. the phenomenon proves that, in terms of tissue invasion, fungal phase is less powerful than yeast phase. conidium in fungal phase is the carrier of pathogen while the cells in yeast phase are the real pathogenic factors. when pm spreads to the target organ along with the blood fl ow, it is engulfed by mononuclear phagocytes. in the cases of replication itself and further spreading, reactive proliferation of phagocytes is caused. mononuclear phagocyte system has strong defense ability. in the cytoplasm of proliferated mononuclear phagocytes, various amounts of pm can be found. pm mainly invades into the body via the respiratory tract, digestive tract and skin defects. in immunocompetent people, local abscesses form in the invasion site, which is characterized by the thick mucus fl uid, with mainly necrosis and liquefaction. vascular reactions and exudation of neutrophil leukocytes and body fl uids is less than abscesses induced by common purulent bacteria. the clinical manifestation is confi ned suppurative infl ammation. when the immunity is compromised, due to the insuffi ciency of immunologic factors, it is diffi cult for the immune cells to restrict and digest the engulfed pathogens, which leads to confi ned suppurative reaction. therefore, it often presents with diffuse lesions. the pulmonary lesions are principally interstitial exudative infl ammation. the typical penicillium marneffei disease has acute or subacute onset, along with fever, chills and shivers, cough and expectoration, hemoptysis, shortness of breath, abdominal pain, diarrhea, bloody stool, fatigue, central necrotic papula mainly in the head and face and scattering in the trunk and extremities as well as hepatosplenomegaly. bone marrow smear and pas staining can be performed to detect the pathogen. blood, bone marrow, pleuroperitoneal fl uid, phlegm and skin defect tissue are collected for the culture at double temperatures with sabouraud'broth medium. at the temperature of °c, the colony is in dark red with villous surface, with surrounding red wine liked pigments to gradually spreading into the medium. biopsy of lymph nodes and skin defects with pas staining and wright & gimsa staining can be performed. wbc count, hemochrome, platelets, ast and cd t cell count. ct scanning and routine chest x-ray are the diagnostic imaging examinations of choice, which can facilitate to understand the size, morphology, location, quantity and density of the lesions. it demonstrates multiple small nodular shadows in the lungs, multiple honeycomb liked cavities in both lungs and mediastinal lymphadenectasis. abdominal scanning demonstrates different degrees of hepatic, splenic and retroperitoneal lymphadenectasis, which can fuse into a huge mass. routine chest x-ray it demonstrates thickened, deranged and blurry pulmonary markings, small cavities, military nodular shadows, mass liked shadows, spots and patchy shadows, ground glass liked changes, pleuritis and pleural effusion. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. her husband had a history of drug abuse and she complained of abdominal pain and fever for more than months, with accompanying face rash and diarrhea. her cd t cell count was /μl. by examinations, she sustained skin palpula, abdominal tenderness, central concave skin rashes on the face, neck, and upper limbs. there was a palpable mass in the upper left abdomen, hard and tenderness, in a size of × cm. more than months before her admission, she had persistent dull abdominal pain that is commonly in the upper left abdomen, with accompanying fever and face skin rashes that is gradually increasing and spreads to the neck and upper limbs. she also had hepatosplenomegaly, abdominal aortic lymphadenectasis and ascites. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she had an unhealthy sexual life, with complaints of fever and cough for more than month. her cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had been found to be hiv positive for years, with complaints of irregular fever, cough, fatigue and dizziness for days to be hospitalized. by examinations, his cd t cell count was /μl, hiv positive, subcultivation of strains demonstrated typical biphasic penicillium. by fungus culture, typical penicillus was found. by bone marrow smear, the round corpuscles mainly located in the macrophages. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had a history of extramarital affair, with complaints of fever, cough, chest distress, shortness of breath, fatigue, poor appetite, poor sleep, weight loss and shortness of breath after activities for more than months. his cd t cell count was /μl. chest x-ray and ct scanning both demonstrate multiple nodules in different sizes and cavity shadows. the cavities cluster into honeycomb liked changes with uneven thickness of the walls, clear boundaries and surrounding infl ammatory exudates. some of the nodules infuse into mass dense shadows. lesions in both lungs have a symmetrical or asymmetric distribution, with no characteristic leions. mediastinal lymph nodes are obviously enlarged. sputum smear for direct microscopy demonstrates candida. pms are found by fi brobronchoscopy lavage smear and biopsy. ( ) candida skin test shows positive. ( ) fluorescent antibody test for pms is performed in procedures of direct smear, fungal colony culture and histopathological examination of the tissue sections. metabolites test of pm and pcr can be performed to determine the gene sequences of pm for the early diagnosis. hiv/aids related penicillium marneffei pneumonia should be differentiated from bronchiectasis and blood borne staphylococcus aureus pulmonary abscess. although the cases of bronchiectasis are demonstrated to have clustering round shadows on the cross sections, the wall is thinner and even, accompanying to the spots liked vascular shadows. some lesions have typical railway liked bronchial dilation signs. it is demonstrated to have multiple small cavity lesions in both lungs in line with the evenly distributing blood borne lesions. the lesions are rarely clustering. the wall of the cavities is thick and even with surrounding marginal exudates and blurry boundaries. with the steady increasing of hiv infections, reports on the complication of pm disease have also been increasing recently. the disease can be localized but mostly disseminated, with the involvement of lungs, liver, skin, lymph nodes and other tissues and organs. therefore, it is known as penicilliosis marneffei or disseminated penicillium marneffei infection in literature reports. due to the insuffi cient knowledge about the disease, diagnosis is delayed or missed. in thailand, penicilliosis marneffei has been the indicator disease of aids. about % aids patients are infected by pm and % have necrotic papula, which is characteristically disseminated penicillium marneffei infection. ct scanning demonstrates hiv/aids complicated by disseminated penicillium marneffei infection as fl aky parenchyma shadows in the lungs, clustering of cavities and nodular shadows, mediastinal lymphadenectasis and pleural infl ammation responses, which can facilitate its clinical diagnosis. mucormycosis is a rare kind of conditional fungal disease, with its pathogen, mucor, distributing widely in the natural world. it generally fails to cause diseases, but can cause systematic infections in immunocompromised people. mucor often invades into the human body via the nose to cause paranasal sinuses and orbital infections, which can further invade into the brain to cause meningitis and frontal abscesses. pulmonary mucormycosis is only second to the nasal-cerebral infection. it can spread via the respiratory tract to cause pulmonary infections. in addition, there are also skin and gastrointestinal mucormycosis as well as disseminated mucormycosis. the pathological changes of hiv/aids related pulmonary mucormycosis are mainly hemorrhagic necrotic infl ammation. the defense mechanism of immunocompetent people is to kill the fungal spores with the phagocytosis of macrophages and oxidation killing mechanism. in immunocompromised or immunodefi cient patients, the macrophages are often too weak to restrain the engulfed spores from germinating. therefore, the disease occurs. vascular vessels are susceptible to the invasion of mucor, especially the arteries. mucor can locally multiply to cause the formation of blood clots and embolization, and disseminate to other organs along with the blood fl ow. the main lesions are hemorrhage and necrosis of local tissues and exudation of neutrophils. the lesions of hemorrhage and necrosis are possibly related to the arteriole lesions caused by hyphae. the clinical manifestation of hiv/aids related pulmonary mucormycosis is a nonspecifi c pneumonia. the most common symptoms reported in literatures are persistent high fever, cough, hemoptysis, chest pain and diffi culty breathing. it has a rapid progression, with a high mortality rate of - %. lung lesions are hemorrhagic infarction or pneumonia, which can cause high fever, cough, expectoration, shortness of breath, chest distress, chest pain, hemoptysis (pulmonary artery involved) and other symptoms. moist rales can be heard in both lungs and pleural rubs can be heard in the cases of pleura involvement. . assisted by bronchofi broscopy, lung biopsy can be performed. . histological examinations include bronchial lavage fl uid examination, exploratory thoracotomy and puncture of lung tissues for biopsy. . chest x-ray and ct scanning are conventional effective examinations. the lesions are frequently found in the dorsal and medial segments of both lungs. early exudation shows miliary shadows, cavity shadows with no wall or with thin wall and small bronchiectasis shadows. their further progression may cause fusion infi ltration, parenchymal changes, nodules, masses, thick-walled cavities and pleural effusion, with accompanying mediastinal lymphadenectasis. . the fi ndings of mucor or their hyphae by sputum and bronchofi broscopic biopsy. . the diagnostic imaging demonstrates lesions commonly in the dorsal and medial segments of both lungs. there are diffuse scattering miliary shadows, cavity shadows with no wall or with thin walls and small bronchiectasis shadows. they further progress into fusion infi ltration, parenchymal changes, nodules, masses, thick-walled cavities and pleural effusion. . often with accompanying mediastinal lymphadenectasis. chest x-ray of pulmonary mucormycosis demonstrates progressive infi ltrated parenchymal changes, or masses, nodules, cavities and pleural effusion. it needs to be differentiated from miliary tuberculosis. hiv/aids related miliary tuberculosis are commonly demonstrated as chronic blood borne disseminated tuberculosis, with lesions distributing symmetrically in both lungs. its long term progression causes fusion into masses. otherwise, it can be cured by anti-tb therapies. the early lesions are no-wall cavities or thin wall cavities and small bronchioectasis shadows, based on which the differential diagnosis can be made. almost all cases of hiv/aids related pulmonary mucormycosis are found in immunocompromised patients. chest x-ray demonstrates parenchyma changes and isolated or multiple nodules or masses. the parenchyma changes are patchy or fuse, with unilateral or bilateral distribution. about % patients have pleural effusion and less than % patients have hilar or mediastinal lymphadenosis. ct scanning demonstrates singular or multiple nodules or masses, commonly with clustering or honeycomb liked cavities. cytomegalovirus pneumonia has extensive pathological changes in the lungs. pathologically, it shows interstitial pneumonia, with the lesions randomly blood borne distributing in the lungs. the distribution can be diffuse, panlobular or focal. the target cells of pathological changes include alveolar cells and macrophages. diffused pulmonary interstitial edema and fi brosis as well as alveolar swelling, focal necrosis, bleeding and hyperplasia occur after cmv infections to cause hypoxemia. gross observation of fresh specimens demonstrates pulmonary surface edema and fl aky blooding spots. fixed specimens demonstrate brown hard lung tissues. under a microscope, pulmonary interstitial congestion as well as infi ltration of lymphocytes and mononuclear cells can be found, with the involved epithelial cells enlarged. in the pulmonary interstitium and alveoli, there are intranuclear inclusions, cytoplasmic inclusions and fl uid containing abundant proteins. the classical intranuclear inclusions can be found in the cells, purplish red or purplish blue, round or oval, with surrounding halos in eagle eyes sign. atypical cytomegalic inclusions in cells are slender, long and round liked with abundant cytoplasm and accentric nucleolus, which are blurry, unclear and atypical ( fig. . a-e ). immunohistochemitry demonstrates hiv p antigen positive. the systemic symptoms of cmv infection include fever, joint and muscle soreness and pain, abdominal distension and orthostatic hypotension. the respiratory symptoms include paroxysmal dry cough, diffi culty breathing, cyanosis and three depressions sign. according to the imaging fi ndings of cmvp, cmv pneumonia can be classifi ed as diffuse, miliary and mass types, among which the diffuse type is the most common. cytomegalovirus can be separated from respiratory secretions culture and urine culture by using human embryonic fi broblasts. by urine sediment smear, giant cell with inclusions can be found. by using immunofl uorescence, indirect hemagglutination inhibition and complement fi xing test, the antibody titer can be found increased. indirect immunofl uorescence test and immunoenzymic staining test can be applied to detect the anti-cmv-igg and igm antibody. in addition, enzyme-linked immuno sorbent assay (elisa) can also be performed to detect the anti-cmv-igg and igm antibody. cmv-igm antibody positive indicates a recent infection, which has diagnostic value. a single serum cmv-igg antibody positive indicates a previous infection. and during the acute and recovery phases, double serum cmv-igg antibody titer being no less than four times increase has diagnostic value, indicating a recent infection. pcr can be applied to quantitatively determine the viral load in the whole blood, blood plasma, leukocytes, urine, bronchoalveolar lavage fl uid (balf), cerebrospinal fl uid and the tissue specimens, which is believed to be the best way for the diagnosis of invasive cmv infection. chest x-ray is the most commonly used examination. chest ct scanning is superior to chest x-ray in terms of resolution and detection rate of the lesions. pulmonary demonstrations by cmvp include diffuse interstitial infi ltration and alveolar infi ltration to form reticular shadows, nodules and parenchymal changes. a baby boy aged months was confi rmatively diagnosed as having aids by the cdc. he was infected via vertical transmission from mother to child, with recurrent cough after being born and the most recent cough for days as well as wheezing cough in throat for day before he was hospitalized. he had a past history of premature birth, with primary apnea and bronchial pneumonia and was hospitalized for treatment. later, he was admitted for three times due to cough, which was diagnosed as interstitial pneumonia. by examinations, wbc . × /l, lym lymphocyte count . × /l, cmv-ab weak positive, blood sedimentation mm/h, and tuberculosis antibody negative. after treated by broad-spectrum antibiotic therapy, the therapeutic effi cacy is unfavorable. cytomegalovirus (cmv) infection is an important cause of pneumonia in patients with compromised immunity. imaging fi ndings include nodular shadows with blurry boundaries and bilateral fl aky parenchymal changes of the lungs. the nodules tend to be bilaterally symmetric or asymmetric, with centrilobular distribution. histopathological manifestations are nodular alveolar hemorrhage, necrosis and infl ammatory lesions, and diffused alveolar lesions. the nodules tend to have a centrilobular distribution, indicating occurrence of bronchiolitis. in aids patients, if the diameter of nodules is under cm, it is most likely to be viral infection. the size of the nodules can facilitate the differential diagnosis of pulmonary infections. herpes simplex viral pneumonia (hsvp) often occurs in the upper respiratory tract, and rarely in the lower respiratory tract. human herpes simplex virus can be divided into two types, namely herpes simplex virus type i (hsv-i) and herpes simplex virus type ii (hsv-ii). herpes simplex viral pneumonia mostly occurs in patients with immunodefi ciency. herpes simplex viral pneumonia can be caused by hsv-i and hsv-ii, both of which have a nucleocapsid with surfaces. the thickness of the nucleocapsid is about nm, which is composed of capsomeres. the nucleocapsid contains the core of the virus dna. the virion gains the phospholipid rich viral envelope when it passes through the nuclear envelope. the nucleocapsid gemmates after it passes through the nuclear membrane and is released to the cell surface. the nucleocapsid can also be released outside the cells or gains its access into the neighbour cells for further reproduction. herpes simplex virus replicates itself in the cell nucleus to produce histopathologic changes of herpes virus replication, with visible cowdry a type intranuclear inclusions. the pathogenesis process of herpes simplex virus infection in the body can be divided into fi ve stages: initial skin mucosa infection, acute ganglia infection, latent infections, re-activation, and recurrent infections in susceptible hosts. patients infected by herpes simplex virus can produce igm, igg and iga antibodies to fi ght directly against virus protein, which may play a role in changing the severity of the infection. interferon also participates in the control of herpes simplex infection by inhibiting the virus or regulating the defense mechanism. genetic factors may be also related to the herpes virus infection. cellular immunity can confi ne the infection. herpes virus cannot reproduce in the alveolar macrophages of human body, which is also the reason why herpes virus is less than cytomegalovirus in lungs. currently, it is believed that herpes simplex virus is an important pathogen of respiratory infections, especially in immunocompromised patients. localized herpes simplex viral pneumonia occurs due to the direct spreading of virus in the upper and lower respiratory tract. diffuse herpes simplex viral pneumonia is caused by the virus spread from the reproductive organs lesions or oral lesions (most possibly blood borne). viremia caused by hsv-i or hsv-ii has been reported, and both are related to diffused infections. but in patients without herpes simplex viral infection in skin mucosa, herpes simplex viral pneumonia can also occur. herpes simplex viral pneumonia is caused by the direct spreading of the virus from the upper and lower respiratory tract. diffuse herpes simplex viral pneumonia is cause by the spreading of the virus from the reproductive organs lesions or oral lesions (most possibly blood borne). viremia cause by either hsv-i and hsv-ii have been reported, both of which are related to diffuse infections. in such cases, the lung tissues may have infl ammatory infi ltration, lung parenchyma necrosis, bleeding, cellular swelling and round, diffuse interstitial pneumonia. and in most cases, there are accompanying cellular changes of herpes virus infection such as the intranuclear eosinophilic inclusions, necrotic herpes simplex viral trachitis. herpes simplex viral bronchitis has demonstrations of mucosa erythema, edema, exudation and ulcer, with coverage of the surface by fi brous purulent membranous secretions. the common initial clinical symptoms of herpes simplex viral pneumonia are shortness of breath, cough, and fever with a body temperature being higher than . °c, decreased wbc count, hypoxemia, respiratory dysfunctioning and azotemia. hsv pneumonia may be accompanied by mucocutaneous lesions by hsv, which show earlier than those of pneumonia. there may be concurrent fungus, cytomegalovirus or bacteria infection. herpes simplex viral tracheobronchitis may show tracheal or bronchial spasm or stenosis. etiological examinations hsv can be detected in tracheobronchial secretions, bronchoalveolar lavage fl uid and lung tissues. early sampling should be performed under the guidance of a bronchofi broscope. tissue culture is the most sensitive and specifi c method for the diagnosis, which can also be used for the classifi cation of the virus. papanicolaou (pap) or tzank test is a fast and cheap method for cellular diagnosis. elisa can be used to detect herpes simplex virus, with a sensitivity of up to % and a high specifi city. chest x-ray demonstrations are less valuable for the differential diagnosis. pulmonary ct scanning can be applied for the differential diagnosis. herpes simplex viral pneumonia includes three types, namely local, multiple or diffuse interstitial infi ltration. in the early stage, typical hilar or diffuse interstitial shadows with increased density can be found, with thickened bronchial wall. as the disease progresses, cloudy or patchy alveolar tamponade and fusion can be found. chest x-ray may demonstrate negative for herpes simplex viral trachitis and bronchitis. herpes simplex viral pneumonia should be differentiated from bacterial pneumonia, cmv pneumonia, and infl uenza pneumonia. hiv/aids related herpes simplex viral pneumonia is mostly demonstrated by multiple signs, including small nodules, ground glass liked shadows and patchy parenchymal changes. the nodules are in centrilobular distribution, mostly with accompanying branches liked shadows (tree buds sign). chest x-ray demonstrates diffuse lung parenchymal changes. imaging fi nding are parenchymal change areas with bilaterally blurry boundaries. generally, the nodules have a diameter of - mm. ct scanning with high resolution demonstrates nodules with surrouding ground glass liked density lesions. lymphoid/lymphocytic interstitial pneumonia (lip) is more common in children with aids. the cdc in the united states has defi ned lip in children under the age of years as the diagnostic indicator of aids. the predictive diagnostic criteria include chest x-ray demonstration reticular nodular changes in pulmonary interstitium of both lungs for no less than months, undetectable pathogens and no responses to the antibiotic therapy. currently, hiv/aids related lymphocytic interstitial pneumonia is considered to be related to hiv and epstein-barr virus, human t cell leukemia-lymphoma type i virus (htlv-i) and hiv-i. the infection of the above viruses causes pulmonary lymphatic hyperplasia and other systemic diseases. about - % children with hiv infection sustain lip, and % in adults. most cases of non-hiv infected patients with lymphoid interstitial pneumonia are women, at average age of years old, more commonly in the age group of - years old and above years old. the pathological manifestations are infi ltration of small and mature lymphocytes as well as plasma cells in alveolar septum and the alveolus, extensive interstitial fi brosis and non-caseous granuloma. it is characterized by diffuse infi ltration of lymphocytes, plasmocytes and histocytes in the pulmonary interstitium. the lymph follicle with germinal center is more common. hyperplasia occurs in type ii alveolar epithelium, and the macrophage increases in the alveolar cavity. there are rare or mild intraalveoli organization and macrophage aggregation. staining of the immune globulin light chain demonstrates poly-clone b cells. the clinical symptoms are in progressive development, with cough and suffocation, rare hemoptysis and sjogren syndrome commonly in mouth and eyes. by examinations, the signs have slight difference between adults and children. in children, there are lymphadenectasis, hepatosplenomegaly, enlargement of parotid gland, clubbing fi ngers and wheezing sound. in adults, there are lymphadenectasis, slight fi ne bubbling rales, as well as hepatosplenomegaly and enlargement of parotid gland in / patients. . peripheral hemogram demonstrates increased lymphocytes and eosinophilic granulocytes. . myelogram demonstrates increased lymphocytes, plasmocytes and eosinophils. . blood biochemical examination demonstrates increased immune globulin, predominantly lgm. . blood gas analysis demonstrates hyoxemia. . pathogenic examinations by bronchofi broscopy, bronchial alveolar lavage and biopsy can defi ne the diagnosis. . pulmonary function examinations demonstrate restrictive ventilatory disorder, lower lung compliance and impaired diffusion function. impaired diffusion function is a more sensitive indicator in monitoring the progress of the disease. . chest x-ray is the most commonly used imaging examination, while chest ct scanning is commonly applied for the differential diagnosis. chest x-ray demonstrates hiv/aids related lymphoid interstitial pneumonia as reticular or reticular nodular shadows of lung markings in both lungs. hrct demonstrates bilateral diffuse ground glass liked density shadows. perivascular thin-walled pneumatocele is common. pneumatocele induced by lip is commonly found in the middle lung fi eld, which probably is due to the valve effects caused by infi ltration of cells around bronchioles. manifestations of pneumatocele, together with ground glass liked density shadows, highly indicate lip. centrilobular and subpleural small nodules and thickened intralobular septa can be occasionally found. dysfunctional diffusion is a more sensitive indicator in monitoring the progress of the disease. hiv/aids related lymphoid interstitial pneumonia should be differentiated from allergic pneumonia, carcinomatous lymphangitis and pneumocystis carinii cysts. ct scanning with high resolution demonstrates characteristic lesions of hiv/aids related lymphoid interstitial pneumonia, including intralobular linear shadows and honeycomb liked changes, with common involvement of the subpleural area and the basal lung. its characteristic manifestations are clustering gas containing thin-walled cyst in a diameter of - mm, with clear cyst wall. shared wall between cysts is its characteristic demonstration. the surrounding ground glass liked density indicates infl ammation. intralobular linear shadows indicate interstitial fi brosis. pulmonary toxoplasmosis (pt) is caused by the toxoplasma parasitizing in cells. ludlam et al. fi rstly proposed the concept of pulmonary toxoplasmosis in [ ] , arguing that toxoplasma can cause atypical pneumonia. later, there are some pathological reports about pulmonary toxoplasmosis or disseminated toxoplasmosis with lung involvement. in recent years, due to the global prevalence of aids, the incidence of pulmonary toxoplasmosis is increasing, with most cases being disseminated toxoplasmosis with lung involvement. pt has been one of the important opportunistic infections in patients with immunosuppression, especially aids patients. hiv/aids related pulmonary toxoplasmosis is a zoonotic disease, with cats as its main transmission source, followed by pigs and sheep. people are infected by intake the water or food contaminated by cats' feces or without cooked meat. immunocompromised aids patients are susceptible to this disease, and its occurrence is rare in immunocompetent people. after its invasion into the human body, the sporozoite in the cystozygote and intracystic cystozoite overfl ows to penetrate the intestinal wall mucosa and spread to the whole body tissues along with blood or lymph fl ow. the brain, heart, lymph nodes, and lung are the most vulnerable tissues and organs for the infection. any abnormality in the process of defense mechanism can cause impaired immune functions to eliminate the toxoplasma, which ultimately causes systemic and pulmonary infections. pulmonary toxoplasma infection may also be caused by the blood borne spreading of reactivated toxoplasma infection in other body parts, with no exclusion of reactivated pulmonary infection or primary pulmonary infection. ludlam et al. generally nominated toxoplasmosis as atypical pneumonia [ ] . catterall et al. divided toxoplasmosis into three types: necrosis, infl ammatory infi ltration and toxoplasma invasion [ ] . it can also be classifi ed as type a: subclinical or occult infection; type b: interstitial and atypical pneumonia; type c: necrotic pneumonia; type d: lobar pneumonia; and type e: granulomas pneumonia (toxoplasmoma). by naked eyes observation, the involved lungs are solid, with congestion and red brown section. the pleura have bleeding spots, with moderate peribronchial lymphadenectasis. under a light microscope, there is exudation of serous fl uids in alveolar cavities, occasional formation of transparent membrane or fi brin purulent exudation, infi ltration of small quantity neutrophils, proliferation and shedding of alveolar wall cells, and trophozoite and/or cysts of toxoplasma in epithelial cells and macrophages. the pulmonary interstitium may have infi ltration of lymphocytes and plasmocytes as well as visible fi broblasts and macrophages. the granuloma changes are also found in the lung tissues, with central stripes or localized necrosis and surrounding lymphocytes and small quantity multinucleated giant cells. it is diffi cult to fi nd toxoplasma in granuloma, but it can be found in the normal tissues around or near the granuloma. almost all cases of aids complicated by pulmonary toxoplasmosis are caused by disseminated toxoplasmosis with pulmonary involvement. it is commonly diffuse pulmonary infl ammation with serious symptoms, including high fever, cough, cyanosis, breathing diffi culty, possible occurrence of skin rashes, lymphadenectasis and meningitis. the chronic cases may have long-term low grade fever, cough, and weight loss. direct light microscopy of the specimen smear and enprint such as blood, cerebrospinal fl uid, bone marrow, anterior aqueous humor, phlegm, urine, saliva, and other osmotic solutions, as well as lymph nodes, muscle tissue or other living tissues can be performed for pathogen examinations. sabin proposed that the staining test have high sensitivity and specifi city according to the fi ndings that mixture of fresh toxoplasma with normal serum can be stained deep by alkaline methylene blue staining, while its mixture with immune serum can be stained light or blank by the same staining. other assays including indirect fl uorescent antibody, indirect blood coagulation, and complement fi xation test can provide valuable reference for the diagnosis. toxoplasm is tested in pathological eaminations that can provide valuable reference for the diagnosis. chest x-ray is the most commonly used diagnostic imaging examination. and chest ct scanning can be applied for the differential diagnosis. imaging fi ndings of hiv/aids related pulmonary toxoplasmosis can be divided into four types: bronchial pneumonia, interstitial pneumonia, pleuritis and complication of cardiovascular disease. the type of bronchial pneumonia is also known as lobular pneumonia, with thickened pulmonary markings that distribute along with the bronchi in the middle and lower lung fi elds, scattered patchy shadows with uneven density and blurry boundaries, fusion of some shadows into large fl aky shadow and widened hilar shadow. the type of interstitial pneumonia is demonstrated as reticular and nodular shadows. the interstitial lesions widen the space between the bronchiole and the alveolar wall, with stripes and fl occulent shadows. the type of pleuritis is rare, with signs of pleural effusion. the type of complication of cardiovascular disease is demonstrated as heart failure (acute pulmonary edema), with signs of pericardial effusion. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of cough and fever. his cd t cell count was /μl. by direct light microscopy, toxoplasma tachyzoites can be found in the specimens such as blood, cerebrospinal fl uid, bone marrow, anterior aqueous humor, phlegm, urine, saliva, and other osmotic solutions, as well as lymph nodes, muscle tissues or other living tissues. the fl uorescent antibody and complement fi xation test are positive. the biopsy tissue culture and inoculation test are positive. in the lesions and their surrounding tissues of interstitial e c d fig. . (continued) pneumonia, necrotic bronchitis or granuloma, toxoplasma can be found. the diagnostic imaging demonstrates any one type of pulmonary toxoplasmosis, including bronchial pneumonia, interstitial pneumonia, pleuritis and cardiovascular disease, can be used as the evidence for the diagnosis of pulmonary toxoplasmosis. the type of bronchial pneumonia is also known as lobular pneumonia, with thickened pulmonary markings with a distribution in both middle and lower lung fi elds along with the bronchi, scattered patchy shadows with uneven density and blurry boundaries, fusion of some patchy shadows into large fl aky shadow and widened hilum. the type of interstitial pneumonia has typical demonstrations of reticular and nodular shadows. the interstitial lesions widen the space between the bronchiole and the alveolar wall, with strip and fl occulent shadows. the type of pleuritis is rare, with signs of pleural effusion. the type of cardiovascular disease may have signs of heart failure (acute pulmonary edema), and signs of pericardial effusion. hiv/aids related pulmonary toxoplasmosis should be clinically differentiated from infectious mononucleosis and mycoplasma pneumonia. with primary pulmonary lesions. pulmonary low malignant b cell lymphoma is the most common primary pulmonary lymphoma which is derived from mucosa related lymphoid tissue. the manifestations include slowly decreased alveolar transparency. pulmonary high malignant b cell lymphoma is extremely rare, which often occurs with singular lesion and primary disease such as immunodefi ciency. hiv/aids related malignant lymphoma is mostly caused by compromised immunity. hiv/aids related hodgkin's lymphoma is relatively rare. there are also reports about hiv/aids related t cell lymphoma with pulmonary involvement. hiv/aids related malignant lymphomas are mostly highly malignant large cells lymphoma. cerebral lymphoma is one of the defi ning diseases of aids. it has been reported that the clinical incidence of pulmonary infi ltration by malignant lymphoma is - %, but - % by autopsy. in the early stage, it is commonly asymptomatic. with its progression, symptoms of dry cough, suffocation, and small quantity clear phlegm occur. mediastinal lymphadenosis includes lymphadenectasis to compress the trachea by, blood vessels and nerves and lead to breathing diffi culty, superior vena caval obstruction syndrome, and hoarse voice. the pulmonary parenchyma lesions include reticular structure in the lungs. the clinical symptoms are cough, expectoration, suffocation and breathing diffi culty. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of chest distress and cough for more than month. his cd t cell count was /μl. in patients with hiv/aids related kaposi's sarcoma, its serologic positive rate is %. kaposi's sarcoma cells can produce il- , during which il- plays a role as an autocrine factor to maintain the cell growth, paracrine cytokines, stim-ulate proliferation of other interstitial cells and induct the vascular growth. therefore, kaposi's sarcoma is a kind of tumor with abundant blood vessels. before the application of harrt, the incidence of kaposi's sarcoma in male homosexuals is %. after the clinical application of harrt treatment, the incidence is decreasing. in addition to hhv- , some studies indicated that most patients with kaposi's sarcoma have hia-dr alleles, suggesting a possible relationship between kaposi's sarcoma and the heredity. there is no obvious difference between hiv/aids related kaposi's sarcoma and classic kaposi's sarcoma in pathological changes. early pathological manifestations are chronic infl ammation or granulomatous infl ammation, with formation of new vascular and lymphatic vessels and accompanying edema and bleeding. the fi ndings of large and protruding endothelial cells in granuloma tissue with accompanying erythrocytic exudation and hemosiderin particles have great signifi cance for the early diagnosis. the pathological changes in the advanced stage are signifi cant proliferation of the endothelial cells, and proliferation of fi broblasts around capillaries. in the advanced stage, the lesions are often accompanied by extensive connective tissue hyperplasia, which presents diffi culty for its differentiation from common sarcoma. when it is diffi cult to defi ne the diagnosis by light microscopy, immunohistochemical examinations can be used to defi ne the diagnosis. the pathological changes are characterized by lesions confi ned to the epithelial lamina propria, gathering of spindle cells with mild heteromorphism around many lacuna vasorum with irregular lumen, erythrocytic exudation and hemosiderin sedimentation. the atypical lacuna vasorum can be compressed by proliferative spindle cells to be absent. vascular endothelial cells and peripheral spindle cells may have mitotic phase in the advanced stage, with increased heteromorphism cells. the infl ammatory cells are mainly plasma cells, with acidophilic corpuscles and pas staining positive, which can assist the pathological diagnosis. pulmonary kaposi's sarcoma in aids patients rarely has symptoms. it is commonly concurrent with pulmonary opportunistic infections, with symptoms of cough, diffi culty breathing and fever. other symptoms are related with the location of the tumors. the involvement of trachea or bronchi can cause luminal stenosis. the mediastinal tumor can compress and obstruct lymph vessels to cause pulmonary edema or a large quantity pleural fl uids, which result in respiratory diffi culty, and even respiratory failure. ( ) sampling by bronchoscopy or endoscopy to prepare pathological section. ( ) chest x-ray demonstrates its typical manifestation of pleural effusion. dr demonstrates enlarged and deranged hilum in both lungs in bird nest liked appearance. there is light density fl aky shadows in the both lower lungs. ct scanning demonstrates multiple rounds liked nodular shadows in the middle and lower lung fi elds of both lungs with clear boundaries. there are also mediastinal and hilar lymphadenectasis, with common involvement of the pleura and bilateral pleural effusion in a small quantity. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had been detected as hiv positive for months, with complaints of recurrent cough and nausea for days and was hospitalized on jan. , . the transmission route was unknown because he denied histories of intraveneous drug abuse, paid blood donation, blood transfusion and unhealthy sexual behaviors. five months ago, he was diagnosed as aids in the stage of aids in our hospital, and hospitalized to treat pcp, with a cd t cell count of /μl. his symptoms were quickly relieved after pcp treatment and he continued the antiviral therapy for almost months after being discharged. by physical examinations, he was in poor spiritual condition, a light blue nodule in size of . × . cm in the left upper chest wall with medium hardness, palpable lymph nodes in size of . × . in the opisthotic area and inguen, no tenderness and being movable. by the digital rectal examination, a palpable prominent nodule with wide base at cm points away from the anus, with fl exible texture and smooth surface. by the auxiliary examinations, wbc . × /l, neμt . %, lym . %, mon . %, eos . %, rbc . × /l, hgb g/l, plt × /l, routine urine test normal, blood sedimentation mm/h. by hepatitis b examinations, hbsag, anti-hbe and anti-hbe positive. his cd t cell count was /μl. by abdominal b ultrasound, multiple low echo nodules in the abdominal cavity, the largest in size of . × . cm, which are suspected to be enlarged lymph nodes. on jan. , he received inguinal lymph node biopsy, with pathological report of kaposi's sarcoma. during the treatment and following up, the involvement of lungs, digestive tract, lymph nodes and skin is suspected, with the diagnosis of phase ii kaposi's sarcoma and chemotherapy was recommended. reexamination by chest x-ray demonstrated normal cardiopulmonary phrenic. abdominal b ultrasound failed to fi nd enlarged lymph nodes. ct scanning demonstrated shrinkage of lesions in both lungs and mediastinal lymph nodes, with only palpable soybean sized submandibular lymph node. by examinations after chemotherapy, cd t cell count /μl, viral load , copies/ml. the patients had multimorphological erythema drug eruptions, which was suspected as drug allergies of chemotherapy, which were absent after symptomatic treatment. the following ups so far show no recurrence of kaposi's sarcoma, with his cd t cell count fl uctuating around /μl. he can work as usual. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had a history of homosexual behaviors, with complaints of fever and cough for months as well as chest distress for more than days. since, july , fever with a body temperature of about . - . °c occurs, with cough, yellowish bloody sputum, and dark purplish patchy skin rashes. by examinations, his anti-treponema pallidum antibody positive, multiple dark purplish patchy skin rashes on the face, eyelid, lower jaw, hairline, chest and abdomen with skin surface desquamation, palpable bilateral cervical lymphadenectasis and the largest in size of × mm. by laboratory tests, wbc . × /l, n . %, rbc . × /l, hgb g/l, plt × /l, cd /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of cough for more than months, chest distress for more than month, and bloody sputum for half a month and was hospitalized. he had a history of homosexual behaviors. by examinations on admission, multiple round purplish blue skin rashes nodules on the limbs. his cd t cell count was /μl. demonstrations can also be fl aky fl occulent areas with blurry density or parenchymal density areas along with bronchi. . lung puncture for histopathological biopsy demonstrates irregular vascular lumen in the dermis, proliferation of endothelial cell with accompanying heteromorphism. in some cases, there are tumor masses composed of spindle cells and epithelial cells. other sarcoma and vascular tumor hiv/aids related kaposi's sarcoma should be differentiated from other sarcoma and vascular tumor. ks invasion of the digestive mucosa can cause bleeding and upper gastrointestinal symptoms. the pathological lesions can be diagnosed by upper gastrointestinal endoscopy or biopsy. in the cases of no fever and exclusion of infections, the typical imaging demonstrations and bronchoscopy fi ndings can defi ne the diagnosis of pulmonary ks. hiv/aids related kaposi's sarcoma should be differentiated from pneumocystis carinii pneumonia. the lesions of pcp are mostly symmetric ground glass liked density shadows extending outwards from the hilum in both lungs. in the middle and advanced stages, nodules, fi brosis and cavities occur, rarely with pleural effusion. lung cancer commonly refers to the cancer in lung parenchyma, usually does not include those mesodermal tumors originating from other pleura, or other malignancies like carcinoid, malignant lymphoma, or metastatic malignancies for other body parts. therefore, the following lung cancer we are discussing about refers to the malignancies originating from bronchial, or bronchiolar epithelial cells, accounting for - % of the lung parenchyma malignancies. the cause of lung cancer is still not completely known. data have indicated that the risk factors of lung cancer include smoking (including second-hand smoke), asbestos, radon, arsenic, ionizing radiation, halogen alkenes, polycyclic aromatic compounds and nickel. long-term smoking can cause proliferation of the bronchial mucosal epithelial cells and proliferation of squamous epithelium to induce squamous epithelium carcinoma or undifferentiated small cell carcinoma. non-smokers can also develop lung cancer, but adenocarcinoma is more common among them. long-term exposure to radioactive substances, like uranium and radium, and its derivatives; carcinogenic hydrocarbons, like arsenic, chromium, nickel, copper, tin, ferri, coal tar, bitumen oil, petroleum, asbestos and mustard gas, all can induce lung cancer, which is commonly squamous carcinoma and undifferentiated small cell carcinoma. some chronic pulmonary diseases, such as tuberculosis, silicosis and pneumoconiosis, can concurrent with lung cancer. in the cases with these chronic pulmonary diseases, the incidence of cancer is higher than the general population. in addition,bronchopulmonary chronic infl ammation and pulmonary fi brous scar lesions may cause metaplasia or hyperplasia of squamous epithelium during their healing processes, based on which some cases can develop into cancer. the internal factors of the human body include family heredity, compromised immunity, metabolism and endocrine dysfunction. the lung cancers distribute more in the right lung than in the left lung, more in the upper lobe than in the lower lobe. its locations range from the major bronchus to the bronchioles. the central type of lung cancer has its origination from the major bronchial lobes and locates adjacent to the pulmonary hilum. the peripheral type of lung cancer has its origination from the lower parts of pulmonary segment bronchi and locates in the peripheral areas in the lungs. in the growth process of the lung cancer, it causes the extension and dilation of the bronchial walls, and penetrates the bronchial walls to invade the adjacent lung tissues and form masses. meanwhile it intrudes into the bronchi to cause luminal stenosis or obstruction. with its further progression and dissemination, it spreads from the lungs and directly extends into the chest walls, mediastinum, heart, major vessels and other adjacent organs and tissues. lung cancer can also transfer to other parts of the body along with blood and lymph fl ows or disseminates to other pulmonary lobes via the respiratory tract. the growth rate and transferring paths of lung cancer depend on its histological types, differentiation degree and other biological characteristics. lung cancer has no special symptoms in the early period, only has the common symptoms with common respiratory diseases, including cough, bloody sputum, low grade fever, chest pain and chest distress. therefore, it is often misdiagnosed. ( ) face and neck edema; ( ) hoarse voice is the most common symptom; ( ) shortness of breath. lung cancer tends to occur distant metastases in the early stage. in the cases with metastatic lesions to the brain, the patients sustain persistent headache and blurry vision. in the cases with metastatic lesions to the bone, bone destruction may occur to cause fracture. ( ) restrictive wheezing sound, mostly occurring in the inspiratory phase and recurring after cough; ( ) hoarse voice, caused by lymph nodes transferring to compress and invade the recurrent laryngeal nerve; ( ) superior vena cava syndrome, caused by the compresses or invasion to the superior vena cava by the mass and venous obstruction, with edema in the head, face, neck, and upper limbs, varicose veins and edema in the upper chest, and accompanying dizziness, chest distress, shortness of breath and other symptoms; ( ) horner's syndrome, with enophthalmos of the affected side, blepharoptosis, shrinkage of the pupils, eye fi ssure stenosis, increased skin temperature in the upper chest of the affected side and no sweating due to compression or invasion of the apical cancer to the cervical sympathetic ganglia; ( ) should and arm pain, which is radial burning pain in the shoulder and upper limbs of the affected side due to compression or invasion of apical cancer to the brachial plexus nerve; ( ) phrenic nerve paralysis, with symptoms of shortness of breath and chest distress due to invasion to the phrenic nerve; ( ) dysphagia, caused by compressed esophagus by mediastinal lymphadenectasis; and diffi culty breathing caused by compressed trachea by mediastinal lymphadenectasis; ( ) pericardial effusion, shortness of breath, arrhythmia and heart dysfunctions due to pericardial invasion; ( ) pleural metastasis, with chest pain and cancerous pleural effusion; ( ) lung cancer metastasis, spreading of lung cancer along with blood fl ow to the bone, liver, brain, kidney, adrenal gland and subcutaneous tissues. intrapulmonary metastasis is also common. metastasis to different locations shows different symptoms and signs. ( ) extrapulmonary signs, commonly including joint pain or joint hypertrophy, clubbing fi ngers and mental disorders. the diagnostic imaging is the most commonly used and an important examination for the diagnosis of lung cancer. it can facilitate to fi nd some specifi c manifestations in the lesions, which provide clues for the diagnosis of lung cancer. it is also the main basis for the staging of lung cancer, but fails to defi ne the qualitative diagnosis. chest x-ray is the main examination for the diagnosis of lung cancer. anteroposterior and lateral chest x-ray are used for preliminary screening. chest ct is the diagnostic imaging examination of the choice for the diagnosis of lung cancer. for the central type of lung cancer in the early stage, there are direct signs to defi ne the diagnosis. in the early stage, thin layer scanning with a layer thickness of . - mm can be performed to observe the bronchial changes. mr imaging can demonstrate intraluminal nodules, luminal thickness and luminal stenosis of the bronchi from the transverse, coronal, and sagittal perspectives. mr imaging demonstrates favorably cancer in the lesions of obstructive pneumonia, and masses covered by the hilum. pet/ct scanning can be used for the screening of lung cancer metastasis and assessing the therapeutic effi cacy after treatment. dsa is used for infusion chemotherapy of bronchial artery in the cases of primary lung cancer. bronchoscopy is an important examination for the diagnosis of lung cancer. the pathological changes of the endothelium and the lumen of bronchi can be directly observed by using bronchoscopy. for the cases with caner or cancerous infi ltration by bronchoscopy, sampling of the tissues under the guidance of bronchoscopy for biopsy can be performed. otherwise, bronchial secretions can be suctioned under the guidance of bronchoscopy for cytological examinations to defi ne the diagnosis and the histological classifi cation. in most cases of primary lung cancer, the shed cancer cells can be found in the sputum, which can also facilitate to defi ne its histological classifi cation. after several examinations and short-term exploratory therapies, the qualitative diagnosis cannot be defi ned and the possibility of lung cancer cannot be excluded. therefore, exploratory thoracotomy can be performed if the patient's physical conditions permit. chest x-ray early lesions are confi ned within the bronchi, causing valve ventilatory disorder and changes of obstructive emphysema. the manifestations include restrictive pulmonary gas increase and sparse lung markings. in the cases with certain degree of bronchostenosis due to unfavorable discharge of the secretions, obstructive pneumonia occurs, showing patchy blurry shadows. in the cases with complete blockage of the bronchi, obstructive atelectasis occurs, showing decreased pulmonary volume, increased density and migration of the mediastinum to the affected side. obstructive pulmonary bronchiectasis has demonstrations of intrapulmonary cords liked shadows. lung a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of repeated cough for more than month and reported to have a history of unhealthy sexual behaviors. his cd t cell count was / μl. cancer in the middle and advanced stages are mainly manifested as hilar mass and atelectasis. the mass has a high density with clear boundary. however, the cancer cannot be observed due to its common immersion in the large fl aky obstructive pneumonia lesion or large quantity pleural effusion. atelectasis is commonly manifested as shrinkage of pulmonary segments or shrinkage of unilateral lung, with high density. the shadow of atelectasis widens at the hilum to show prominent mass. in the cases of central type lung cancer in the right upper lobe, a transverse s shape is at the hilum (commonly known as pancoast cancer). early diagnosis of central type lung cancer by plain chest x-ray only shows some indirect pulmonary manifestations caused by bronchial obstruction. and these indirect signs are not characteristically lung cancer. in the cases of local obstructive emphysema, these indirect signs can be caused by foreign substances in the bronchi or early infl ammation. obstructive pneumonia is diffi cult to be differentiated from common pneumonia. obstructive atelectasis needs to be differentiated from many other conditions. ( ) pathological changes in the bronchial lumen including polypoid, nodular or fl at papula masses. benign tumor has smooth boundary and malignant tumor has unsmooth boundary, commonly with wider base and thickened lumen wall. even the slight bronchial changes caused by the central type of lung cancer can be demonstrated by thin layer ct scanning, including slightly thickened bronchial wall, intraluminal small nodules and lumen stenosis or obstruction. in the middle and advanced stages, the direct signs of the central type lung cancer include thickened bronchial wall, irregular or unsmooth lining of the bronchial lumen. bronchial obstruction is suddenly truncation or gradual thinning of the lumen to obstruction. ( ) hilar mass locates adjacent or around the bronchi, with smooth or arch shaped boundary. the indirect signs of the central type lung cancer in the middle and advanced stages include secondary changes to bronchial stenosis. obstructive pneumonia is manifested as patchy blurry shadows or parenchymal changes of the pulmonary segments/lobes, and decreased lung volume. mr imaging demonstrates the tumor as long t and long t signals. in the cases of central type lung cancer with secondary obstructive atelectasis and obstructive pneumonia, enhanced t demonstrates the tumor in the lesion of pulmonary atelectasis and obstructive pneumonia. the signal of atelectasis is higher than that of the tumor. pet/ct scanning can demonstrates increased and thick stained metabolites of metastatic lesions or residual lesions, which has a diagnostic sensitivity of above %, and a reported specifi city of - %. in addition, it can be applied for the clinical consideration of it hilar, mediastinal lymph node metastasis and extrathoracic distant metastasis, which is an important method to decide clinical stages before lung cancer therapy. but pet has false negative diagnosis in the diagnosis of lung cancer with decreased metabolites, especially the alveolar cell carcinoma. for the diagnosis of pneumonia and pulmonary tuberculosis, it also has false positive results. dsa can demonstrate the blood supply of the tumors. miliary tuberculosis is more common in young adults, with obvious symptoms of systemic toxicity. anti-tuberculosis drug therapy can relieve the symptoms, with gradually absorbed lesions. ( ) chest x-ray demonstrates hilar lymph node tuberculosis as mass shadows in the hilum of lung, which may be misdiagnosed as the central type lung cancer. hilar lymph node tuberculosis is more common in teenagers, commonly with symptoms of tuberculosis infection but rarely hemoptysis. lung cancer can be concurrent with pulmonary tuberculosis. ( ) bronchial pneumonia; obstructive pneumonia induced by early lung cancer can be misdiagnosed as bronchial pneumonia. bronchial pneumonia has an acute onset with more obvious symptoms of infection. chest x-ray demonstrates patchy or spots shadows, with blurry boundaries and uneven density. the lesions are not confi ned within one segment or one lobe. ( ) pulmonary abscesses; central necrosis and liquefaction of the lung cancer results in cancerous cavities. by chest x-ray, the central type lung cancer can be misdiagnosed as pulmonary abscesses. in the acute period, a pulmonary abscess has obvious symptoms of infection, with large quantity purulent sputum. chest x-ray demonstrates thin cavity wall, smooth inner wall, liquid level and infl ammatory changes in the surrounding lung tissues or pleura. pulmonary benign tumors including hamartomas, fi broma and chondroma have slow growth. chest x-ray demonstrates round liked mass shadow, with homogeneous density without lobation. joint united nations programme on hiv/aids (unaids) surveillance for aidsdefi ning opportunistic illnesses, - imaging and pathology of hiv related cytomegalovirus pneumonia roentgenographic patterns of pneumocystis carinii pneumonia in patients with radiology distinction of pyogenic pulmonary infection from pneumocystis carinii pneumonia in aids patients atlas of differential diagnosis in hiv/aids. beijing: pmph the national institutes of health (nih) the centers for disease control and prevention (cdc), and the hiv medicine association of the infectious diseases society of america (hivma/idsa) guidelines for prevention and treatment of opportunistic infections in hiv-infected adults and adolescents acute respiratory failure associated with cryptococcosis in patients with aids: analysis of predictive factors pulmonary cryptococcosis: localized and disseminated infections in patients with aids penicillium marneffei agent d'une mycose du system reticuloendothelial infection caused by penicillium marneffei description of fi rst natural infection in man cd + t cell-mediated fatal hyperinfl ammatory reactions in mice infected with penicillium marneffei infections caused by penicillium marneffei in china and southeast asia: review of eighteen published case and report of our mo re chinese cases disseminated histoplasmosis in the acquired immune defi 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library for the yeast yarrowia lipolvtica rhodococcus equi infection in hiv infected patients rhodococcus equi infection in patients with and without human immunodefi ciency virus infection radiological fi ndings in nine aids patients with rhodococcus equi pneumonia comparison of nucleic acid amplifi cation, serology, and microbiologic culture for diagnosis of rhodococcus equi pneumonia in foals cytokine modulation alters pulmonary clearance of rhodococcus equi and development of granulomatous pneumonia diseases of the lung: radiologic and pathologic correlations pneumonia: high-resolution ct fi ndings in patients radiologic distinction of pyogenic pulmonary infection from pneumocystis carinii pneumonia in aids patients high-resolution ct in the evaluation of clinically suspected pneumocystis carinii pneumonia in aids patients with normal, equivocal, or nonspecifi c radiographic fi ndings pneumocystis carinii pneumonia: spectrum of parenchymal ct fi ndings pulmonia in patient with aids 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in hiv-infected patients mycobacterium avium complex infection in the acquired immunodefi ciency syndrome pulmonary disease due to infection by mycobacterium avium complex in patients with aids cd t lymphocyte count and the radiographic presentation of pulmonary tuberculosis. a study of the relationship between these factors in patients with human immunodefi ciency virus infection tuberculosis in the aids era mycobacterial pseudotumors of lymph node mycobacterial spindle cell pseudotumor of lymph node managenent of the hiv-infected patient tuberculosis in the aids era cytomegalovirus pneumonia in aids patients atypical cytomegalic cells are diagnostic for cytomegaloviral infection in aids cytomegalovirus as a primary pulmonary pathogen in aids infections with cryptococcus neoformans in the acquired immunodefi ciency syndrome endemic fungal pneumonia in immunocompromised patients disseminated histoplasmosis in adis: fi ndings on chest radiographs opportunistic fungal pneumonia pulmonary aspergillosis in the acquired immunodeficiency syndrome coccidioidomycosis during human immunodefi ciency virus infection. a review of patients cryptococcal pulmonary infection in patients with aids: radiographic appearance pulmonary aspergillosis in patients with aids. clinical and radiographic correlations cryptococcal pneumonia in aids: is cryptococcal meningitis preceded by clinically recognizable pneumonia pulmonary manifestations of disseminated cryptococcosis in patients with clinical and bacteriological aspects of nocardiasis lung abscess in patients with aids focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced hiv- disease rhodococcus equi endobronchial mass with lung abscess in a patient with primary pulmonary aids-related lymphoma: radiographic and ct fi ndings the expanding challenge of hiv-associated malignancies the pulmonary manifestations of aids-related non-hodgkin's lymphoma varied appearance of aids-related lymphoma in the chest lymphoma versus aids intrathoracic kaposi's sarcoma in women with intrathoracic kaposi's sarcoma. ct fi ndings distribution of human herpesvirus dna in tumorous and nontumorous tissue of patients with acquired immunodefi ciency syndrome with and without kaposi's sarcoma kaposi's sarcoma in lymphnodes concurrent with hodgkin's disease the natural history of kaposi's sarcoma in the acquired immunodefi ciency syndrome pulmonary toxoplasmosis in patients in-fected with human immunodefi ciency virus: a french national survey diagnostic imaging, preautopsy imaging and autopsy fi ndings of aids cases analysis on the imaging features of aids with pulmonary fungal infection liver injury in hiv- -infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy mri demonstrations of aids complicated by toxoplasma gondii infection in cervical spinal cord: with cases reports diagnostic imaging in aids in china: current status and clinical application imaging and pathological fi ndings of aids complicated by pulmonary rhodococcus equi infection magnetic resonance spectroscopy in the diagnosis of cognitive impairment in aids patients ct image demonstrations of hiv-seropositive tuberculosis and their relationship with cd + t-lymphocyte count positron emission tomography of fdg uptake in localized pulmonary infl ammation penicilliosisde rhizomys sinensis accumulation of nuclear mitochondrial dna in the frontal cortex cells of patients with hivassociated neurocognitive disorders imaging fi ndings of aids complicated with pulmonary rhodococcus equi infection and correlated with pathology pulmonary toxoplasmosis? pathogenesis and prevention of rhodococcus equi infection pulmonary toxoplasmosis a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of cough, fever and no sputum. her cd t cell count was / μl. filariform larvae of strongyloides stercoralis invade into skin or mucosa and reach the lungs through lymphatic vessels or venous system and the right heart. they develop into schistosomula in - days. a few schistosomula develop mature in the lungs or bronchi. most schistosomula penetrate the pulmonary capillaries into alveoli to cause a series of respiratory symptoms. in the cases of serious infection and in patients with compromised immunity, disseminated lesions occur in lungs and other organs. hiv/aids related pulmonary strongyloidiasis can have manifestations of local small bleeding spots, pimples, migratory linear or strips urticaria on skin, as well as manifestations of allergic bronchitis, lobular pneumonia or asthma. aids patient may have severe diffuse infection and systemic infection, with symptoms of fever, severe cough, expectoration, hemoptysis, shortness of breath, breathing diffi culty, and asthma. . laboratory tests . the pathological examinations include biopsy tissue culture and inoculation test. . chest x-ray is the most commonly used examination. there are demonstrations of small spots and fl aky shadows, thickened hilar shadow and thickened pulmonary markings. mitchell reported in that interstitial or alveolar infi ltration in both lungs accounts for %, nodular shadows in both lungs %, hilar or mediastinal lymphadenectasis %, pleural fl uids %, septal line %, mediastinal lymphadenectasis and ascites are the important clues for the diagnosis. . the clinical manifestations of hiv/aids related pulmonary strongyloidiasis are non-specifi c. its diagnosis depends on the etiological examinations. the fi ndings of strongyloides sterocralis in the patient's sputum and feces can defi ne the diagnosis. increases to × ⁄l; eosinophils granulocytes - %, or even as high as - %; the serum total lge level increases by %; % cases with blood serum lgg and lge of fi lariform larvae antigen positive. in the cases with femal strongyloides stercoralis parasitizing in the bronchial epithelium, rhabditiform larva, fi lariform larva, schistosomula, adult strongyloides stercoralis and the eggs can be found in fresh phlegm, which can defi ne the diagnosis. . pathological examinations including biopsy tissue culture and inoculation test are positive. . by chest x-ray, the lungs have small spots and fl akes of shadows, thickened hilar shadow and thickened pulmonary markings. hiv/aids related pulmonary strongyloidiasis should be differentiated from hiv/aids related pulmonary toxoplasmosis, infectious mononucleosis and mycoplasma pneumonia. pulmonary infi ltration of hiv/aids related malignant lymphoma commonly has three types: primary pulmonary lymphoma, which is rare and accounts for . . the diagnostic imaging examinations are the most commonly used examinations for the diagnosis. the imaging demonstrations of hiv/aids related malignant lymphomas include: . mediastinal lymphadenectasis is the most commonly found pulmonary manifestations of malignant lymphoma. the lesions are mainly located in anterior and middle mediastinum, in asymmetric wave liked or lobulated mass. it occurs unilaterally or bilaterally, isolated or fusion. . the incidence of pulmonary parenchymal lesions is - %. chest x-ray demonstrates mediastinal lymph nodes extending directly into the lungs, which is susceptible to confusion with pneumonia. they are demonstrated as round shadows in the lung fi elds or distribute in the whole lung fi elds. chest x-ray demonstrates the lymphatic spread of lesions as military nodules in different sizes or isolated intrapulmonary nodules or cavities, commonly accompanying with mediastinal hilar lymphadenectasis. in the cases with its occurrence secondary to endobronchial membrance, obstructive pneumonia or atelectasis can be caused. some patients may have diffuse pulmonary interstitial changes. pulmonary infi ltration by non-hodgkin's lymphoma can also be divided into four types: ( ) nodular type; ( ) pneumoniaalveolar type; ( ) bronchial-vascular-lymphatic type, which can be further divided into the central bronchialvascular type, and diffuse lymphatic type; ( ) diffuse lymphatic type can have lesions of reticular or reticular nodular infi ltration and its progression into patchy changes. . miliary-blood borne spreading type is rare. . the pleural lesions is mainly pleural effusion, with bloody or serous pleural fl uid. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of chest distress and chest pain for more than months. his cd t cell count was /μl. ( ) tuberculoma is diffi cult to be differentiated from the peripheral type of lung cancer. tuberculoma is more common in young adults, with a long term course of illness. the lesions are commonly found in the apical posterior segment of the upper lobe or dorsal segment of the lower lobe. chest x-ray demonstrates the lesions with uneven density and satellite lesions. ( ) miliary tuberculosis is diffi cult to be differentiated from diffuse bronchioloalveolar carcinoma. key: cord- -xqphom x authors: papanikolaou, ilias c; sharma, om p title: tropical lung diseases date: - - journal: hunter's tropical medicine and emerging infectious disease doi: . /b - - - - . - sha: doc_id: cord_uid: xqphom x nan the term "tropics" refers to the region of the earth lying between the tropic of cancer and the tropic of capricorn. in the tropics, warm climate, poverty, lack of education, and poor sanitation provide an ideal environment for pathogens, vectors and intermediate hosts to flourish [ ] . in this vast landmass, respiratory infections are a major cause of morbidity and mortality in children and adults [ ] . in a typical tropical clinic, - % of outpatients have respiratory complaints, and - % of inpatients have lung disease (table - ) [ ] . many tropical patients suffer from lung diseases that are found worldwide, e.g. asthma, bronchiectasis, chronic obstructive lung disease, hiv infection-related lung disease, and lung cancer. numerous dust diseases, e.g. silicosis, asbestosis, byssinosis, hypersensitivity pneumonitis, and diseases due to microbial contamination of agricultural products, remain under-recognized. diseases associated with pulmonary symptoms and infection that are concentrated in the tropics include malaria, pulmonary schistosomiasis, melioidosis, paragonimiasis, echinococcal cysts, tropical eosinophilia, and diseases related to nutritional deficiencies [ ] . in addition, individuals who come in contact with birds or animals may develop zoonoses such as tularemia, psittacosis, q fever and leptospirosis [ ] . in the tropics, indoor air pollution caused by biomass fuels used for cooking and heating of the homes and huts is an important cause of obstructive lung disease and chronic lung infections [ ] . the following are the common tropical pulmonary conditions: l pneumonia: typical and atypical l eosinophilic pneumonias and tropical pulmonary eosinophilia l bronchiectasis, asthma and chronic obstructive pulmonary disease (copd) l pleural effusion l nontuberculous granulomatous lung disease l occupational lung diseases. a reasonable approach to the patient with lung disease in the tropic starts with age, occupational exposure, physical examination, hiv status, chest x-ray and blood tests. in children, bacterial pneumonia is the most common and life-threatening disorder. known immunodeficiency suggests tuberculosis, fungi and opportunistic pathogens. peripheral blood eosinophilia with either a pleural effusion or diffuse parenchymal consolidation may suggest a parasitic infection, or, when combined with wheezing, tropical pulmonary eosinophilia. worldwide diseases like copd may affect nonsmoking individuals due to indoor pollutants. streptococcus pneumoniae is the most common bacterial cause of pneumonia. upper respiratory involvement often precedes the onset of pneumococcal pneumonia, which is characterized by fever, chills, malaise and sweating. the patient is flushed and febrile with a rapid pulse and respiratory rate. dyspnea is associated with a nonproductive cough, and sputum, if present, may be thick, tenacious or "rusty". severe pleuritic chest pain causing tachypnea and grunting respiration is often present. such symptoms are abrupt in young, immunocompetent patients ( fig. . ) [ ] . in elderly patients, symptoms may be few and can be dominated by confusion, delirium and prostration [ ] . physical examination of the affected lung, usually the lower lobe, reveals diminished lung expansion, impaired percussion note, decreased breath sounds, crepitations (crackles/rales) and bronchial breath sounds. cyanosis is common and a herpes simplex eruption may be seen on the lips. with proper treatment, most patients with pneumococcal pneumonia improve clinically and radiographically within - weeks. when resolution occurs, fever subsides within a week as the temperature decreases following a crisis pattern ( fig. . a) . delayed resolution is seen in smokers, the elderly, and in those with poor nutrition, diabetes or other comorbid illnesses. staphylococcal pneumonia (staphylococcus aureus), accounts for - % of acute community-acquired pneumonias. it is an important cause of pneumonia in children, the elderly, patients recovering from influenza, people with diabetes mellitus, and those who are immunocompromised. methicillin-resistant staphylococcus aureus (mrsa) causes illness in % of cases of upper or lower respiratory tract infection in the community and in % of patients who are hospitalized. patients with staphylococcal pneumonia are usually ill with high fever, shaking chills, chest pain, cough and purulent sputum. chest x-ray films show patchy consolidation and cavities. sputum examination is an important aid in the diagnosis of pneumonia. color, amount, consistency and odor are helpful: mucopurulent sputum is commonly found in bacterial pneumonia or bronchitis; scanty watery sputum is often noted in atypical pneumonia; "rusty" sputum is seen in pneumococcal pneumonia; and currant-jelly or dark-red sputum suggests klebsiella pneumoniae. foul-smelling expectoration is associated with anaerobic infections due to aspiration, ilias c papanikolaou, om p sharma give an inhaled bronchodilator for days* • soothe the throat and relieve the cough with a safe remedy • if coughing for more than weeks or if having recurrent wheezing, refer for assessment for tb or asthma • advise the mother when to return immediately • follow-up in days • if wheezing (even if it disappeared after rapidly acting bronchodilator) give an inhaled bronchodilator for days* • soothe the throat and relieve the cough with a safe remedy • if coughing for more than weeks or if having recurrent wheezing, refer for assessment for tb or asthma • advise the mother when to return immediately • follow-up in days if not improving a blood count usually reveals leukocytosis in bacterial pneumonia, leukopenia in viral infection, and eosinophilia in parasitic infestation. when available, chest x-ray is extremely helpful ( table - ). tuberculosis is omnipresent in the tropics; upper lobe lesions with or without cavities strongly suggest tuberculosis. in children, the integrated management of childhood illness (imci) guidelines for treating pneumonia are recommended (see fig. . ) [ ] . nevertheless, a patient's illness has to be assessed based on geography, prevalence of potential etiologies, virulence of the organism, and the drug sensitivity pattern (box . ). in some areas, particularly papua new guinea, south africa and spain, resistance of the pneumococcus to penicillin is common. for children with non-severe pneumonia, the world health organization (who) recommends oral trimethoprim-sulfamethoxazole (tmp-smx) or oral amoxicillin for days [ ] . in severe pneumonia in hospitalized children, the policy in low-income countries is to first give benzylpenicillin injections, changing the therapy to oral amoxicillin when the child responds. in very severe pneumonia, in children in low-income settings, chloramphenicol may be given first with benzylpenicillin and gentamicin in combination as an alternative [ , ] . atypical pneumonia is caused by mycoplasma pneumoniae, chlamydia pneumoniae, legionella spp., viruses, tuberculosis, fungi and parasites. this syndrome is not extensively studied in the tropics because of the expense involved in culturing and isolating various organisms and obtaining serologic and immunologic tests. mycoplasma pneumoniae infections occur worldwide, affecting mostly school-aged children and young adults. a typical patient with mycoplasma pneumonia is an older child or young adult with an insidious onset of fever, malaise, tightness of the chest, and dry brassy cough. constitutional symptoms are out of proportion to the respiratory symptoms. hemoptysis, pleural pain and gastrointestinal symptoms are uncommon. the tropical physician should be aware of the non-respiratory manifestations of mycoplasma infection, including anemia, myringitis, stevens-johnson syndrome, hepatitis and neuritis [ ] (see table - ). leptospirosis is common in tropical areas where sanitation is poor and water supply primitive. epidemics of leptospirosis occur after high rainfall in monsoon seasons when the water supply is contaminated by sewage or animal urine. about half of the patients with leptospirosis have fever, cough, hemoptysis and pneumonitis [ ] . other features are jaundice, conjunctivitis and impaired renal function. melioidosis, caused by burkholderia pseudomallei, is endemic in southeast asia (vietnam, cambodia, myanmar), northern australia and west africa. melioidosis is hyperendemic in northern australia, and in parts of northeastern thailand it is an important cause of fatal community-acquired pneumonia [ ] . patients become infected while wading through fields, paddies, and flooded roads. clinical presentation is protean and nonspecific. the radiologic picture of upper lobe infiltration and cavity formation can be indistinguishable from tuberculosis [ ] . diagnosis requires isolation of the organism. the mortality rate ranges from % to % but is higher in hivinfected and immunocompromised hosts. respiratory symptoms of cough and chest pain in typhoid are present in up to % of cases at the onset of the disease. pulmonary infiltrates may be associated with positive sputum cultures for salmonella typhi. a fever chart showing continuous fever is highly suggestive of enteric fever. diagnosis may be difficult without blood and stool culture facilities. in brucellosis, the lungs are involved in about % to % of cases, usually following inhalation of organisms. abnormalities include bronchopneumonia, solitary or multiple lung nodes, miliary interstitial lung disease, lung abscess and pleural effusion. organisms can be identified on stains or sputum cultures. tularemia is a generalized infection caused by francisella tularensis and occurs after skin or mucous membrane contact with infected mammals or through the bite of an arthropod, usually a tick or biting fly. diagnosis should be considered in the presence of a skin ulcer associated with fever, generalized lymphadenopathy, cough and signs of pneumonia. pneumonia, either primary from inhalation of an infected aerosol or secondary to systemic infection, occurs in about % of cases. children with malnutrition and edema should be admitted to hospital pneumonic plague is less common than either bubonic or septicemic disease. nevertheless, fatal bronchopneumonia can occur without lymphadenopathy and is characterized by watery, bloody sputum. a sputum gram stain can show bipolar stunted rods. pneumonic plague and tularemic pneumonia should be considered when a severe, rapidly progressive bronchopneumonia is reported in an endemic area, and "typical" bacterial pneumonias have been ruled out. in slaughterhouses, meat-processing plants, and areas with sheep and goat husbandry, q fever (coxiella burnetii) can cause epidemics of atypical pneumonia. inhalation of dried infected material is the chief source, and fever, headache and dry cough are the main symptoms. occasionally, the sputum is blood-streaked. bornholm disease (caused by coxsackieviruses and occasionally other enteroviruses), also known as epidemic pleurodynia or devil's grip, causes chest discomfort and cough. widespread epidemics of bornholm disease occur in the pacific islands and south africa. in - , an unusual coronavirus was responsible for more than cases of a severe acute respiratory syndrome (sars) that spread via international travel across continents from its origin in guandong province, china. the sars coronavirus was previously unknown in humans; a possible reservoir was identified in civet cats and raccoons. after droplet inhalation of the virus, there was an incubation period of - days, then fever, cough, malaise and headache occurred. pulmonary inflammation was characterized by desquamation of pneumocytes, hyaline membrane formation and acute respiratory distress syndrome (ards). the chest x-ray showed diffuse opacities or consolidation, especially in the lower lung fields. recovery could be slow and some patients developed fibrosis. mortality was - %, with the elderly and those with cardiovascular problems being especially at risk. kawasaki disease occurs in children under years of age. this acute multisystem disease of unknown cause is characterized by fever of days duration and four of five clinical features: non-purulent conjunctivitis; injected (or fissured) lips or pharynx or strawberry tongue; cervical adenopathy; a maculopapular rash; and changes in the extremities (erythema and edema of the palms and soles, associated with desquamation). pneumonitis occurs in % of the children and coronary artery dilatation and aneurysms in - % of untreated cases. in brazil there has been a seasonal rise of the condition at the beginning and end of the monsoon season [ ] . cryptococcus neoformans and c. gatti are saprophytic fungi distributed worldwide and are particularly abundant in soil contaminated by pigeon droppings in the tropics as well as in temperate countries. pulmonary infection results from inhalation of the organisms from environmental sources [ ] . systemic helminth infection usually elicits eosinophilia and increased ige. although eosinophilia can be a clue to a pulmonary helminth infestation, the definitive diagnosis requires demonstration of ova or larvae in sputum, bronchial alveolar lavage fluid, pleural fluid or lung biopsy [ ] . loeffler's syndrome refers to "simple" pulmonary eosinophilia with no or minimal systemic and pulmonary symptoms. in many helminth infestations (ascaris, strongyloidiasis, hookworm), the larvae migrate through the lung and can cause fever, cough, dyspnea, wheezing, hemoptysis and lung infiltrate. schistosomes cause two clinical syndromes. in acute disease, immature schistosomula pass through the lung, and can lead to fever, eosinophilia and pulmonary infiltrate. in chronic schistosomiasis, especially when portal hypertension has led to venous shunts, eggs can bypass the liver and plug pulmonary capillaries and arterioles, producing granuloma and pulmonary hypertension. radiographs may show dilated pulmonary arteries ( fig. . ). in paragonimiasis, the lung is the predominantly involved organ. the diagnosis must be considered in a patient from southeast asia with cough, hemoptysis (which is recurrent in > % of cases), a pulmonary cavity and pleural effusion. tropical pulmonary eosinophilia, typically in india and other south asian countries, causes immunologic hyperresponsiveness to wuchereria bancrofti, brugia malayi or other microfilariae. clinical presentation consists of nocturnal cough, wheezing, fever and weight loss. chest radiographs show diffuse interstitial miliary infiltrates ( fig. . ) ; there is a high eosinophil count. in developed countries, serum ige and antifilarial antibodies can be used to confirm the diagnosis (table - ) . bronchiectasis is a chronic, debilitating condition. dilatation and distortion of the airways leads to impaired mucociliary clearance, which encourages bacterial colonization and bronchial inflammation. patients have fever, chronic cough, mucopurulent sputum, hemoptysis (table - ) , wheezing, dyspnea and malaise (box . ) . the primary cause of copd is smoking l copd affects men and women equally l copd is not curable but can be prevented the diagnosis of bronchiectasis in developed countries is confirmed by computed tomography of the chest (fig. . ) ; whereas, in the tropics, the diagnosis is mainly clinical and depends upon a compatible history, presence of finger clubbing, sputum that settles into three layers (mucoid or frothy, mucopurulent, and purulent) and a chest x-ray, if available. treatment includes regular chest percussion, broadspectrum antibiotics for exacerbations, and influenza and pneumococcal vaccinations. the incidence of asthma in the tropics is low for unclear reasons; however, the disease remains underdiagnosed and untreated. "all that wheezes is not asthma" is a dictum that is true in the tropics, as there are many entities that cause wheezing and difficulty in breathing, including tropical eosinophilia and mitral stenosis. asthma monitoring in the tropics can be achieved by using an inexpensive peak flow meter. treatment should fit the frequency and severity of attacks. betaagonists and cromolyn sodium (sodium cromoglycate) are usually available. oral corticosteroids in short courses can be used to control severe episodes; however, long-term use of systemic corticosteroids, without adequate monitoring, is not safe. aerosol inhalers are of great value but they are expensive, difficult to use, and require painstaking teaching. chronic obstructive lung disease is a progressive disease which is characterized by airway obstruction that is only partially reversible by bronchodilator therapy. the term copd encompasses chronic bronchitis and emphysema. once a common disease of men, copd is now as frequent in women because of increased tobacco use and the widespread use of dung and biomass for indoor cooking and heating in low-income countries (box . ) . the most common symptoms are dyspnea and chronic cough. it is mild and occurs only on heavy exertion. with progression of airway obstruction, patients become more short of breath and eventually cannot breathe at rest. physical examination in the early stage is normal, but in advanced disease, prolonged expiration and expiratory wheezes are audible. in severe cases, the thoracic cage becomes barrelshaped with increased anterior-posterior diameter; percussion note is hyperresonant. when chest x-ray and pulmonary function testing are not available, a peak-flow meter is an inexpensive device to assess severity of airway obstruction and monitor the response to treatment. cessation of smoking is essential. oral theophylline and beta-agonist drugs control symptoms. antibiotics (ampicillin, tetracycline and sulfa drugs) are available to treat copd exacerbations in the tropics. pleural effusion is a frequent condition with variable clinical signs and symptoms. small effusions can remain silent and are often detected only on chest radiography. large effusions are associated with dyspnea and diminished chest movements on the affected side. vocal fremitus is reduced; percussion note is stony dull; and auscultation reveals diminished breath sounds and decreased vocal resonance. sometimes, bronchial breathing is heard at the upper level of dullness. in addition there may be a pleural friction sound. exudative effusions typically have cell counts, protein and biochemical markers opposite to those of transudates. exudates can be further classified into neutrophilic, lymphocytic and eosinophilic. neutrophilic exudates may be due to bacterial infection, gastrointestinal diseases, pulmonary embolism, collagen-vascular diseases (cvd) and asbestos-related benign effusion. pleural effusion occurs in about % cases of pneumonia, and can progress to a complicated effusion (pleural fluid ph< . , positive gram stain) or to an empyema, both necessitating pleural fluid drainage with a chest tube thoracostomy in addition to antibiotic treatment. empyema can occur in pneumococcal, staphylococcal (most often) and klebsiella infections. a right-sided pleural effusion may be associated with amebic liver abscess. the disease presenting with the highest pleural fluid lymphocytosis is tuberculous pleuritis; however, early in the course, there can be a neutrophilic exudate. a large volume of pleural fluid should be obtained for examination for acid-fast bacilli. in about one-third of cases, the tuberculin skin test is negative initially and converts to positive after - weeks. knowledge of the hiv status of a patient with pleural effusion, if positive, significantly inclines to a tuberculosis. an eosinophilic exudate is more common in the tropics. endemic parasitic and fungal infections are major causes of such an effusion. ascariasis, echinococcosis and paragonimiasis are some of the causative parasitic infections. paragonimiasis is associated with low pleural fluid glucose and low ph. fungal diseases responsible for such an effusion are histoplasmosis, cryptococcosis and coccidioidomycosis. in the absence of chest x-ray or biopsy evidence, it is not possible to diagnose pulmonary involvement due to sarcoidosis and other granulomatous diseases. consequently, in the tropics, these disorders remain undiagnosed. the possibility of sarcoidosis should be considered in a patient with dyspnea, uveitis, hepatosplenomegaly, peripheral lymphadenopathy, chronic skin lesions, and a chest x-ray film showing bilateral hilar adenopathy [ ] . the occupational disorders result from human social activity, and as such are preventable. the dusts that provoke occupational disorders can be classified into: those that induce granulomatous reaction (e.g. beryllium, talc and organic antigens); those that cause fibrosis (e.g. silica, asbestos and coal); and those that cause neither inflammation nor fibrosis, thus remaining inert (e.g. iron, barium and tin) ( podoconiosis is an endemic nonfilarial elephantiasis occurring in individuals exposed to red clay soil derived from alkaline rock. a chronic and debilitating disease, it exerts a large economic burden. the silica particles are found in the skin, lymph nodes and lymphatics of affected and unaffected individuals. these individuals have reduced lung function as compared with adults living in areas of low silica concentration [ ] . immunological aspects of tropical lung disease pneumonia: the forgotten killer of children. geneva: unicef/ who parasitic lung infections tropical infections and the lung pulmonary disease world health organization, family and community health cluster, department of child and adolescent health and development. consultative meeting to review evidence and research priorities in the management of acute respiratory infections (ari) influence of age on symptoms and presentation in patients with community acquired pneumonia integrated management of childhood illness (imci) for high hiv settings clinical efficacy of co-trimoxazole versus amoxicillin twice daily for treatment of pneumonia: a randomised controlled clinical trial in pakistan chloramphenicol alone versus chloramphenicol plus penicillin for severe pneumonia in children chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in papua new guinea: a randomised trial approach to the patient with tropical pulmonary disease pulmonary complications of leptospirosis the epidemiology of melioidosis in australia and papua new guinea melioidosis after brief exposure: a serological survey in us marines kawasaki disease: a clinical and epidemiological study of children in brazil lung biology in health and disease: tropical lung disease lung biology in health and disease: tropical lung disease assessment of respiratory function in patients with podoconiosis key: cord- -b qsnxr authors: ramjug, sheila; weatherald, jason; sahay, sandeep; khoury, johad; foris, vasile; chandran, nagaraj; bokan, aleksandar; godinas, laurent; delcroix, marion title: ers international congress, madrid, : highlights from the pulmonary vascular diseases assembly date: - - journal: erj open res doi: . / . - sha: doc_id: cord_uid: b qsnxr the european respiratory society (ers) international congress, held in madrid, spain, had exciting sessions regarding the field of pulmonary vascular disease. the symposia related to the new ers/european society of cardiology (esc) guidelines for the diagnosis and management of acute pulmonary embolism were well received, as were sessions on pulmonary hypertension related to lung disease, demonstrating the concept of pulmonary hypertension not being the rarity that it was previously thought to be. the use of risk stratification in relation to pulmonary arterial hypertension (pah) was heavily featured and the scientific sessions informing the respiratory community of potential biomarkers and targets for future therapies were thought-provoking. this article discusses highlights of the pulmonary vascular disease sessions as a summary of current knowledge and practice. we have summarised the key points from the sessions pertaining to the new ers/esc guidelines for the management of acute pulmonary embolism. we have also focused on prognostic factors and potential therapies in pulmonary hypertension related to interstitial lung disease. relating to pah, we have reviewed the symposia on risk stratification, along with the use of noninvasive measures and the sessions relating to biomarkers in pah. the new ers/esc guidelines for the diagnosis and management of acute pulmonary embolism during the european respiratory society (ers) international congress in madrid, spain, there was a huge focus on pulmonary embolism (pe) sessions, which was well received by congress delegates as it coincided with the recent publication and update of the ers/european society of cardiology (esc) guidelines for the diagnosis and management of acute pe. in this and the following sections, we will focus on the updated areas in the guidance for the acute management of pe. stavros konstantinides started the proceedings by reiterating the usefulness of transthoracic echocardiography (tte) to assess the right ventricle for signs of dysfunction when faced with the haemodynamically unstable patient. in the new guidance, the definition of haemodynamic instability has also altered to include "obstructive shock", implying there is evidence of end-organ hypoperfusion with a systolic blood pressure < mmhg [ ] . fortunately, however, many patients we assess are not unstable and prof. konstantinides emphasised the importance of performing a wells or geneva score and only a d-dimer test if there is a low or intermediate probability of a venous thromboembolism (vte) event (figure ). relating to the use of d-dimer, classically we would consider a level > ng·ml − as raised. since the results of the adjust-pe study in , its use with an age-adjusted cut-off is advocated in those who are aged ⩾ years, e.g. in a -year-old using a d-dimer cut-off level of ng·ml − [ ] . the adapted d-dimer cut-off based on clinical probability, as per the years study group publication in [ ] , has also been recommended in the current guidance. this simplified diagnostic tool utilises the years clinical decision rule of ) signs of deep venous thrombosis, ) haemoptysis, and ) pe more likely than an alternative diagnosis, with an adapted d-dimer cut-off dependent on the answers to the "rule" [ ] . suspected for example, if there is no evidence of these points, a d-dimer cut-off of < ng·ml − is used to exclude a pe; if, however, there is a positive clinical point then a d-dimer cut-off level of < ng·ml − is used. by utilising these methods, we are ensuring the judicious use of computed tomography pulmonary angiography (ctpa) in our clinical environments. it was also highlighted that we must not overlook the role of ventilation/perfusion (v′/q′) single-photon emission computed tomography in the diagnosis of pe. the new guidance also usefully illustrates the radiation of each imaging modality; this is especially relevant when considering female breast tissue [ ] . prof. konstantinides discussed the importance of examining for right ventricular (rv) dysfunction, even in those with a simplified pulmonary embolism severity index (spesi) score of . this stems from a meta-analysis by barco et al. [ ] in patients with a low pulmonary embolism severity index (pesi), or spesi of . the investigators discovered the acute mortality was - % in those with evidence of rv dysfunction. this dysfunction can initially be assessed by biomarkers such as troponin or n-terminal pro-brain natriuretic peptide (nt-probnp), right to left ventricular diameter (rv/lv) ratio at end-systole on ctpa and clearly by tte [ ] . the role of precise risk stratification is vital to identify those patients with low-risk pe (figure ). therefore, patients with a pesi class i or ii, spesi score of , or meeting no hestia criteria (with no evidence of rv dysfunction) are considered to have a low-risk pe and are eligible for safe early discharge with careful outpatient management [ ] . in the study by barco et al. [ ] in , this represented % of their cohort. patients with haemodynamic instability, i.e. high-risk pe, should be strongly considered for thrombolysis. with reference to intermediate-risk pe, the peitho investigators demonstrated no benefit from thrombolysis in the long term; in the immediate setting it does reduce haemodynamic instability but with an increased major bleed risk [ ] . there has been much attention given to the use of "reduced-dose" thrombolysis [ , ] ; the guidelines, however, still recommend only standard dosing regimens. in patients with contraindications for thrombolytic therapy, surgical pulmonary embolectomy is still preferred above percutaneous interventional procedures [ ] . prof. konstantinides was also very clear that extracorporeal membrane oxygenation should only be utilised as a bridge to therapy, i.e. surgical embolectomy or catheter-directed therapy. the new guidance also states that inferior vena cava filters should only be utilised in two groups of patients: patients with acute pe and an absolute contraindication to anticoagulation therapy, and patients with well-managed anticoagulation therapy and recurrent pe [ , ] . a new section of the guidance, which has been especially well received, is that for pe in relation to pregnancy, as it is the highest cause of maternal death in high-income countries. vte risk factors in the specific context of pregnancy were underlined, especially the increased risk linked to in vitro fertilisation, particularly in the first trimester [ ] . at the ers international congress, the assessment of suspected pe in pregnancy was explained by guy meyer (figure ). by utilising the outcomes of two prospective multicentre studies, a combination of a pregnancy-adapted years algorithm with d-dimer levels substantially increases the probability of safely excluding pe without ctpa [ , ] . local radiology experience and chest radiography results should aid the decision as to whether to perform ctpa or a scintigraphy scan. the radiation exposure to the fetus is minimal but is high to female breast tissue, particularly with ctpa [ ] . those with a proven pe should be managed in a centre with experience of managing pe in pregnancy. low-molecular-weight heparin (lmwh) remains the treatment of choice and the dosing regimen should be based on an early pregnancy weight. also, fondaparinux could be considered if there is an allergy to lmwh. finally, amniotic fluid embolism should be excluded in cases of severe cardiac or respiratory impairment, especially in the context of disseminated intravascular coagulation. cancer and direct oral anticoagulants prof. meyer underlined the role of direct oral anticoagulants in the treatment and secondary prevention of pe in patients with cancer [ , ] . in patients with non-gastrointestinal cancer and a low risk of bleeding, edoxaban and rivaroxaban can be safely used. for those with active gastrointestinal or genitourinary cancer, lmwh remains the recommended treatment [ ] . extension treatment after months should be strongly considered, especially in those with active cancer. the risk of recurrence of pe in cancer patients was also assessed using a score incorporating factors such as breast or lung cancer, involvement of lymphatic node, female sex and previous vte [ ] . a noteworthy point is that, in patients with cancer, an incidental pe should be managed in the same way as a symptomatic pe, if involving segmental, proximal, multiple subsegmental or a single subsegmental branch in association with a proven deep venous thrombosis. the new guidelines advise the clinician to avoid terms such as "provoked", "unprovoked" and "idiopathic". the rationale is to prevent potentially erroneous decisions regarding the duration of anticoagulation therapy [ ] . the guidance is very clear that the duration of anticoagulation therapy is based on the risk of recurrence of pe and risk of bleeding. persistent factors and cases in whom the index pe event occurred in the absence of any identifiable risk factors, and the high-risk group is composed of patients where risk factors persist, e.g. active cancer [ ] . prof. meyer echoed the importance of re-assessing patients on anticoagulation therapy at months. the minimum duration of anticoagulation recommended for patients with pe is related to major reversible risk factors. one should consider extension if there is evidence of recurrent vte not related to a major transient or reversible risk factor, if there is no identifiable risk factor and in those with a persistent risk factor, as well as in patients with a minor transient or reversible risk factor for the index pe event. when considering extended therapy after months of therapeutic anticoagulation, it is feasible to consider reduced-dose rivaroxaban and apixaban. however, it is important to re-assess the tolerance of the anticoagulant with monitoring of renal and liver function, as well as assessing the bleed risk. the guidelines recommend a follow-up visit at - months. if there is persistent dyspnoea and/or functional limitation, tte should be organised, with a cardiopulmonary exercise test also being useful. it is also important to consider risk factors for possible chronic thromboembolic pulmonary hypertension (cteph) or chronic thromboembolic disease in both the symptomatic and asymptomatic patient, which are helpfully listed in the new guidance [ ] [ ] [ ] . if there is a high probability of pulmonary hypertension (ph) on tte or evidence of functional limitation, it is recommended to obtain a v′/q′ scan and to refer the patient to an expert pulmonary vascular disease institute (figure ). the recommended cteph treatment for proximal disease remains pulmonary endarterectomy. medical therapy (specifically riociguat) and balloon pulmonary angioplasty are additional therapeutic options for patients with inoperable disease or persistent ph after pulmonary endarterectomy [ , ] . pulmonary hypertension in interstitial lung disease ph frequently affects those with chronic lung disease (cld). commonly, there are patients with evidence of mild elevation of pulmonary arterial pressure when measured at echocardiography, but there is also a cohort with indicators of severe ph that may appear out of proportion to the degree of their cld. unsurprisingly, the development of ph in this cohort of patients is associated with a poorer life expectancy and increased symptom burden, including worse functional capacity, increased oxygen requirements and more frequent acute exacerbations [ ] . kapasi et al. [ ] presented a large retrospective study whereby over a -year period they identified patients with idiopathic pulmonary fibrosis (ipf) from their scientific registry of transplant recipients. these patients were classified into six groups using mean pulmonary arterial pressure (mpap) and pulmonary vascular resistance (pvr), measured in mmhg and wood units (wu), respectively: ) ph absent (mpap < mmhg); ) borderline ph, preserved pvr (mpap - mmhg, pvr < wu); ) borderline ph, high pvr (pvr ⩾ wu); ) ph, preserved pvr (mpap - mmhg, pvr < wu); ) ph, high pvr (pvr ⩾ wu); and ) severe ph (mpap ⩾ mmhg). of their patients with ipf, % had evidence of ph and ( %) had severe ph. groups , and demonstrated that those with a high pvr had an increased risk of death when compared to those with a preserved pvr, suggesting that in ipf patients increased pvr appears to predict poorer survival regardless of the mpap [ ] . this reinforces the study by awerbach et al. [ ] , who showed in interstitial lung disease (ild)-related ph that pvr > wu was associated with three-fold higher mortality than pvr < . awerbach et al. [ ] also demonstrated that ild-related ph patients, at right heart catheterisation, had lower mpap and pvr when compared to their idiopathic pulmonary arterial hypertension (pah) cohort; despite these findings, mortality was high in both groups. another area of interest is that of pulmonary arterial compliance and its changes during exercise. panagiotidou et al. [ ] presented the pulmonary arterial compliance of patients with either ipf or ild related to connective tissue disease. pulmonary arterial compliance at rest and exercise correlated well with diffusing capacity of the lung for carbon monoxide (d lco ), -min walking distance ( mwd) and new york heart association (nyha) functional class. the decrease in pulmonary arterial compliance may represent a valuable factor in the symptoms and prognosis of ild-ph and further exploration of this is warranted. an important noninvasive measure that has previously been reported by bax et al. [ ] is that of rv/lv ratio of > at ctpa. it is a significantly prognostic indicator of mortality at a multivariate level and appears to be superior to haemodynamic data in this cohort of patients. the instage trial disappointingly showed no additional benefit of nintedanib plus sildenafil compared with nintedanib plus placebo in patients with ipf and a d lco of < %. its primary end-point was a change in score from baseline in the st george's respiratory questionnaire over a -week period. it did, however, show a numerically lower decline in forced vital capacity in the nintedanib plus sildenafil group [ ] . a further sub-analysis of this cohort compared those ipf patients with evidence of right heart dysfunction (rhd) to those without rhd as demonstrated by echocardiography. the investigators found that the ipf group with rhd on nintedanib and sildenafil showed stabilisation of their brain natriuretic peptide (bnp) levels ( p< . ) when compared to the ipf group with no rhd (− . ng·l − , % ci − . -− . ng·l − , and − . ng·l − , % ci − . - . ng·l − , respectively) [ ] . further to this, at the ers international congress, the instage researchers presented data pertaining to biomarkers relevant to the pathophysiology of ipf, namely biomarkers of inflammation, lung cell damage and extracellular matrix damage. of the patients treated with nintedanib plus sildenafil, there was an association with statistically significant reductions in collagen degraded by matrix metalloproteinase (mmp)- / and citrullinated vimentin degraded by mmp- / , versus nintedanib alone [ ] . during the same session, chandran et al. [ ] presented their study findings of the effect of nintedanib on the pulmonary vasculature in a murine model. by utilising fra -overexpressing mice (which have a propensity to develop spontaneous ild and ph) and wildtype mice, they were able to ascertain the effects of nintedanib on the pulmonary vasculature by employing wire myography. nintedanib was shown to induce significant pulmonary artery relaxation, which was endothelium independent and more pronounced in the fra mice. this noteworthy finding certainly warrants further investigation. according to the preliminary data of the recently completed increase trial of inhaled treprostinil in group ph patients (clinicaltrials.gov, identifier nct ), this trial has met its primary end-point of an improvement in mwd and all its secondary end-points, thus substantiating the careful use of pulmonary vasodilators in appropriate patients with ild-related ph under the care of expert pulmonary vascular disease centres. nathan et al. [ ] have provided a useful algorithm (figure ) to aid the pulmonologist when deciding which cld patients should be further assessed at an expert pulmonary vascular disease centre for consideration of pah therapy on an individualised basis. risk assessment and prognostication in pah has been a hot topic in recent years, with many new studies presented at the ers international congress. the updated reveal . risk score was published in , which includes revised cut-off points for some variables compared with the original reveal score and now includes the presence of all-cause hospitalisation within the previous months [ ] . an external validation of the reveal . was presented using a retrospective cohort of patients from the pulmonary hypertension society of australia and new zealand (phsanz) registry, for which at least seven variables were available [ ] . although lacking information for renal function and nt-probnp or bnp, reveal . discriminated short-term ( -month) and long-term ( -month) survival in the phsanz cohort. there was overlap in survival estimates according to the -tier risk strata but excellent discrimination (c-statistic . , % ci . - . ) using -tier risk strata (low, intermediate, high). the efort study (clinicaltrials.gov, identifier nct ) was a prospective, modern cohort of treatment-naïve patients with idiopathic, heritable or drug-induced pah. the aim of efort was to determine transplant-free survival, prognostic factors and treatment goal cut-offs using a dynamic survival prediction model. for patients enrolled between and , the -, -and -year rates for transplant-free survival were %, % and %, respectively. increasing age was the only baseline variable independently associated with death or transplantation. using cox models with time-dependent variables, optimal treatment goal thresholds identified in this study were nyha functional class i or ii (hazard ratio (hr) . , % ci . - . ), mwd > m (hr . , % ci . - . ), cardiac index ⩾ . l·min − ·m − (hr . , % ci . - . ), and either bnp ⩽ ng·l − or nt-probnp ⩽ ng·l − (hr . , % ci . - . ). achievement of at least two of these goals decreases the instantaneous risk of death or lung transplant, whereas achievement of none or only one of these goals was associated with higher instantaneous risk [ ] . there has been limited study on risk stratification in congenital heart disease (chd)-associated pah. ramjug et al. [ ] analysed survival in chd-pah patients according to the number of low-risk factors present: nyha/world health organization functional class i/ii, incremental shuttle walk test (iswt) > m, presence of a post-tricuspid defect, and a d lco > %. the vast majority of patients had none or only one of these low-risk features. in the overall chd-pah population (n= ), survival was lowest for patients without any low-risk factors, slightly better for those with one low-risk factor and similar long-term survival in those with two to four low-risk factors [ ] . noninvasive parameters in pah kiely et al. [ ] presented a prospective study that evaluated the reproducibility and sensitivity to change of noninvasive end-points in pah. they compared changes in biomarkers, mwd and the iswt on repeat tests within h and at - months between healthy volunteers and pah patients. intraclass correlation was excellent (> . ) for the mwd and iswt, as well as for nt-probnp and almost all magnetic resonance imaging (mri)-derived volumes and flow measures. for sensitivity to change, the mri-derived right ventricular ejection fraction (rvef) had the largest cohen's d change, whereas mwd and nt-probnp had only fair change, indicating less sensitivity to change. rvef on mri may be the most suitable noninvasive end-point for pah, due to its excellent repeatability and large change in pah patients undergoing treatment initiation or escalation [ ] . in a retrospective study of pah patients not at treatment goal with oral therapies, olsson et al. [ ] evaluated the effect of add-on intravenous treprostinil on transplant-free survival and risk strata. their risk assessment was based on six variables, which were given an integer risk score ( , or ) depending on whether the variable was in the low-, intermediate-or high-risk range. the majority ( %) were intermediate risk at baseline and % were on double combination therapy. the median treprostinil dose achieved at follow-up was ng·kg − ·min − . long-term transplant-free survival was markedly better for the minority of patients ( %) who achieved a low-risk status by - months. however, lack of response within - months was associated with an approximately % risk of death or transplant in the subsequent years. haemodynamics did not differ between responders and non-responders. in a multivariable analysis, only mwd and d lco predicted a good treatment response. this study suggests that add-on intravenous treprostinil can "rescue" about % of pah patients but the majority do not obtain treatment targets within - months and these patients should be considered for lung transplantation, if eligible. endostatin is an angiogenic peptide derived from collagen xviii alpha (col a ), an extracellular matrix protein. in recent reports it is correlated with invasive haemodynamics and is shown to be elevated in pah compared to healthy individuals [ ] . furthermore, a genetic variant in col a has been associated with differences in serum endostatin levels and outcomes in pah [ ] . at the ers international congress, simpson et al. [ ] hypothesised that endostatin is a mechanistic biomarker of disease severity and survival in pah. they performed whole-genome genotyping and elisa measurements on patients with pah. the investigators found that a higher level of circulating endostatin correlated with higher invasive haemodynamics and lower mwd. additionally, high endostatin levels were independently associated with a poorer prognosis. based on the sequencing data, the team were also able to demonstrate that serum endostatin levels are influenced by genetic variants in col a , which are consequently associated with phenotypes and outcomes, hence suggesting that endostatin may serve as a biomarker of disease severity in pah. another promising biomarker is asymmetric dimethylarginine (adma), which has been shown to be of relevance in different forms of ph [ ] [ ] [ ] [ ] [ ] . skoro-sajer et al. [ ] aimed to validate adma as a biomarker to monitor disease progression in pah and cteph patients on targeted pah therapy or undergoing balloon pulmonary angioplasty. adma levels were measured in patients ( pah, cteph). the patients were stratified into risk groups (low, intermediate, high) according to the ers/esc guidelines [ ] . adma did not change significantly between the therapy groups; however, at follow-up in those patients who improved, it correlated with follow-up bnp and risk assessment scores (r = . ). blood count with its broad availability is receiving more attention in the field of biomarker research. red cell distribution width, for example, has been shown to be prognostic for pah [ ] . the mechanisms that determine the levels of these markers are unclear; however, a study presented at the congress highlighted the importance of cell-free haemoglobin as a source of oxidative stress [ ] . in vitro data on human pulmonary endothelial cells treated with methaemoglobin (methb) showed that reactive oxygen species (ros) production and interleukin- secretion were increased. this finding implies a strong relationship between methb-induced oxidated damage and further amplification of endothelial dysfunction through overproduction of cellular ros. the prostacyclin pathway is implicated in pah. it includes prostacyclin, which is associated with vasodilation, and thromboxane, which promotes vasoconstriction. thromboxane is mainly excreted by platelets; therefore, oliveira et al. [ ] retrospectively analysed patients with pah at baseline with right heart catheterisation haemodynamics, platelet count and mean platelet volume. when comparing a subset of this cohort to healthy volunteers, they found that pah individuals had a lower platelet count. subsequently, platelet count was correlated with an improved survival in the pah cohort. conversely, the same brazilian group demonstrated that cteph patients had similar platelet counts to controls, but they showed lower platelet volume. platelet count or volume was not different between patients who underwent pulmonary endarterectomy and those who were treated conservatively [ ] . iron deficiency is common in those with ph and conveys a worse prognosis [ ] [ ] [ ] . at the congress, campean et al. [ ] revealed that there was a high prevalence of iron deficiency in ( %) cteph patients, defined either by ferritin < μg·l − , or by ferritin - μg·l − with transferrin saturation < % and raised levels of soluble transferrin receptor (> . nmol·l − for females and > . nmol·l − for males). this correlated with lower exercise capacity but not with haemodynamics or survival. noncoding rna noncoding rna molecules have gained attention over the last decade as mediators of ph pathogenesis. it has been postulated that they even may become effective targets for future ph therapies [ , ] . the noncoding transcriptome can be classified into small noncoding rnas (< nt), including the micrornas, and long noncoding rnas (> nt). little is known about their role in rv failure. utilising a rodent model with monocrotaline treatment to induce ph, connolly et al. [ ] studied the microrna mir- , which has been shown to be downregulated in hypertrophying rodent hearts. they were able to clearly demonstrate that transforming growth factor (tgf)-βr (alk ) is targeted by mir- and mir- reduced tgf-β activation and its downstream smad / , proposing that it may regulate cardiac hypertrophy. a study presented by omura et al. [ ] utilising rv biopsies from donors with compensated rv hypertrophy (cardiac index > . l·min − ·m − ) and decompensated rv hypertrophy (drvh; pah patients who died of rv failure), compared to controls, showed that the long noncoding rna h and its encoded microrna mir- were upregulated in drvh. this was also displayed in a monocrotaline rat model. the team also found that the upregulation of h /mir- was specific to the right ventricle in both rats and humans, as no change was seen in either the left ventricle or lungs of drvh subjects. they also found in patients with pah that h was upregulated in plasma and correlated with haemodynamics and prognosis. plasma also contains microparticles, which are phospholipid-rich submicron particles that are released from the membranes of endothelial cells, platelets, leukocytes and erythrocytes. micrornas were isolated from microparticles by oto et al. [ ] in control subjects as well as pah, operable cteph and non-operable cteph patients. microrna differential expression in microparticles and plasma differed between the four groups. it was noted that mir- a- p was found to be dysregulated in both microparticles and plasma, signifying that it may play an important role in ph. in the current pandemic of coronavirus disease , much attention has been given to the topic of the prevention and management of vte in patients infected with the virus. we are all soon to see if there are any sequelae related to this. it is hoped that the new ers/esc guidance related to the definitions, diagnosis and management of ph will be realised in . in the meantime, the update articles from the sixth world symposium on pulmonary hypertension in nice, france, have provided us with helpful suggestions. as an ers assembly, we aspire in the near future, with the advent of the severe pulmonary hypertension management across europe (pharos) clinical research collaboration, to be better placed to phenotype our ph patients in order to offer them more personalised and holistic care. ultimately, as a community, we have all found innovative ways to connect with one another across europe and the world. barriers to progressing with research, both at the bedside and bench side, appear to have been reduced in an attempt to work together as a respiratory community with a common goal. may this ethos continue. esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the age-adjusted d-dimer cutoff levels to rule out pulmonary embolism: the adjust-pe study simplified diagnostic management of suspected pulmonary embolism (the years study): a prospective, multicentre, cohort study prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis british thoracic society guideline for the initial outpatient management of pulmonary embolism (pe) fibrinolysis for patients with intermediate-risk pulmonary embolism low-dose alteplase for the treatment of submassive pulmonary embolism: a case series half-dose versus full-dose alteplase for treatment of pulmonary embolism inferior vena cava filters to prevent pulmonary embolism: systematic review and meta-analysis incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study diagnosis of pulmonary embolism during pregnancy a multicenter prospective management outcome study pregnancy-adapted years algorithm for diagnosis of suspected pulmonary embolism perfusion scintigraphy versus -slice ct angiography in pregnant patients suspected of pulmonary embolism: comparison of radiation risks edoxaban for the treatment of cancer-associated venous thromboembolism comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (select-d) development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism chronic thromboembolic pulmonary hypertension (cteph): results from an international prospective registry factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. a case-control study risk factors for chronic thromboembolic pulmonary hypertension updates in pulmonary hypertension and other pulmonary vascular diseases chronic thromboembolic pulmonary hypertension (cteph): updated recommendations of the cologne consensus conference pulmonary hypertension due to interstitial lung disease elevated pulmonary vascular resistance is associated with increased risk of death in ipf outcomes of lung disease-associated pulmonary hypertension and impact of elevated pulmonary vascular resistance rest and exercise pulmonary arterial compliance in patients with pulmonary fibrosis right ventricular to left ventricular ratio at ct pulmonary angiogram predicts mortality in interstitial lung disease nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis nintedanib and sildenafil in patients with idiopathic pulmonary fibrosis and right heart dysfunction. a prespecified subgroup analysis of a double-blind randomized clinical trial (instage) changes in biomarkers in patients with idiopathic pulmonary fibrosis (ipf) treated with nintedanib and sildenafil nintedanib has acute pulmonary vasodilatory effects in transgenic fra mice with spontaneous progressive pulmonary hypertension and lung fibrosis pulmonary hypertension in chronic lung disease and hypoxia predicting survival in patients with pulmonary arterial hypertension: the reveal risk score calculator . and comparison with esc/ers-based risk assessment strategies retrospective validation of the reveal . risk score with the australian and new zealand pulmonary hypertension registry cohort a dynamic prognostic model to predict survival and determine treatment goals in pulmonary arterial hypertension (pah): the efort study risk stratification of pulmonary arterial hypertension (pah) associated with adult congenital heart disease (achd) a prospective study comparing the repeatability and sensitivity to change of non-invasive endpoints in pulmonary arterial hypertension: the respire study intravenous treprostinil as an add-on therapy in patients with pulmonary arterial hypertension compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of ipah patients serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension serum endostatin as a genetically-influenced biomarker in pah clinical value of asymmetrical dimethylarginine detection in patients with connective tissue disease-associated pulmonary arterial hypertension asymmetric dimethylarginine at sea level is a predictive marker of hypoxic pulmonary arterial hypertension at high altitude asymmetric dimethyl-l-arginine is a biomarker for disease stage and follow-up of pulmonary hypertension associated with congenital heart disease plasma levels of asymmetrical dimethyl-l-arginine in patients with congenital heart disease and pulmonary hypertension asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension asymmetric dimethylarginine (adma) to monitor treatments of pulmonary hypertension esc/ers guidelines for the diagnosis and treatment of pulmonary hypertension red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension cell free haemoglobin and pulmonary artery endothelial cell dysfunction platelets and pulmonary arterial hypertension (pah) platelets and chronic thromboembolic pulmonary hypertension iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice unexplained iron deficiency in idiopathic and heritable pulmonary arterial hypertension iron deficiency in chronic thromboembolic pulmonary hypertension long noncoding rnas: past, present, and future discerning functional hierarchies of micrornas in pulmonary hypertension mir- - p targets tgf-βr and is suppressed in the hypertrophying hearts of rats with pulmonary arterial hypertension long non-coding rna h in right ventricular failure associated with pulmonary arterial hypertension differential expression of mirnas present in plasma and contained within circulating microparticles in precapillary pulmonary hypertension conflict of interest: s. ramjug reports nonfinancial support from janssen, and grants and nonfinancial support from actelion, during the writing of the manuscript. j. weatherald reports grants, personal fees and nonfinancial support from janssen inc. and actelion, personal fees and nonfinancial support from bayer, personal fees from novartis, and grants from the alberta lung association, the canadian vascular network, the european respiratory society and the canadian thoracic society, outside the submitted work. s. sahay reports personal fees and nonfinancial support from bayer pharmaceuticals, united therapeutics, actelion pharmaceuticals, and liquidia. j. khoury has nothing to disclose. v. foris has nothing to disclose. n. chandran has nothing to disclose. a. bokan has nothing to disclose. l. godinas has nothing to disclose. m. delcroix reports grants and personal fees from actelion, and personal fees from bayer, gsk, msd, reata, bellarophon and eli lilly, outside the submitted work. key: cord- -fvii nsv authors: mcnaughton, amanda; levack, william; mcnaughton, harry title: taking charge: a proposed psychological intervention to improve pulmonary rehabilitation outcomes for people with copd date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: fvii nsv pulmonary rehabilitation (pr) is an important, evidence-based treatment that improves outcomes for people with copd. individualized exercise programmes aim to improve exercise capacity; self-management education and psychological support are also provided. translating increased exercise capacity into sustained behavioural change of increased physical activity is difficult. other unresolved problems with pr programmes include improving uptake, completion, response and sustaining long-term benefit. we offer a different perspective drawn from clinical experience of pr, quantitative and qualitative studies of singing groups for people with copd, and stroke rehabilitation research that gives psychological factors a more central role in determining outcomes after pr. we discuss take charge; a simple but effective psychological intervention promoting self-management––that could be used as part of a pr programme or in situations where pr was declined or unavailable. this may be particularly relevant now when traditional face-to-face group programmes have been disrupted by covid- precautions. people living with chronic obstructive pulmonary disease (copd) commonly carry substantial psychological morbidity along with their chest disease. , furthermore, psychological factors can influence uptake and outcomes of the most effective therapy available for people with copd -pulmonary rehabilitation (pr). , pr service providers aim to be "patient-centred" in their approach , and "empower patients" with both personalized exercise prescription, self-management education and psychological supports. pr audit reports also recommend services be responsive to people from ethnic minorities. these goals are challenging, especially as face-to-face pr services are likely to remain significantly disrupted in a covid- world. interventions that help people with copd self-manage their condition without face-to-face input would be a real advantage. "take charge" is a psychological intervention that potentially meets all these criteria. it is low-cost, requires minimal training and is effective as an adjunct to community rehabilitation for people after acute stroke -another group with significant psychological comorbidities that affect outcomes. it is also fully personcentred and of proven effectiveness in ethnic minority groups. with minor modifications from the version used in the stroke trials, take charge was used in a feasibility study for people with copd following acute exacerbations requiring hospitalization. the stroke study booklet and training manual are available, free to use (www.mrinz.ac.nz/programmes/stroke). in this article, we briefly describe the take charge intervention and evidence for benefit for people with stroke. we will draw parallels between the evidence concerning stroke rehabilitation and pulmonary rehabilitation, dominated in stroke by physical therapy approaches, and by exercise training in pr and suggest an alternative perspective based on hope, purpose and motivation. finally, we will propose options for using take charge for people with copd as part of pulmonary rehabilitation. although the abrupt onset of stroke requires a different model of rehabilitation from that of pulmonary rehabilitation (pr), pr and stroke rehabilitation (sr) share similarities. both are supported by overwhelming evidence of effectiveness. , nearly randomized controlled trials (rcts) confirm a significant reduction in mortality of patients managed in inpatient stroke and stroke rehabilitation units compared to management in general medical wards. both pr and sr are "black box" interventionsa complex mixture of components with considerable uncertainty as to which parts are critical to successful outcomes. finally, both pr and sr aim for behaviour change on the part of participants which is likely influenced by the nature and strength of the relationship between participants and health professionals; an unequivocally "psychological" variable. following on from the sr trials, coordinated, therapistled interventions are the recommended approach to stroke rehabilitation. , however, large randomized controlled trials aimed at optimizing the timing, dose and specific type of therapy-led intervention (compared to "usual care") have failed to show any additional benefit for patients at the level of independence or quality of life. this has led some to question the idea that the improved outcomes in the sr trials were solely the result of coordinated therapy. one alternative hypothesis is that sr has an important psychological component helping to increase motivation in the person with stroke. most of the sr rcts were conducted at a time when patients with stroke were managed on general medical wards, with no specific treatments apart from nursing care, and a significant expectation from health professionals, families and patients that this was a life-ending or life-changing event. a key component of stroke rehabilitation units was a shared enthusiasm for managing stroke, mobilizing patients and working with an expectation that there was "life after stroke". it is possible that patients (and their families) with this hope of a positive future, simply did not die as frequently as those without it. having hope could substantially affect engagement in physical therapy both in the hospital and at home, enhancing physical recovery. so enhancing personal motivation, in addition to a therapy-led rehabilitation approach, may improve outcomes, where a purely therapy-led approach does not. evidence to support this hypothesis comes from two large rcts involving participants after stroke, testing a psychological intervention aimed at increasing personal motivation. , the take charge intervention was tested in the early community phase of stroke rehabilitation, - weeks after acute stroke, in addition to usual community stroke rehabilitation. one of these studies was with participants from ethnic minority populations. this very brief intervention (one or two minute sessions in the person's home) uses simple images and prompts, to help the person look beyond their medical condition -in this case, strokeand transform from a "stroke person" into "the real 'me' who happens to have had a stroke" (see figure ). twelve months after stroke, people exposed to the take charge intervention in the taking charge after stroke (tacas) trial were performing significantly more advanced activities of daily living, were less likely to be dependent on another person for help, and reported better quality of life. these are the first trials of a specific stroke rehabilitation intervention that have shown a sustained benefit at the level of independence or quality of life. "taking charge" embraces four fundamental components: a sense of autonomy, a sense of purpose, a sense of competence or mastery and connectedness with others. these components have been extensively studied in the fields of education and psychology as part of self-determination theory. a facilitator, trained to be completely non-directive, guides the person through the taking charge booklet. the first three pages concentrate on sense of purpose, personal identity and hopes for the future, modified as necessary for the specific medical condition of interest (see figure ). further pages consider the issues of importance for the person (eg physical activity, mood, finances, supports, information, disease prevention) with a structure that allows them to break down their hopes for the future into "do-able" steps and identify their key support person/people. all ideas come from the person or their family, and the facilitator is trained not to provide 'helpful suggestions' ie this is all about the unique individual and is therefore fully person-centred. pr is also a complex intervention. exercise-training is a core component of pr programmes; guidelines indicate minimum levels of both dose and frequency, tailored to the individual, aiming to increase exercise capacity. , there is growing evidence of both the importance of increased physical activity as part of the efficacy of pr, and the substantial independent contribution this makes to health and survival. [ ] [ ] [ ] translating a personalized exercise programme into the sustained behavioural change of increased physical activity remains a significant challenge the first page of the take charge booklet from a feasibility study for people with exacerbations of copd requiring hospitalization showing the translation from the "taking charge" concept in figure to a specific medical condition, in this case, copd. the words "matua", "whaea", "koro", and "kuia" are in the māori language, with english equivalents of parent, mother, male and female elders/grandparents. for pr. this will be potentially more difficult in covid- pandemic environments. other problems with pr include gross under-utilization of pr (low rates of pr referral, uptake and completion) and considerable heterogeneity in patient responses to pr, as measured by exercise capacity, breathlessness scores, and health-related quality of life. , universal barriers to attendance include: travel and transport, depression, comorbidities, reduced perceived benefit, and socio-economic deprivation; others are patient or place-specific, eg ethnicity. , there is evidence that adaptive coping strategies to illhealth affect response to pr. but although anxiety ( %) and depression ( %) are common in patients with copd, there is no evidence that these conditions impact on rates of completion or response to pr. , , so how can we facilitate behaviour change to increase physical activity? various groups have studied the use of counselling, coaching and goal setting after pr, generally showing small improvements in physical activity. , the barriers and enablers to increasing physical activity for people living with copd are complex and varied, including physical, environmental and psychosocial factors. living with copd has social and psychological consequences besides physical constraints. anxiety, depression, impaired ability to work, problems with sexual function and limitations in social activities impact on wellbeing. an individual's symptoms of breathlessness, and level of disability are complex. the breathe oxford group argue that this is beyond the complicated pathophysiology, incorporating prior experiences and expectations as well as the personal perception of body signals. most pr programmes include an educational component usually concentrating on self-management, including how to manage breathlessness, medication adherence, inhaler technique, action plans for exacerbations and nutrition, as well as promotion of mental health and facilitation of advanced care plans. delivered as education, they are by definition health-professional-centred, and in terms of sustained behavioural change, their effectiveness is variable. , outside of pr, many non-pharmacological interventions have shown positive outcomes in terms of mood for people with copd, including home-based cognitive behavioural therapy, mindfulness, motivational interviewing and singing. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] two randomized controlled trials of singing group interventions in copd report improvements in quality of life and reduction in anxiety, although not in lung function. , in our singing group study, there was a significant reduction in the hospital anxiety and depression scale (hads) anxiety score between baseline and one year, as well as a significant increase in mwt. one explanation for the improvement in mwt after singing group programmes is that participants are personally motivated -they attempt more themselves (autonomy), have realistic personal goals for improvement (competence/mastery), look forward to the activity and the future (purpose), and feel more socially connected -all components of take charge. in our qualitative study of a copd singing group, it was clear that social connection in a safe place was a key priority for participants, confirmed in other studies of pr. the participants in these studies appreciated the camaraderie of the singing group, with the once-weekly sessions at a community venue being a crucial part of their social schedule. many of the group overcame significant barriers -transport, weather, intermittent ill-health, exercise restriction -to attend at unexpectedly high rates ( %) over a full year. we think that the social connection component of the singing group, while at the same time doing something that is both challenging and enjoyable, was influential in maintaining the high attendance rate as well as the improved outcomes. the importance of social connection for health and wellbeing is well established. social isolation, loneliness, and living alone are associated with a - % increased likelihood of mortality in the general population, and there is no reason to think the copd population is any different. furthermore, in the general population, social isolation has a significant bidirectional relationship with depression and anxiety. it makes sense that the same should hold for people with copd. just as people with stroke managed on dedicated stroke rehabilitation wards may be more likely to hope (and believe) in a "life after stroke", we feel one of the key contributors to the consistent benefits of pr, cognitive behavioural therapy and community activities such as copd singing groups, is that involvement provides a person with copd the hope (and belief) in "life beyond copd". for people living with progressive dyspnoea and exercise limitation, often accompanied by social isolation, that hope may be the catalyst for engaging in physical and social activities that were previously thought "too hard". other evidence supports this view. arnold and colleagues showed that improvements in quality of life scores after pr were associated with increases in measures of self-efficacy and suggested that "focussing more explicitly on the enhancement of perceptions of personal control in copd patients may be an important aim of pulmonary rehabilitation". there is nothing stroke-specific about take charge and early qualitative work showed that patients with a range of medical conditions valued this idea. morgan and others have called for a more "person-centred" approach to the person with copd without being specific about how to go about this. take charge is such a person-centred intervention. a feasibility study using a modified take charge intervention for people with a recent exacerbation of copd requiring hospitalization is complete, and results are awaited. in that study, there was no problem modifying take charge for people with copd. building on that work, take charge could be tested as an adjunct to standard pr programmes, or for people who decline pr, as a standalone intervention. meantime, some services wanting to provide a validated tool for person-centred interaction, might choose to incorporate the take charge approach into existing pr programmes, at minimal cost. service configurations have changed dramatically with the advent of covid- , both for people with stroke and copd. although take charge has, so far, only been tested face-to-face, it is possible to deliver the facilitator input by telephone, video link or online chat with the person interacting with a hard copy of the booklet. in a covid- world of limited face-to-face interactions and restrictions on group activities, the built-in social interaction of a regular pr group or singing group will be diminished. there will be a greater onus on the individual with copd to undertake some or all components of a pr programme on their own. an intervention like take charge that explicitly encourages self-management, along with identification of key supporters would be a significant advantage. the psychological dimension of pr may be crucial to its effectiveness and enhancing that effect is worthy of further consideration by providers, audit authorities and researchers. a better understanding of this idea and trials of focussed psychosocial interventions may allow a broader range of effective interventions for people with copd. our view is we should help the person with copd get as much out of their life as they want rather than settling for self-management of their condition alone-ie to become "a person who happens to have copd" rather than remain a "copd patient". the take charge intervention is one option to help make this happen. the authors report no conflicts of interest in this work. anxiety disorders in patients with copd: a systematic review depression and anxiety in patients with copd the impact of anxiety and depression on outcomes of pulmonary rehabilitation in patients with differential response to pulmonary rehabilitation in copd: multidimensional profiling expanding pulmonary rehabilitation capacity. one size won't fit all personalized medicine and chronic obstructive pulmonary disease pulmonary rehabilitation for chronic obstructive pulmonary disease: has it peaked? socio-economic deprivation and the outcome of pulmonary 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stroke. cochrane database syst rev self-determination theory and the facilitation of intrinsic motivation, social development, and well-being pulmonary rehabilitation for chronic obstructive pulmonary disease. cochrane database syst rev british thoracic society guideline on pulmonary rehabilitation in adults physical activity is the strongest predictor of all-cause mortality in patients with copd: a prospective cohort study improving physical activity in copd: towards a new paradigm pulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary disease the covid- pandemic confronts the motivation fallacy within pulmonary rehabilitation programs pulmonary rehabilitation. an exercise in improvement -combined clinical and organizational audit rcp london whakawhanaungatanga: the importance of culturally meaningful connections to improve uptake of pulmonary rehabilitation by māori with copd -a qualitative study action plans and coping strategies in elderly copd patients influence the result of pulmonary rehabilitation: an observational study have we underestimated the efficacy of pulmonary rehabilitation in improving mood short-and long-term effects of a physical activity counselling programme in copd: a randomized controlled trial a patient-centered walking program for copd. chronic obstr pulm dis chronic breathlessness: re-thinking the symptom self-management in patients with copd: theoretical context, content, outcomes, and integration into clinical care self management for patients with chronic obstructive pulmonary disease efficacy of a minimal home-based psychoeducative intervention in patients with advanced copd: a randomized controlled trial mindfulnessbased cognitive therapy in copd: a cluster randomized controlled trial mindfulness and motivational interviewing: two candidate methods for promoting self-management singing teaching as a therapy for chronic respiratory disease-a randomized controlled trial and qualitative evaluation singing classes for chronic obstructive pulmonary disease: a randomized controlled trial sing your lungs out-a community singing group for chronic obstructive pulmonary disease: a -year pilot study sing your lungs out: a qualitative study of a community singing group for people with chronic obstructive pulmonary disease (copd) singing for adults with chronic obstructive pulmonary disease (copd). cochrane database syst rev loneliness and social isolation as risk factors for mortality: a meta-analytic review social disconnectedness, perceived isolation, and symptoms of depression and anxiety among older americans (nshap): a longitudinal mediation analysis what really matters to patients living with chronic obstructive pulmonary disease? an exploratory study the relationship between self-efficacy, functional exercise capacity and physical activity in people with copd: a systematic review and meta-analyses changes in personal control as a predictor of quality of life after pulmonary rehabilitation consequences of stroke, arthritis and chronic pain -are there important similarities? the international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols. this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- -sgdqhtns authors: lee, hanjun title: vitamin e acetate as linactant in the pathophysiology of evali date: - - journal: med hypotheses doi: . /j.mehy. . sha: doc_id: cord_uid: sgdqhtns the recent identification of vitamin e acetate as one of the causal agents for the e-cigarette, or vaping, product use associated lung injury (evali) is a major milestone. in membrane biophysics, vitamin e is a linactant and a potent modulator of lateral phase separation that effectively reduces the line tension at the two-dimensional phase boundaries and thereby exponentially increases the surface viscosity of the pulmonary surfactant. disrupted dynamics of respiratory compression-expansion cycling may result in an extensive hypoxemia, leading to an acute respiratory distress entailing the formation of intraalveolar lipid-laden macrophages. supplementation of pulmonary surfactants which retain moderate level of cholesterol and controlled hypothermia for patients are recommended when the hypothesis that the line-active property of the vitamin derivative drives the pathogenesis of evali holds. effectively reduces the line tension at the two-dimensional phase boundaries and thereby exponentially increases the surface viscosity of the pulmonary surfactant. disrupted dynamics of respiratory compression-expansion cycling may result in an extensive hypoxemia, leading to an acute respiratory distress entailing the formation of intraalveolar lipid-laden macrophages. supplementation of pulmonary surfactants which retain moderate level of cholesterol and controlled hypothermia for patients are recommended when the hypothesis that the line-active property of the vitamin derivative drives the pathogenesis of evali holds. as of january , , there were , reported hospitalized cases of e-cigarette, or vaping, product use associated lung injury (evali) in the united states [ ] . patients with evali typically exhibit respiratory symptoms, such as dyspnea and tachypnea, and often require the receipt of supplemental oxygen due to progressive hypoxemia [ , ] . computed tomography (ct) scans of the chest of these patients mostly display diffuse ground-glass opacity, a non-specific sign characteristic of lung injury that is often indistinguishable from those induced by viral infections [ ] . extensive investigation into evali has revealed an emerging link between the disease and tetrahydrocannabinol (thc). reportedly, as many as % of patients with evali used thc-containing e-cigarettes, while those who solely used nicotine-containing products accounted for a mere % of all cases [ ] . correspondingly, on october , , the food and drug administration issued a public warning against thc-containing vaping products, and the rate of emergency department (ed) visits due to evali has significantly declined since then [ ] . the pathophysiology and the definitive cause of evali are yet to be established. initial efforts to elucidate the pathophysiology of the disease have mainly focused on its association with thc. providers still mostly rely on a diagnosis of exclusion when a patient with a history of thccontaining vaping product usage exhibits severe respiratory symptoms indicative of evali [ ] . since the epidemic of evali has already reached its post-peak period and is expected to enter a post-epidemic one in a near future [ ] , thanks to global efforts to strengthen regulations against e-cigarettes, it is likely that we might not be able to fully characterize the disease before the epidemic is finally over. nonetheless, for thousands of hospitalized patients who still suffer from the disorder and for the deceased who died without knowing what they were exactly dying from, the pathophysiological characterization of the disease should be continued and recent breakthroughs in the field are tremendously supporting us. recently, investigators at the centers for disease control and prevention (cdc) identified vitamin e acetate, a chemical widely utilized as a diluent for thc-containing vaping fluids, as one of the potential causal agents of evali [ ] . among submitted samples of bronchoalveolar lavage (bal) fluid from patients, samples contained high content of vitamin e acetate exceeding . nm, while none was observed in those of healthy e-cigarette users without evali. primary toxicants other than vitamin e acetate were nearly absent in bal fluid samples from patients, indicating a strong association of vitamin e acetate in the pathology. in a field predominated by confusion, this discovery sets an important milestone. vitamin e has long been thought of as an antioxidant dwelling in the lipid bilayer. in fact, the discovery of the vitamin itself has come from reports of fetal resorption in murine models which were depleted of the vitamin [ ] . the lethality of vitamin e deficiency was later attributed to the lack of its antioxidative capacities, and it is now well-established that the vitamin is required for the protection of polyunsaturated fatty acids from being unwantedly oxidized [ ] . however, vitamin e acetate, given the additional ester moiety, is deprived of the antioxidative property and is markedly more thermostable. furthermore, its affinity to α-tocopherol transfer protein (αttp) is ~ -fold lower than that of the natural stereoisomer of vitamin e [ ] , indicating the significance of an extensive water bridge between the hydroxyl group and residues tyr , ser , and ser in the binding of the vitamin to αttp [ ] . despite αttp often being recognized as a hepatocyte-specific protein which presents vitamin e from endosomal compartments to the plasma membrane for secretion [ ] , it is also expressed in the lung where it non-canonically increases the level of vitamin e upon hypercapnia [ ] . due to these significant differences between vitamin e and vitamin e acetate, it is important to clarify whether the lung injury observed in patients with evali is induced solely by the esterified derivative of the vitamin. unfortunately, the distinguishment between the two compounds has largely been neglected in the field of evali, and the scarcity of information on the esterified derivative of the vitamin has forced many investigators to rely on reported biochemical properties of unmodified vitamin e in elucidating the pathophysiology of evali. unlike those administered via dietary uptake [ ] , wherein the compound is readily hydrolyzed by cellular esterases, including pancreatic carboxyl ester hydrolase and cholesteryl ester hydrolase [ , ] , inhaled vitamin e acetate does not undergo esterase-mediated hydrolysis in the time scale of several hours [ , ] . this indicates that most of the inhaled vitamin e acetate would remain unhydrolyzed in the lung of e-cigarette users even until the next vaping session in a typical setting. this is analogous to those observations made in skin, wherein the hydrolysis rate of the esterified derivative was measured as mere % [ ] . the mechanistic detail on why inhaled vitamin e acetate is resistant to esterase-mediated hydrolysis, however, is poorly understood. despite the remaining controversy on which of these compounds is responsible for the pathogenesis of evali, there is ample amount of evidence to rule out the antioxidative property of vitamin e as its driving force. antioxidative activities have long been recognized as a protective mechanism against injury in respiratory disorders. indeed, pulmonary surfactants contain significant amounts of superoxide dismutase and catalase activities, which act to scavenge extracellular reactive oxygen species, such as hydrogen peroxide, within the pulmonary system [ ] . similarly, type ii alveolar pneumocytes secrete vitamin e alongside pulmonary surfactants to protect the respiratory system against inhaled oxidants [ , ] . however, it is worth to note that the protective effect of vitamin e in the pulmonary system is not solely due to its antioxidative property. indeed, the transcriptional activation of αttp, which increases the level of vitamin e in the pulmonary system, protects against ventilator-induced lung injury in murine models without affecting antioxidant response signaling, such as those dependent on nuclear factor erythroid -related factor (nrf ) [ ] . recent investigations on the biological action of the vitamin have raised an emerging appreciation of its non-antioxidative properties [ , ] . although it remains a matter of controversy whether non-antioxidative properties of the vitamin can be strictly discriminated from its antioxidative property [ ] , thorough examination of the effects of vitamin e other than antioxidation in this poorly characterized respiratory disorder remains valuable. in this regard, herein i discuss several possible mechanisms by which vitamin e acetate in vaping fluids may drive the pathogenesis of evali. as the biochemical properties of the vitamin derivative have been insufficiently characterized, i focus on those of an unmodified vitamin. currently, there are five established non-antioxidative properties of vitamin e in the biological system: i) its ability to induce gel-liquid crystalline phase transition, ii) its active deposition in the lipid droplet of macrophages, iii) its modulation of the antidiabetic cascade involving diacylglycerol kinase (dgk) and protein kinase c (pkc), iv) its activation of the xenobiotic-sensing pregnane x receptor (pxr) signaling, and v) its ability to modulate lateral phase separation. in each section, i discuss possible ways by which these properties may contribute to the pathophysiology of evali and whether these properties are expected to be shared by vitamin e acetate. at last, i argue that the line-active property of the vitamin deserves academic attention. although toxic byproducts of heating vitamin e acetate have recently garnered considerable interest [ ] , i instead focus on the biological action of the vitamin derivative itself, as there is yet lacking amount of evidence that pinpoints toxic byproducts as the pathological driving force for evali. indeed, lanzarotta and colleagues have recently shown that the majority of vaporized vitamin e acetate exist either as an equimolar complex with thc or as a dimer [ ] . among the five non-antioxidative properties of vitamin e, investigators from the lung injury response laboratory working group have focused on its peculiar ability to induce gel (l β ) to liquid crystalline (l c ) phase transition in model saturated phosphatidylcholine bilayers [ ] (l in the notation stands for lamellar). this property of the vitamin is believed to be the consequence of its structural deviance from phospholipids. as the structure of vitamin e greatly differs from a typical phospholipid, especially in its rigid chromane double ring, the vitamin greatly perturbs the packing of phospholipids within the l β phase, resulting in a facilitated gel-liquid crystalline phase transition ( fig. ) [ ] . for instance, the addition of either vitamin e or vitamin e acetate in molar ratios as high as mol% in cholesterol-free model dimyristoylphosphatidylcholine (dmpc) membranes lowers the critical temperature required for gel-liquid crystalline phase transition for ~ . k [ , ] . however, since cholesterol, a major constituent of biological membranes, also exhibits profound structural deviance from a typical phospholipid, it also facilitates gel-liquid crystalline phase transition in a similar manner. compared to free cholesterol, vitamin e acetate is . times more potent in modulating the phase behavior of the lipid bilayer. as a consequence, one possible mechanism by which vitamin e acetate intoxication may lead to a fatal lung injury is its induction of liquid crystalline phase in pulmonary surfactants, which would likely influence the respiratory compression-expansion cycling. a major downfall of blount and his colleagues' hypothesis is the abundance of free cholesterol in human pulmonary surfactants. indeed, free cholesterol level in bal fluids were measured as ~ . mm in murine models of pulmonary alveolar proteinosis (pap) [ ] , while the level of vitamin e acetate observed in patients with evali, who occasionally feature signs of pap [ ] , was in nanomolar range [ ] . in contrast, the decrease in the critical temperature induced by the addition of vitamin e acetate was of roughly the same orders of magnitude compared to that of free cholesterol. this indicates that the overall contribution of vitamin e acetate in the modulation of phase behavior is at least three orders of magnitude smaller compared to that of endogenously available free cholesterol. furthermore, the existence of cholesterol in human pulmonary surfactants is known to completely abrogate gel-liquid crystalline phase transition [ ] . in explanation, the driving force for gel-liquid crystalline phase transition induced by vitamin e acetate in model saturated phosphatidylcholine bilayers has been its perturbation of phospholipid packing by structural deviance. the abundance of free cholesterol, of which structure is as rigid as the head portion of the vitamin, in biological membranes offsets the structural deviance of vitamin e in lipid bilayers, resulting in an inability to induce gel-liquid crystalline phase transition (fig. ) . indeed, the observation of gel-liquid crystalline phase transition has been limited to the cholesterol-free model saturated phosphatidylcholine bilayers [ , ] and the membrane of mycoplasma laidlawii, which is depleted of cholesterol and is enriched with saturated fatty acids [ ] . accounting for the rationale behind the selection of mycoplasma laidlawii as the model system for investigating gel-liquid crystalline phase transition, steim and colleagues concisely stated, "because cholesterol interferes, to detect a phase change above the ice point in a membrane, an organism containing rather saturated fatty acids but little or no cholesterol must be chosen" [ ] . another important characteristic of vitamin e acetate in the biological system is its deposition in lipid droplets [ , ] , and many investigators have especially focused on the observation of intraalveolar lipid-laden macrophages as it has been proven to be one of the most prominent features of lung biopsies from patients with evali [ ] . indeed, intraalveolar lipid-laden macrophages were also evident in a murine model of vitamin e acetate inhalation (daily inhalation of . - . μg vitamin e acetate per gram of body weight, two weeks of exposure), of which effect was largely absent in mice inhaled a mixture of propylene glycol and vegetable glycerin [ ] . intriguingly, when a single dose of vitamin e acetate (inhalation of . μg vitamin e acetate per gram of body weight) was inhaled into the lipopolysaccharide-treated lungs of murine models, the substance greatly attenuated the inflammatory response, despite being -fold less potent than vitamin e [ ]. this indicates that it is the excessive accumulation of vitamin e acetate, rather than its transient exposure, which is responsible for the pathogenesis of evali. although it is tempting to speculate that intraalveolar lipid-laden macrophages observed are merely the consequence of excessive deposition of vitamin e acetate within the pulmonary system, increasing amount of reports suggest that such assumptions are erroneous. importantly, there is a lacking histological evidence of exogenous lipoid pneumonia (elp) in patients suffering from evali, despite the prevalence of intraalveolar lipid-laden macrophages in bal fluids. for instance, when a -year-old woman had regularly smoked cod-liver oil, she acquired a non-oncologic perihilar mass in the right middle lobe of her lung, indicative of elp [ ] , but these elp-like histological signs were mostly absent in patients with evali [ ] . as guerrini and colleagues importantly mention, intraalveolar lipid-laden macrophages do not always originate from an excessive uptake of exogenous lipids, but may often emerge as a common immunopathological response following sustained inflammation [ ] . however, unmodified vitamin e is indicated in the downregulation of cd [ ] , which functions to promote the formation of lipid-laden macrophages (foam cells) [ ] . furthermore, vitamin e also ameliorates this hypothesis also does not provide us with an exact mechanism by which vitamin e acetate may initiate inflammation. since vitamin e acetate is a viscous liquid at physiological temperature, activation of the nlrp inflammasome through crystal-induced lysosomal rupture as in models of silicosis [ ] seems unlikely, despite robust activation of the inflammasome in e- cigarette users [ ] . vitamin e is also indicated in an active inhibition of -lipoxygenase ( -lo), which converts fatty acids to leukotrienes, promoting inflammation [ , ] . importantly, vitamin e acetate is also reported to inhibit -lo activity [ ], despite being twice less potent than the unmodified vitamin, supporting the view that vitamin e acetate does not induce elp in patients with evali via the inflammatory response. in the field of diabetes mellitus, vitamin e is a potent agonist of dgkα, which catalyzes the conversion of diacylglycerol (dag) to phosphatidic acid (pa) and thereby inhibits the catalytic activity of pkcα [ ] [ ] [ ] . agonism of dgkα by vitamin e derivatives are known to be dependent on the chromane double ring of the molecule, as both vitamin e analogs containing the moiety, such as troglitazone and trolox, and non-antioxidative vitamin e derivatives, such as vitamin e succinate, exhibited robust activation and subsequent plasmalemmal translocation of the kinase [ ] . vitamin e acetate may also antagonize the catalytic activity of pkcα in a dgkindependent manner, as there are studies indicating that the substance is capable of competing with dag for its binding site in pkcα [ ]. intriguingly, d-α-tocopherol, but not d-β-tocopherol nor d-γ-tocopherol exhibited robust inactivation of pkcα, indicating a pivotal role of methylation at c and c of the chromanol structure [ ] . supplementation of vitamin e acetate in murine models of diabetic cardiomyopathy showed largely protective role for the chemical [ ] , but it is worth to note that most of the substances supplemented via dietary uptake undergo hydrolysis to yield vitamin e. the protective effect of vitamin e derivatives in diabetes mellitus was completely ameliorated in dgkα knockout mice, indicating a pivotal role of the kinase in this antidiabetic signaling cascade [ ] . since the observed level of vitamin e acetate in bal fluids is of same orders of magnitude with that of dag, a potent second messenger with which vitamin e acetate competes for binding [ ] , the activity of the substance as a modulator of dgk-pkc pathway is physiologically relevant. however, the reported anti-inflammatory effects of d-α-tocopherol in the pulmonary system through post-translational inactivation of pkcα significantly undermines this hypothesis [ , ] . since many observations suggest that the antagonism of pkcα by d-α-tocopherol is independent of its antioxidative property [ ], it is anticipated that vitamin e acetate might play an analogous anti-inflammatory role in the pulmonary system [ , ] . however, whether the esterified derivative antagonizes pkcα still remains to be investigated. overall, the modulation of dgk-pkc pathway by vitamin e acetate seems yet incapable of accounting for the observation of pro-inflammatory intraalveolar lipid-laden macrophages in patients with evali, although there is yet lacking amount of evidence to completely rule out this hypothesis. when vitamin e is administered into the biological system, it transforms into a plethora of bioactive metabolites [ ]. this includes several of the pxr agonists, such as α-tocopherol- '-cooh, γ-tocotrienol, and garcinoic acid [ , ] . since pxr forms a heterodimer with cis retinoic acid receptor (nr b) to activate the transcription of cytochrome p monooxygenase genes indicated in the clearance and detoxification of xenobiotic substances [ ] , pro-agonist role of vitamin e acetate may be relevant in the pathophysiology of evali. indeed, polymorphisms in the cytochrome p genes have been associated with drug-induced interstitial lung diseases (diild), characterized by coarse reticular opacity and intraalveolar lipid-laden macrophages [ ] . this pathology is consistent with that of evali, wherein patients often reported patterns of giant-cell interstitial pneumonia [ ] . in this picture, evali can be seen as a variant of diild caused by an excessive accumulation of vitamin e acetate in the pulmonary system. despite its pathophysiology being not fully characterized, diild often involves the generation of reactive oxygen species [ , ] . vitamin e acetate, however, is known to protect the biological system against reactive oxygen species even in the absence of apparent hydrolysis [ ] , possibly through its inhibition of -lo [ ] or through infinitesimal hydrolysis to vitamin e as previously speculated [ ] . furthermore, diild is a highly heterogenous disorder, that is often dependent on genetic polymorphisms rare enough to avert federal regulations during drug approval [ , ] . for instance, the demonstration of respiratory symptom after oral administration of fenfluramine or dexfenfluramine was on a patient with a rare cyp d * /* haplodeficient variant of the cytochrome p d (cyp d ) gene [ ] . how haplodeficiency of the cyp d gene contributes to the pathogenesis of diild remains unclear. if vitamin e acetate behaves as a pro-agonist of pxr, a transcriptional activator of cytochrome p genes, and thereby contributes to the pathogenesis of evali, the symptoms of evali should be replicated by inhalation of other well-established pxr agonists, such as corticosteroids [ ] [ ] [ ] . nebulized budesonide or fluticasone, however, did not induce respiratory distress when inhaled repeatedly (inhalation of - μg corticosteroids each session, - times daily, days) in young children with a severe onset of asthma [ ] . furthermore, even in the absence of vitamin e acetate, vaping induced significant increase in the activity of cytochrome p enzymes, including those hydroxylates vitamin e, such as cyp b , cyp c , and cyp a , but without apparent respiratory distress [ ] . however, it remains to be studied whether an excessive accumulation of vitamin e acetate produces pxr-agonizing metabolites above a certain threshold such that it may induce an acute respiratory distress. overall, the pro-agonist role of vitamin e acetate on pxr seems relevant in the pathophysiology of evali, but there is yet lacking amount of evidence which indicates that the pxr agonism drives the pathogenesis of evali. recent developments in membrane biophysics indicate that an unmodified vitamin e has an active role in lateral phase separation. due to the rigid chromane double ring, which significantly reduces the entropic cost required for its association with cholesterol [ ] , unmodified vitamin e efficiently releases the line tension (i.e. two-dimensional counterpart of a surface tension) between the liquid-disordered l α and the liquid-ordered l o phase of lipid polymorphs [ ] . indeed, oral supplementation of vitamin e acetate in hiv/aids patients, which is readily converted to vitamin e by cellular esterases, has been successful in reducing the viral load [ ] , as the molecule disrupts the tensile two-dimensional l α /l o phase boundary required for viral entry [ , ] . in membrane biophysics, this vitamin is classified as a linactant [ ] , which is a two-dimensional counterpart of a surfactant, as it reduces the line tension at the two-dimensional phase boundaries (fig. a) . in explanation, when one puts a drop of oil into the water, gravity and surface tension compete to generate the lobular shape of the droplet. the addition of sodium dodecyl sulfate (sds), a well-known surfactant, reduces the surface tension such that the oil droplet loses its ability to maintain its structure against gravitational force. as a consequence, oil emulsifies into the water, if not become completely miscible [ ] . similarly, when one adds vitamin e onto the lipid bilayer exhibiting l α /l o phase separation, it reduces the line tension, which competes with entropy to form an enlarged cholesterol-enriched microdomain. as it has been shown that the molar ratio of vitamin e within a typical lipid bilayer is insufficient to completely abolish lateral phase separation [ ] , vitamin e acts to reduce the size of the microdomain and thereby emulsifies cholesterol-enriched l o into cholesterol-depleted l α (fig. c) . despite the fact that the line-active property of vitamin e acetate has not yet been explicitly tested, the small size and the abundance of ideally localized nonbonding electron donors of the ester moiety provide ample reason to hypothesize that the substance is a linactant. the content of vitamin e within the lipid mixture that is sufficient to function as a potent linactant is typically below mol% [ , ] , which is comparable to that of vitamin e acetate, estimated based on its concentration in bal fluid samples from patients with evali. an important consequence of the dissemination of the cholesterol-enriched microdomain is a profound increment in the surface viscosity of pulmonary surfactants [ ] . lateral phase separation is an important source of free area, defined as the difference between observed and minimum area per molecule [ ] . this is analogous to the observation of reduction in the total volume after mixing ethanol with water. in such a case, the phenomenon can be interpreted as if the free volume of each molecule has decreased following mixing. similarly, mixing of l o with l α results in a substantial decrease in the free area, while demixing induces its subsequent increase. according to the free area theory of surface viscosity [ ] , surface viscosity exponentially increases following the reduction of free area, driven by reduced tensile force along the two-dimensional phase boundaries. indeed, a mere % decrease in the free area resulted in a striking -fold increase in the surface viscosity of pulmonary surfactants [ ] . in accordance, upon hyperpnea, the biological system increases free cholesterol level in pulmonary surfactants, to reduce surface viscosity, which is required for facilitated respiration [ ] . similarly, the reduced free area following the inhalation of vitamin e acetate may considerably increase the surface viscosity of the pulmonary surfactant, resulting in a disrupted respiratory compression-expansion cycling and a subsequent hypoxemia (fig. b) . in this picture, intraalveolar lipid-laden macrophages are consequences of hypoxemia-induced excessive intracellular accumulation of triglycerides [ ] , and extensive vacuolization, multinucleation, and reactive hyperplasia observed in type ii alveolar pneumocytes are products of an extensive tissue hypoxia [ , ] . taking into account that the pulmonary-associated surfactant protein b (sp-b) often cooperates with cholesterol in reducing the surface viscosity of pulmonary surfactants during respiratory compression-expansion cycling [ ], other than its known role in the reduction of surface tension in the steady state, it is worth to note that the partial deficiency of the protein results in a respiratory distress analogous to those observed in patients with evali [ ] . in sum, vaporized vitamin e acetate, a thermostable derivative of the well-established linactant, may substantially increase the surface viscosity of pulmonary surfactants and thereby confer the pathogenesis of evali. evaluating the hypothesis the above-described biological actions of vitamin e derivatives are closely intertwined to each other [ , ] , and the effect of vitamin e acetate on the pulmonary system in patients with evali is likely to be the sum of all these actions, rather than originating from a single action of the vitamin derivative. for instance, cholesterol-enriched microdomains, or lipid rafts [ ] , are involved in a plethora of cellular activities, including pkcα [ ] and -lo signaling [ ] . as a consequence, it is worth to note that the evaluation of these hypotheses should focus on identifying the major driving force for the pathogenesis of evali, rather than a sole cause, which most likely does not exist. to evaluate whether the line-active property of vitamin e acetate is driving the pathogenesis of evali, we must answer the following questions. first, is vitamin e acetate, like d-α-tocopherol, a potent linactant? if it is, to what extent does the substance reduce the line tension at the twodimensional phase boundaries and increase the surface viscosity? molecular dynamics simulations, such as those previously introduced by rosetti and colleagues [ ] , would particularly be useful, as they enable us to roughly estimate the fold change in the surface viscosity of pulmonary surfactants and thereby to evaluate the validity of the hypothesis. second, are linactants, in general, capable of inducing respiratory distress when inhaled through ecigarettes? one obvious experiment that must be done is the repeated inhalation of hybrid lipids in murine models. hybrid lipids, which are phospholipids that contain both saturated and unsaturated acyl chains, are one of the most widely accepted class of linactants [ ] [ ] [ ] [ ] . as a consequence, repeated inhalation of hybrid lipids, analogous to those attempted by bhat and colleagues, should induce similar histological signs, for the hypothesis to hold. to rule out the potential role of vitamin e acetate as an inducer of gel-liquid crystalline phase transition, rescue experiments using an inhalation setup for dimethyl sulfoxide (dmso), which abrogates gelliquid crystalline phase transition [ ] , can be attempted. to rule out the possibility that vitamin e acetate drives the pathogenesis of evali through modulating dgk-pkc or pxr signaling, vitamin e acetate inhalation experiment using either pkcα [ ] or pxr knockout mice [ ] can be pursued. characterization of the lipid composition of the intraalveolar lipidladen macrophages is also crucial, as it may assist us to rule out the hypothesis that an acute respiratory distress associated with evali is indeed a form of elp. lastly, as we still suffer from the lack of characterization of the type of injury in evali, i propose an rna sequencing (rna-seq) experiment for lung tissues obtained from murine models of evali [ ] . analyses on the level of transcripts associated with the biological action of the vitamin, such as cytochrome p monooxygenase genes, hypoxia-inducible factor (hif- ), and nrf , as well as gene ontology analyses would greatly assist us to better define the pathology of the new respiratory disorder. rna-seq experiment would also allow us to develop reliable biomarkers for evali to better assist health care providers in the differential diagnosis of the vaping-induced respiratory disorder against viral infections. living in the era of the pandemic outbreak of the coronavirus disease (covid- ), wherein tens of millions of people worldwide are being hospitalized with symptoms often indistinguishable from those of evali [ , ] , establishing diagnostic biomarkers for evali would particularly be valuable. in summary, i discussed several possible mechanisms by which vitamin e acetate may drive the pathogenesis of evali and specifically advocated the role of vitamin e acetate as a linactant (table ) . based on recent discoveries from the field of membrane biophysics, i proposed that the alleged linactivity of vitamin e acetate, a thermostable derivative of a well-established linactant, significantly increases the surface viscosity of pulmonary surfactants in the alveoli to confer acute respiratory distress associated with evali. this hypothesis leads to new possible medication approaches for the new pulmonary disease. if it is true that the line-active property of the vitamin derivative is what is causing the disease, supplementation of pulmonary surfactants as well as corticosteroid treatments should be valid. to reduce the elevated viscosity of pulmonary surfactants, pulmonary surfactants which retain a moderate level of cholesterol, such as infasurf [ ] , may be recommended for use. in addition, in a biophysical perspective, since the entropy component of the free energy, which is proportional to the temperature of the system, works against lateral phase separation in regular solutions [ , ] , one can reverse the effects of vitamin e acetate by slightly lowering the temperature of the system. controlled hypothermia to rescue lateral phase separation and thereby reduce surface viscosity, as introduced by autilio and colleagues [ ] , might be a useful way to manage acute respiratory distress syndrome associated with evali. the current outbreak of evali is an emerging crisis affecting a great portion of the global population. as pathophysiologists, we have a duty to decipher the pathophysiology of evali for the good of all patients suffering from the disease, especially after the recent identification of the widely utilized derivative of the vitamin as one of the causal agents for the new catastrophic pulmonary disease. that vitamin e acetate may facilitate gel-liquid crystalline phase transition to confer acute respiratory distress [ ] . in this picture, vitamin e acetate perturbs the packing of phospholipids within the lipid bilayer such that the system thermodynamically prefers the liquid crystalline phase over the gel phase. however, cholesterol, which exists in large excess to vitamin e acetate in the biological membrane, not only exerts similar effect in model saturated phospholipid bilayers, but also reportedly abolishes gel-liquid crystalline phase transition [ ] . therefore, gel- liquid crystalline phase transition may be irrelevant in the pathogenesis of evali. reduced line tension within the two-dimensional phase boundary confers smaller microdomains and decreases the free area of lipids [ ] . as a result, the surface viscosity of pulmonary surfactants exponentially increases to perturb the dynamics of respiratory compressionexpansion cycling, causing acute respiratory distress analogous to those seen in patients with evali. update: characteristics of a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury -united states pulmonary illness related to e-cigarette use in illinois and wisconsin -final report update: interim guidance for health care providers evaluating and caring for patients with suspected e-cigarette, or vaping, product use associated lung injury -united states imaging of vaping-associated lung disease syndromic surveillance for e-cigarette, or vaping, product use-associated lung injury tolerance to hypothermic and antinoceptive effects of ∆ -tetrahydrocannabinol (thc) vapor inhalation in rats lasting effects of repeated ∆ -tetrahydrocannabinol vapour inhalation during adolescence in male and female rats tree-in-bloom": severe acute lung injury induced by vaping cannabis oil pathology of 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coexisting in the lumen of the small intestine during digestion could explain its low bioavailability supercritical fluid-aerosolized vitamin e pretreatment decreases leak in isolated oxidant-perfused rat lungs aerosol-administered α-tocopherol attenuates lung inflammation in rats given lipopolysaccharide intratracheally hydrolysis of rrr-αtocopheryl acetate (vitamin e acetate) in the skin and its uv protecting activity (an in vivo study with the rat) characterization of antioxidant activities of pulmonary surfactant mixtures type ii pneumocytes secrete vitamin e together with surfactant lipids oxidative stress and antioxidants at biosurfaces: plants, skin, and respiratory tract surfaces vitamin e: non-antioxidant roles the rise, the fall and the renaissance of vitamin e vitamin e: emerging aspects and new directions potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin e acetate hydrogen bonding between tetrahydrocannabinol and vitamin e acetate in unvaped, aerosolized, and condensed aerosol e-liquids interaction of vitamin e with saturated phospholipid bilayers modulated phases of phospholipid bilayers induced by tocopherols targeting cholesterol homeostasis in lung diseases a unique case of secondary pulmonary alveolar proteinosis following e-cigarette, or vaping, product use-associated lung injury (evali) studies on lecithin-cholesterol-water interactions by differential scanning calorimetry and x-ray diffraction calorimetric evidence for the liquid-crystalline state of lipids in a biomembrane lipid droplet functions beyond energy storage nonalcoholic fatty liver disease impairs the cytochrome p- -dependent metabolism of α-tocopherol (vitamin e) vaping-associated acute respiratory failure due to acute lipoid pneumonia an animal model of inhaled vitamin e acetate and evali-like lung injury a woman who took cod-liver oil and smoked lipid-laden macrophages as biomarkers of vaping-associated lung injury antagonistic effects of oxidized low density lipoprotein and α-tocopherol on cd scavenger receptor expression in monocytes: involvement of protein kinase b and peroxisome proliferatoractivated receptor-γ a cd -dependent signaling cascade is necessary for macrophage foam cell formation vitamin e ameliorates ox-ldl-induced foam cells formation through modulating the activities of oxidative stress-induced nf-κb pathway silica crystals and aluminum salts activate the nalp inflammasome through phagosomal destabilization electronic versus combustible cigarette effects on inflammasome component release into human lung inhibition of -lipoxygenase by vitamin e endogenous metabolites of vitamin e limit inflammation by targeting -lipoxygenase diacylglycerol-protein kinase c activation by vitamin e in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels α-tocopherol specifically inactivates cellular protein kinase c α by changing its phosphorylation state diacylglycerol kinase alpha is involved in the vitamin e-induced amelioration of diabetic nephropathy in mice importance of chroman ring and tyrosine endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant intracellular diacylglycerol: a mitogenic second messenger proposable as marker of transformation in squamous cell carcinoma of the lung α-tocopherol inhibits the respiratory burst in human monocytes: attenuation of p (phox) membrane translocation and phosphorylation opposing immunoregulatory functions during inflammation by regulating leukocyte recruitment the α-tocopherol form of vitamin e reverses age-associated susceptibility to streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment the alpha-tocopherol form of vitamin e boosts elastase activity of human pmns and their ability to kill streptococcus pneumoniae vitamin e biotransformation in humans the long chain α-tocopherol metabolite α- '-cooh and γ-tocotrienol induce p-glycoprotein expression and activity by activation of the pregnane x receptor in the intestinal cell line ls garcinoic acid is a natural and selective agonist of pregnane x receptor the nuclear pregnane x receptor: a key regulator of xenobiotic metabolism relationship between drug-induced interstitial lung diseases and cytochrome p polymorphisms drug induced interstitial lung disease drug-induced interstitial lung disease: mechanisms and best diagnostic approaches role of cytochrome p polymorphisms in the development of pulmonary drug toxicity: a case-control study in the netherlands whole genome sequencing to identify predictive markers for the risk of drug-induced interstitial lung disease pregnane x receptor and retinoid x receptor-α expression in human hepatocytes: synergistic increase of cyp a induction by pregnane x receptor activators pxr-mediated induction of human cyp a and mouse cyp a by the glucocorticoid budesonide identification and validation of novel human pregnane x receptor activators among prescribed drugs via ligand-based virtual screening effectiveness of high repeated doses of inhaled budesonide or fluticasone in controlling acute asthma exacerbations in young children e-cigarettes induce toxicological effects that can raise the cancer risk cholesterol as a co-solvent and a ligand for membrane proteins tuning membrane phase separation using nonlipid amphiphiles effects of vitamin e and c supplementation on oxidative stress and viral load in hiv-infected subjects line tension at lipid phase boundaries as driving force for hiv fusion peptide-mediated fusion hiv virions sense plasma membrane heterogeneity for cell entry line active molecules promote inhomogeneous structures in membranes: theory, simulations and experiments capillarity and wetting phenomena the antioxidant vitamin e as a membrane raft modulator: tocopherols do not abolish lipid domains effect of cholesterol and surfactant protein b on the viscosity of phospholipid mixtures effect of cholesterol nanodomains on monolayer morphology and dynamics in-plane steady shear viscosity of monolayers at the air/water interface and its dependence on free area effect of hyperpnea on the cholesterol to disaturated phospholipid ratio in alveolar surfactant of rats hypoxia converts human macrophages into triglyceride-loaded foam cells lysosomal alterations in hypoxic and reoxygenated hearts. i ultrastructural and cytochemical changes hif and the lung: role of hypoxia-inducible factors in pulmonary development and disease partial deficiency of surfactant protein b in an infant with chronic lung disease vitamin e: regulatory role on signal transduction functional rafts in cell membranes the nk receptor localizes to the plasma membrane microdomains, and its activation is dependent on lipid raft integrity protein profiling of plasma membranes defines aberrant signaling pathways in mantle cell lymphoma molecular insight into the line tension of bilayer membranes containing hybrid polyunsaturated lipids partitioning of lipids at domain boundaries in model membranes modulation of a small two-domain lipid vesicle by linactants physical properties of the hybrid lipid popc on micrometer-sized domains in mixed lipid membranes insights into the dynamics of dmso in phosphatidylcholine bilayers enac activity and expression is decreased in the lungs of protein kinase c-α knockout mice pregnane x receptor knockout mice display aging-dependent wearing of articular cartilage clinical features of patients infected with novel coronavirus in wuhan, china notes from the field : e-cigarette, or vaping, product use-associated lung injury cases during the covid- response -california commercial versus native surfactants: surface activity, molecular components, and the effect of calcium themodynamics of high polymer solutions solutions of long chain compounds controlled hypothermia may improve kim at the republic of korea army for their administrative assistance. key: cord- -f khcjdy authors: lópez, alfonso; martinson, shannon a. title: respiratory system, mediastinum, and pleurae date: - - journal: pathologic basis of veterinary disease doi: . /b - - - - . - sha: doc_id: cord_uid: f khcjdy nan diseases of the respiratory system (respiratory apparatus) are some of the leading causes of morbidity and mortality in animals and a major source of economic losses. thus veterinarians are routinely called to diagnose, treat, and implement health management practices to reduce the impact of these diseases. in companion animals, diseases of the respiratory tract are also common and, although of little economic significance, are important to the health of the animals and thus to clinicians and pet owners. in the past few years, animal shelters have been recognized as a major risk factor for respiratory diseases in dogs and cats, a comparable situation to what is reported in human beings with nosocomial infections. to facilitate the understanding of the structure and function, it is convenient to arbitrarily divide the respiratory system into conducting, transitional, and gas exchange systems ( fig. - ). the conducting system includes nostrils, nasal cavity, paranasal sinuses, nasopharynx, larynx, trachea, and extrapulmonary and intrapulmonary bronchi, all of which are largely lined by pseudostratified, ciliated columnar cells, plus a variable proportion of secretory goblet (mucous) and serous cells (figs. - and - and e- fig. - ). the transitional system of the respiratory tract is composed of bronchioles, which are microscopic structures that serve as a transition zone between the conducting system (ciliated) and the gas exchange (alveolar) system (see fig. - ). the disappearance of cilia in the transitional system is not abrupt; the ciliated cells in the proximal bronchiolar region become scarce and progressively attenuated, until the point where distal bronchioles no longer have ciliated cells. normal bronchioles also lack goblet cells but instead have other types of secretory cells, notably club cells (formerly clara cells) and neuroendocrine cells. club cells, also referred to as secretory bronchiolar cells, contain numerous biosynthetic organelles that play an active role in detoxification of xenobiotics (foreign substances), similar to the role of hepatocytes ( fig. - ) . club cells are also critical stem cells in the repair and remodeling of not only the bronchioles but also of most of the respiratory tract. in addition, club cells contribute to the innate immunity of the lung by secreting protective proteins (collectins) and pulmonary surfactant (see b) . in carnivores and monkeys, and to a much lesser extent in horses and human beings, the terminal portions of bronchioles are lined not only by cuboidal epithelium but also by segments of alveolar capillaries. these unique bronchioloalveolar structures are known as respiratory bronchioles ; also see fig. - ). the gas exchange system of the respiratory tract in all mammals is formed by alveolar ducts and millions of alveoli ( fig. - ; also see fig. - ). the surface of the alveoli is lined by two distinct types of epithelial cells known as type i (membranous) pneumonocytes and type ii (granular) pneumonocytes ( fig. - ) . all three-the conducting, transitional, and exchange systems of the respiratory system-are vulnerable to injury because of constant exposure to a myriad of microbes, particles and fibers, and toxic gases and vapors present in the air. vulnerability of the respiratory system to aerogenous (airborne) injury is primarily because of ( ) the extensive area of the alveoli, which are the interface between the blood in alveolar capillaries and inspired air; ( ) the large volume of air passing continuously into the lungs; and ( ) the high concentration of noxious elements that can be present in the air (table - ). for human beings, it has been estimated that the surface of the pulmonary alveoli is approximately m , roughly the area animal and cultured for microbes, yeasts, and fungi, many species of bacteria are recovered, such as mannheimia (pasteurella) haemolytica in cattle; pasteurella multocida in cats, cattle, and pigs; and bordetella bronchiseptica in dogs and pigs. the organisms that constitute the normal flora of the respiratory tract are restricted to the most proximal (rostral) region of the conducting system (nasal cavity, pharynx, and larynx). the thoracic portions of the trachea, bronchi, and lungs are considered to be essentially sterile. the types of bacteria present in the nasal flora vary considerably among animal species and in different geographic regions of the world. some present in the nasal flora are pathogens that can cause important respiratory infections under some circumstances. for instance, mannheimia (pasteurella) haemolytica is part of the bovine nasal flora, yet this bacterium causes a devastating disease in cattle-pneumonic mannheimiosis (shipping fever). experimental studies have established that microorganisms from the nasal flora are continuously carried into the lungs via tracheal air. despite this constant bacterial bombardment from the nasal flora and from contaminated air, normal lungs remain sterile because of their remarkably effective defense mechanisms. the conducting portion of the respiratory system is lined by pseudostratified columnar ciliated epithelium (most of the nasal cavity, paranasal sinuses, part of the larynx, and all of the trachea and bronchi), olfactory epithelium (part of the nasal cavity, particularly ethmoidal conchae), and squamous epithelium (nasal vestibulum and parts of the larynx). the pattern of injury, inflammation, and host response (wound healing) are characteristic for each of these three types of epithelium independent of its anatomic location. pseudostratified ciliated epithelium, which lines most of the nasal cavity and nasopharynx, part of the larynx, and all of the trachea and bronchi, is exquisitely sensitive to injury. when these cells are irreversibly injured, whether caused by viral infection, trauma, or inhalation of toxic gases, the ciliated cells swell, typically lose their attachment to underlying basement membrane, and rapidly exfoliate ( fig. - ) . a transient and mild exudate of fluid, plasma proteins, and neutrophils covers the ulcer. in the absence of of a tennis court. the alveolar surface of the equine lung is estimated to be approximately m . it has also been estimated that the volume of air reaching the human lung every day is approximately l. lungs are also susceptible to blood-borne (hematogenous) microbes, toxins, and emboli. this fact is not surprising because the entire cardiac output of the right ventricle goes into the lungs, and approximately % of the total blood volume is within the pulmonary vasculature. the pulmonary capillary bed is the largest in the body, with a surface area of m in the adult human; this area is equivalent to a length of km of capillaries, with ml of blood occupying up to km of capillary bed. the respiratory system has its own normal flora (microbiota), as does any other body system in contact with the external environment. if a sterile swab is passed deep into the nasal cavity of any healthy (rhinoviruses), infectious bovine rhinotracheitis (bovine herpesvirus ), feline rhinotracheitis (felid herpesvirus ), and viruses of the canine infectious respiratory disease (cird) group such as canine adenovirus (cav- ) and canine parainfluenza virus (cpiv) . if damage to the mucociliary blanket becomes chronic, goblet cell hyperplasia takes place, leading to excessive mucus production (hypersecretion) and reduced mucociliary clearance, and when there is loss of basement membrane, repair is by fibrosis and granulation tissue (scarring). in the most severe cases, prolonged injury causes squamous metaplasia, which together with scarring causes airway obstruction and an impediment to mucociliary clearance. in laboratory rodents, hyperplastic and metaplastic changes, such as those seen in nasal polyps and squamous metaplasia, are considered a prelude to neoplasia. the second type of epithelium lining the conducting system is the sensory olfactory epithelium, present in parts of the nasal mucosa, notably in the ethmoidal conchae. the patterns of degeneration, exfoliation, and inflammation in the olfactory epithelium are similar to those of the ciliated epithelium, except that olfactory complications or secondary bacterial infections, a specific type of progenitor cells known as basal cells or nonciliated secretory cells (preciliated cells) , which are normally present in the mucosa, migrate to cover the denuded basement membrane and undergoes mitosis, eventually differentiating into new ciliated epithelial cells (see fig. - ). cellular migration, proliferation, and attachment are regulated by locally released interleukins (il- β, il- , il- , and il- ), growth factors, integrins and extracellular matrix (ecm) proteins such as collagen, and fibronectin. the capacity of ciliated epithelium to repair itself is remarkably effective. for example, epithelial healing in an uncomplicated ulcer of the tracheal mucosa can be completed in only days. this sequence of cell degeneration, exfoliation, ulceration, mitosis, and repair is typically present in many viral infections in which viruses replicate in nasal, tracheal, and bronchial epithelium, causing extensive mucosal ulceration. examples of transient infections of this type include human colds epithelium. neurons in the olfactory mucosa have the unique ability to regenerate, a fact that is being explored as a potential source of new neurons in the treatment of spinal cord injury. squamous epithelium, located in the vestibular region of the nose (mucocutaneous junction), is the third type of epithelium present in the nasal passages. compared with ciliated and olfactory epithelia, nasal squamous epithelium is quite resistant to all forms of injury. the pharyngeal mucosa, composed of squamous epithelium, has similar patterns of necrosis and inflammation as the oral mucosa (see chapter ). the patterns of necrosis, inflammation, and repair in intrapulmonary bronchi are similar to those previously described for the nasal and tracheal epithelium. in brief, injury to ciliated bronchial epithelium may result in degeneration, detachment, and exfoliation of necrotic cells. under normal circumstances, cellular exfoliation is promptly followed by inflammation, mitosis, cell proliferation, cell differentiation, and finally by repair ( fig. - and see . depending on the type of exudate, bronchitis can be fibrinous, catarrhal, purulent, fibrinonecrotic (diphtheritic), and sometimes granulomatous. when epithelial injury becomes chronic, production of mucus is increased via goblet cell hyperplasia (chronic catarrhal inflammation). this form of chronic bronchitis is well illustrated in habitual smokers who continually need to cough out excessive mucus secretions (sputum). unfortunately, in some cases, excessive mucus cannot be effectively cleared from airways, which of the bronchial wall or cylindrical when destruction involves a large segment of a bronchus. grossly, bronchiectasis is manifested by prominent lumps in the lungs (bosselated appearance or having rounded eminences) resulting from distention of bronchi with exudate, which results in a concurrent obstructive atelectasis of surrounding parenchyma ( fig. - ). the cut surfaces of dilated bronchi are filled with purulent exudates; for this reason, bronchiectasis is often mistaken for pulmonary abscesses. careful inspection, usually requiring microscopic examination, confirms that exudate is contained and surrounded by remnants of a bronchial wall lined by squamous epithelium and not by a pyogenic membrane (connective tissue) as it is in the case of a pulmonary abscess. the squamous metaplasia further interferes with the normal function of the mucociliary escalator. the epithelial lining of the bronchiolar region (transitional zone) is exquisitely susceptible to injury, particularly to that caused by some respiratory viruses (bovine parainfluenza virus , bovine respiratory syncytial virus, adenovirus, or canine distemper virus), oxidant gases (nitrogen dioxide [no ], sulfur dioxide [so ], or ozone [o ]), and toxic substances ( -methylindole or paraquat). the precise explanation as to why bronchiolar epithelium is so prone to injury is still not clear, but it is presumably due in part to ( ) its high vulnerability to oxidants and free radicals; ( ) the presence of leads to chronic obstructive bronchitis and emphysema (see . chronic bronchial irritation causes squamous metaplasia of highly functional but vulnerable ciliated epithelium to nonfunctional, but more resistant, squamous epithelium. squamous metaplasia has a calamitous effect on pulmonary clearance because it causes a structural loss and functional breakdown of portions of the mucociliary escalator. hyperplasia of bronchial glands occurs frequently in chronic bronchitis, which translates to an increase of the reid index (bronchial-gland to bronchial-wall ratio) (e- fig. - ). this index is less than % in the healthy human lung and in the lungs of most domestic species, except for cats, which generally have an index higher than %. the term airway remodeling encompasses all the structural changes that accompany chronic bronchitis such as hypertrophy and hyperplasia of smooth muscle, submucosal glands, and goblet cells; fibrosis; and increased bronchial vascularity. bronchiectasis is one of the most devastating sequelae to chronic remodeling of the bronchi. it consists of a pathologic and permanent dilation of a bronchus with rupture of the bronchial wall as a result of obstruction or chronic inflammation. destruction of walls occurs in part when proteolytic enzymes and oxygen radicals released from phagocytic cells during chronic inflammation degrade and weaken the smooth muscle and cartilage (chondromalacia) that help to maintain normal bronchial diameter ( fig. - ). bronchiectasis may be saccular when destruction affects only a small localized portion . this same type of lesion is seen in viral or mechanical injury to the mucosa of the conducting system. two days after exposure, the basement membrane is lined by rapidly dividing preciliated cells, some of which exhibit mitotic activity (inset). ten days after injury, the nasal epithelium is completely repaired. h&e stain. b, schematic representation of the events of injury and repair in the respiratory mucosa of the conducting system. blue cell, ciliated mucosal epithelial cell; pink cell, goblet cell; red cell, neutrophil. (a from lópez a, prior m, yong s, et al: am j vet res : - , into well-organized, microscopic polyps inside the bronchiolar lumen. the external surface of the exudate eventually becomes covered by ciliated cells. this lesion is referred to as bronchiolitis obliterans, and the polyps may become so large as to cause airflow impairment ( fig. - and see fig. - ). in mild but persistent bronchiolar injury, goblet cells normally absent from bronchioles proliferate from basal cells, resulting in goblet cell metaplasia and causing a profound alteration in the physicochemical properties of bronchiolar secretions ( fig. - ). the normally serous bronchiolar fluid released by club (clara) cells becomes a tenacious material when mucus produced by goblet cells is added. as a result of increased viscoelasticity of the mucus, bronchiolar secretions cannot be removed effectively by ciliary action, leading to plugging and obstruction of distal airways. under such conditions, often grouped as chronic obstructive pulmonary disease, coughing is required to clear mucus from obstructed bronchioles. pulmonary emphysema and atelectasis are further sequelae to bronchiolar metaplasia and mucous hypersecretion blocking or partially blocking the lumens of these bronchioles. these two inflation abnormalities are characteristically present in chronic obstructive pulmonary disease (copd), which is called "recurrent airway obstruction (rao or "heaves") in horses (see recurrent airway obstruction, under disorders of horses). peribronchiolar club (clara) cells rich in mixed function oxidases, which locally generate toxic metabolites (see fig. - ); and ( ) the tendency for pulmonary alveolar macrophages and leukocytes to accumulate in this region of the lungs. depending on the types of injury and inflammatory response, bronchiolitis is classified as necrotizing, suppurative, catarrhal (mucous metaplasia), or granulomatous. once injury to bronchiolar ciliated cells becomes irreversible, the cells degenerate and exfoliate into the bronchiolar lumen, leaving a denuded basement membrane. repair in the bronchiolar region is similar to, but less effective than, that in the tracheal or nasal mucosa. under normal circumstances, recruited phagocytic cells remove exudate and cell debris from the lumina of affected bronchioles, thus preparing the basement membrane to be repopulated with new, undifferentiated cells originating from a rapidly dividing pool of club (clara) cells. after several days, these proliferating cells fully differentiate into normal bronchiolar cells. in severe acute injury, such as that caused by aspiration pneumonia or by highly pathogenic microorganisms, exudate attaches and cannot be removed from the basement membrane of bronchioles. the exudate becomes infiltrated by fibroblasts, which form small nodular masses of fibrovascular tissue that develop postviral bronchiolitis is associated with increased expression of tlrs and unusual susceptibility to inhaled endotoxin. hyperreactive animals typically have an increased number of mast cells, eosinophils, and t lymphocytes in the airway mucosa. clinically, airway hyperresponsiveness is characterized by an exaggerated bronchoconstriction after natural exposure to mild stimuli, such as cold air, or after animals are experimentally exposed to aerosols of histamine or methacholine. because of their extremely delicate structure, alveoli are quite vulnerable to injury once the local defense mechanisms have been overwhelmed. the alveolar wall is a thin membrane formed by a core of interstitium supporting an extensive network of alveolar capillaries. fibroblasts (septal cells), myofibroblasts, collagen, elastic fibers, and few interstitial macrophages and mast cells constitute the alveolar interstitium. the wall of the alveolar capillaries facing the airspace is remarkably thin and has three layers composed of vascular endothelium, basal lamina, and alveolar epithelium. these three layers of the alveolar capillaries constitute what is customarily referred to as the blood-air barrier (see fig. - ). the epithelial side of the alveolus is primarily lined by rather thin type i proliferation of lymphocytes (balt hyperplasia) is also a common microscopic lesion seen in chronic bronchiolitis. airway hyperresponsiveness, or hyperreactive airway disease, is another sequela of bronchiolar injury arising from gene-environment interactions. it develops in human beings and animals (experimentally) after a transient and often innocuous viral infection of the lower respiratory tract or from exposure to certain allergens. experimental work has shown that airway hyperreactivity in club (clara) cell edema. alveolar repair is possible as long as the basement membrane remains intact and lesions are not complicated by further injury or infection. within days, cuboidal type ii (granular) pneumonocytes, which are the precursor cells and more resistant to injury, undergo mitosis and provide a large pool of new undifferentiated cells . these new cells repave the denuded alveolar basement membrane and finally differentiate into type i pneumonocytes. when alveolar injury is diffuse, proliferation pneumonocytes, which are arranged as a very delicate continuous membrane extending along the alveolar surface (see fig. - ). type i pneumonocytes are particularly susceptible to noxious agents that reach the alveolar region either aerogenously or hematogenously. injury to type i pneumonocytes rapidly causes swelling and vacuolation of these cells . when cellular damage has become irreversible, type i cells detach, resulting in denudation of the basement membrane, increased alveolar permeability, and alveolar figure - hyperplasia of type ii pneumonocytes. a, acute alveolar injury, crude oil aspiration, cow. note proliferation of cuboidal epithelial cells (type ii pneumonocytes) (arrows) along the luminal surface of the alveolar wall. during alveolar repair, type ii pneumonocytes are the precursor cell for necrotic and lost type i pneumonocytes. h&e stain. b, chronic alveolar injury, interstitial pneumonia, horse. note entire alveolar membrane lined with cuboidal type ii pneumonocytes (arrowheads). the alveolar interstitium is expanded with inflammatory cells, and the alveolar lumens contain cell debris mixed with leukocytes. h&e stain. ( ( ). necrosis of these cells leads to transient alveolar edema (area that is pink) ( ), which is followed by hyperplasia of type ii pneumonocytes ( ), stem cells that differentiate ( ) into type i pneumonocytes as part of alveolar repair and healing ( ). (courtesy dr. a. lópez, atlantic veterinary college.) more information on postmortem examination of the lung can be found at www.expertconsult.com. information on this topic is available at www.expertconsult.com. information on this topic is available at www.expertconsult.com. microbes, toxins, and pneumotoxicants can gain access into the respiratory system by the following routes (table - ; also see table - ): aerogenous, hematogenous, direct extension, and by local production of free radicals and toxic metabolites. pathogens, such as bacteria, mycoplasmas, and viruses, along with toxic gases and foreign particles, including food, can gain access to the respiratory system via inspired air. this is the most common route in the transmission of most respiratory infections in domestic animals. some viruses, bacteria, parasites, and toxins can enter the respiratory system via the circulating blood. this portal of entry is commonly seen in septicemias, bacteremias, and with protozoa and viruses that target endothelial cells. also, circulating leukocytes may release infectious organisms such as retroviruses and listeria monocytogenes while traveling through the lungs. of type ii pneumonocytes becomes so spectacular that the microscopic appearance of the alveolus resembles that of a gland or fetal lung; this lesion has been termed epithelialization or fetalization. although it is part of the normal alveolar repair, hyperplasia of type ii pneumonocytes can interfere in gas exchange and cause hypoxemia. in uncomplicated cases, type ii pneumonocytes eventually differentiate into type i pneumonocytes, thus completing the last stage of alveolar repair (see fig. - ). in some forms of chronic interstitial lung injury, the surface of the alveolar basement membrane could become populated with migrating bronchiolar cells, a process known as alveolar bronchiolization or lambertosis. in severe cases, lambertosis, a metaplastic change, can be mistaken microscopically with alveolar adenomas. type i pneumonocytes are one of the three structural components of the blood-air barrier, so when these epithelial cells are damaged, there is an increase in alveolar capillary permeability and transient leakage of plasma fluid, proteins, and fibrin into the alveolar lumen (see fig. - ) . under normal circumstances, these fluids are rapidly cleared from the alveolus by alveolar and lymphatic absorption, and necrotic pneumonocytes (type i) and fibrin strands are phagocytosed and removed by pulmonary alveolar macrophages. when there is persistent and severe injury, fibroblasts and myofibroblasts may proliferate in the alveolar walls (alveolar interstitium), causing alveolar septal fibrosis, whereas in other forms of severe injury, fibroblasts and myofibroblasts actively migrate from the interstitium into the alveolar spaces, causing intraalveolar fibrosis. these two types of alveolar fibrosis are most commonly seen in toxic and allergic pulmonary diseases and have a devastating effect on lung function. endothelial cells are also major players in the normal and abnormal physiology of the alveolus (see . these cells trap and share circulating antigens with intravascular and interstitial macrophages. the junction between alveolar endothelial cells is not as tight as that of the type i pneumonocytes, allowing some movement of fluid and small-size molecular weight proteins into the alveolar interstitium. endothelial cells maintain an intimate cell contact with erythrocytes and leukocytes passing through the lung, since the lumen of alveolar capillaries is slightly smaller ( . µm) than the diameter of red and white blood cells. erythrocytes are easily deformable, so their transit time through the alveolar capillaries is shorter than that of leukocytes, which are less deformable cells. this longer transit time of leukocytes and their close cellular contact with alveolar endothelial cells have major impacts in lung inflammation and acute respiratory distress syndrome (ards). on a minute-to-minute basis, the pulmonary defense mechanisms deal effectively with noxious stimuli and mild tissue injury without the need for an inflammatory response. however, if normal defense mechanisms are ineffective or insufficient (overwhelmed), the inflammatory process is rapidly turned on as a second line of defense. postmortem examination of the respiratory tract should always be conducted in a thorough and systematic manner and include the conducting system (trachea, bronchi, and bronchioles), the lungs, and the thoracic cavity and pleura. detailed record keeping and photographic documentation are essential elements of a thorough examination. normal lungs typically have a homogeneous pink color and are slightly deflated from loss of negative intrathoracic pressure. the e-sections that follow describe a systematic approach to this process. .e chapter respiratory system, mediastinum, and pleurae the respiratory tract should always be examined in a systematic manner. to determine whether negative pressure is present in the thoracic cavity, the diaphragm is punctured through the abdominal cavity before the thoracic cavity has been opened. when the diaphragm is punctured in a fresh carcass, the loss of negative pressure in the thorax causes the diaphragmatic cupola to drop back caudally toward the abdominal cavity, and at the same time, there is an audible sound caused by the inrush of air into the thorax. lack of this movement may be an indication of advanced pneumothorax, pleural effusion, or the presence of uncollapsed lungs caused by pulmonary edema, pneumonia, fibrosis, or emphysema. in carcasses that have been dead for a long time, pulmonary air and gas produced by saprophytic bacteria leak into the pleural cavity, reducing the negative thoracic pressure and collapsing the lung. the rib cage must be removed by cutting along the costosternal joints and along the neck of the ribs (close to the costovertebral joints) in such a way that pleural adhesions and abnormal thoracic contents can be observed and grossly quantified (e.g., ml of clear, yellow fluid). the tongue, pharynx, esophagus, larynx, trachea, and thoracic viscera (lungs, heart, and thymus) should be removed as a unit (often called the pluck) and placed on the necropsy table. the pharynx and esophagus are opened starting at the pharynx by a single cut with scissors along the dorsal midline and are inspected for ulcers, foreign bodies, and neoplasms. the larynx and trachea must be examined by opening both along the dorsal midline from cranial to caudal ends and then extending the incision into the large bronchi of the caudal lung lobes. normal tracheobronchial mucosa has a smooth and glistening pearl-colored surface with empty lumina in airways. the presence of foamy fluid in airways indicates pulmonary edema. feed particles may suggest aspiration; however, careful examination of the mucosa is required because aspiration of ingesta from stomach or rumen into the lungs commonly takes place agonally or can be displaced into these areas when the carcass is moved. the lungs should be examined before incision. normal lungs typically have a homogeneous pink color (see fig. - ). external changes include the presence of rib imprints on the pleural surface when lungs fail to collapse. in addition, the lungs should be inspected for changes in color and texture and distribution of lesions. color changes can be various shades of red, indicating hypostatic congestion, hyperemia (acute pneumonia), and hemorrhage; dark blue collapsed lobules or areas are indicative of atelectasis; pale pink to white lungs indicate notable anemia, fibrosis, or emphysema; and uniformly or patchy yellow-brown lungs indicate chronic passive congestion and pulmonary fibrosis likely secondary to chronic heart failure. lungs from exsanguinated animals are generally paler than the normal pink color because of reduced blood in the pulmonary tissue. lungs with postmortem autolysis show green discoloration, a change that is also seen in other organs (e- fig. - ). a covering of yellowish material on the pleural surface indicates accumulation of fibrin. because it is impossible to describe the texture of normal lungs, experience in palpation is required to appreciate the actual texture of a normal lung. texture is determined by gently palpating the surface and parenchyma of the lungs. normal texture can change to firm, hard, elastic (rubbery), or crepitus (with a crackling sound or feeling). for a detailed description of lung texture, see the section on classification of pneumonias in domestic animals. palpation of the lungs, which should be gentle, also permits detection of nonvisible nodules or abscesses in the parenchyma. knowing the distribution of a lesion in the lungs also facilitates diagnosis because particular etiologic agents cause lesions with specific distribution. distribution of lesions is generally described as focal, multifocal, locally extensive, or diffuse. according to their topography, pulmo-nary lesions can also be classified as cranioventral, dorsocaudal, and so on. necropsy reports must also contain an estimate of the extent of the pulmonary lesions, preferably expressed as a percentage of the volume of the lungs affected. for instance, a report may read "cranioventral consolidation involving % of the lungs." if the lungs have focal lesions, a rough estimate of the number should also be included in the report. for instance, "numerous (approximately ), small ( to cm in diameter), hard nodules were randomly distributed in all lung lobes." two methods are used to examine the nasal structures. the first is making a midsagittal cut through the head and removing the nasal septum; the second is making several transverse sections of the nose at the level of the second premolar teeth. this latter method is preferred when examining pigs suspected of having atrophic rhinitis or animals suspected of having nasal neoplasms. microscopic examination of pulmonary tissue is routinely done in diagnostic laboratories. samples of normal and abnormal lungs, along with other appropriate tissue, should always be submitted in % buffered-neutral formalin for histopathologic evaluation. a minimum of four lung samples (left cranial, left caudal, right cranial, and right caudal) should be taken for histopathologic examination in animals with a history of respiratory signs. to improve fixation, a paper towel can be placed over the samples of lung floating in fixative. when detailed evaluation of the alveolar walls is required, lungs can be fixed by a gentle intratracheal injection of fixative; however, this technique displaces transudates and exudates and can artificially cause distention of the perivascular and peribronchial spaces. lung biopsy specimens are taken only sporadically because complications often outweigh the diagnostic value. however, the use of new techniques, such as endoscopic-directed biopsies, has notably reduced some of these complications. biopsies of the lungs are recommended in cases of chronic persistent pulmonary disease unresponsive to treatment or intrathoracic masses of undetermined origin. endoscopic-directed biopsies of the nasal and bronchial mucosa are routinely used in clinical practice and generally have a much better diagnostic value. two valuable diagnostic tools in human medicine, bronchoalveolar lavage (bal) and transtracheal wash (ttw), have in recent years become more widely used in veterinary clinical diagnosis of respiratory ailments, particularly in horses, dogs, and cats. the basis of bal and ttw is sampling the lung or trachea of a living animal by infusing sterile fluid into the trachea or deep lung (respectively) and retrieving it to determine the cellular and biochemical composition of this fluid. in other words, the composition of the fluid reflects what is present in the bronchioloalveolar spaces and trachea. these procedures are performed by inserting a tube directly through the larynx into the trachea or bronchus, or transtracheally by inserting a tube through a needle percutaneously into the cervical trachea. microscopic examination of properly collected, stored, and processed samples may reveal many erythrocytes and siderophages in pulmonary hemorrhage or left-sided heart failure; inclusion bodies or syncytial cells in viral pneumonias; increased number of leukocytes in pulmonary inflammation; abundant mucus in asthma or equine recurrent airway obstruction (rao); the presence of pulmonary pathogens, such as parasites, fungi, and bacteria; or tumor cells in cases of pulmonary neoplasia. in the healthy animal, % to % of the bal cells are pulmonary alveolar macrophages (see fig. - , a) . clearance, or a combination of both is the underlying pathogenetic mechanism in many pulmonary diseases ( fig. - ) . the anatomic configuration of the nasal cavity and bronchi plays a unique role in preventing or reducing the penetration of noxious material into the lungs, especially into the alveoli, which is the most vulnerable portion of the respiratory system. the narrow nasal meatuses and the coiled arrangement of the nasal conchae generate enormous turbulence of airflow, and as a result, physical forces are created that forcefully impact particles larger than µm onto the surface of the nasal mucosa ( fig. - ). although particles smaller than µm could escape trapping in the nasal cavity, these mediumsized particles meet a second barrier at the tracheal and bronchial in some instances, pathogenic organisms can also reach the pleura and lungs through penetrating injuries, such as gunshot wounds, migrating awns, or bites, or by direct extension from a ruptured esophagus or perforated diaphragm. the lungs, particularly the bronchioles and alveoli, are vulnerable to endogenous injury caused by the local generation of free radicals during inflammation or by toxic metabolites generated by club (clara) cells (see fig. - , b). inflammatory processes in the respiratory system, particularly those caused by infectious organisms, can spread to contiguous or distant tissues. for instance, rhinitis may spread into the sinuses causing rhinosinusitis. similarly, laryngeal inflammation may spread into the lungs when exudate in the larynx is aspirated. lung disease can have profound systemic effects when cytokines, produced locally during necrosis or inflammation, are released into circulation. as a result of the enormous vascular bed present in the lung, sepsis and septic shock often develop when proinflammatory molecules overwhelm the antiinflammatory response during the so-called "cytokine storm." it is axiomatic that a particle, microbe, or toxic gas must first gain entry to a vulnerable region of the respiratory system before it can induce an adaptive immune response or have a pathologic effect. the characteristics of size, shape, dispersal, and deposition of particles present in inspired air are studied in aerobiology. it is important to recognize the difference between deposition, clearance, and retention of inhaled particles. deposition is the process by which particles of various sizes and shapes are trapped within specific regions of the respiratory tract. clearance is the process by which deposited particles are destroyed, neutralized, or removed from the mucosal surfaces. the difference between what is deposited and what is cleared from the respiratory tract is referred to as retention. the main mechanisms involved in clearance are sneezing, coughing, mucociliary transport, and phagocytosis (table - ). abnormal retention of particles resulting from increased deposition, decreased same rate in all levels of a conducting system, a "bottleneck" effect would be created in major airways as the minor but more numerous airways enter the bronchi. for this reason, the mucociliary transport in proximal (rostral) airways is physiologically faster than that of the distal (caudal) ones. ciliary activity and mucus transport increase notably in response to stimuli such as in respiratory infections. the mucociliary blanket of the nasal cavity, trachea, and bronchi also plays an important role in preventing injury from toxic gases. if a soluble gas contacts the mucociliary blanket, it mixes with the mucus, thus reducing the concentration of gas reaching deep into the alveoli. in other words, mucus acts as a "scavenger system," whereby gases are solubilized and subsequently cleared from the respiratory tract via mucociliary transport. if ciliary transport is reduced (loss of cilia) or mucus production is excessive, coughing becomes an important mechanism for clearing the airways. in addition to the mechanical barrier and physical transport provided by the mucociliary escalator, other cells closely associated with ciliated epithelium contribute to the defense mechanism of the conducting and transitional systems. among the most notable are the microfold (m) cells, which are modified epithelial cells covering the bronchial-associated lymphoid tissue (balt), both of which are strategically situated at the corner of the bifurcation of bronchi and bronchioles, where inhaled particles often collide with the mucosa because of inertial forces. from here, inhaled particles and soluble antigens are phagocytosed and transported by macrophages, dendritic cells, and other professional antigen-presenting cells (apcs) into the balt, thus providing a unique opportunity for b and t lymphocytes to enter into close contact with inhaled pathogenic substances. pulmonary lymphocytes are not quiescent in the balt but are in continual traffic to other organs and contribute to both cellular (cytotoxic, helper, and suppressor t lymphocytes) and humoral immune responses. immunoglobulin a (iga), produced by mucosal plasma cells, and, to a lesser extent, immunoglobulin g (igg) and m (igm) play important roles in the local immunity of the conducting and transitional systems, especially with regard to preventing attachment of pathogens to the cilia. chronic airway diseases, especially those caused by infectious agents such as mycoplasmas or retroviruses, are often accompanied by severe hyperplasia of the balt. the mucociliary clearance terminates at the pharynx, where mucus, propelled caudally from the nasal cavity and cranially from the tracheobronchial tree, is eventually swallowed and thus eliminated from the conducting system of the respiratory tract. some respiratory pathogens, such as rhodococcus equi, can infect the intestines after having been removed and swallowed from the respiratory tract into the alimentary system. alveoli lack ciliated and mucus-producing cells; thus the defense mechanism against inhaled particles in the alveolar region cannot be provided by mucociliary clearance. instead, the main defense mechanisms of alveoli (exchange system) are phagocytosis provided by the pulmonary alveolar macrophages and antimicrobial molecules of the alveolar lining fluid ( fig. - ). pulmonary alveolar macrophages are highly phagocytic cells, which are not to be confused with pulmonary intravascular macrophages, and are derived largely from blood monocytes and, to a much lesser extent, from a slowly dividing population of interstitial macrophages. after a temporary adaptive stage within alveolar interstitium, blood monocytes reduce their glycolytic metabolism and increase their oxidative metabolism to function in an aerobic rather than an anaerobic environment. pulmonary alveolar macrophages contribute to the bifurcations. abrupt changes in the direction of air (inertia), which occurs at the branching of major airways, cause particles in the -to -µm size range to collide with the surface of bronchial mucosa (see fig. - ). because the velocity of inspired air at the level of the small bronchi and bronchioles has become rather slow, inertial and centrifugal forces no longer play a significant role in the trapping of inhaled particles. here, in the transitional (bronchiolar) and exchange (alveolar) regions, particles µm or smaller may come into contact with the mucosa by means of sedimentation because of gravitation or by diffusion as a result of brownian movement. infective aerosols containing bacteria and viruses are within the size range ( . to µm) that can gain access to the bronchiolar and alveolar regions. in addition to size, other factors, such as shape, length, electrical charge, and humidity, play an important role in mucosal deposition, retention, and pathogenicity of inhaled particles. for example, particles longer than µm may also reach the lower respiratory tract provided their mean aerodynamic diameter is less than µm. asbestos is a good example of a large but slender fiber that can bypass the filtrating mechanisms by traveling parallel to the airstream. once in the terminal bronchioles and alveoli, asbestos fibers cause asbestosis, a serious pulmonary disease in human beings. in summary, the anatomic features of the nasal cavity and airways provide an effective barrier, preventing the penetration of most large particles into the lungs. once larger particles are trapped in the mucosa of conducting airways and small particles are deposited on the surface of the nasal, tracheal, or bronchoalveolar mucosa, it is crucial that these exogenous materials be promptly removed to prevent or minimize injury to the respiratory system. for these purposes, the respiratory system is equipped with several defense mechanisms, all of which are provided by specialized cells operating in a remarkably well-coordinated manner. conducting system (nose, trachea, and bronchi) mucociliary clearance is the physical unidirectional movement and removal of deposited particles and gases dissolved in the mucus from the respiratory tract. mucociliary clearance, also referred to as the waste disposal system, is provided by the mucociliary blanket (mucociliary escalator) and is the main defense mechanism of the conducting system (nasal cavity, trachea, and bronchi) (see figs. - and - ). mucus acts primarily as a barrier and a vehicle, and it is a complex mixture of water, glycoproteins, immunoglobulins, lipids, and electrolytes. these substances are produced by goblet (mucous) cells, serous cells, submucosal glands, and fluid from transepithelial ion and water transport. once serous fluid and mucus are secreted onto the surface of the respiratory mucosa, a thin, double-layer film of mucus is formed on top of the cells. the outer layer of this film is in a viscous gel phase, whereas the inner layer, which is in a fluid or sol phase, is directly in contact with cilia (see fig. - and see e- fig. - ). the respiratory system of a healthy human produces approximately ml of mucus per day. each ciliated cell in the conducting system has approximately to motile and chemosensory cilia ( µm long), beating metachronously (forming a wave) at a ciliary beat frequency of approximately strokes per minute, and in a horse, for example, mucus moves longitudinally at a rate of up to mm per minute. rapid and powerful movement of cilia creates a series of waves that, in a continuous and synchronized manner, propel the mucus, exfoliated cells, and entrapped particles out of the respiratory tract to the pharynx. the mucus is finally swallowed or, when present in large amounts, is coughed up out of the conducting system. if mucus flow were to move at the activated alveolar macrophages. similarly, inhaled particles, such as dust, pollen, spores, carbon, or erythrocytes from intraalveolar hemorrhage, are all phagocytosed and eventually removed from alveoli by pulmonary alveolar macrophages. most alveolar macrophages leave the alveoli by migrating toward the bronchiolar (transitional) region until the mucociliary blanket is reached. once there, pulmonary macrophages are removed in the same way as any other particle: along the mucociliary flow to the pharynx and swallowed. in the cat, as many as million macrophages per hour move out from the alveoli into the conducting system and pharynx. destruction and removal of inhaled microbes and particles by alveolar macrophages is a well-orchestrated mechanism that engages many cells, receptors (i.e., toll-like receptors [tlrs]), and pulmonary secretions in the lung. the cell-to-cell interactions are complex and involve pulmonary alveolar macrophages, pneumonocytes, endothelial cells, lymphocytes, plasma cells, natural killer (nk) cells, and dendritic cells. antibodies are also important in the protection (acquired immune response) of the respiratory tract against inhaled pathogens. iga is the most abundant antibody in the nasal and tracheal secretions and prevents the attachment and absorption of antigens (immune exclusion). igg and, to a lesser extent, ige and igm promote the uptake and destruction of inhaled pathogens by phagocytic cells (immune elimination). igg is the most abundant antibody in the alveolar surface and acts primarily as an opsonizing antibody for alveolar macrophages and neutrophils. in addition to antibodies, there are several secretory molecules locally released into the alveoli that constitute the alveolar lining material and contribute to the pulmonary defense mechanisms. the most important of these antimicrobial products are transferrin, anionic peptides, and pulmonary surfactant (table - ). to facilitate phagocytosis and discriminate between "self" and "foreign" antigens, pulmonary alveolar macrophages are furnished with a wide variety of specific receptors on their cell surfaces. among the most important ones are fc receptors for antibodies; complement receptors (for c b, c a, and c a); tumor necrosis factor (tnf) receptor; and cd receptors, which facilitate phagocytosis and destruction of opsonized particles. toll-like receptors (tlrs) recognize microbial components, and apoptosis stimulating fragment (fas) receptors are involved in apoptosis and in the phagocytosis of apoptotic cells in the lung. "scavenger receptors," which are responsible for the recognition and uptake of foreign particulates, such as dust and fibers, are also present on pulmonary alveolar macrophages. lungs are also susceptible to hematogenously borne microbes, toxins, or emboli. the hepatic (kupffer cells) and splenic macrophages are the primary phagocytic cells responsible for removing circulating bacteria and other particles from the blood of dogs, some rodents, and human beings. in contrast, the cell responsible for the removal of circulating particles, bacteria, and endotoxin from the blood of ruminants, cats, pigs, and horses is mainly the pulmonary intravascular macrophage, a distinct population of phagocytes normally residing within the pulmonary capillaries (see fig. - ). in pigs, % of the pulmonary capillary surface is lined by pulmonary intravascular macrophages. in ruminants, % of intravenously injected tracer particles or bacteria are rapidly phagocytosed by these intravascular macrophages. studies have shown that an abnormally reduced number of kupffer cells in diseased liver results in a compensatory increase in pulmonary intravascular macrophages, even in animal species in which these phagocytic cells are normally absent from the lung. in some abnormal conditions, such as sepsis, pulmonary innate and adaptive immune response by rapidly attaching and phagocytosing bacteria and any other particles reaching the alveolar lumens. the number of free macrophages in the alveolar space is closely related to the number of inhaled particles reaching the lungs. this ability to increase, within hours, the number of available phagocytic cells is vital in protecting the distal lungs against foreign material, particularly when the inhaled particle load is high. unlike that of tissue macrophages, the life span of alveolar macrophages in the alveoli is notably short, only a few days, and thus they are continuously being replaced by newly migrated blood monocytes. alveolar phagocytosis plays a prominent role in the innate defense mechanism against inhaled bacteria without the need of an inflammatory reaction. bacteria reaching the alveoli are rapidly phagocytosed, and bactericidal enzymes present in lysosomes are discharged into the phagosome containing the bacteria (see b) . except for some facultative pathogens that are resistant to intracellular killing (e.g., mycobacterium tuberculosis, listeria monocytogenes, brucella abortus, rhodococcus equi, and some salmonella spp.), most bacteria reaching the lungs are rapidly destroyed by (ros) not only induce extensive pulmonary injury but also impair the defense and repair mechanisms in the lung. oxygen and free radical scavengers, such as catalase, superoxide dismutase, ubiquinone, and vitamins e and c, are largely responsible for protecting pulmonary cells against peroxidation. these scavengers are present in alveolar and bronchiolar epithelial cells and in the extracellular spaces of the pulmonary interstitium. in summary, the defense mechanisms are so effective in trapping, destroying, and removing bacteria that, under normal conditions, animals can be exposed to aerosols containing massive numbers of bacteria without any ill effects. if defense mechanisms are impaired, inhaled bacteria colonize and multiply in bronchi, bronchioles, and alveoli, and they produce infection, which can result in fatal pneumonia. similarly, when blood-borne pathogens, inhaled toxicants, or free radicals overwhelm the protective defense mechanisms, cells of the respiratory system are likely to be injured, often causing serious respiratory diseases. for many years, factors such as viral infections, toxic gases, stress, and pulmonary edema have been implicated in predisposing human beings and animals to secondary bacterial pneumonia. there are many pathways by which the defense mechanisms can be impaired; only those relevant to veterinary species are discussed. viral agents are notorious in predisposing human beings and animals to secondary bacterial pneumonias by what is known as viral-bacterial synergism. a good example of the synergistic effect of combined virus-bacterial infections is documented from epidemics of human beings with influenza virus in which the mortality rate has been significantly increased from secondary bacterial pneumonia. the most common viruses incriminated in predisposing animals to secondary bacterial pneumonia include influenza virus in pigs and horses; bovine herpesvirus (bohv- ), bovine parainfluenza virus (bpiv- ), and bovine respiratory syncytial virus (brsv) in cattle; canine distemper virus (cdv) in dogs; and felid herpesvirus (fehv- ) and feline calicivirus (fcv) in cats. the mechanism of the synergistic effect of viral-bacterial infections was previously believed to be the destruction of the mucociliary blanket and a concurrent reduction of mucociliary clearance, but in experimental studies, viral infections did not significantly reduce the physical removal of particles or bacteria out of the lungs. now, it is known that to days after a viral infection, the phagocytic function of pulmonary alveolar macrophages and, to a lesser extent, the mucociliary clearance are notably impaired (see fig. - ). other mechanisms by which viruses impair defense mechanisms are multiple and remain poorly understood (box - ). immunization against viral infections in many cases prevents or reduces the synergistic effect of viruses and thus the incidence of secondary bacterial pneumonia. certain gases also impair respiratory defense mechanisms, rendering animals more susceptible to secondary bacterial infections. for instance, hydrogen sulfide and ammonia, frequently encountered on farms, especially in buildings with poor ventilation, can impair pulmonary defense mechanisms and increase susceptibility to bacterial pneumonia. the effects of environmental pollutants on the defense mechanisms of human beings and animals living in crowded and polluted cities remain to be determined. excessive release of cytokines by pulmonary intravascular macrophages may result in acute lung injury. existing in an oxygen-rich environment and being the site of numerous metabolic reactions, the lungs also require an efficient defense mechanism against oxidant-induced cellular damage (oxidative stress). this form of damage is caused by inhaled oxidant gases (e.g., nitrogen dioxide, ozone, sulfur dioxide, or tobacco smoke), by xenobiotic toxic metabolites produced locally, by toxins reaching the lungs via the bloodstream (e.g., -methylindole and paraquat), or by free radicals (reactive oxygen species) released by phagocytic cells during inflammation. free radicals and reactive oxygen species anomalies localized congenital anomalies of the nasal cavity are rare in domestic animals and are often merely part of a more extensive craniofacial deformity (e.g., cyclops) or a component of generalized malformation (e.g., chondrodysplasia). congenital anomalies involving the nasal cavity and sinuses, such as choanal atresia (lack of communication between the nasal cavity and pharynx), some types of chondrodysplasia, and osteopetrosis, are incompatible with life. examples of nonfatal congenital anomalies include cystic nasal conchae, deviation of the nasal septum, cleft upper lip (harelip and cheiloschisis), hypoplastic turbinates, and cleft palate (palatoschisis) (see fig. - ). bronchoaspiration and aspiration pneumonia are common sequelae to cleft palate. nasal and paranasal sinus cysts are slowly growing and expansive lesions that mimic neoplasia and cause severe cranial deformation in horses. as in other organs or systems, it is extremely difficult to determine the actual cause (genetic vs. congenital) of anomalies based on pathologic evaluation. metabolic disturbances affecting the nasal cavity and sinuses are rare in domestic animals. immunodeficiency disorders, whether acquired or congenital, are often associated with increased susceptibility to viral, bacterial, and protozoal pneumonias. for example, human beings with acquired immunodeficiency syndrome (aids) are notably susceptible to pneumonia caused by proliferation of pneumocystis (carinii) jirovecii. a similar ubiquitous organism, which under normal circumstances is not pathogenic, is also found in the pneumonic lungs of immunosuppressed pigs, foals, dogs, and rodents. pigs infected with the porcine reproductive and respiratory syndrome (prrs) virus frequently develop pneumocystis carinii infection ( fig. - ) . arabian foals born with combined immunodeficiency disease easily succumb to infectious diseases, particularly adenoviral pneumonia. combined infections with two respiratory viruses, such as canine distemper virus (cdv) and canine adenovirus (cav- ), are sporadically reported in immunosuppressed puppies. also, large doses of chemotherapeutic agents, such as steroids and alkylating agents, cause immunosuppression in dogs, cats, and other animals, increasing susceptibility to secondary viral and bacterial infections. stress, uremia, endotoxemia, dehydration, starvation, hypoxia, acidosis, pulmonary edema, anesthesia, and ciliary dyskinesia are only some of the many conditions that have been implicated in impairing respiratory defense mechanisms and consequently predisposing animals to develop secondary bacterial pneumonia. the mechanisms by which each of these factors suppresses pulmonary defenses are diverse and sometimes not well understood. for example, hypoxia and pulmonary edema decrease phagocytic function of pulmonary alveolar macrophages and alter the production of surfactant (abnormal head tilt and abnormal gait), which in severe cases may lead to emaciation. based on the nature of exudate, rhinitis can be classified as serous, fibrinous, catarrhal, purulent, or granulomatous. these types of inflammatory reactions can progress from one to another in the course of the disease (i.e., serous to catarrhal to purulent), or in some instances exudates can be mixed, such as those seen in mucopurulent, fibrinohemorrhagic, or pyogranulomatous rhinitis. microscopic examination of impression smears or nasal biopsy, and bacterial or fungal cultures are generally required in establishing the cause of inflammation. common sequelae of rhinitis are hemorrhage, ulcers, and, in some cases, nasopharyngeal polyps (hyperplasia) arising from inflamed mucosa. rhinitis also can be classified according to the age of the lesions as acute, subacute, or chronic; to the severity of the insult as mild, moderate, or severe; and to the etiologic agent as viral, allergic, bacterial, mycotic, parasitic, traumatic, or toxic. serous rhinitis. serous rhinitis is the mildest form of inflammation and is characterized by hyperemia and increased production of a clear fluid locally manufactured by serous glands present in the nasal submucosa. serous rhinitis is of clinical interest only. it is caused by mild irritants or cold air, and it occurs during the early stages of viral infections, such as the common cold in human beings, upper respiratory tract infections in animals, or in mild allergic reactions. catarrhal rhinitis. catarrhal rhinitis is a slightly more severe process and has, in addition to serous secretions, a substantial increase in mucus production by hypersecretion of goblet cells and mucous glands. a mucous exudate is a thick, translucent, or slightly turbid viscous fluid, sometimes containing a few exfoliated cells, leukocytes, and cellular debris. in chronic cases, catarrhal rhinitis is characterized microscopically by notable hyperplasia of goblet cells. as the inflammation becomes more severe, the mucus is infiltrated with neutrophils, giving the exudate a cloudy appearance. this exudate is referred to as mucopurulent. purulent (suppurative) rhinitis. purulent (suppurative) rhinitis is characterized by a neutrophilic exudate, which occurs when the nasal mucosa suffers a more severe injury that generally is accompanied by mucosal necrosis and secondary bacterial infection. cytokines, leukotrienes, complement activation, and bacterial products cause exudation of leukocytes, especially neutrophils, which mix with nasal secretions, including mucus. grossly, the exudate in suppurative rhinitis is thick and opaque, but it can vary from white to green to brown, depending on the types of bacteria and type of leukocytes (neutrophils or eosinophils) present in the exudate . in severe cases, the nasal passages are completely blocked by the exudate. microscopically, neutrophils can be seen in the submucosa and mucosa and form plaques of exudate on the mucosal surface. neutrophils are commonly found marginated in vessels, in the lamina propria, and in between epithelial cells in their migration to the surface of the mucosa. fibrinous rhinitis. fibrinous rhinitis is a reaction that occurs when nasal injury causes a severe increase in vascular permeability, resulting in abundant exudation of plasma fibrinogen, which coagulates into fibrin. grossly, fibrin appears as a yellow, tan, or gray rubbery mat on nasal mucosa. fibrin accumulates on the surface and forms a distinct film of exudate sometimes referred to as pseudomembrane ( fig. - ). if this fibrinous exudate can be removed, leaving an intact underlying mucosa, it is termed a croupous or pseudodiphtheritic rhinitis. conversely, if the pseudomembrane is difficult to remove and leaves an ulcerated mucosa, it is referred to as diphtheritic or fibrinonecrotic rhinitis. the term diphtheritic was derived from human diphtheria, which causes a severe and destructive inflammatory process of the nasal, tonsillar, pharyngeal, and laryngeal mucosa. nasal amyloidosis. amyloidosis, the deposition of amyloid protein (fibrils with a β-pleated configuration) in various tissues, has been sporadically reported as a localized lesion in the nasal cavity of horses and human beings (see nasal amyloidosis, in disorders of horses). congestion and hyperemia. the nasal mucosa is well vascularized and is capable of rather dramatic variation in blood flow, whether passively as a result of interference with venous return (congestion) or actively because of vasodilation (hyperemia). congestion of the mucosal vessels is a nonspecific lesion commonly found at necropsy and presumably associated with the circulatory failure preceding death (e.g., heart failure, bloat in ruminants in which the increased intraabdominal pressure causes increased intrathoracic pressure impeding the venous return from the head and neck). hyperemia of the nasal mucosa is seen in early stages of inflammation, whether caused by irritation (e.g., ammonia and regurgitated feed), viral infections, secondary bacterial infections, toxemia, allergy, or trauma. hemorrhage. epistaxis is the clinical term used to denote blood flow from the nose (nosebleed) regardless of whether the blood originates from the nasal mucosa or from deep in the lungs, such as in horses with "exercise-induced pulmonary hemorrhage." unlike blood in the digestive tract, where the approximate anatomic location of the bleeding can be estimated by the color the blood imparts to fecal material, blood in the respiratory tract is always red. this fact is due to the rapid transport of blood out of the respiratory tract by the mucociliary blanket and during breathing. hemorrhages into the nasal cavity can be the result of local trauma, can originate from erosions of submucosal vessels by inflammation (e.g., guttural pouch mycosis), or can be caused by neoplasms. hemoptysis refers to the presence of blood in sputum or saliva (coughing or spitting blood) and is most commonly the result of pneumonia, lung abscesses, ulcerative bronchitis, pulmonary thromboembolisms or hemorrhage, and pulmonary neoplasia. inflammation of the nasal mucosa is called rhinitis, and inflammation of the sinuses is called sinusitis. these conditions usually occur together, although mild sinusitis can be undetected. clinically, rhinosinusitis is characterized by nasal discharge. rhinitis. the occurrence of infectious rhinitis presupposes an upset in the balance of the normal microbial flora of the nasal cavity. innocuous bacteria present normally protect the host through a process called competitive exclusion, whereby potential pathogens are kept at a harmless level. disruption of this protective mechanism can be caused by respiratory viruses, pathogenic bacteria, fungi, irritant gases, environmental changes, immunosuppression, local trauma, stress, or prolonged antibacterial therapy. inflammatory processes in the nasal cavity are not life-threatening and usually resolve completely. however, some adverse sequelae in cases of infectious rhinitis include bronchoaspiration of exudate leading to bronchopneumonia. chronic rhinitis often leads to destruction of the nasal conchae (turbinates), deviation of the septum, and, eventually, craniofacial deformation. also, nasal inflammation may extend into the sinuses causing sinusitis; into facial bones causing osteomyelitis; through the cribriform plate causing meningitis; into the eustachian tubes causing otitis media or guttural pouch empyema (eustachitis) in horses; and even into the inner ear causing otitis interna and vestibular syndrome the nasal septum has been removed to expose nasal conchae. the nasal mucosa is hyperemic and covered by yellow-white purulent exudate (arrows). inset, histological section showing submucosal congestion and edema and also large aggregates of neutrophils on the superficial mucosa (asterisk). h&e stain. (courtesy dr. a. lópez, atlantic veterinary college.) microscopically, the lesions include a perivascular edema with fibrin, a few neutrophils infiltrating the mucosa, and superficial plaques of exudate consisting of fibrin strands mixed with leukocytes and cellular debris covering a necrotic and ulcerated epithelium. fungal infections, such as aspergillosis, can cause a severe fibrinonecrotizing rhinitis. granulomatous rhinitis. granulomatous rhinitis is a reaction in the nasal mucosa and submucosa that is characterized by infiltration of numerous activated macrophages mixed with a few lymphocytes and plasma cells (figs. - and - ). in some cases, chronic inflammation leads to the formation of polypoid nodules that in severe cases are large enough to cause obstruction of the nasal passages ( fig. - ). granulomatous rhinitis is generally associated with chronic allergic inflammation or infection with specific organisms, such as fungi (see fig. - ), tuberculosis, systemic mycosis (see section on granulomatous pneumonia), and rhinosporidiosis ; also see fig. - ). in some cases, the cause of granulomatous rhinitis cannot be determined. sinusitis. sinusitis occurs sporadically in domestic animals and is frequently combined with rhinitis (rhinosinusitis), or it occurs as extend into the adjacent bone (osteomyelitis) or through the ethmoidal conchae into the meninges and brain (meningitis and encephalitis). nasal amyloidosis. amyloidosis, the deposition of amyloid protein (fibrils with a β-pleated configuration) in various tissues, has been sporadically reported as a localized lesion in the nasal cavity of horses. unlike amyloidoses in other organs of domestic animals where amyloid is generally of the reactive type (amyloid aa), equine nasal amyloidosis appears to be of the immunocytic type (amyloid al). affected horses with large amyloid masses have difficulty breathing because of nasal obstruction and may exhibit epistaxis and reduced athletic performance; on clinical examination, large, firm nodules resembling neoplasms (amyloidoma) can be observed in the alar folds, rostral nasal septum, and floor of nasal cavity. microscopic lesions are similar to those seen in other organs and consist of a deposition of hyaline amyloid material in nasal mucosa that is confirmed by a histochemical stain, such as congo red. progressive ethmoidal hematoma. progressive ethmoidal hematoma (peh) is important in older horses and is characterized clinically by chronic, progressive, often unilateral nasal bleeding. grossly or endoscopically, an ethmoidal hematoma appears as a single, soft, tumor-like, pedunculated, expansive, dark red mass arising from the mucosa of the ethmoidal conchae ( fig. - ) . microscopic examination reveals a capsule lined by epithelium and hemorrhagic stromal tissue infiltrated with abundant macrophages, most of which are siderophages. viral infections. viruses, such as equine viral rhinopneumonitis virus, influenza virus, adenovirus, and equine picornavirus, cause mild and generally transient respiratory infections in horses. the route of infection for these respiratory viruses is typically aerogenous. all of these infections are indistinguishable clinically; signs consist mainly of malaise, fever, coughing, conjunctivitis, and nasal a sequela to penetrating or septic wounds of the nasal, frontal, maxillary, or palatine bones; improper dehorning in young cattle, which exposes the frontal sinus; or maxillary tooth infection in horses and dogs (maxillary sinus). based on the type of exudate, sinusitis is classified as serous, catarrhal, fibrinous (rare), purulent, or granulomatous. paranasal sinuses have poor drainage; therefore exudate tends to accumulate, causing mucocele (accumulation of mucus) or empyema (accumulation of pus) ( fig. - ). chronic sinusitis may promised horses, particularly in arabian foals with inherited combined immunodeficiency disease. bacterial infections. strangles, glanders, and melioidosis of horses are all systemic bacterial diseases that cause purulent rhinitis and suppuration in various organs. these diseases are grouped as upper respiratory diseases because nasal discharge is often the most notable clinical sign. strangles. strangles is an infectious and highly contagious disease of equidae that is caused by streptococcus equi ssp. equi (streptococcus equi) . it is characterized by suppurative rhinitis and lymphadenitis (mandibular and retropharyngeal lymph nodes) with occasional hematogenous dissemination to internal organs. unlike streptococcus equi ssp. zooepidemicus (streptococcus zooepidemicus) and streptococcus dysgalactiae ssp. equisimilis (streptococcus equisimilis), streptococcus equi is not part of the normal nasal flora. infection occurs when susceptible horses come into contact with feed, exudate, or air droplets containing the bacterium. after penetrating through the nasopharyngeal mucosa, streptococcus equi drains to the regional lymph nodes-mandibular and retropharyngeal lymph nodes-via lymphatic vessels. the gross lesions in horses with strangles (mucopurulent rhinitis) correlate with clinical findings and consist of copious amounts of mucopurulent exudate in the nasal passages with notable hyperemia of the nasal mucosa. affected lymph nodes are enlarged and may contain abscesses filled with thick purulent exudate (purulent lymphadenitis). the term bastard strangles is used in cases in which hematogenous dissemination of streptococcus equi results in metastatic abscesses in such organs as the lungs, liver, spleen, kidneys, or brain or in the joints. this form of strangles is often fatal. common sequelae to strangles include bronchopneumonia caused by aspiration of nasopharyngeal exudate; laryngeal hemiplegia ("roaring"), resulting from compression of the recurrent laryngeal nerves by enlarged retropharyngeal lymph nodes; facial paralysis and horner syndrome caused by compression of sympathetic nerves that run dorsal to the medial retropharyngeal lymph node; and purpura hemorrhagica as a result of vasculitis caused by deposition of streptococcus equi antigen-antibody complexes in arterioles, venules, and capillaries of the skin and mucosal membranes. in severe cases, nasal infection extends directly into the paranasal sinuses or to the guttural pouches via the eustachian tubes, causing inflammation and accumulation of pus (guttural pouch empyema). rupture of abscesses in the mandibular and retropharyngeal lymph nodes leads to suppurative inflammation of adjacent subcutaneous tissue (cellulitis), and in severe cases the exudate escapes through cutaneous fistulas. strangles can affect horses of all ages, but it is most commonly seen in foals and young horses. it is clinically characterized by cough, nasal discharge, conjunctivitis, and painful swelling of regional lymph nodes. some horses become carriers and a source of infection to other horses. glanders. glanders is an infectious world organization for animal health (oie)-notifiable disease of equidae caused by burkholderia mallei (pseudomonas mallei) that can be transmitted to carnivores by consumption of infected horsemeat. human beings are also susceptible, and untreated infection is often fatal. this gramnegative bacterium has been listed as a potential agent for biologic warfare and bioterrorism. in the past, burkholderia mallei was found throughout the world, but today, glanders has been eradicated from most countries, except for some areas in north africa, asia, and eastern europe. there also have been sporadic outbreaks reported in brazil. the pathogenesis of glanders is not fully understood. results from experimental infections suggest that infection occurs discharge varying from serous to purulent. viral respiratory infections are common medical problems in adult horses. equine viral rhinopneumonitis. equine viral rhinopneumonitis (evr) is caused by two ubiquitous equine herpesviruses (ehv- and ehv- ) and may be manifested as a mild respiratory disease in weanling foals and young racehorses, as a neurologic disease (myeloencephalopathy), or as abortion in mares. the portal of entry for the respiratory form is typically aerogenous, and the disease is generally transient; thus the primary viral-induced lesions in the nasal mucosa and lungs are rarely seen at necropsy unless complicated by secondary bacterial rhinitis, pharyngitis, or bronchopneumonia. studies with polymerase chain reaction (pcr) techniques have demonstrated that, like other herpesviruses, ehv- and ehv- persist in the trigeminal ganglia for long periods of time (latency). reactivation because of stress or immunosuppression and subsequent shedding of the virus are the typical source of infection for susceptible animals on the farm. equine influenza. equine influenza is a common, highly contagious, and self-limiting upper respiratory infection of horses caused by aerogenous exposure to type a strains of influenza virus (h n [a/equi- ] and h n [a/equi- ]). equine influenza has high morbidity (outbreaks) but low mortality, and it is clinically characterized by fever, conjunctivitis, and serous nasal discharge. it occurs mainly in -to -year-old horses at the racetrack. as with human influenza, equine influenza is usually a mild disease, but occasionally it can cause severe bronchointerstitial pneumonia with pulmonary edema. in some horses, impaired defense mechanisms caused by the viral infection are complicated by a secondary bacterial bronchopneumonia caused by opportunistic organisms (streptococcus zooepidemicus, staphylococcus aureus, or bacteroides sp.) found in the normal flora of the upper respiratory tract. uncomplicated cases of equine influenza are rarely seen in the postmortem room. equine influenza virus (h n ) recently did an equine to canine "host-jump" causing extensive outbreaks of respiratory disease in dogs (see pneumonias of dogs). other equine respiratory viruses. equine picornavirus, adenovirus, and parainfluenza virus produce mild and transient upper respiratory infections (nasopharynx and trachea) in horses, unless complicated by secondary pathogens. in addition to reduced athletic performance, infected horses may have a temporary suppression of cell-mediated immunity leading to opportunistic infections such as pneumocystis carinii pneumonia. fatal adenoviral infections with severe pneumonia or enteritis occur commonly in immunocom- disorders of ruminants (cattle, sheep, and goats) infectious bovine rhinotracheitis. infectious bovine rhinotracheitis (ibr), or "rednose," occurs worldwide and is a disease of great importance to the cattle industry because of the synergism of the ibr virus with mannheimia haemolytica in producing pneumonia. the causative agent, bovine herpesvirus (bohv- ), has probably existed as a mild venereal disease in cattle in europe since at least the mid- s, but the respiratory form was not reported until intensive management feedlot systems were first introduced in north america around the s. typically, the disease is manifested as a transient, acute, febrile illness, which results in inspiratory dyspnea caused by obstruction of the airways by exudate only in very severe cases. other forms of bohv- infection include ulcerative rumenitis; enteritis; multifocal hepatitis in neonatal calves; nonsuppurative meningoencephalitis; infertility; and in experimental infections, mastitis, mammillitis, and ovarian necrosis. except for the encephalitic form, the type of disease caused by bohv- depends more on the site of entry than the viral strain. like other herpesviruses, bohv- also can remain latent in nerve ganglia, with recrudescence after stress or immunosuppression. this virus also causes bovine abortion, systemic infections of calves, and genital infections such as infectious pustular vulvovaginitis (ipv) and infectious balanoposthitis (ibp). the respiratory form of ibr is characterized by severe hyperemia and multifocal necrosis of nasal, pharyngeal, laryngeal, tracheal, and sometimes bronchial mucosa ( fig. - and see fig. - ). as in other respiratory viral infections, ibr lesions are microscopically characterized by necrosis and exfoliation of ciliated cells followed by repair. secondary bacterial infections of these areas of necrosis result in the formation of a thick layer of fibrinonecrotic material (diphtheritic) in the nasal, tracheal, and bronchial mucosa (see fig. - ). intranuclear inclusion bodies, commonly seen in herpesvirus infections, are rarely seen in field cases because inclusion bodies occur only during the early stages of the disease. the most important sequela to ibr is bronchopneumonia, which is caused either by direct aspiration of exudate from airways or as a result of an impairment in pulmonary defense mechanisms, thus predisposing the animal to secondary bacterial infection, most frequently mannheimia haemolytica (see pneumonic mannheimiosis discussion). postmortem diagnosis of ibr is confirmed by isolation of the virus or its identification by immunohistochemistry or pcr in affected tissues. other causes of rhinitis. nasal granulomas occur in cattle presumably as a result of repeated exposure to an unidentified inhaled antigen. nasal granulomas (atopic rhinitis) are reported mainly in cattle in australia, south africa, and the united kingdom, where affected cattle develop multiple, small, pink or red, polypoid nodules, starting in the nasal vestibule that in time extend into the caudal aspect of the nasal septum (see fig. - ). these nodules are composed of fibrovascular tissue mixed with lymphocytes (granulation tissue) superficially lined by hyperplastic epithelium with abundant mast cells and eosinophils in the lamina propria (nasal eosinophilia). the microscopic features suggest that hypersensitivity type i (immediate), type iii (immune complex), and type iv (delayed) may be involved in nasal granulomas of cattle. bovine (idiopathic) nasal granuloma must be differentiated from nasal mycetomas, nasal rhinosporidiosis, and nasal schistosomiasis, which also cause the formation of nodules in the nasal mucosa of cattle. an eosinophilic material consistent with the splendore-hoeppli phenomenon is occasionally observed in bovine mycotic granulomas. this phenomenon seen in some mycotic or bacterial infections is microscopically via the ingestion of contaminated feed and water and, very rarely, via inhalation of infectious droplets. the portals of entry are presumed to be the oropharynx or intestine, in which bacteria penetrate the mucosa and spread via lymph vessels to regional lymph nodes, then to the bloodstream, and thus hematogenously to the internal organs, particularly the lungs. lesions in the nasal cavity start as pyogranulomatous nodules in the submucosa; these lesions subsequently ulcerate, releasing copious amounts of burkholderia mallei-containing exudate into the nasal cavity (see fig. - , a) . finally, ulcerative lesions in conchal mucosa heal and are replaced by typical stellate (star-shaped), fibrous scars. in some cases, the lungs also contain numerous gray, hard, small ( to mm), miliary nodules (resembling millet seeds) randomly distributed in one or more pulmonary lobes because of the hematogenous route. microscopically, these nodules are typical chronic granulomas composed of a necrotic center, with or without calcification, surrounded by a layer of macrophages enclosed by a thick band of connective tissue infiltrated with macrophages, fewer giant cells, lymphocytes, and plasma cells. cutaneous lesions, often referred to as equine farcy, are the result of severe suppurative lymphangitis characterized by nodular thickening of extended segments of lymph vessels in the subcutaneous tissue of the legs and ventral abdomen (see fig. - , c). eventually, affected lymph vessels rupture and release large amounts of purulent exudate through sinuses to the surface of the skin. melioidosis (pseudoglanders). melioidosis (pseudoglanders) is an important, life-threatening disease of human beings, horses, cattle, sheep, goats, pigs, dogs, cats, and rodents caused by burkholderia pseudomallei (pseudomonas pseudomallei). this disease in horses is clinically and pathologically similar to glanders, hence the name pseudoglanders. in human beings, this infection can cause severe sepsis and septic shock and has also been considered to have potential for biologic welfare. melioidosis is currently present in southeast asia and, to a much lesser extent, in northern australia and some european countries where the causative organism is frequently found in rodents, feces, soil, and water. ingestion of contaminated feed and water appears to be the main route of infection; direct transmission between infected animals and insect bites has also been postulated as a possible mechanism of infection. after gaining entrance to the animal, burkholderia pseudomallei is disseminated by the bloodstream and causes suppuration and abscesses in most internal organs, such as nasal mucosa, joints, brain and spinal cord, lungs, liver, kidneys, spleen, and lymph nodes. the exudate is creamy or caseous and yellow to green. the pulmonary lesions in melioidosis are those of an embolic bacterial infection with the formation of pulmonary abscesses, which can become confluent. focal adhesive pleuritis develops where abscesses rupture through the pleura and heal. rhinosporidiosis. the protistan parasite, rhinosporidium seeberi, causes nasal infection in human beings, horses, mules, cattle, dogs, and cats. gross lesions vary from barely visible granulomas to large expansive polypoid nodules that may be mistaken as tumors. these granulomatous nodules are detected by direct observation when present in the nasal mucosa close to the nares or by rhinoscopy when located in the deep nasal cavity. the offending organism, rhinosporidium seeberi, is readily visible in histologic preparations and in impression smears, appearing as a large ( µm), oval sporangium containing thousands of endospores (see fig. - ). rhinosporidium seeberi was once considered a mycotic agent, but recent phylogenetic investigations suggest that it is an aquatic protistan parasite of the class mesomycetozoea. giant, basophilic, intranuclear inclusion bodies in the nasal epithelium, particularly in the nasal glands ( fig. - ). immunosuppressed piglets can develop a systemic cytomegalovirus infection characterized by necrosis of the liver, lungs, adrenal glands, and brain with intralesional inclusion bodies. inclusion body rhinitis is clinically a characterized by a deeply eosinophilic homogeneous material surrounded by bacteria or mycelia. it is thought to result from a localized antigen-antibody response in tissue. oestrus ovis. oestrus ovis (diptera: oestridae; nasal bot) is a brownish fly about the size of a honeybee that deposits its first-stage larvae in the nostrils of sheep in most areas of the world. microscopic larvae mature into large bots (maggots), which spend most of their larval stages in nasal passages and sinuses, causing irritation, inflammation, and obstruction of airways. mature larvae drop to the ground and pupate into flies. this type of parasitism in which living tissues are invaded by larvae of flies is known as myiasis ( fig. - ). although oestrus ovis is a nasal myiasis primarily of sheep, it sporadically affects goats, dogs, and sometimes human beings (shepherds). the presence of the larvae in nasal passages and sinuses causes chronic irritation and erosive mucopurulent rhinitis and sinusitis; bots of oestrus ovis can be found easily if the head is cut to expose the nasal passages and paranasal sinuses. rarely, larvae of oestrus ovis penetrate the cranial vault through the ethmoidal plate, causing direct or secondary bacterial meningitis. other causes of rhinitis. infectious rhinitis is only sporadically reported in goats, and most of these cases are caused by pasteurella multocida or mannheimia haemolytica. the lesions range from a mild serous to catarrhal or mucopurulent inflammation. foreign body rhinitis caused by plant material is sporadically seen cattle, sheep, and goats ( fig. - ). inclusion body rhinitis. inclusion body rhinitis is a disease of young pigs with high morbidity and low mortality caused by a porcine cytomegalovirus (suid herpesvirus- ) and characterized by a mild rhinitis. this virus commonly infects the nasal epithelium of piglets younger than weeks and causes a transient viremia. because this disease is seldom fatal, lesions are seen only incidentally or in euthanized animals. in uncomplicated cases, the gross lesion is hyperemia of the nasal mucosa, but with secondary bacterial infections, mucopurulent exudate can be abundant. microscopic lesions are typical and consist of a necrotizing, nonsuppurative rhinitis with toxigenic strains of pasteurella multocida. the only lesion associated with infection with bordetella bronchiseptica alone is a mild to moderate turbinate atrophy (nonprogressive atrophic rhinitis), but this bacterium actively promotes the colonization of the nasal cavity by pasteurella multocida. the toxigenic strains of pasteurella multocida produce potent cytotoxins that inhibit osteoblastic activity and promote osteoclastic reabsorption in nasal bones, particularly in the ventral nasal conchae, where abnormal bone remodeling results in progressive atrophy of conchae. the degree of conchal atrophy in pigs with atrophic rhinitis varies considerably, and in most pigs, the severity of the lesions does not correspond to the severity of the clinical signs. the best diagnostic method of evaluating this disease at necropsy is to make a transverse section of the snout between the first and second premolar teeth. in normal pigs, conchae are symmetric and fill most of the cavity, leaving only narrow airspaces (meatuses) between coiled conchae. the normal nasal septum is straight and divides the cavity into two mirror-image cavities. in contrast, the septum in pigs with atrophic rhinitis is generally deviated and the conchae appear smaller and asymmetric ( fig. - ). conchal atrophy causes dorsal and ventral meatuses to appear rather enlarged, and in the most advanced cases, the entire nasal conchae may be missing, leaving a large, empty space. it may seem logical to assume that after loss of conchae in an obligate nasal breather, such as the pig, the filtration defense mechanism of the nasal cavity would be impaired, thus enhancing the chances of aerogenous infections in the lung. however, the relationship between atrophic rhinitis, pneumonia, and growth rates in pigs is still controversial. osteoclastic hyperplasia and osteopenia of the conchae are the key microscopic lesions in atrophic rhinitis. depending on the stage of the disease, mucopurulent exudate may be found on the surface of the conchae. hyperplastic or metaplastic changes can occur in the nasal epithelium and glands, and infiltrates of lymphoplasmacytic cells can be present in the lamina propria. in summary, atrophic rhinitis is an important disease in pigs worldwide; morphologic characterized by a mild and transient rhinitis, causing sneezing, nasal discharge, and excessive lacrimation. atrophic rhinitis. a common worldwide disease of pigs, atrophic rhinitis (progressive atrophic rhinitis) is characterized by inflammation and atrophy of nasal conchae (turbinates). in severe cases, atrophy of the conchae may cause a striking facial deformity in growing pigs because of deviation of the nasal septum and nasal bones. the etiopathogenesis of atrophic rhinitis is complex and has been a matter of controversy for many years. pathogens historically associated with atrophic rhinitis include bordetella bronchiseptica, pasteurella multocida, haemophilus parasuis, and viral infections such as porcine cytomegalovirus (inclusion body rhinitis). in addition, predisposing factors have included genetic makeup, environment, and nutritional deficiencies. the cause of atrophic rhinitis is currently believed to be a combined infection by specific strains of bordetella bronchiseptica producing dermonecrotic toxin and linguatula serrata. linguatula serrata is a rare but highly specialized pentastomid parasite that shares some morphologic features with arthropods and annelids and causes infection when dogs consume uncooked ruminant meat containing infective larvae. it occurs primarily in carnivores, although sheep and goats may become aberrant hosts. human beings can also acquire the infection by ingesting raw ovine or caprine meat. the adult parasite is found throughout the nasal passages and sometimes can reach the sinuses and middle ear by moving through the exudate in the eustachian tubes. in common with other nasal parasites, linguatula serrata acts as an irritant, causing sneezing, catarrhal inflammation, and epistaxis. the eggs of this parasite leave the host in the exudate, which is coughed up or swallowed and eliminated in the feces. the nasal cavity and paranasal sinuses of dogs can occasionally be infested with other parasites, including mites (pneumonyssus caninum) and rhinosporidium seeberi (see figs. - and - ). allergic rhinitis. allergic rhinitis (hay fever; nasolacrimal urticaria), which is so common in human beings sensitized and reexposed to inhaled pollens or allergens, has been reported only sporadically in dogs and cats. hay fever in human beings and animals is a type i hypersensitivity reaction in which an ige-mediated degranulation of mast cells results in an acute rhinitis and conjunctivitis. microscopically, the nasal mucosa is edematous and infiltrated with numerous eosinophils, neutrophils, and some macrophages. clinically, allergic rhinitis is characterized by profuse serous nasal discharge and lacrimation. other causes of rhinitis. a nonspecific (idiopathic) chronic lymphoplasmacytic rhinitis is occasionally seen in dogs. immotile cilia syndrome (ciliary dyskinesia), a congenital disease, reduces mucociliary clearance and is an important factor in recurrent canine rhinosinusitis, bronchitis, bronchiectasis, and pneumonia. feline viral rhinotracheitis. feline viral rhinotracheitis (fvr) is a common, worldwide respiratory disease of cats caused by felid herpesvirus (fehv- ). the disease causes an impairment of pulmonary defense mechanisms predisposing cats to secondary bacterial pneumonia or to a coinfection with feline calicivirus. the virus also can remain latent in ganglia. the vast majority of cats that recover from fvr become carriers and shed fehv- , either spontaneously or following stress. susceptible animals, particularly kittens with low maternal immunity, become infected after exposure to a diseased or carrier cat. replication of fehv- in the nasal, conjunctival, pharyngeal, and, to a lesser extent, tracheal epithelium causes degeneration and exfoliation of cells. lesions caused by fehv- are fully reversible, but secondary infections with bacteria, such as pasteurella multocida, bordetella bronchiseptica, streptococcus spp., and mycoplasma felis, can cause a chronic, severe suppurative rhinitis and also conjunctivitis. intranuclear inclusion bodies are rarely seen in cats with fvr because inclusions are only present during the early stages of infection and have already disappeared by the time the cat is presented for diagnosis. respiratory sequelae to fvr can include chronic bacterial rhinitis and sinusitis with persistent purulent discharge; lysis of nasal bones, which can lead to conchal atrophy; permanent damage to the olfactory epithelium; and secondary bacterial pneumonia. in addition to rhinitis and interstitial pneumonia, fvr also causes ulcerative keratitis, hepatic necrosis, emaciation, abortion, and diagnosis is simple, but additional understanding of the pathogenesis will be necessary before effective preventive measures can be established. atrophic rhinitis is clinically characterized by sneezing, coughing, and nasal discharge. obstruction of the nasolacrimal duct is common and results in accumulation of dust and dried lacrimal secretions on the skin inferior to the medial canthus of the eye. viral infections. dogs have no specific viral infections affecting exclusively the nasal cavity or sinuses. acute rhinitis and sinusitis occurs as part of the canine infectious respiratory disease (cird) group caused by several distinct viruses, such as canine distemper virus, cav- and - , canine parainfluenza virus, reovirus, and canine herpesvirus. the viral lesions in the respiratory tract are generally transient, but the effect of the virus on other tissues and cells can be fatal, as in distemper encephalitis in dogs. bacterial infections. as in other species, secondary bacterial rhinitis, sinusitis, and pneumonia are possible sequelae of respiratory viral infections; bordetella bronchiseptica, escherichia coli, and pasteurella multocida are the most common isolates in dogs with bacterial rhinitis. mycotic infections. aspergillus spp. and penicillium spp. cause mycotic rhinitis and sinusitis in dogs (canine nasal aspergillosis) ( fig. - ). nasal biopsies reveal extensive necrosis of the nasal epithelium and thick plaques of fibrinopurulent exudate mixed with many fungal hyphae. cryptococcus neoformans and blastomyces dermatitides infections of the nasal cavity occur sporadically in dogs ( fig. - ). lesions are characterized by mucosal granulomas containing periodic acid-schiff (pas)-positive fungal organisms, and the infection is clinically characterized by mucopurulent nasal discharge. fvr; these two viral infections account for % of all cases of feline respiratory diseases. a febrile systemic hemorrhagic syndrome with high mortality (up to %) has been reported in cats infected with virulent strains of fcv. feline chlamydiosis. feline chlamydiosis is a persistent respiratory infection of cats caused by chlamydophila felis. infection results in a conjunctivitis (similar to the conjunctivitis seen in human trachoma caused by chlamydia trachomatis) and serous or mucopurulent rhinitis. in the past, chlamydophila felis was incriminated as the agent responsible for "feline pneumonitis," but its role in causing bronchointerstitial pneumonia in cats has been seriously challenged in recent years (see pneumonias of cats). mycotic infections. the most common mycotic infection in the feline nasal cavity is caused by cryptococcus neoformans and cryptococcus gatti, but not all animals exposed to these fungi necessarily develop cryptococcosis unless they are immunosuppressed. stillbirths. clinical signs of fvr infection are characterized by lethargy, oculonasal discharge, severe rhinitis, and conjunctivitis. feline calicivirus. feline rhinitis can be caused by different strains of feline calicivirus (fcv). it is an important infection of the respiratory tract of cats, and depending on the virulence of the strain, lesions vary from a mild oculonasal discharge to severe rhinitis, mucopurulent conjunctivitis, and ulcerative gingivitis and stomatitis. the lesions, in addition to rhinitis and conjunctivitis, include acute, diffuse interstitial pneumonia with necrotizing bronchiolitis (see pneumonias of cats) and in some cases prominent ulcers of the tongue and hard palate. primary viral lesions are generally transient, but secondary bacterial infections (bordetella bronchiseptica, pasteurella multocida, or escherichia coli) are a common complication. some kittens develop lameness after infection or vaccination with calicivirus because of an acute and self-limiting arthritis ("limping kitten syndrome"). carrier state and virus shedding from oronasal secretions and feces are natural sequelae after recovery from the acute phase of the disease. clinical and pathologic features of fcv disease are strikingly similar but not identical to those of hemorrhage, increased lacrimation as a result of obstruction of nasolacrimal ducts, and sneezing. in some instances, it is not possible to clinically or grossly differentiate neoplasms from hyperplastic nodules or granulomatous rhinitis. some neoplasms may infiltrate adjacent bone structures and produce notable facial deformities, loss of teeth, exophthalmus, and nervous signs. large neoplasms also project into the meatuses, narrow the lumen, and interfere with airflow, causing stertorous breathing (see . biopsies, as well as brush and imprint cytology, have proven effective in the antemortem diagnosis of nasal neoplasms, particularly in those of epithelial lineage. a unique group of nasal carcinomas (enzootic nasal tumors, enzootic intranasal tumors, and enzootic nasal carcinoma) of sheep and goats arise from the surface epithelium and glands of the ethmoidal conchae. these types of carcinomas are caused by betaretroviruses in sheep (entv- ) and goats (entv- ). the enzootic nasal tumor has been successfully transmitted to susceptible animals by the lesions vary from discrete nasal granulomas to large confluent masses of mucopurulent exudate filling the entire nasal cavity and paranasal sinuses. microscopic examination of the exudate reveals the typical thick-walled pas-positive organisms (see fig. - ). mycoplasma felis can also cause mucopurulent conjunctivitis and a mild upper respiratory infection, with clinical signs and lesions overlapping those seen with chlamydiosis, fvr, and fcr infections. respiratory infections and bronchopneumonia in cats may also be associated with the immunosuppressive effects of feline retroviruses such as feline leukemia virus (felv) and feline immunodeficiency virus (fiv). nasal aspergillosis and allergic rhinosinusitis are sporadically reported in cats (see disorders of the conducting system: species-specific diseases of the nasal cavity and paranasal sinuses: disorders of dogs: mycotic infections). neoplasms of the nasal cavity and paranasal sinuses may arise from any of the tissues forming these structures, including bone (osteoma or osteosarcoma), cartilage (chondroma or chondrosarcoma), connective tissue (fibroma or fibrosarcoma, myxoma or myxosarcoma), and blood vessels (hemangioma or hemangiosarcoma), and from all the different types of cells of glands and lining epithelium (adenoma, carcinoma, or adenocarcinoma). nasal tumors originating from stromal tissues, such as bone, cartilage, and connective tissue, are morphologically indistinguishable from those seen in other sites. in general, nasal neoplasms are rare in domestic animals, except for enzootic ethmoidal tumor (retroviral) in sheep and goats, which can occur in several animals in a herd (see the next section). in companion animals, nasal neoplasms are most common in dogs, particularly in medium to large breed dogs such as the collie, airedale terrier, basset hound, and german shepherd. the cat and the horse are less frequently affected. the main sites in order of frequency are the nasal passages and sinuses for dogs, the tip of the nose and nasal passages for cats, and the maxillary sinus and nasal passages for horses. the majority of neoplasms in the nasal cavity are malignant. benign nasal neoplasms (papilloma and adenoma) are rare and generally are either solitary or multiple, well-delineated nodules. in contrast, nasal carcinomas and nasal sarcomas are generally larger but vary in size and are often pale and multilobulated masses composed of fleshy to friable tissue (figs. - and - ). malignant neoplasms are locally invasive and tend to infiltrate sinuses, meninges, frontal brain, olfactory nerves, and vessels resulting in epistaxis. carcinomas vary from anaplastic (poorly differentiated) to well differentiated, in which cell and tissue morphology retains some glandular (adenocarcinoma) or squamous cell patterns. because nasal tumors in dogs and cats are usually large and invasive at the time of diagnosis, prognosis is usually poor and survival times are short. sarcomas originating in the nasal cavity and paranasal sinuses are less common than carcinomas. mesenchymal tumors can arise from bone (osteoma or osteosarcoma), cartilage (chondroma or chondrosarcoma), blood vessels (hemangioma or hemangiosarcoma), and connective tissue (fibroma or fibrosarcoma). overall, benign epithelial and mesenchymal tumors are less common than their malignant counterparts. secondary tumors in the nasal cavity are rare, with lymphoma being the most common secondary tumor in the nasal cavity of domestic animals ( fig. - ). nasal neoplasms become secondarily infected by bacteria, and clinical signs often overlap with those of infectious rhinitis and include catarrhal or mucopurulent nasal discharge, periodic anomalies congenital anomalies of the pharynx, guttural pouches, larynx, and trachea are rare in all species. depending on their location and severity, they may be inconsistent with postnatal life, pose little or no problem, interfere with quality of life, or manifest themselves in later life. if clinical signs of respiratory distress, such as stridor, coughing, dyspnea, or gagging, do occur, they are usually exacerbated by excitement, heat, stress, or exercise. brachycephalic airway syndrome. see disorders of the conducting system: species-specific diseases of the pharynx, guttural inoculation of cell-free tumor filtrates. enzootic nasal tumors are typically invasive but do not metastasize ( fig. - ). in some regions of the world, ethmoid tumors have been reported in horses and pigs, particularly in those farms where the endemic nasal tumors of ruminants are known to occur. nonneoplastic exophytic masses that resemble neoplasms are commonly found in horses, cats, and, to a lesser extent, other species. in horses, polyps tend to form in the ethmoidal region, whereas in cats, polyps are most frequently found in the nasopharynx and eustachian tubes. the pathogenesis of these benign growths is uncertain, although in many cases they follow chronic rhinitis or sinusitis. most recently, lymphatic obstruction secondary to inflammation has been postulated as the main culprit. grossly, polyps appear as firm, pedunculated nodules of various sizes protruding from the nasal mucosa into the nasal passages or nasopharynx ( fig. - ); the surface may be smooth, ulcerated, secondarily infected, and hemorrhagic. microscopically, polyps are characterized by a core of wellvascularized stromal tissue that contains inflammatory cells and are covered by pseudostratified or squamous epithelium (see fig. - ). nasal and paranasal sinus cysts are common idiopathic lesions in horses and are medically important because they clinically mimic table - for potential, suspected, or known genetic disorders. tracheal collapse and tracheal stenosis. tracheal collapse with reduction in tracheal patency occurs in toy, miniature, and brachycephalic breeds of dogs, in which the condition is also called tracheobronchial collapse or central airway collapse. the defect also occurs in horses, cattle, and goats. by radiographic, endoscopic, or gross examination, there is dorsoventral flattening of the trachea with concomitant widening of the dorsal tracheal membrane, which may then prolapse ventrally into the lumen ( fig. - ). most commonly, the defect extends the entire length of the trachea and only rarely affects the cervical portion alone. affected segments with a reduced lumen contain froth and even are covered by a diphtheritic membrane. in horses, the so-called scabbard trachea is characterized allergic reactions. grossly, the mucosa of the epiglottis and vocal cords is thickened and swollen, often protrudes dorsally onto the epiglottic orifice, and has a gelatinous appearance ( fig. - ). laryngeal and tracheal hemorrhage. hemorrhages in these sites occur as mucosal petechiae and are most commonly seen in coagulopathies; inflammation; septicemia and sepsis, particularly in pigs with classical swine fever (hog cholera); african swine fever or salmonellosis; and horses with equine infectious anemia. severe dyspnea and asphyxia before death can cause congestion, ecchymosis, and petechiae in the laryngeal and tracheal mucosa; this lesion must be differentiated from postmortem imbibition of hemoglobin in autolyzed carcasses (see chapter ). by lateral flattening so that the tracheal lumen is reduced to a narrow vertical slit. segmental tracheal collapse causing stenosis has been associated with congenital and acquired abnormalities. in severe cases, abnormal cartilaginous glycoproteins and loss of elasticity of tracheal rings causes the trachea to collapse. in some other cases, it is an acquired tracheal lesion that follows trauma, compression caused by extraluminal masses, peritracheal inflammation, and flawed tracheotomy or transtracheal aspirate techniques. other tracheal anomalies include tracheoesophageal fistula, which is most commonly found in human beings and sporadically in dogs and cattle. congenital fistulas can occur at any site of the cervical or thoracic segments of the trachea. acquired tracheoesophageal fistula can be a complication of improper intubation, tracheotomy, or esophageal foreign body. laryngeal hemiplegia. laryngeal hemiplegia (paralysis), sometimes called roaring in horses, is a common but obscure disease characterized by atrophy of the dorsal and lateral cricoarytenoid muscles (abductor and adductor of the arytenoid cartilage), particularly on the left side. muscular atrophy is most commonly caused by a primary denervation (recurrent laryngeal neuropathy) of unknown cause (idiopathic axonopathy) and, to a much lesser extent, secondary nerve damage (see the section on denervation atrophy in chapters and ). idiopathic laryngeal hemiplegia is an incurable axonal disease (axonopathy) of the cranial laryngeal nerve that affects mostly larger horses. secondary laryngeal hemiplegia is rare and occurs after nerve damage caused by other pathologic processes such as compression or inflammation of the left recurrent laryngeal nerve. the medial retropharyngeal lymph nodes are located immediately ventral to the floor of the guttural pouches. as a result of this close anatomic relationship, swelling or inflammation of the guttural pouches or retropharyngeal lymph nodes often results in secondary damage to the laryngeal nerve. common causes of secondary nerve damage (wallerian degeneration) include guttural pouch mycosis, retropharyngeal abscesses, inflammation because of iatrogenic injection into the nerves, neck injury, and metastatic neoplasms involving the retropharyngeal lymph nodes (e.g., lymphosarcoma). grossly, the affected laryngeal muscle in a horse with laryngeal hemiplegia is pale and smaller than normal (muscle atrophy) . microscopically, muscle fibers have lesions of denervation atrophy (see chapters and ). atrophy of laryngeal muscles also occurs in dogs as an inherited condition (siberian husky and bouvier des flanders), as a degenerative neuropathy in older dogs, secondary to laryngeal trauma in all species (e.g., choke chain damage), or secondary to hepatic encephalopathy in horses. the abnormal inspiratory sounds (roaring) during exercise in horses with laryngeal hemiplegia are caused by paralysis of the left dorsal and lateral cricoarytenoid muscles, which cause incomplete dilation of the larynx, obstruction of airflow, and vibration of vocal cords. laryngeal edema. laryngeal edema is a common feature of acute inflammation, but it is particularly important because swelling of the epiglottis and vocal cords can obstruct the laryngeal orifice, resulting in asphyxiation. laryngeal edema occurs in pigs with edema disease; in horses with purpura hemorrhagica; in cattle with acute interstitial pneumonia; in cats with systemic anaphylaxis; and in all species as a result of trauma, improper endotracheal tubing, inhalation of irritant gases (e.g., smoke), local inflammation, and animal species is classified as fibrinous, catarrhal, purulent, or granulomatous (figs. - and - ). chronic polypoid tracheitis occurs in dogs and cats, probably secondary to chronic infection. the most common causes of tracheitis are viral infections, such as those causing infectious bovine rhinotracheitis (see fig. - ), equine viral rhinopneumonitis, canine distemper, and feline rhinotracheitis. viral lesions are generally mild and transient but often become complicated with secondary bacterial infections. at the early stages, the mucosa is notably hyperemic and can show white foci of necrosis. in the most severe cases, the affected mucosa detaches from the underlying basement membrane, causing extensive tracheal ulceration. chemical tracheitis is also commonly seen after aspiration (see fig. - ). also, inhalation of fumes during barn fires can cause extensive injury and necrosis of the tracheal mucosa. in forensic cases, the presence of carbon pigment in the mucosal surface of trachea, bronchi, and bronchioles indicates that the burned animal was alive during the fire. parasitic infections of the larynx and trachea can cause obstruction with dramatic consequences, but burdens sufficient to cause such effects are not commonly seen in veterinary practice. besnoitiosis (besnoitia spp.) . besnoitiosis (besnoitia spp.) is caused by several species of this apicomplexan coccidian parasite, whose life cycle is still unknown. this parasite can cause pedunculated lesions on the skin, sclera, mucosa of the nasal cavity, and larynx of horses and donkeys, cattle, goats, and wild animals. besnoitiosis has been reported from africa, central and south america, north america, and europe. grossly, pale, round, exophytic nodules up to cm in diameter can be observed protruding from mucosal surfaces. microscopically, these nodules consist of finger-like projections covered by hyperplastic and sometimes ulcerated epithelium containing numerous thick-walled parasitic cysts with little inflammatory response. cattle. see disorders of cattle. inflammation of the pharynx, larynx, and trachea are important because of their potential to obstruct airflow and to lead to aspiration pneumonia. the pharynx is commonly affected by infectious diseases of the upper respiratory and upper digestive tracts, and the trachea can be involved by extension from both the lungs and larynx. pharyngeal obstruction and perforation. intraluminal foreign bodies in the pharynx, such as medicament boluses, apples, or potatoes, can move down and obstruct the larynx and trachea. also, pharyngeal obstruction can be caused by masses in the surrounding tissue, such as neoplasms of the thyroid gland, thymus, and parathyroid glands. a number of nonspecific insults can cause lesions and clinical signs. trauma may take the form of penetrating wounds in any species: perforation of the caudodorsal wall of the pharynx from the improper use of drenching or balling guns in sheep, cattle, and pigs; choking injury because of the use of collars in dogs and cats; and the shearing forces of bite wounds. the results of the trauma may be minimal (local edema and inflammation) or as serious as complete luminal obstruction by exudate. foreign bodies may be lodged anywhere in the pharyngeal region; the location and size determine the occurrence of dysphagia, regurgitation, dyspnea, or asphyxiation. pigs have a unique structure known as the pharyngeal diverticulum ( cm long in adult pigs), which is located in the pharyngeal wall rostral and dorsal to the esophageal entrance. it is important because barley awns may lodge in the diverticulum, causing an inflammatory swelling that affects swallowing. the diverticular wall may be perforated by awns or drenching syringes, which results in an exudate that can extend down the tissue planes between muscles of the neck and even into the mediastinum. the pharynx of the dog may also be damaged by trauma from chicken bones, sticks, and needles, resulting in the formation of a pharyngeal abscess. equine inflammation of the trachea (tracheitis). the types of injury and host inflammatory responses in the trachea are essentially the same as those described for the nasal mucosa. although tracheal mucosa is prone to aerogenous injury and necrosis, it has a remarkable capacity for repair. according to the exudate, tracheitis in all palate, are important causes of respiratory problems and reduced athletic performance in horses. an undersized epiglottis is prone to being entrapped below the arytenoepiglottic fold, causing an equine syndrome known as epiglottic entrapment. this syndrome also occurs in horses with lateral deviation and deformity of epiglottis, epiglottic cysts, or necrosis of the tip of the epiglottis. hypoplastic epiglottis also occurs in pigs. dorsal displacement of the soft palate, particularly during exercise, narrows the lumen of the nasopharynx and creates abnormal air turbulence in the conducting system of horses. epiglottic entrapment is clinically characterized by airway obstruction, exercise intolerance, respiratory noise, and cough. subepiglottic and pharyngeal cysts. anomalous lesions, such as subepiglottic and pharyngeal cysts, are occasionally seen in horses, particularly in standardbred and thoroughbred racehorses. these cysts vary in size ( to cm) and occur most commonly in the subepiglottic area and to a lesser extent in the dorsal pharynx, larynx, and soft palate. cysts are lined by squamous or pseudostratified epithelium and contain thick mucus. large cysts cause airway obstruction, reduced exercise tolerance, or dysphagia and predispose to bronchoaspiration of food. equine pharyngeal lymphoid hyperplasia. equine pharyngeal lymphoid hyperplasia, or pharyngitis with lymphoid follicular hyperplasia, is a common cause of partial upper airway obstruction in horses, particularly in -and -year-old racehorses. lymphoid hyperplasia is also seen in healthy horses as part of a response to mild chronic pharyngitis, which in many instances tends to regress with age in older animals. the cause is undetermined, but chronic bacterial infection combined with environmental factors may cause excessive antigenic stimulation and lymphoid hyperplasia. the gross lesions, visible endoscopically or at necropsy, consist of variably sized ( to mm) white foci located on the dorsolateral walls of the pharynx and extending into the openings of the guttural pouches and onto the soft palate. in severe cases, lesions may appear as pharyngeal polyps. microscopically, the lesions consist of large aggregates of lymphocytes and plasma cells in the pharyngeal mucosa. clinical signs consist of stertorous inspiration, expiration, or both. inflammation of guttural pouches. the guttural pouches of horses are large diverticula ( to ml) of the ventral portion of the auditory (eustachian) tubes. these diverticula are therefore exposed to the same pathogens as the pharynx and have drainage problems similar to the sinuses. although it is probable that various pathogens, including viruses, can infect them, the most common pathogens are fungi, which cause guttural pouch mycosis and guttural pouch empyema in the horse. eustachitis is the term used for inflammatory processes involving the eustachian (pharyngotympanic) tube. because of the close anatomic proximity of guttural pouches to the internal carotid arteries, cranial nerves (vii, ix, x, xi, and xii), and atlantooccipital joint, disease of these diverticula may involve these structures and cause a variety of clinical signs in horses. guttural pouch mycosis occurs primarily in stabled horses and is caused by aspergillus fumigatus and other aspergillus spp. infection is usually unilateral and presumably starts with the inhalation of spores from moldy hay. grossly, the mucosal surfaces of the dorsal and lateral walls of the guttural pouch mucosa are first covered by focal, rounded, raised plaques of diphtheritic (fibrinonecrotic) exudate, which with time can become confluent and grow into a large fibrinonecrotic mass ( fig. - ) . microscopically, the lesions are severe necrotic inflammation of the mucosa and submucosa with widespread vasculitis and intralesional fungal hyphae. necrosis of the mammomonogamus (syngamus) spp. mammomonogamus (syngamus) laryngeus is a nematode that is seen attached to the laryngeal mucosa of cattle in tropical asia and south america, and cats (gapeworm: mammomonogamus ierei) in the caribbean and southern united states. occasionally, human beings with a persistent cough or asthma-like symptoms have the parasite in the larynx or bronchi. oslerus (filaroides) osleri. see disorders of dogs. b a c empyema of guttural pouches is a sequela to suppurative inflammation of the nasal cavities, most commonly from streptococcus equi infection (strangles). in severe cases, the entire guttural pouch can be filled with purulent exudate ( fig. - ). the sequelae are similar to those of guttural pouch mycosis except that there is no erosion of the internal carotid artery. it is clinically characterized by nasal discharge, enlarged retropharyngeal lymph nodes, painful swelling of the parotid region, dysphagia, and respiratory distress. guttural pouch tympany develops sporadically in young horses when excessive air accumulates in the pouch from the one-way valve effect caused by inflammation or malformation of the eustachian tube. arabian and german warm-blooded horses are particularly susceptible to develop guttural pouch tympany. it is generally unilateral and characterized by nonpainful swelling of the parotid region. cattle. tracheal edema and hemorrhage syndrome of feeder cattle, also known as the honker syndrome or tracheal stenosis of feedlot cattle, is a poorly documented acute disease of unknown cause, most often seen during the summer months. severe edema and a few hemorrhages are present in the mucosa and submucosa of the dorsal surface of the trachea, extending caudally from the midcervical area as far as the tracheal bifurcation. on section, the tracheal mucosa is diffusely thickened and gelatinous. clinical signs include inspiratory wall of the guttural pouches can extend into the wall of the adjacent internal carotid artery causing hemorrhage into the lumen of the guttural pouch and recurrent epistaxis. invasion of the internal carotid artery causes arteritis, which can also lead to formation of an aneurysm and fatal bleeding into the guttural pouches. in other cases, the fungi may be angioinvasive, leading to the release of mycotic emboli into the internal carotid artery, generally resulting in multiple cerebral infarcts. dysphagia, another clinical sign seen in guttural pouch mycosis, is associated with damage to the pharyngeal branches of the vagus and glossopharyngeal nerves, which lie on the ventral aspect of the pouches. horner's syndrome results from damage to the cranial cervical ganglion and sympathetic fibers located in the caudodorsal aspect of the pouches. finally, equine laryngeal paralysis (hemiplegia) can result from damage to the laryngeal nerves as previously described in the section on laryngeal hemiplegia. pekingese, and others. the defects are a result of a mismatch of the ratio of soft tissue to cranial bone and the obstruction of airflow by excessive length of the palatine soft tissue. secondary changes, such as nasal and laryngeal edema caused by forceful inspiration, eventually lead to severe upper airway obstruction, respiratory distress, and exercise intolerance. tracheal hypoplasia. tracheal hypoplasia occurs most often in english bulldogs and boston terriers; the tracheal lumen is decreased in diameter throughout its length. canine infectious respiratory disease. canine infectious respiratory disease (cird), formerly called canine tracheobronchitis or kennel cough, is a highly contagious group of infectious diseases characterized clinically by an acute onset of coughing notably exacerbated by exercise. the term is nonspecific, much like the dyspnea that can progress to oral breathing, recumbency, and death by asphyxiation in less than hours. necrotic laryngitis. necrotic laryngitis (calf diphtheria, laryngeal necrobacillosis) is a common disease of feedlot cattle and cattle affected with other diseases, with nutritional deficiencies, or housed under unsanitary conditions. it also occurs sporadically in sheep and pigs. necrotic laryngitis, caused by fusobacterium necrophorum, is part of the syndrome termed necrotic stomatitis or laryngeal necrobacillosis, which can include lesions of the tongue, cheeks, palate, and pharynx. an opportunistic pathogen, fusobacterium necrophorum produces potent exotoxins and endotoxins after gaining entry either through lesions of viral infections, such as ibr and vesicular stomatitis in cattle, or after traumatic injury produced by feed or careless use of specula or balling guns. the gross lesions, regardless of location in the mouth or larynx (most common in the mucosa overlying the laryngeal cartilages), consist of well-demarcated, dry, yellow-gray, thick-crusted, and fibrinonecrotic exudate ( fig. - ) that in the early stages is bounded by a zone of active hyperemia. deep ulceration develops, and if the lesion does not result in death, healing is by granulation tissue formation. microscopically, the necrotic foci are first surrounded by congested borders, then by a band of leukocytes, and finally the ulcers heal by granulation tissue and collagen (fibrosis). the lesions can extend deep into the submucosal tissue. numerous bacteria are evident at the advancing edge. there are numerous and important sequelae to calf diphtheria; the most serious is death from severe toxemia or overwhelming fusobacteremia. sometimes, the exudate may be copious enough to cause laryngeal obstruction and asphyxiation or be aspirated and cause bronchopneumonia. the clinical signs of necrotic laryngitis are fever, anorexia, depression, halitosis, moist painful cough, dysphagia, and inspiratory dyspnea and ventilatory failure because of fatigue of the respiratory muscles (diaphragmatic and intercostal). laryngeal contact ulcers. ulcerative lesions in the larynx are commonly found in feedlot cattle. grossly, the laryngeal mucosa reveals circular ulcers (up to cm in diameter), which may be unilateral or bilateral and sometimes deep enough to expose the underlying arytenoid cartilages. the cause has not been established, but causal agents, such as viral, bacterial, and traumatic, have been proposed, along with increased frequency and rate of closure of the larynx (excessive swallowing and vocalization) when cattle are exposed to market and feedlot stresses such as dust, pathogens, and interruption of feeding. contact ulcers predispose a calf to diphtheria (fusobacterium necrophorum) and laryngeal papillomas. ulceration of the mucosa and necrosis of the laryngeal cartilages have also been described in calves, sheep, and horses under the term laryngeal chondritis. laryngeal abscesses involving the mucosa and underlying cartilage occur as a herd or flock problem in calves and sheep, presumably caused by a secondary infection with trueperella (arcanobacterium) pyogenes. anomalies brachycephalic airway syndrome. brachycephalic airway syndrome is a clinical term that refers to increased airflow resistance caused by stenotic nostrils and nasal meatuses and an excessively long soft palate. these abnormalities are present in brachycephalic canine breeds such as bulldogs, boxers, boston terriers, pugs, a "common cold" in human beings or bovine respiratory disease complex (brdc) in cattle. the infection occurs commonly as a result of mixing dogs from different origins such as occurs at commercial kennels, animal shelters, and veterinary clinics. between bouts of coughing, most animals appear normal, although some have rhinitis, pharyngitis, tonsillitis, or conjunctivitis; some with secondary pneumonia become quite ill. the pathogenesis of cird is complex, and many pathogens and environmental factors have been incriminated. bordetella bronchiseptica, canine adenovirus- (cav- ), and canine parainfluenza virus- (cpiv- ) are most commonly implicated. the severity of the disease is increased when more than one agent is involved or if there are extreme environmental conditions (e.g., poor ventilation). for example, dogs asymptomatically infected with bordetella bronchiseptica are more severely affected by superinfection with cav- than those not carrying the bacterium. other agents are sometimes isolated but of lesser significance and include canine adenovirus- (cav- : infectious canine hepatitis virus), reovirus type , canid herpesvirus- (cahv- ), canine respiratory coronavirus (crcov), and mycoplasma species. depending on the agents involved, gross and microscopic lesions are completely absent or they vary from catarrhal to mucopurulent tracheobronchitis, with enlargement of the tonsils and retropharyngeal and tracheobronchial lymph nodes. in dogs with bordetella bronchiseptica infection, the lesions are suppurative or mucopurulent rhinitis and tracheobronchitis, and suppurative bronchiolitis. in contrast, when lesions are purely viral, microscopic changes are focal necrosis of the tracheobronchial epithelium. sequelae can include spread either proximally or distally in the respiratory tract, the latter sometimes inducing chronic bronchitis and bronchopneumonia. oslerus (filaroides) osleri. oslerus (filaroides) osleri is a nematode parasite of dogs and other canidae that causes characteristic protruding nodules into the lumen at the tracheal bifurcation. they are readily seen on endoscopic examination or at necropsy. in severe cases, these nodules can extend cm cranially or caudally from the tracheal bifurcation and even into primary and secondary bronchi. the disease occurs worldwide, and oslerus osleri is considered the most common respiratory nematode of dogs. the gross lesions are variably sized, up to cm, submucosal nodules that extend up to cm into the tracheal lumen ( fig. - , a). microscopically, nodules contain adult parasites with a mild mononuclear cell reaction; with the death of the parasite, an intense foreign body reaction develops with neutrophils and giant cells b) . clinically, it can be asymptomatic, although it most often causes a chronic cough that can be exacerbated by exercise or excitement. severe infestations can result in dyspnea, exercise intolerance, cyanosis, emaciation, and even death in young dogs. neoplasms of the guttural pouches occur rarely in horses and are usually squamous cell carcinomas. laryngeal neoplasms are rare in dogs and extremely so in other species, although they have been reported in cats and horses. the most common laryngeal neoplasms in dogs are papillomas and squamous cell carcinomas. other less common tumors are laryngeal rhabdomyoma, previously referred to as laryngeal oncocytoma, and chondromas and osteochondromas. lymphoma involving the laryngeal tissue is sporadically seen in cats. when large enough to be obstructive, neoplasms may cause a change or loss of voice, cough, or respiratory distress with cyanosis, collapse, and syncope. other signs include dysphagia, anorexia, and exercise intolerance. the neoplasm is sometimes visible from the oral cavity and causes swelling of the neck. the prognosis is poor because most lesions recur after excision. tracheal neoplasms are even more uncommon than those of the larynx. the tracheal cartilage or mucosa can be the site of an osteochondroma, leiomyoma, osteosarcoma, mast cell tumor, and carcinoma. lymphoma in cats can extend from the mediastinum to involve the trachea. each lung is subdivided into various numbers of pulmonary lobes (see fig. - ). in the past, these were defined by anatomic fissures. however, in current anatomy, lobes are defined by the ramification of the bronchial tree. following this criterion, the left lung of all domestic species is composed of cranial and caudal lobes, whereas the right lung, depending on species, is composed of cranial, middle (absent in horse), caudal, and accessory lobes. each pulmonary lobe is further subdivided by connective tissue into pulmonary lobules, which in some species (cattle and pigs) are rather prominent and in others are much less conspicuous. from a practical standpoint, identification of the lungs among different species could be achieved by carefully observing the degree of lobation (external fissures) and the degree of lobulation (connective tissue between lobules). cattle and pigs have well-lobated and well-lobulated lungs; sheep and goats have well-lobated but poorly lobulated lungs; horses have both poorly lobated and poorly lobulated lungs and resemble human lungs; finally, dogs and cats have well-lobated but not well-lobulated lungs. the degree of lobulation determines the degree of air movement between the lobules. in pigs and cattle, movement of air between lobules is practically absent because of the thick connective tissue of the interlobular septa separating individual lobules. this movement of air between lobules and between adjacent alveoli (via the pores of kohn) constitutes what is referred to as collateral ventilation. this collateral ventilation is poor in cattle and pigs and good in dogs. the functional implications of collateral ventilation are discussed in the section on pulmonary emphysema. the lungs have an interconnecting network of interstitial stromal tissue supporting the blood and lymphatic vessels, nerves, bronchi, bronchioles, and alveoli. for purposes of simplicity, the pulmonary interstitium can be anatomically divided into three contiguous compartments: ( ) bronchovascular interstitium, where main bronchi and pulmonary vessels are situated; ( ) interlobular interstitium separating pulmonary lobules and supporting small blood and lymph vessels; and ( ) alveolar interstitium supporting the alveolar walls that contain pulmonary capillaries and alveolar epithelial cells (no lymphatic vessels here) (see discussion on the blood-air barrier in the section on alveoli). pulmonary changes, such as edema, emphysema, and inflammation, may affect one or more of these interstitial compartments. anomalies congenital anomalies of the lungs are rare in all species but are most commonly reported in cattle and sheep. compatibility with life largely depends on the type of structures involved and the proportion of functional tissue present at birth. accessory lungs are one of the most common anomalies and consist of distinctively lobulated masses of incompletely differentiated pulmonary tissue present in the thorax, abdominal cavity, or subcutaneous tissue virtually anywhere in the trunk. large accessory lungs can cause dystocia. ciliary dyskinesia (immotile cilia syndrome, kartagener's syndrome) is characterized by defective ciliary movement, which results in reduced mucociliary clearance because of a defect in the microtubules of all ciliated cells and, most important, in the ciliated respiratory epithelium and spermatozoa. primary ciliary dyskinesia often associated with situs inversus has been reported in dogs, which as a result usually have chronic recurrent rhinosinusitis, pneumonia, and infertility. pulmonary agenesis, pulmonary hypoplasia, abnormal lobulation, congenital emphysema, lung hamartoma, and congenital bronchiectasis are occasionally seen in domestic animals. congenital melanosis is a common incidental finding in pigs and ruminants and is usually seen at slaughter (fig. - ). it is characterized by black spots, often a few centimeters in diameter, in various organs, mainly the lungs, meninges, intima of the aorta, and caruncles of the uterus. melanosis has no clinical significance, and the texture of pigmented lungs remains unchanged. congenital emphysema is sporadically seen in dogs (e- fig. - ). pulmonary calcification ("calcinosis"). calcification of the lungs occurs in some hypercalcemic states, generally secondary to hypervitaminosis d or from ingestion of toxic (hypercalcemic) plants, such as solanum malacoxylon (manchester wasting disease), that contain vitamin d analogs. it is also a common sequela to uremia and hyperadrenocorticism in dogs and to pulmonary necrosis (dystrophic calcification) in most species. calcified lungs may fail to collapse when the thoracic cavity is opened and have a characteristic "gritty" texture ( fig. - ) . microscopically, lesions vary from calcification of the alveolar basement membranes (see by pathologists. recent investigations suggest that excessive lipid originates from the breakdown products of neoplastic cells. bronchial and bronchiolar obstructions such as those caused by lungworms can also cause alveolar lipidosis. the pathogenesis relates to the inability of alveolar macrophages that normally remove part of the surfactant lipids to exit the lung via the mucociliary escalator. exogenous lipid pneumonia. another form of lipid pneumonia occurs accidentally in cats or horses given mineral oil by their owners in an attempt to remove hairballs or treat colic (aspiration pneumonia). to achieve gaseous exchange, a balanced ratio of the volumes of air to capillary blood must be present in the lungs (ventilation/perfusion ratio), and the air and capillary blood must be in close proximity across the alveolar wall. a ventilation-perfusion mismatch occurs if pulmonary tissue is either collapsed (atelectasis) or overinflated (hyperinflation and emphysema). the term atelectasis means incomplete distention of alveoli and is used to describe lungs that have failed to expand with air at the time of birth (congenital or neonatal atelectasis) or lungs that have collapsed after inflation has taken place (acquired atelectasis or alveolar collapse) (figs. - and - ). during fetal life, lungs are not fully distended, contain no air, and are partially filled with a locally produced fluid known as fetal lung fluid. not surprisingly, lungs of aborted and stillborn fetuses sink when placed in water, whereas those from animals that have breathed float. at the time of birth, fetal lung fluid is rapidly reabsorbed and replaced by inspired air, leading to the normal distention of alveoli. congenital atelectasis occurs in newborns that fail to inflate their lungs after taking their first few breaths of air; it is caused by obstruction of airways, often as a result of aspiration of amniotic fluid and meconium (described in the section on meconium aspiration syndrome) (see fig. - ). congenital atelectasis also develops when alveoli cannot remain distended after initial aeration because of an alteration in quality and quantity of pulmonary surfactant produced by type ii pneumonocytes and club (clara) cells. this infant form of congenital atelectasis is referred to in human neonatology as infant respiratory distress syndrome (irds) or as hyaline membrane disease because of the clinical and microscopic features of the disease. it commonly occurs in babies who are premature or born to diabetic or alcoholic mothers and is occasionally found in animals, particularly foals and piglets. the pathetic, gasping attempts of affected foals and pigs to breathe have prompted the use of the name "barkers"; foals that survive may have brain damage from cerebral hypoxia (see chapter ) and are referred to as "wanderers" due to their aimless behavior and lack of a normal sense of fear. acquired atelectasis is much more common and occurs in two main forms: compressive and obstructive (see fig. - ). compressive atelectasis has two main causes: space-occupying masses in the pleural cavity, such as abscesses and tumors, or transferred pressures, such as that caused by bloat, hydrothorax, hemothorax, chylothorax, and empyema ( fig. - ). another form of compressive atelectasis occurs when the negative pressure in the thoracic cavity is lost because of pneumothorax. this form generally has massive atelectasis and thus is also referred to as lung collapse. obstructive (absorption) atelectasis occurs when there is a reduction in the diameter of the airways caused by mucosal edema and inflammation, or when the lumen of the airway is blocked by fig. - ) to heterotopic ossification of the lungs (e- fig. - ). in most cases, pulmonary calcification in itself has little clinical significance, although its cause (e.g., uremia or vitamin d toxicosis) may be very important. alveolar filling disorders are a heterogeneous group of lung diseases characterized by accumulation of various chemical compounds in the alveolar lumens. the most common are alveolar proteinosis, in which the alveoli are filled with finely granular eosinophilic material; pulmonary lipidosis, in which alveoli are filled with macrophages containing endogenous or exogenous lipid; and alveolar microlithiasis, in which the alveoli contain numerous concentric calcified "microliths" or "calcospherites." a similar but distinct concretion is known as corpora amylacea, which is an accumulation of laminated bodies composed of cellular debris, lipids, proteins, and possibly amyloid. for most alveolar filling disorders, there is little host response, and in many cases, it is an incidental finding. most of the alveolar filling disorders originate from inherited metabolic defects in which alveolar cells (epithelial or macrophages) cannot properly metabolize or remove lipids or proteins, whereas others result from an excessive synthesis of these substances in the lung. endogenous lipid (lipoid) pneumonia. endogenous lipid pneumonia is an obscure, subclinical pulmonary disease of cats and occasionally of dogs, which is unrelated to aspiration of foreign material. although the pathogenesis is not understood, it is presumed that lipids from pulmonary surfactant and from degenerated cells accumulate within alveolar macrophages. accumulation of surfactant lipids can occur in metabolic abnormalities of alveolar macrophages or in bronchial obstruction where surfactant-laden macrophages cannot exit the lungs via the mucociliary escalator. the gross lesions are multifocal, white, firm nodules scattered throughout the lungs (e- fig. - ) . microscopically, the alveoli are filled with foamy lipid-laden macrophages accompanied by interstitial infiltration of lymphocytes and plasma cells, fibrosis, alveolar epithelialization, and, in some cases, cholesterol clefts and lipid granulomas. lipid (lipoid) pneumonia occurs frequently in the vicinity of cancerous lung lesions in human beings, cats, and dogs. the reason for this association remains unknown and frequently unrecognized appearance of atelectasis is more common in species with poor collateral ventilation, such as cattle and pigs. the extent and location of obstructive atelectasis depends largely on the size of the affected airway (large vs. small) and on the degree of obstruction (partial vs. complete). atelectasis also occurs when large animals are kept recumbent for prolonged periods, such as during anesthesia (hypostatic atelectasis). the factors contributing to hypostatic atelectasis are a combination of blood-air imbalance, shallow breathing, airway obstruction because of mucus and fluid that has not been drained from bronchioles and alveoli, and from inadequate local production of surfactant. atelectasis can also be a sequel to paralysis of respiratory muscles and prolonged use of mechanical ventilation or general anesthesia in intensive care. in general, the lungs with atelectasis appear depressed below the surface of the normally inflated lung. the color is generally dark blue, and the texture is flabby or firm; they are firm if there is concurrent edema or other processes, such as can occur in ards or "shock" lungs (see the section on pulmonary edema). distribution and extent vary with the process, being patchy (multifocal) in congenital atelectasis, lobular in the obstructive type, and of various degrees in between in the compressive type. microscopically, the alveoli are collapsed or slitlike and the alveolar walls appear parallel and close together, giving prominence to the interstitial tissue even without any superimposed inflammation. pulmonary emphysema. pulmonary emphysema, often simply referred to as emphysema, is an extremely important primary disease in human beings, whereas in animals, it is always a secondary condition resulting from a variety of pulmonary lesions. in human medicine, emphysema is strictly defined as an abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of alveolar walls (alveolar emphysema). this definition separates it from simple airspace enlargement or hyperinflation, in which there is no destruction of alveolar walls and which can occur congenitally (down syndrome) or be acquired with age (aging lung, sometimes misnamed "senile emphysema"). the pathogenesis of emphysema in human beings is still controversial, but current thinking overwhelmingly suggests that destruction of mucus plugs, exudate, aspirated foreign material, or lungworms (see fig. - ). when the obstruction is complete, trapped air in the lung eventually becomes reabsorbed. unlike the compression type, obstructive atelectasis often has a lobular pattern as a result of blockage of the airway supplying that lobule. this lobular lungs are extremely well-vascularized organs with a dual circulation provided by pulmonary and bronchial arteries. disturbances in pulmonary circulation have a notable effect on gaseous exchange, which may result in life-threatening hypoxemia and acidosis. in addition, circulatory disturbances in the lungs can have an impact on other organs, such as the heart and liver. for example, impeded blood flow in the lungs because of chronic pulmonary disease results in cor pulmonale, which is caused by unremitting pulmonary hypertension followed by cardiac dilation, right heart failure, chronic passive congestion of the liver (nutmeg liver), and generalized edema (anasarca). hyperemia is an active process that is part of acute inflammation, whereas congestion is the passive process resulting from decreased outflow of venous blood, as occurs in congestive heart failure ( fig. - ). in the early acute stages of pneumonia, the lungs appear notably red, and microscopically, blood vessels and alveolar capillaries are engorged with blood from alveolar walls is largely the result of an imbalance between proteases released by phagocytes and antiproteases produced in the lung as a defense mechanism (the protease-antiprotease theory). the destructive process in human beings is markedly accelerated by defects in the synthesis of antiproteases or any factor, such as cigarette smoking or pollution, that increases the recruitment of macrophages and leukocytes in the lungs. this theory originated when it was found that human beings with homozygous α -antitrypsin deficiency were remarkably susceptible to emphysema and that proteases (elastase) inoculated intratracheally into the lungs of laboratory animals produced lesions similar to those found in the disease. more than % of the problem relates to cigarette smoking, and airway obstruction is no longer considered to play a major role in the pathogenesis of emphysema in human beings. primary emphysema does not occur in animals, and thus no animal disease should be called simply emphysema. in animals, this lesion is always secondary to obstruction of outflow of air or is agonal at slaughter. secondary pulmonary emphysema occurs frequently in animals with bronchopneumonia, in which exudate plugging bronchi and bronchioles causes an airflow imbalance where the volume of air entering exceeds the volume leaving the lung. this airflow imbalance is often promoted by the so-called one-way valve effect caused by the exudate, which allows air into the lung during inspiration but prevents movement of air out of the lung during expiration. depending on the localization in the lung, emphysema can be classified as alveolar or interstitial. alveolar emphysema characterized by distention and rupture of the alveolar walls, forming variably sized air bubbles in pulmonary parenchyma, occurs in all species. interstitial emphysema occurs mainly in cattle, presumably because of their wide interlobular septa, and lack of collateral ventilation in these species does not permit air to move freely into adjacent pulmonary lobules. as a result, accumulated air penetrates the alveolar and bronchiolar walls and forces its way into the interlobular connective tissue, causing notable distention of the interlobular septa. it is also suspected that forced respiratory movements predispose to interstitial emphysema when air at high pressure breaks into the loose connective tissue of the interlobular septa ( fig. - ). sometimes these bubbles of trapped air in alveolar or interstitial emphysema become confluent, forming large (several centimeters in diameter) pockets of air that are referred to as bullae (singular: bulla) (see e- fig. - ); the lesion is then called bullous emphysema. this lesion is not a specific type of emphysema and does not indicate a different disease process but, rather, is a larger accumulation of air at one focus. in the most severe cases, air moves from the interlobular septa into the connective tissue surrounding the main stem bronchi and major vessels (bronchovascular bundles), and from here it leaks into the mediastinum, causing pneumomediastinum first, and eventually exits via the thoracic inlet into the cervical and thoracic subcutaneous tissue causing subcutaneous emphysema. note that mild and even moderate alveolar emphysema is difficult to judge at necropsy and by light microscopy unless special techniques are used to prevent collapse of the lung when the thorax is opened. these techniques include plugging of the trachea or intratracheal perfusion of fixative ( % neutral-buffered formalin) before the thorax is opened to prevent collapse of the lungs. important diseases that cause secondary pulmonary emphysema in animals include small airway obstruction (e.g., heaves) in horses and pulmonary edema and emphysema (fog fever) in cattle (see fig. - ) and exudates in bronchopneumonia. congenital emphysema occurring secondary to bronchial cartilage hypoplasia with subsequent bronchial collapse is occasionally reported in dogs. severe and persistent cases of heart failure, the lungs fail to collapse because of edema and pulmonary fibrosis. terminal pulmonary congestion (acute) is frequently seen in animals euthanized with barbiturates and should not be mistaken for an antemortem lesion. hypostatic congestion is another form of pulmonary congestion that results from the effects of gravity and poor circulation on a highly vascularized tissue, such as the lung. this type of gravitational congestion is characterized by the increase of blood in the lower side of the lung, particularly the lower lung of animals in lateral recumbency, and is most notable in horses and cattle. the affected portions of the lung appear dark red and can have a firmer texture. in animals and human beings who have been prostrated for extended periods of time, hypostatic congestion may be followed by hypostatic edema, and hypostatic pneumonia as edema interferes locally with the bacterial defense mechanisms. pulmonary hemorrhage. pulmonary hemorrhages can occur as a result of trauma, coagulopathies, and disseminated intravascular coagulation (dic), vasculitis, sepsis, and pulmonary thromboembolism from jugular thrombosis or from embolism of exudate from a hepatic abscess that has eroded the wall and ruptured into the caudal vena cava (cattle). a gross finding often confused with intravital pulmonary hemorrhage is the result of severing both the trachea and the carotid arteries simultaneously at slaughter. blood is aspirated from the transected trachea into the lungs, forming a random pattern of irregular red foci ( to mm) in one or more lobes. these red foci are readily visible on both the pleural and the cut surfaces of the lung, and free blood is visible in the lumens of bronchi and bronchioles. rupture of a major pulmonary vessel with resulting massive hemorrhage occurs occasionally in cattle when a growing abscess in a lung invades and disrupts the wall of a major pulmonary artery or vein ( fig. - ). in most cases, animals die rapidly, often with spectacular hemoptysis, and on postmortem examination, bronchi are filled with blood (see fig. - ). pulmonary edema. in normal lungs, fluid from the vascular space slowly but continuously passes into the interstitial tissue, where it is rapidly drained by the pulmonary and pleural lymphatic vessels. clearance of alveolar fluid across the alveolar epithelium is also a major mechanism of fluid removal from the lung. edema develops when the rate of fluid transudation from pulmonary vessels into the interstitium or alveoli exceeds that of lymphatic and alveolar removal ( fig. - ). pulmonary edema can be physiologically classified as cardiogenic (hydrostatic; hemodynamic) and noncardiogenic (permeability) types. hydrostatic (cardiogenic) pulmonary edema develops when there is an elevated rate of fluid transudation because of increased hydrostatic pressure in the vascular compartment or decreased osmotic pressure in the blood. once the lymph drainage has been overwhelmed, fluid accumulates in the perivascular spaces, causing distention of the bronchovascular bundles and alveolar interstitium, and eventually leaks into the alveolar spaces. causes of hemodynamic pulmonary edema include congestive heart failure (increased hydrostatic pressure); iatrogenic fluid overload; and disorders in which blood osmotic pressure is reduced, such as with hypoalbuminemia seen in some hepatic diseases, nephrotic syndrome, and protein-losing enteropathy. hemodynamic pulmonary edema also occurs when lymph drainage is impaired, generally secondary to neoplastic invasion of lymphatic vessels. permeability edema (inflammatory) occurs when there is excessive opening of endothelial gaps or damage to the cells that constitute the blood-air barrier (endothelial cells or type i pneumonocytes). hyperemia. pulmonary congestion is most frequently caused by heart failure, which results in stagnation of blood in pulmonary vessels, leading to edema and egression of erythrocytes into the alveolar spaces. as with any other foreign particle, erythrocytes in alveolar spaces are rapidly phagocytosed (erythrophagocytosis) by pulmonary alveolar macrophages. when extravasation of erythrocytes is severe, large numbers of macrophages with brown cytoplasm may accumulate in the bronchoalveolar spaces. the brown cytoplasm is the result of accumulation of considerable amounts of hemosiderin; these macrophages filled with iron pigment (siderophages) are generally referred to as heart failure cells ( fig. - ). the lungs of animals with chronic heart failure usually have a patchy red appearance with foci of brown discoloration because of accumulated hemosiderin. in this type of edema is an integral and early part of the inflammatory response, primarily because of the effect of inflammatory mediators, such as leukotrienes, platelet-activating factor (paf), cytokines, and vasoactive amines released by neutrophils, macrophages, mast cells, lymphocytes, endothelial cells, and type ii pneumonocytes. these inflammatory mediators increase the permeability of the blood-air barrier. in other cases, permeability edema results from direct damage to the endothelium or type i pneumonocytes, allowing plasma fluids to move freely from the vascular space into the alveolar lumen ( fig. - and see fig. - ). because type i pneumonocytes are highly vulnerable to some pneumotropic viruses (influenza and brsv), toxicants (nitrogen dioxide [no ], sulfur dioxide [so ], hydrogen sulfide [h s], and -methylindole), and particularly to free radicals, it is not surprising that permeability edema commonly accompanies many viral or toxic pulmonary diseases. a permeability edema also occurs when endothelial cells in the lung are injured by bacterial toxins, sepsis, ards, dic, anaphylactic shock, milk allergy, paraquat toxicity, adverse drug reactions, and smoke inhalation (e- fig. - ) . the concentration of protein in edematous fluid is greater in permeability edema (exudate) than in hemodynamic edema (transudate); this difference has been used clinically in human medicine to differentiate one type of pulmonary edema from another. microscopically, because of the higher concentration of protein, edema fluid in lungs with inflammation or damage to the blood-air barrier tends to stain more intensely eosinophilic than that of the hydrostatic edema from heart failure. grossly, the edematous lungs-independent of the cause-are wet and heavy. the color varies, depending on the degree of congestion or hemorrhage, and fluid may be present in the pleural cavity. if edema is severe, the bronchi and trachea contain considerable amounts of foamy fluid, which originates from the mixing of edema fluid and air ( fig. - ). on cut surfaces, the lung parenchyma oozes fluid like a wet sponge. in cattle and pigs that have distinct lobules, the lobular pattern becomes rather accentuated because of edematous distention of lymphatic vessels in the interlobular septa and the edematous interlobular septum itself ( fig. - ). severe pulmonary edema may be impossible to differentiate from peracute pneumonia; (h&e)-stained sections (see fig. - ), particularly if a fixative such as zenker's solution, which precipitates protein, is used. acute respiratory distress syndrome. acute (adult) respiratory distress syndrome (ards; shock lung) is an important condition in human beings and animals characterized by pulmonary hypertension, intravascular aggregation of neutrophils in the lungs, acute lung injury, diffuse alveolar damage, permeability edema, and formation of hyaline membranes ( fig. - ) . these membranes are a mixture of plasma proteins, fibrin, surfactant, and cellular debris from necrotic pneumonocytes (see fig. - , b) . the pathogenesis of ards is complex and multifactorial but in general terms can be defined as diffuse alveolar damage that results from lesions in distant organs, from generalized systemic diseases, or from direct injury to the lung. sepsis, major trauma, aspiration of gastric contents, extensive burns, and pancreatitis are some of the disease entities known to trigger ards. all these conditions provoke "hyperreactive macrophages" to directly or indirectly generate overwhelming amounts of cytokines causing what is known as a "cytokine storm." the main cytokines that trigger ards are tnf-α, interleukin (il)- , il- , and il- , which prime neutrophils previously recruited in the lung capillaries and alveoli to release cytotoxic enzymes and free radicals. these substances cause severe and diffuse endothelial and alveolar damage that culminates in a fulminating pulmonary edema (see fig. - ). ards occurs in domestic animals and explains why pulmonary edema is one of the most common lesions found in many animals dying of sepsis, toxemia, aspiration of gastric contents, and pancreatitis, for example. a familial form of ards has been reported in dalmatians. the pulmonary lesions in this syndrome are further discussed in the sections on interstitial pneumonia and aspiration pneumonia in dogs. neurogenic pulmonary edema is another distinctive but poorly understood form of life-threatening lung edema in human beings that follows cns injury and increased intracranial pressure (i.e., head injury, brain edema, brain tumors, or cerebral hemorrhage). this type of pulmonary edema can be experimentally reproduced in laboratory animals by injecting fibrin into the fourth ventricle. it involves both hemodynamic and permeability pathways presumably from massive sympathetic stimulation and overwhelming release of catecholamines. neurogenic pulmonary edema has sporadically been reported in animals with brain injury or severe seizures or after severe stress and excitement. pulmonary embolism. with its vast vascular bed and position in the circulation, the lung acts as a safety net to catch emboli before they reach the brain and other tissues. however, this positioning is often to its own detriment. the most common pulmonary emboli in domestic animals are thromboemboli, septic (bacterial) emboli, fat emboli, and tumor cell emboli. pulmonary thromboembolism (pte) refers to both local thrombus formation and translocation of a thrombus present elsewhere in the venous circulation ( fig. - ). fragments released inevitably reach the lungs and become trapped in the pulmonary vasculature ( fig. - and see fig. - ). small sterile thromboemboli are generally of little clinical or pathologic significance because they can be rapidly degraded and disposed of by the fibrinolytic system. larger thromboemboli may cause small airway constriction, reduced surfactant production, pulmonary edema, and atelectasis resulting in hypoxemia, hyperventilation, and dyspnea. parasites (e.g., dirofilaria immitis and angiostrongylus vasorum), endocrinopathies (e.g., hyperadrenocorticism and hypothyroidism), glomerulopathies, and hypercoagulable states can be responsible for pulmonary arterial thrombosis and pulmonary thromboembolism in dogs (e- fig. - ) . pieces of this fact is not surprising because pulmonary edema occurs in the very early stages of inflammation (see e- fig. - ) . careful observation of the lungs at the time of necropsy is critical because diagnosis of pulmonary edema cannot be reliably performed microscopically. this is due in part to the loss of the edema fluid from the lungs during fixation with % neutral-buffered formalin and in part to the fact that the fluid itself stains very poorly or not at all with eosin because of its low protein content (hemodynamic edema). a protein-rich (permeability) edema is easier to visualize microscopically because it is deeply eosinophilic in hematoxylin and eosin fig. - ) . , normal alveolar capillary externally covered by type i and type ii pneumonocytes and internally by vascular endothelium (see fig. - for more detail). , at the early stages of sepsis, proinflammatory cytokines (interleukin [il- ] and tumor necrosis factor [tnf]) cause circulating neutrophils to adhere to the endothelial surface. following a "cytokine storm," the marginated neutrophils further activated by inflammatory mediators suddenly release their cytoplasmic granules (proteolytic enzymes and elastases myeloperoxidase) into the surrounding milieu (arrows). , enzymes released by these neutrophils cause injury to type i pneumonocytes (arrows) and endothelial cells (arrowheads), disrupting the blood-air barrier and causing permeability edema (curved arrows), alveolar hemorrhage (double-headed arrow), and exocytosis of neutrophils into the alveolar space (double-headed arrow). , extravasated plasma proteins admixed with surfactant and cell debris form thick hyaline membranes along the alveolar wall. , in the unlikely event that the animal survives, the healing process starts with alveolar macrophages removing cellular debris, reabsorption of edema, and hyperplasia of type ii pneumonocytes (double-headed curved arrow) that subsequently differentiate into type i pneumonocytes (see fig. b a recognized in the bovine lung after strong pneumatic stunning at slaughter (captive bolt) ( fig. - , a) . although obviously not important as an antemortem pulmonary lesion, brain emboli are intriguing as a potential risk for public health control of bovine spongiform encephalopathy (bse). fragments of hair can also embolize to the lung following intravenous injections (see fig. - , b). hepatic emboli formed by circulating pieces of fragmented liver occasionally become trapped in the pulmonary vasculature after severe abdominal trauma and hepatic rupture (see fig. - , c) . megakaryocytes trapped in alveolar capillaries are a common but incidental microscopic finding in the lungs of all species, particularly dogs (see fig. - , d) . tumor emboli (e.g., osteosarcoma and hemangiosarcoma in dogs and uterine carcinoma in cattle) can be numerous and striking and the ultimate cause of death in malignant neoplasia. in experimental studies, cytokines released during pulmonary inflammation are chemotactic for tumor cells and promote pulmonary metastasis. pulmonary infarcts. because of a dual arterial supply to the lung, pulmonary infarction is rare and generally asymptomatic. however, pulmonary infarcts can be readily caused when pulmonary thrombosis and embolism are superimposed on an already compromised pulmonary circulation such as occurs in congestive heart c d thrombi breaking free from a jugular, femoral, or uterine vein can cause pulmonary thromboembolism. pulmonary thromboembolisms occur in heavy horses after prolonged anesthesia (deep vein thrombosis), recumbent cows ("downer cow syndrome"), or in any animal undergoing long-term intravenous catheterization in which thrombi build up in the catheter and then break off (see fig. - ). septic emboli, pieces of thrombi contaminated with bacteria or fungi and broken free from infected mural or valvular thrombi in the heart and vessels, eventually become entrapped in the pulmonary circulation. pulmonary emboli originate most commonly from bacterial endocarditis (right side) and jugular thrombophlebitis in all species, hepatic abscesses that have eroded and discharged their contents into the caudal vena cava in cattle, and septic arthritis and omphalitis in farm animals (see fig. - ). when present in large numbers, septic emboli may cause unexpected death because of massive pulmonary edema; survivors generally develop pulmonary arteritis and thrombosis and embolic (suppurative) pneumonia, which may lead to pulmonary abscesses. bone marrow and bone emboli can form after bone fractures or surgical interventions of bone. these are not as significant a problem in domestic animals as they are in human beings. brain emboli (i.e., pieces of brain tissue) in the pulmonary vasculature reported in severe cases of head injury in human beings have recently been pulmonary macrophages (alveolar, intravascular, and interstitial), which have an immense biologic armamentarium, are the single most important effector cell and source of cytokines for all stages of pulmonary inflammation. these all-purpose phagocytic cells modulate the recruitment and trafficking of blood-borne leukocytes in the lung through the secretion of chemokines (see e- table - ). before reviewing how inflammatory cells are recruited in the lungs, three significant features in pulmonary injury must be remembered: ( ) leukocytes can exit the vascular system through the alveolar capillaries, unlike in other tissues, where postcapillary venules are the sites of leukocytic diapedesis (extravasation); ( ) the intact lung contains within alveolar capillaries a large pool of resident leukocytes (marginated pool); and ( ) additional neutrophils are sequestered within alveolar capillaries within minutes of a local or systemic inflammatory response. these three pulmonary idiosyncrasies, along with the enormous length of the capillary network in the lung, explain why recruitment and migration of leukocytes into alveolar spaces develops so rapidly. experimental studies with aerosols of endotoxin or gram-negative bacteria have shown that within minutes of exposure, there is a significant increase in capillary leukocytes, and by hours the alveolar lumen is filled with neutrophils. not surprisingly, the bal fluid collected from patients with acute pneumonia contains large amounts of inflammatory mediators such as tnf-α, il- , and il- . also, the capillary endothelium of patients with acute pneumonia has increased "expression" of adhesion molecules, which facilitate the migration of leukocytes from capillaries into the alveolar interstitium and from there into the alveolar lumen. in allergic pulmonary diseases, eotaxin and il- are primarily responsible for recruitment and trafficking of eosinophils in the lung. movement of plasma proteins into the pulmonary interstitium and alveolar lumen is a common but poorly understood phenomenon in pulmonary inflammation. leakage of fibrinogen and plasma proteins into the alveolar space occurs when there is structural damage to the blood-air barrier. this leakage is also promoted by some types of cytokines that enhance procoagulant activity, whereas others reduce fibrinolytic activity. excessive exudation of fibrin into the alveoli is particularly common in ruminants and pigs. the fibrinolytic system plays a major role in the resolution of pulmonary inflammatory diseases. in some cases, excessive plasma proteins leaked into alveoli mix with necrotic type i pneumonocytes and pulmonary surfactant, forming microscopic eosinophilic bands (membranes) along the lining of alveolar septa. these membranes, known as hyaline membranes, are found in specific types of pulmonary diseases, particularly in ards, and in cattle with acute interstitial pneumonias such as bovine pulmonary edema and emphysema and extrinsic allergic alveolitis (see pneumonias of cattle). in the past few years, nitric oxide has been identified as a major regulatory molecule of inflammation in a variety of tissues, including the lung. produced locally by macrophages, pulmonary endothelium, and pneumonocytes, nitric oxide regulates the vascular and bronchial tone, modulates the production of cytokines, controls the recruitment and trafficking of neutrophils in the lung, and switches on/off genes involved in inflammation and immunity. experimental work has also shown that pulmonary surfactant upregulates the production of nitric oxide in the lung, supporting the current view that pneumonocytes are also pivotal in amplifying and downregulating the inflammatory and immune responses in the lung (see e- table - ). as the inflammatory process becomes chronic, the types of cells making up cellular infiltrates in the lung change from mainly neutrophils to largely mononuclear cells. this shift in cellular composition is accompanied by an increase in specific cytokines, such as failure. it also occurs in dogs with torsion of a lung lobe (fig. - ) . the gross features of infarcts vary considerably, depending on the stage, and they can be red to black, swollen, firm, and cone or wedge shaped, particularly at the lung margins. in the early acute stage, microscopic lesions are severely hemorrhagic, and this is followed by necrosis. in or days, a border of inflammatory cells develops, and a few days later, a large number of siderophages are present in the necrotic lung. if sterile, pulmonary infarcts heal as fibrotic scars; if septic, an abscess may form surrounded by a thick fibrous capsule. in the past three decades, an information explosion has increased the overall understanding of pulmonary inflammation, with so many proinflammatory and antiinflammatory mediators described to date that it would be impossible to review them all here (see chapters and ). pulmonary inflammation is a highly regulated process that involves a complex interaction between cells imported from the blood (platelets, neutrophils, eosinophils, mast cells, and lymphocytes) and pulmonary cells (type i and ii pneumonocytes; endothelial and club [clara] cells; alveolar and intravascular macrophages; and stromal interstitial cells, such as mast cells, interstitial macrophages, fibroblasts, and myofibroblasts). blood-borne leukocytes, platelets, and plasma proteins are brought into the areas of inflammation by an elaborate network of chemical signals emitted by pulmonary cells and resident leukocytes. long-distance communication between pulmonary cells and blood cells is largely done by soluble cytokines; once in the lung, imported leukocytes communicate with pulmonary and vascular cells through adhesion and other inflammatory molecules. the best known inflammatory mediators are the complement system (c a, c b, and c a), coagulation factors (factors v and vii), arachidonic acid metabolites (leukotrienes and prostaglandins), cytokines (interleukins, monokines, and chemokines), adhesion molecules (icam and vcam), neuropeptides (substance p, tachykinins, and neurokinins), enzymes and enzyme inhibitors (elastase and antitrypsin), oxygen metabolites (o •, oh•, and h o ), antioxidants (glutathione), and nitric oxide (e -table - ). acting in concert, these and many other molecules send positive or negative signals to initiate, maintain, and, it is hoped, resolve the inflammatory process without causing injury to the lung. chapter respiratory system, mediastinum, and pleurae e- with several episodes of hemorrhage are characterized by large areas of dark brown discoloration, largely in the caudal lung lobes. microscopically, lesions are alveolar hemorrhages, abundant alveolar macrophages containing hemosiderin (siderophages), mild alveolar fibrosis, and occlusive remodeling of pulmonary veins. recurrent airway obstruction. recurrent airway obstruction (rao) of horses, also referred to as copd, heaves, chronic bronchiolitis-emphysema complex, chronic small airway disease, alveolar emphysema, and "broken wind," is a common clinically asthma-like syndrome of horses and ponies. rao is characterized by recurrent respiratory distress, chronic cough, poor athletic performance, airway neutrophilia, bronchoconstriction, mucus hypersecretion, and airway obstruction. the pathogenesis is still obscure, but genetic predisposition, t h (allergic) immune response, and the exceptional sensitivity of airways to environmental allergens (hyperreactive airway disease) have been postulated as the basic underlying mechanisms. what makes small airways hyperreactive to allergens is still a matter of controversy. epidemiologic and experimental studies suggest that it could be the result of preceding bronchiolar damage caused by viral infections; ingestion of pneumotoxicants ( -methylindole); or prolonged exposure to organic dust, endotoxin, and environmental allergens (molds). it has been postulated that sustained inhalation of dust particles, whether antigenic or not, upregulates the production of cytokines (tnf-α, il- , and monokine-inducible protein ) and neuropeptides (neurokinin a [nka], neurokinin b [nkb], and substance p), attracting neutrophils into the bronchioloalveolar region and promoting leukocyte-induced bronchiolar injury. summer pasture-associated obstructive pulmonary disease (spaopd) is a seasonal airway disease also reported in horses with similar clinical and pathologic findings. more recently, the term inflammatory airway disease (iad) has been introduced in equine medicine to describe rao-like syndrome in young horses to years old. the lungs of horses with heaves are grossly unremarkable, except for extreme cases in which alveolar emphysema may be present. microscopically, the lesions are often remarkable and include goblet cell metaplasia in bronchioles; plugging of bronchioles with mucus mixed with few eosinophils and neutrophils (see fig. - ); peribronchiolar infiltration with lymphocytes, plasma cells, and variable numbers of eosinophils; and hypertrophy of smooth muscle in bronchi and bronchioles. in severe cases, accumulation of mucus leads to the complete obstruction of bronchioles and alveoli and resultant alveolar emphysema characterized by enlarged "alveoli" from the destruction of alveolar walls. feline asthma syndrome. feline asthma syndrome, also known as feline allergic bronchitis, is a clinical syndrome in cats of any age characterized by recurrent episodes of bronchoconstriction, cough, or dyspnea. the pathogenesis is not well understood but is presumed to originate, as in human asthma, as a type i hypersensitivity (igemast cell reaction) to inhaled allergens. dust, cigarette smoke, plant and household materials, and parasitic proteins have been incriminated as possible allergens. this self-limited allergic disease responds well to steroid therapy; thus it is rarely implicated as a primary cause of death except when suppressed defense mechanisms allow a secondary bacterial pneumonia. bronchial biopsies from affected cats at the early stages reveal mild to moderate inflammation characterized by mucosal edema and infiltration of leukocytes, particularly eosinophils. increased numbers of circulating eosinophils (blood eosinophilia) are present in some but not all cats with feline asthma. il- , interferon-γ (ifn-γ), and interferon-inducible protein (ip- ), which are chemotactic for lymphocytes and macrophages. under appropriate conditions, these cytokines activate t lymphocytes, regulate granulomatous inflammation, and induce the formation of multinucleated giant cells such as in mycobacterial infections. inflammatory mediators locally released from inflamed lungs also have a biologic effect in other tissue. for example, pulmonary hypertension and right-sided heart failure (cor pulmonale) often follows chronic alveolar inflammation, not only as a result of increased pulmonary blood pressure but also from the effect of inflammatory mediators on the contractibility of smooth muscle of the pulmonary and systemic vasculature. cytokines, particularly tnf-α, that are released during inflammation are associated, both as cause and as effect, with the systemic inflammatory response syndrome (sirs), sepsis, severe sepsis with multiple organ dysfunction, and septic shock (cardiopulmonary collapse). as it occurs in any other sentinel system where many biologic promoters and inhibitors are involved (coagulation, the complement and immune systems), the inflammatory cascade could go into an "out-of-control" state, causing severe damage to the lungs. acute lung injury (ali), extrinsic allergic alveolitis, ards, pulmonary fibrosis, and asthma are archetypical diseases that ensue from an uncontrolled production and release of cytokines (cytokine storm). as long as acute alveolar injury is transient and there is no interference with the normal host response, the entire process of injury, degeneration, necrosis, inflammation, and repair can occur in less than days. on the other hand, when acute alveolar injury becomes persistent or when the capacity of the host for repair is impaired, lesions can progress to an irreversible stage in which restoration of alveolar structure is no longer possible. in diseases, such as extrinsic allergic alveolitis, the constant release of proteolytic enzymes and free radicals by phagocytic cells perpetuates alveolar damage in a vicious circle. in other cases, such as in paraquat toxicity, the magnitude of alveolar injury can be so severe that type ii pneumonocytes, basement membranes, and alveolar interstitium are so disrupted that the capacity for alveolar repair is lost. fibronectins and transforming growth factors (tgfs) released from macrophages and other mononuclear cells at the site of chronic inflammation regulate the recruitment, attachment, and proliferation of fibroblasts. in turn, these cells synthesize and release considerable amounts of ecm (collagen, elastic fibers, or proteoglycans), eventually leading to fibrosis and total obliteration of normal alveolar architecture. in summary, in diseases in which there is chronic and irreversible alveolar damage, lesions invariably progress to a stage of terminal alveolar and interstitial fibrosis. for pneumonia, see section species-specific pneumonia of domestic animals. exercise-induced pulmonary hemorrhage. exercise-induced pulmonary hemorrhage (eiph) is a specific form of pulmonary hemorrhage in racehorses that occurs after exercise and clinically is characterized by epistaxis. because only a small percentage of horses with bronchoscopic evidence of hemorrhage have clinical epistaxis, it is likely that eiph goes undetected in many cases. the pathogenesis is still controversial, but current literature suggests laryngeal paralysis, bronchiolitis, and extremely high pulmonary vascular and alveolar pressures during exercise, alveolar hypoxia, and preexisting pulmonary injury as possible causes. eiph is seldom fatal; postmortem lesions in the lungs of horses that have been affected disease may be known by different names. in pigs, for instance, enzootic pneumonia and mycoplasma pneumonia refer to the same disease caused by mycoplasma hyopneumoniae. the word pneumonitis has been used by some as a synonym for pneumonia; however, others have restricted this term to chronic proliferative inflammation generally involving the alveolar interstitium and with little or no evidence of exudate. in this chapter, the word pneumonia is used for any inflammatory lesion in the lungs, regardless of whether it is exudative or proliferative, alveolar, or interstitial. on the basis of texture, distribution, appearance, and exudation, pneumonias can be grossly diagnosed into four morphologically distinct types: bronchopneumonia, interstitial pneumonia, embolic pneumonia, and granulomatous pneumonia. by using this classification, it is possible at the time of a necropsy to predict with some degree of certainty the likely cause (virus, bacteria, fungi, or parasites), routes of entry (aerogenous vs. hematogenous), and possible sequelae. these four morphologic types allow the clinician or pathologists to predict the most likely etiology and therefore facilitate the decision as to what samples need to be taken and which tests should be requested to the diagnostic laboratory (i.e., histopathology, bacteriology, virology, or toxicology). however, overlapping of these four types of pneumonias is possible, and sometimes two morphologic types may be present in the same lung. the criteria used to classify pneumonias grossly into bronchopneumonia, interstitial pneumonia, embolic pneumonia, and granulomatous pneumonia are based on morphologic changes, including distribution, texture, color, and general appearance of the affected lungs (table - ). distribution of the inflammatory lesions in the lungs can be ( ) cranioventral, as in most bronchopneumonias; ( ) multifocal, as in embolic pneumonias; ( ) diffuse, as in interstitial pneumonias; or ( ) locally extensive, as in granulomatous in the most advanced cases, chronic bronchoconstriction and excess mucus production may result in smooth muscle hyperplasia and obstruction of the bronchi and bronchioles and infiltration of the airway mucosa by eosinophils. a syndrome known as canine asthma has been reported in dogs but is not as well characterized as the feline counterpart. few subjects in veterinary pathology have caused so much debate as the classification of pneumonias. historically, pneumonias in animals have been classified or named based on the following: . presumed cause, with names such as viral pneumonia, pasteurella pneumonia, distemper pneumonia, verminous pneumonia, chemical pneumonia, and hypersensitivity pneumonitis . type of exudation, with names such as suppurative pneumonia, fibrinous pneumonia, and pyogranulomatous pneumonia . morphologic features, with names such as gangrenous pneumonia, proliferative pneumonia, and embolic pneumonia . distribution of lesions, with names such as focal pneumonia, cranioventral pneumonia, diffuse pneumonia, and lobar pneumonia . epidemiologic attributes, with names such as enzootic pneumonia, contagious bovine pleuropneumonia, and "shipping fever" . geographic regions, with names such as montana progressive pneumonia . miscellaneous attributes, with names such as atypical pneumonia, cuffing pneumonia, progressive pneumonia, aspiration pneumonia, pneumonitis, farmer's lung, and extrinsic allergic alveolitis until a universal and systematic nomenclature for animal pneumonias is established, veterinarians should be acquainted with this heterogeneous list of names and should be well aware that one the parts of the face with the tip of your finger has been advocated by some pathologists. the texture of a normal lung is comparable to the texture of the center of the cheek. firm consolidation is comparable to the texture of the tip of the nose, and hard consolidation is comparable to the texture of the forehead. the term consolidation is frequently used to describe a firm or hard lung filled with exudate. pneumonias ( fig. - ) . texture of pneumonic lungs can be firmer or harder (bronchopneumonias), more elastic (rubbery) than normal lungs (interstitial pneumonias), or have a nodular feeling (granulomatous pneumonias). describing in words the palpable difference between the texture of a normal lung compared with the firm or hard texture of a consolidated lung can be a difficult undertaking. an analogy illustrating this difference based on touching changes in the gross appearance of pneumonic lungs include abnormal color, the presence of nodules or exudate, fibrinous or fibrous adhesions, and the presence of rib imprints on serosal surfaces (see fig. - ). on cut surfaces, pneumonic lungs may have exudate, hemorrhage, edema, necrosis, abscesses, bronchiectasis, granulomas or pyogranulomas, and fibrosis, depending on the stage. palpation and careful observation of the lungs are essential in the diagnosis of pneumonia. (for details, see the section on examination of the respiratory tract.) bronchopneumonia refers to a particular morphologic type of pneumonia in which injury and the inflammatory process take place primarily in the bronchial, bronchiolar, and alveolar lumens. bronchopneumonia is undoubtedly the most common type of pneumonia seen in domestic animals and is with few exceptions characterized grossly by cranioventral consolidation of the lungs (fig. - and see fig. - ). the reason why bronchopneumonias in animals are almost always restricted to the cranioventral portions of the lungs is not well understood. possible factors contributing to this topographic selectivity within the lungs include ( ) gravitational sedimentation of the exudate, ( ) greater deposition of infectious organisms, ( ) inadequate defense mechanisms, ( ) reduced vascular perfusion, ( ) shortness and abrupt branching of airways, and ( ) regional differences in ventilation. the term cranioventral in veterinary anatomy is the equivalent of "anterosuperior" in human anatomy. the latter is defined as "in front (ventral) and above (cranial)." thus, applied to the lung of animals, "cranioventral" means the ventral portion of the cranial lobe. however, by common usage in veterinary pathology, the term cranioventral used to describe the location of lesions in pneumonias has come to mean "cranial and ventral." thus it includes pneumonias affecting not only the ventral portion of the cranial lobe (true cranioventral) but also those cases in which the pneumonia has involved the ventral portions of adjacent lung lobes-initially the middle and then caudal on the right and the caudal lobe on the left side. bronchopneumonias are generally caused by bacteria and mycoplasmas, by bronchoaspiration of feed or gastric contents, or by improper tubing. as a rule, the pathogens causing bronchopneumonias arrive in the lungs via inspired air (aerogenous), either from infected aerosols or from the nasal flora. before establishing infection, pathogens must overwhelm or evade the pulmonary defense mechanisms. the initial injury in bronchopneumonias is centered on the mucosa of bronchioles; from there, the inflammatory process can spread downward to distal portions of the alveoli and upward to the bronchi. typically, for bronchopneumonias, the inflammatory exudates collect in the bronchial, bronchiolar, and alveolar lumina leaving the alveolar interstitium relatively unchanged, except for hyperemia and possibly edema. through the pores of kohn, the exudate can spread to adjacent alveoli until most or all of the alveoli in an individual lobule are involved. if the inflammatory process cannot control the inciting cause of injury, the lesions spread rapidly from lobule to lobule through alveolar pores and destroyed alveolar walls until an entire lobe or large portion of a lung is involved. the lesion tends to spread centrifugally, with the older lesions in the center, and exudate can be coughed up and then aspirated into other lobules, where the inflammatory process starts again. at the early stages of bronchopneumonia, the pulmonary vessels are engorged with blood (active hyperemia), and the bronchi, bronchioles, and alveoli contain some fluid (permeability edema). in cases in which pulmonary injury is mild to moderate, cytokines locally released in the lung cause rapid recruitment of neutrophils and alveolar macrophages into bronchioles and alveoli ( fig. - and see fig. - ). when pulmonary injury is much more severe, proinflammatory cytokines induce more pronounced vascular changes by further opening endothelial gaps, thus increasing vascular permeability resulting in leakage of plasma fibrinogen (fibrinous exudates) and sometimes hemorrhage in the alveoli. alterations in permeability can be further exacerbated by structural damage to pulmonary capillaries and vessels directly caused by microbial toxins. filling of alveoli, bronchioles, and small bronchi with inflammatory exudate progressively obliterates airspaces, and as a consequence of this process, portions of severely affected (consolidated) lungs sink to the bottom of the container when placed in fixative. the replacement of air by exudate also changes the texture of the lungs, and depending on the severity of bronchopneumonia, the texture varies from firmer to harder than normal. the term consolidation is used at gross examination when the texture of pneumonic lung becomes firmer or harder than normal as a result of loss of airspaces because of exudation and atelectasis. (for details, see the discussion of lung texture in the section on classification of pneumonias in domestic animals). inflammatory consolidation of the lungs has been referred to in the past as hepatization because the affected lung had the appearance and texture of liver. the process was referred to as red hepatization in acute cases in which ( ) congestion, ( ) red hepatization (liver texture), ( ) gray hepatization, and ( ) resolution. because of the use of effective antibiotics and prevention, pneumococcal pneumonia and its four classic stages are rarely seen; thus this terminology has been largely abandoned. currently, the term bronchopneumonia is widely used for both suppurative and fibrinous consolidation of the lungs because both forms of inflammation have essentially the same pathogenesis in which the pathogens reach the lung by the aerogenous route, injury occurs initially in the bronchial and bronchiolar regions, and the inflammatory process extends centrifugally deep into the alveoli. it must be emphasized that it is the severity of pulmonary injury that largely determines whether bronchopneumonia becomes suppurative or fibrinous. in some instances, however, it is difficult to discriminate between suppurative and fibrinous bronchopneumonia because both types can coexist (fibrinosuppurative bronchopneumonia), and one type can progress to the other. suppurative bronchopneumonia. suppurative bronchopneumonia is characterized by cranioventral consolidation of lungs (see figs. - and - ), with typically purulent or mucopurulent exudate present in the airways. this exudate can be best demonstrated by expressing intrapulmonary bronchi, thus forcing exudate out of the bronchi (see fig. - ). the inflammatory process in suppurative bronchopneumonia is generally confined to individual lobules, and as a result of this distribution, the lobular pattern of the lung becomes notably emphasized. this pattern is particularly obvious in cattle and pigs because these species have prominent lobulation of the lungs. the gross appearance often resembles an irregular checkerboard because of an admixture of normal and abnormal (consolidated) lobules (see fig. - ). because of this typical lobular distribution, suppurative bronchopneumonias are also referred to as lobular pneumonias. different inflammatory phases occur in suppurative bronchopneumonia where the color and appearance of consolidated lungs varies considerably, depending on the virulence of offending organisms and chronicity of the lesion. the typical phases of suppurative bronchopneumonia can be summarized as follows: . during the first hours when bacteria are rapidly multiplying, the lungs become hyperemic and edematous. . soon after, neutrophils start filling the airways, and by hours the parenchyma starts to consolidate and becomes firm in texture. . three to days later, hyperemic changes are less obvious, but the bronchial, bronchiolar, and alveolar spaces continue to fill with neutrophils and macrophages, and the affected lung sinks when placed in formalin. at this stage, the affected lung has a gray-pink color, and on cut surface, purulent exudate can be expressed from bronchi. . in favorable conditions where the infection is under control of the host defense mechanisms, the inflammatory processes begin to regress, a phase known as resolution. complete resolution in favorable conditions could take to weeks. . in animals in which the lung infection cannot be rapidly contained, inflammatory lesions can progress into a chronic phase. approximately to days after infection, the lungs become pale gray and take a "fish flesh" appearance. this appearance is the result of purulent and catarrhal inflammation, obstructive atelectasis, mononuclear cell infiltration, peribronchial and peribronchiolar lymphoid hyperplasia, and early alveolar fibrosis. complete resolution is unusual in chronic bronchopneumonia, and lung scars, such as pleural and pulmonary fibrosis; bronchiectasis as a consequence of chronic destructive bronchitis (see bronchiectasis [dysfunction/responses to injury and patterns of injury]); atelectasis; pleural adhesions; and lung abscesses may remain unresolved there was notable active hyperemia with little exudation of neutrophils; conversely, the process was referred to as gray hepatization in those chronic cases in which hyperemia was no longer present, but there was abundant exudation of neutrophils and macrophages. this terminology, although used for and applicable to human pneumonias, is rarely used in veterinary medicine primarily because the evolution of pneumonic processes in animals does not necessarily follow the red-to-gray hepatization pattern. bronchopneumonia can be subdivided into suppurative bronchopneumonia if the exudates are predominantly composed of neutrophils and fibrinous bronchopneumonia if fibrin is the predominant component of the exudates (see table - ). it is important to note that some veterinarians use the term fibrinous pneumonia or lobar pneumonia as a synonym for fibrinous bronchopneumonia, and bronchopneumonia or lobular pneumonia as a synonym for suppurative bronchopneumonia. human pneumonias for many years have been classified based on their etiology and morphology, which explains why pneumococcal pneumonia (streptococcus pneumoniae) has been synonymous with lobar pneumonia. in the old literature, four distinct stages of pneumococcal pneumonia were described as lumen of bronchiole capillary pulmonary defense mechanisms to allow them to colonize the lungs and establish an infection. suppurative bronchopneumonia can also result from aspiration of bland material (e.g., milk). pulmonary gangrene may ensue when the bronchopneumonic lung is invaded by saprophytic bacteria (aspiration pneumonia). fibrinous bronchopneumonia. fibrinous bronchopneumonia is similar to suppurative bronchopneumonia except that the predominant exudate is fibrinous rather than neutrophilic. with only a few exceptions, fibrinous bronchopneumonias also have a cranioventral distribution (fig. - and see fig. - ) . however, exudation is not restricted to the boundaries of individual pulmonary lobules, as is the case in suppurative bronchopneumonias. instead, the inflammatory process in fibrinous pneumonias involves numerous contiguous lobules and the exudate moves quickly through pulmonary tissue until the entire pulmonary lobe is rapidly affected. because of the involvement of the entire lobe and pleural surface, fibrinous bronchopneumonias are also referred to as lobar pneumonias or pleuropneumonias. in general terms, fibrinous bronchopneumonias are the result of more severe pulmonary injury and thus cause death earlier in the sequence of the inflammatory process than suppurative bronchopneumonias. even in cases in which fibrinous bronchopneumonia involves % or less of the total area, clinical signs and death can occur as a result of severe toxemia and sepsis. the gross appearance of fibrinous bronchopneumonia depends on the age and severity of the lesion and on whether the pleural surface or the cut surface of the lung is viewed. externally, early stages of fibrinous bronchopneumonias are characterized by severe congestion and hemorrhage, giving the affected lungs a characteristically intense red discoloration. a few hours later, fibrin starts to permeate and accumulate on the pleural surface, giving the pleura a ground glass appearance and eventually forming plaques of fibrinous exudate over a red, dark lung (see fig. - ). at this stage, a yellow fluid starts to accumulate in the thoracic cavity. the color of fibrin deposited over the pleural surface is also variable. it can be bright yellow when the exudate is formed primarily by fibrin, tan when fibrin is mixed with blood, and gray when a large number of leukocytes and fibroblasts are part of the fibrinous plaque in more chronic cases. because of the tendency of fibrin to deposit on the pleural surface, some pathologists use the term pleuropneumonia as a synonym for fibrinous bronchopneumonia. on the cut surface, early stages of fibrinous bronchopneumonia appear as simple red consolidation. in more advanced cases ( hours), fibrinous bronchopneumonia is generally accompanied by notable dilation and thrombosis of lymph vessels and edema of interlobular septa (see fig. - , b) . this distention of the interlobular septa gives affected lungs a typical marbled appearance. distinct focal areas of coagulative necrosis in the pulmonary parenchyma are also common in fibrinous bronchopneumonia such as in shipping fever pneumonia and contagious bovine pleuropneumonia. in animals that survive the early stage of fibrinous bronchopneumonia, pulmonary necrosis often develops into pulmonary "sequestra," which are isolated pieces of necrotic lung encapsulated by connective tissue. pulmonary sequestra result from extensive necrosis of lung tissue either from severe ischemia (infarct) caused by thrombosis of a major pulmonary vessel such as in contagious bovine pleuropneumonia or from the effect of necrotizing toxins released by pathogenic bacteria such as mannheimia haemolytica. sequestra in veterinary pathology should not be confused with "bronchopulmonary sequestration," a term used in human pathology to describe a congenital malformation in which whole lobes or parts of the lung develop without normal connections to the airway or vascular systems. for a long time. "enzootic pneumonias" of ruminants and pigs are typical examples of chronic suppurative bronchopneumonias. microscopically, acute suppurative bronchopneumonias are characterized by hyperemia, abundant neutrophils, macrophages, and cellular debris within the lumen of bronchi, bronchioles, and alveoli (see fig. - ). recruitment of leukocytes is promoted by cytokines, complement, and other chemotactic factors that are released in response to alveolar injury or by the chemotactic effect of bacterial toxins, particularly endotoxin. in most severe cases, purulent or mucopurulent exudates completely obliterate the entire lumen of bronchi, bronchioles, and alveoli. if suppurative bronchopneumonia is merely the response to a transient pulmonary injury or a mild infection, lesions resolve uneventfully. within to days, cellular exudate can be removed from the lungs via the mucociliary escalator, and complete resolution may take place within weeks. in other cases, if injury or infection is persistent, suppurative bronchopneumonia can become chronic with goblet cell hyperplasia, an important component of the inflammatory process. depending on the proportion of pus and mucus, the exudate in chronic suppurative bronchopneumonia varies from mucopurulent to mucoid. a mucoid exudate is found in the more chronic stages when the consolidated lung has a "fish flesh" appearance. hyperplasia of balt is another change commonly seen in chronic suppurative bronchopneumonias; it appears grossly as conspicuous white nodules (cuffs) around bronchial walls (cuffing pneumonia). this hyperplastic change merely indicates a normal reaction of lymphoid tissue to infection. further sequelae of chronic suppurative bronchopneumonia include bronchiectasis (see figs. - and - ), pulmonary abscesses, pleural adhesions (from pleuritis) ( fig. - ) , and atelectasis and emphysema from completely or partially obstructed bronchi or bronchioles (e.g., bronchiectasis). clinically, suppurative bronchopneumonias can be acute and fulminating but are often chronic, depending on the etiologic agent, stressors affecting the host, and immune status. the most common pathogens causing suppurative bronchopneumonia in domestic animals include pasteurella multocida, bordetella bronchiseptica, trueperella (arcanobacterium) pyogenes, streptococcus spp., escherichia coli, and several species of mycoplasmas. most of these organisms are secondary pathogens requiring a preceding impairment of the fulminating hemorrhagic bronchopneumonia can be caused by highly pathogenic bacteria such as bacillus anthracis. although the lesions in anthrax are primarily related to a severe septicemia and sepsis, anthrax should always be suspected in animals with sudden death and exhibiting severe acute fibrinohemorrhagic pneumonia, splenomegaly, and multisystemic hemorrhages. animals are considered good sentinels for anthrax in cases of bioterrorism. interstitial pneumonia refers to that type of pneumonia in which injury and the inflammatory process take place primarily in any microscopically, in the initial stage of fibrinous bronchopneumonia, there is massive exudation of plasma proteins into the bronchioles and alveoli, and as a result, most of the airspaces become obliterated by fluid and fibrin. leakage of fibrin and fluid into alveolar lumina is due to extensive disruption of the integrity and increased permeability of the blood-air barrier. fibrinous exudates can move from alveolus to alveolus through the pores of kohn. because fibrin is chemotactic for neutrophils, these types of leukocytes are always present a few hours after the onset of fibrinous inflammation. as inflammation progresses ( to days), fluid exudate is gradually replaced by fibrinocellular exudates composed of fibrin, neutrophils, macrophages, and necrotic debris ( fig. - ). in chronic cases (after days), there is notable fibrosis of the interlobular septa and pleura. in contrast to suppurative bronchopneumonia, fibrinous bronchopneumonia rarely resolves completely, thus leaving noticeable scars in the form of pulmonary fibrosis and pleural adhesions. the most common sequelae found in animals surviving an acute episode of fibrinous bronchopneumonia include alveolar fibrosis and bronchiolitis obliterans, in which organized exudate becomes attached to the bronchiolar lumen (see fig. - ) . these changes are collectively referred to as bronchiolitis obliterans organizing pneumonia (boop), a common microscopic finding in animals with unresolved bronchopneumonia. other important sequelae include pulmonary gangrene, when saprophytic bacteria colonize necrotic lung; pulmonary sequestra; pulmonary fibrosis; abscesses; and chronic pleuritis with pleural adhesions. in some cases, pleuritis can be so extensive that fibrous adhesions extend onto the pericardial sac. pathogens causing fibrinous bronchopneumonias in domestic animals include mannheimia (pasteurella) haemolytica (pneumonic mannheimiosis), histophilus somni (formerly haemophilus somnus), actinobacillus pleuropneumoniae (porcine pleuropneumonia), mycoplasma bovis, and mycoplasma mycoides ssp. mycoides small colony type (contagious bovine pleuropneumonia). fibrinous broncho- a b n alveolar epithelium. inhaled antigens, such as fungal spores, combine with circulating antibodies and form deposits of antigen-antibody complexes (type iii hypersensitivity) in the alveolar wall, which initiate a cascade of inflammatory responses and injury (allergic alveolitis). hematogenous injury to the vascular endothelium occurs in septicemias, sepsis, dic, larva migrans (ascaris suum), toxins absorbed in the alimentary tract (endotoxin) or toxic metabolites locally generated in the lungs ( -methylindole and paraquat), release of free radicals in alveolar capillaries (ards), and infections with endotheliotropic viruses (canine adenovirus and classical swine fever [hog cholera]). interstitial pneumonias in domestic animals and human beings are subdivided based on morphologic features into acute and chronic. it should be kept in mind, however, that not all acute interstitial pneumonias are fatal and that they do not necessarily progress to the chronic form. acute interstitial pneumonias. acute interstitial pneumonias begin with injury to either type i pneumonocytes or alveolar capillary endothelium, which provokes a disruption of the blood-air barrier and a subsequent exudation of plasma proteins into the alveolar space (see fig. - ) . this leakage of proteinaceous fluid into the alveolar lumen constitutes the exudative phase of acute interstitial pneumonia. in some cases of diffuse alveolar damage, exuded plasma proteins mix with lipids and other components of pulmonary surfactant and form elongated membranes that become partially attached to the alveolar basement membrane and bronchiolar walls. these membranes are referred to as hyaline membranes because of their hyaline appearance (eosinophilic, homogeneous, and amorphous) microscopically (see figs. - and - ). in addition to intraalveolar exudation of fluid, inflammatory edema and neutrophils accumulate in the alveolar interstitium and cause thickening of the alveolar walls. this acute exudative phase is generally followed a few days later by the proliferative phase of acute interstitial pneumonia, which is characterized by hyperplasia of type ii pneumonocytes to replace the lost type i pneumonocytes (see fig. - ). type ii pneumonocytes are in fact progenitor cells that differentiate and replace necrotic type i pneumonocytes (see fig. - ) . as a consequence, the alveolar walls become increasingly thickened. this process is in part the reason why lungs become rubbery on palpation, what prevents their normal collapse after the thorax is opened, and why the cut surface of the lung has a "meaty" appearance (see fig. - ). of the three layers of the alveolar walls (endothelium, basement membrane, and alveolar epithelium) and the contiguous bronchiolar interstitium (see fig. - ) . this morphologic type of pneumonia is the most difficult to diagnose at necropsy and requires microscopic confirmation because it is easily mistaken in the lung showing congestion, edema, hyperinflation, or emphysema. in contrast to bronchopneumonias, in which distribution of lesions is generally cranioventral, in interstitial pneumonias, lesions are more diffusely distributed and generally involve all pulmonary lobes, or in some cases, they appear to be more pronounced in the dorsocaudal aspects of the lungs (see fig. - ). three important gross features of interstitial pneumonia are ( ) the failure of lungs to collapse when the thoracic cavity is opened, ( ) the occasional presence of rib impressions on the pleural surface of the lung indicating poor deflation, and ( ) the lack of visible exudates in airways unless complicated with secondary bacterial pneumonia. the color of affected lungs varies from diffusely red in acute cases to diffusely pale gray to a mottled red, pale appearance in chronic ones. pale lungs are caused by severe obliteration of alveolar capillaries (reduced blood-tissue ratio), especially evident when there is fibrosis of the alveolar walls. the texture of lungs with uncomplicated interstitial pneumonia is typically elastic or rubbery, but definitive diagnosis based on texture alone is difficult and requires histopathologic examination. on a cut surface, the lungs may appear and feel more "meaty" (having the texture of raw meat) and have no evidence of exudate in the bronchi or pleura (fig. - ). in acute interstitial pneumonias, particularly in cattle, there is frequently pulmonary edema (exudative phase) and interstitial emphysema secondary to partial obstruction of bronchioles by edema fluid and strenuous air gasping before death. because edema tends to gravitate into the cranioventral portions of the lungs, and emphysema is often more obvious in the dorsocaudal aspects, acute interstitial pneumonias in cattle occasionally have a gross cranioventral-like pattern that may resemble bronchopneumonia, although the texture is different. lungs are notably heavy because of the edema and the infiltrative and proliferative changes. the pathogenesis of interstitial pneumonia is complex and can result from aerogenous injury to the alveolar epithelium (type i and ii pneumonocytes) or from hematogenous injury to the alveolar capillary endothelium or alveolar basement membrane. aerogenous inhalation of toxic gases (i.e., ozone and no ) or toxic fumes (smoke inhalation) and infection with pneumotropic viruses (influenza, herpesviruses, or canine distemper virus) can damage the figure - interstitial pneumonia, lung, feeder pig. a, the lung is heavy, pale, and rubbery in texture. it also has prominent costal (rib) imprints (arrows), a result of hypercellularity of the interstitium and the failure of the lungs to collapse when the thorax was opened. b, transverse section. the pulmonary parenchyma has a "meaty" appearance and some edema, but no exudate is present in airways or on the pleural surface. this type of lung change in pigs is highly suggestive of a viral pneumonia. (courtesy dr. a. lópez, atlantic veterinary college.) pneumonia are centered in the alveolar wall and its interstitium, a mixture of desquamated epithelial cells, macrophages, and mononuclear cells are usually present in the lumens of bronchioles and alveoli. ovine progressive pneumonia, hypersensitivity pneumonitis in cattle and dogs, and silicosis in horses are good veterinary examples of chronic interstitial pneumonia. pneumoconioses (silicosis and asbestosis), paraquat toxicity, pneumotoxic antineoplastic drugs (bleomycin), and extrinsic allergic alveolitis (farmer's lung) are well-known examples of diseases that lead to chronic interstitial pneumonias in human beings. massive pulmonary migration of ascaris larvae in pigs also causes interstitial pneumonia ( fig. - ). there is an insidious and poorly understood group of chronic idiopathic interstitial diseases, both in human beings and in animals, that eventually progress to terminal interstitial fibrosis. these were originally thought to be the result of repeated cycles of alveolar injury, inflammation, and fibroblastic/myoblastic response to an unknown agent. however, aggressive antiinflammatory therapy generally fails to prevent or reduce the severity of fibrosis. now, it is acute interstitial pneumonias are often mild and transient, especially those caused by some respiratory viruses, such as those responsible for equine and porcine influenza. these mild forms of pneumonia are rarely seen in the postmortem room because they are not fatal and do not leave significant sequelae (see the section on defense mechanisms/barrier systems). in severe cases of acute interstitial pneumonias, animals may die of respiratory failure, usually as a result of diffuse alveolar damage, a profuse exudative phase (leakage of proteinaceous fluid) leading to a fatal pulmonary edema. examples of this type of fatal acute interstitial pneumonia are bovine pulmonary edema and emphysema, and ards in all species. chronic interstitial pneumonia. when the source of alveolar injury persists, the exudative and proliferative lesions of acute interstitial pneumonia can progress into a morphologic stage referred to as chronic interstitial pneumonia. the hallmark of chronic interstitial pneumonia is fibrosis of the alveolar walls (with or without intraalveolar fibrosis) and the presence of lymphocytes, macrophages, fibroblasts, and myofibroblasts in the alveolar interstitium (figs. - and - ). in other cases, these chronic changes are accompanied by hyperplasia and persistence of type ii pneumonocytes, squamous metaplasia of the alveolar epithelium, microscopic granulomas, and hyperplasia of smooth muscle in bronchioles and pulmonary arterioles. it should be emphasized that although the lesions in interstitial the term bronchointerstitial pneumonia is used in veterinary pathology to describe cases in which microscopic lesions share some histologic features of both bronchopneumonia and interstitial pneumonia (e- fig. - ). this combined type of pneumonia is in fact frequently seen in many viral infections in which viruses replicate and cause necrosis in bronchial, bronchiolar, and alveolar cells. damage to the bronchial and bronchiolar epithelium causes an influx of neutrophils similar to that in bronchopneumonias, and damage to alveolar walls causes proliferation of type ii pneumonocytes, similar to that which takes place in the proliferative phase of acute interstitial pneumonias. it is important to emphasize that bronchointerstitial pneumonia is a microscopic not a gross diagnosis. examples include uncomplicated cases of respiratory syncytial virus infections in cattle and lambs, canine distemper, and influenza in pigs and horses. embolic pneumonia refers to a particular type of pneumonia in which gross and microscopic lesions are multifocally distributed in all pulmonary lobes. by definition, lung injury is hematogenous, and the inflammatory response is typically centered in pulmonary arterioles and alveolar capillaries. lungs act as a biologic filter for circulating particulate matter. sterile thromboemboli, unless extremely large, are rapidly dissolved and removed from the pulmonary vasculature by fibrinolysis, causing little, if any, ill effects. experimental studies have confirmed that most types of bacteria when injected intravenously (bacteremia) are phagocytosed by pulmonary intravascular macrophages, or they bypass the lungs and are finally trapped by macrophages in the liver, spleen, joints, or other organs. to cause pulmonary infection, circulating bacteria must first attach to the pulmonary endothelium with specific binding proteins or simply attach to intravascular fibrin and then evade phagocytosis by intravascular macrophages or leukocytes. septic thrombi facilitate entrapment of bacteria in the pulmonary vessels and provide a favorable environment to escape phagocytosis. once trapped in the pulmonary vasculature, usually in small arterioles or alveolar capillaries, offending bacteria disrupt endothelium and basement membranes, spread from the vessels to the interstitium and then to the surrounding lung, finally forming a new nidus of infection. embolic pneumonia is characterized by multifocal lesions randomly distributed in all pulmonary lobes (see fig. - and e-figs. - and - ). early lesions in embolic pneumonia are characterized grossly by the presence of very small ( to mm), white foci surrounded by discrete, red, hemorrhagic halos ( fig. - ). unless emboli arrive in massive numbers, causing fatal pulmonary edema, embolic pneumonia is seldom fatal; therefore these acute lesions are rarely seen at postmortem examination. in most instances, if unresolved, acute lesions rapidly progress to pulmonary abscesses. these are randomly distributed in all pulmonary lobes and are not restricted to the cranioventral aspects of the lungs, as is the case of abscesses developing from suppurative bronchopneumonia. the early microscopic lesions in embolic pneumonias are always focal or multifocal ( fig. - ) ; thus they differ from those of endotoxemia or septicemia, in which endothelial damage and interstitial reactions (interstitial pneumonia) are diffusely distributed in the lungs. when embolic pneumonia or its sequela (abscesses) is diagnosed at necropsy, an attempt should be made to locate the source of septic emboli. the most common sources are hepatic abscesses that have ruptured into the caudal vena cava in cattle, omphalophlebitis in farm animals, chronic bacterial skin or hoof infections, and a contaminated catheter in all species (see fig. - ) . valvular or mural endocarditis in the right heart is a common source of septic emboli and embolic pneumonia in all species. most frequently, bacterial proposed that a genetic mutation alters the cell-cell communication between epithelial and mesenchymal cells in the lung. this aberrant cellular communication leads to an overexpression of inflammatory and repair molecules (i.e., il- , il- , tgf-β , and caveolin), leading to increased apoptosis and interstitial deposition of extracellular matrix (ecm). the chronic interstitial (restrictive) diseases in human medicine include "idiopathic pulmonary fibrosis," "nonspecific interstitial pneumonia," "unusual interstitial pneumonia," and "cryptogenic organizing pneumonia," also referred to as idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic boop). feline idiopathic pulmonary fibrosis is an example of this type of progressive interstitial disease in veterinary medicine. it has been reported that in rare cases, chronic alveolar remodeling and interstitial fibrosis can progress to lung cancer. the lung has numerous circular areas of hemorrhage distributed randomly throughout all lung lobes (embolic pattern [see fig. - ]). these foci arise from injury to the microvasculature in alveolar septa and the visceral pleura secondary to lodgment of bacterial or fungal emboli (septic emboli) from valvular or mural endocarditis in the right heart or from other bacterial or fungal diseases where the bacterium or fungus gains access to the circulatory system as occurs in many bacterial and fungal enteritides or pneumonias caused by salmonella spp., e. coli, or aspergillus spp. the pathogenesis of granulomatous pneumonia shares some similarities with that of interstitial and embolic pneumonias. not surprisingly, some pathologists group granulomatous pneumonias within one of these types of pneumonias (e.g., granulomatous interstitial pneumonia). what makes granulomatous pneumonia a distinctive type is not so much the portal of entry or site of initial injury in the lungs but, rather, the unique type of inflammatory response that results in the formation of granulomas, which can be easily recognized at gross and microscopic examination. as a rule, agents causing granulomatous pneumonias are resistant to intracellular killing by phagocytic cells and to the acute inflammatory response, allowing prolonged persistence of these agents in tissues. the most common causes of granulomatous pneumonia in animals include systemic fungal diseases, such as cryptococcosis (cryptococcus neoformans and cryptococcus gatti), coccidioidomycosis (coccidioides immitis), histoplasmosis (histoplasma capsulatum), and blastomycosis (blastomyces dermatitidis) (see fig. - ). in most of these fungal diseases, the port of entry is aerogenous, and from the lungs the fungi disseminate systemically to other organs, particularly the lymph nodes, liver, and spleen. filamentous fungi such as aspergillus spp. or mucor spp. can also reach the lung by the hematogenous route. granulomatous pneumonia is also seen in some bacterial diseases, such as tuberculosis (mycobacterium bovis) in all species and rhodococcus equi in horses. sporadically, aberrant parasites such as fasciola hepatica in cattle and aspiration of foreign bodies can also cause granulomatous pneumonia (e- fig. - granulomatous pneumonia is characterized by the presence of variable numbers of caseous or noncaseous granulomas randomly distributed in the lungs (see fig. - ). on palpation, lungs have a typical nodular character given by well-circumscribed, variably sized nodules that generally have a firm texture, especially if calcification has occurred ( fig. - ) . during postmortem examination, granulomas in the lungs occasionally can be mistaken for neoplasms. microscopically, pulmonary granulomas are composed of a center of necrotic tissue, surrounded by a rim of macrophages (epithelioid cells) and giant cells and an outer delineated layer of connective tissue commonly infiltrated by lymphocytes and plasma cells ( fig. - ). unlike other types of pneumonias, the causative agent in granulomatous pneumonia can, in many cases, be identified isolates from septic pulmonary emboli in domestic animals are trueperella (arcanobacterium) pyogenes (cattle), fusobacterium necrophorum (cattle, pigs, and human beings), erysipelothrix rhusiopathiae (pigs, cattle, dogs, and human beings), streptococcus suis (pigs), staphylococcus aureus (dogs and human beings), and streptococcus equi (horses). granulomatous pneumonia refers to a particular type of pneumonia in which aerogenous or hematogenous injury is caused by organisms or particles that cannot normally be eliminated by phagocytosis and that evoke a local inflammatory reaction with numerous alveolar and interstitial macrophages, lymphocytes, a few neutrophils, and sometimes giant cells. the term granulomatous is used here to describe an anatomic pattern of pneumonia typically characterized by the presence of granulomas. g g but yet unproven that viral infections may also predispose horses to airway hyperresponsiveness and recurrent airway obstruction (rao). equine influenza. equine influenza is an important and highly contagious flulike respiratory disease of horses characterized by high morbidity and low mortality and explosive outbreaks in susceptible populations. it is an oie-notifiable disease. two antigenically unrelated subtypes of equine influenza virus have been identified (h n [a/equi- ] and h n [a/equi- ]). the course of the disease is generally mild and transient, and its importance is primarily because of its economic impact on horse racing. the types of injury and host response in the conducting system are described in the section on disorders of the nasal cavity and paranasal sinuses of horses. uncomplicated lesions in the lungs are mild and self-limiting bronchointerstitial pneumonia. in fatal cases, the lungs are hyperinflated with coalescing areas of dark red discoloration. microscopically, there is a bronchointerstitial pneumonia characterized by necrotizing bronchiolitis that is followed by hyperplastic bronchiolitis, hyperplasia of type ii pneumonocytes, hyaline membranes in alveoli, and sporadic multinucleated giant cells. the microscopic changes are ards in severe and fatal cases. the influenza virus antigen can be readily demonstrated in ciliated cells and alveolar macrophages. clinical signs are characterized by fever, cough, abnormal lung sounds (crackles and wheezes), anorexia, and depression. secondary bacterial infections (streptococcus equi, streptococcus zooepidemicus, staphylococcus aureus, and escherichia coli) commonly complicate equine influenza. equine viral rhinopneumonitis. equine viral rhinopneumonitis (evr), or equine herpesvirus infection, is a respiratory disease of young horses that is particularly important in weanlings between and months of age and to a much lesser extent in young foals and adult horses. the causative agents are ubiquitous equine herpesviruses (ehv- and ehv- ) that in addition to respiratory disease can cause abortion in pregnant mares and neurologic disease (equine herpes myeloencephalopathy) (see the section on disorders of the nasal cavity and paranasal sinuses of horses). the respiratory form of evr is a mild and a transient bronchointerstitial pneumonia seen only by pathologists when complications with secondary bacterial infections cause a fatal bronchopneumonia microscopically in sections by pas reaction or grocott-gomori's methenamine silver (gms) stain for fungi or by an acid-fast stain for mycobacteria. viral infections of the respiratory tract, particularly equine viral rhinopneumonitis and equine influenza, are important diseases of horses throughout the world. the effects of these and other respiratory viruses on the horse can be manifested in three distinct ways. first, as pure viral infections, their severity may range from mild to severe, making them a frequent interfering factor in training and athletic performance. second, superimposed infections by opportunistic bacteria, such as streptococcus spp., escherichia coli, klebsiella pneumoniae, rhodococcus equi, and various anaerobes, can cause fibrinous or suppurative bronchopneumonias. third, it is possible equine henipavirus (hendra virus). fatal cases of a novel respiratory disease in horses and human beings suddenly appeared in approximately in hendra, a suburb of brisbane, australia. this outbreak was attributed to a newly recognized zoonotic virus that was tentatively named equine morbillivirus. now called hendra virus (hev), this emerging viral pathogen is currently classified as a member of the genus henipavirus (includes hendra virus and nipah virus), in the family paramyxoviridae. fruit bats (flying foxes) act as natural reservoirs and are involved in the transmission by poorly understood mechanisms. the lungs of affected horses are severely edematous with gelatinous distention of pleura and subpleural lymph vessels. microscopically, the lungs have diffuse alveolar edema associated with vasculitis, thrombosis, and the presence of multinucleated syncytial cells in the endothelium of small pulmonary blood vessels and alveolar capillaries. the lymphatic vessels are notably distended with fluid. the characteristic inclusion bodies seen in other paramyxovirus infections are not seen in horses; however, the virus can be easily detected by immunohistochemistry in pulmonary endothelial cells and alveolar epithelial cells (pneumonocytes). clinical signs are nonspecific and include fever, anorexia, respiratory distress, and nasal discharge. equine multinodular pulmonary fibrosis. equine multinodular pulmonary fibrosis is a lung disease characterized by well-demarcated fibrotic nodular lesions in the lung (e- fig. - ). until recently, the pathogenesis was unclear, but recent studies proposed equine herpesvirus (ehv- ) as the putative etiology. grossly, the lungs show multifocal to coalescing, firm tan nodules scattered in all pulmonary lobes, which resemble pulmonary neoplasia. microscopically, alveolar walls are thickened due to collagen deposition, infiltration of lymphocytes and macrophages, and cuboidal cells lining the alveolar walls. the alveolar lumens contain neutrophils and macrophages, some of which may contain a large eosinophilic intranuclear inclusion body. typical clinical signs include weight loss, low-grade fever, and progressive exercise intolerance. this condition has a poor prognosis. rhodococcus equi. rhodococcus equi is an important cause of morbidity and mortality in foals throughout the world. this facultative intracellular gram-positive bacterium causes two major forms of disease: the first involves the intestine, causing ulcerative enterocolitis, and the second severe and often fatal bronchopneumonia. although half of foals with pneumonia have ulcerative enterocolitis, it is rare to find animals with intestinal lesions alone. occasionally, infection disseminates to lymph nodes, joints, bones, the genital tract, and other organs. because rhodococcus equi is present in soil and feces of herbivores (particularly foals), it is common for the disease to become enzootic on farms ("hot spots") where the organism has been shed earlier by infected foals. serologic evidence of infection in horses is widespread, yet clinical disease is sporadic and largely restricted to young foals or to adult horses with severe immunosuppression. virulence factors encoded by plasmids (virulenceassociated protein a [vapa gene]) are responsible for the survival and replication of rhodococcus equi in macrophages, thus determining the evolution of the disease. this bacterium has also been sporadically incriminated with infections in cattle, goats, pigs, dogs, and cats, and quite often in immunocompromised human beings, for example, those infected with the aids virus, after organ transplantation, or undergoing chemotherapy. it is still debatable whether natural infection starts as a bronchopneumonia (aerogenous route) from which rhodococcus equi reaches the intestine via swallowed sputum or whether infection starts as an enteritis (oral route) with a subsequent bacteremia into the lungs. (streptococcus equi, streptococcus zooepidemicus, or staphylococcus aureus) . uncomplicated lesions in evr are seen only in aborted fetuses or in foals that die within the first few days of life. they consist of focal areas of necrosis ( . to mm) in various organs, including liver, adrenal glands, and lungs. in some cases, intranuclear inclusion bodies are microscopically observed in these organs. outbreaks of interstitial pneumonia in donkeys have been attributed to multiple strains of asinine herpesviruses (ahv- and - ). clinically, horses and donkeys affected with the respiratory form of evr exhibit fever, anorexia, conjunctivitis, cough, and nasal discharge. equine viral arteritis. equine viral arteritis (eva), a pansystemic disease of horses, donkeys, and mules caused by an arterivirus (equine arteritis virus [eav]), occurs sporadically throughout the world, sometimes as an outbreak. this virus infects and causes severe injury to macrophages and endothelial cells. gross lesions are hemorrhage and edema in many sites, including lungs, intestine, scrotum, and periorbital tissues and voluminous hydrothorax and hydroperitoneum. the basic lesion is fibrinoid necrosis and inflammation of the vessel walls (vasculitis), particularly the small muscular arteries (lymphocytic arteritis), which is responsible for the edema and hemorrhage that explain most of the clinical features. pulmonary lesions are those of interstitial pneumonia with hyperplasia of type ii pneumonocytes and vasculitis with abundant edema in the bronchoalveolar spaces and distended pulmonary lymphatic vessels. viral antigen can be detected by immunoperoxidase techniques in the walls and endothelial cells of affected pulmonary vessels and in alveolar macrophages. clinical signs are respiratory distress, fever, abortion, diarrhea, colic, and edema of the limbs and ventral abdomen. respiratory signs are frequent and consist of serous or mucopurulent rhinitis and conjunctivitis with palpebral edema. like most viral respiratory infections, eva can predispose horses to opportunistic bacterial pneumonias. african horse sickness. african horse sickness (ahs) is an arthropod-borne, oie-notifiable disease of horses, mules, donkeys, and zebras that is caused by an orbivirus (family reoviridae) and characterized by respiratory distress or cardiovascular failure. ahs has a high mortality rate-up to % in the native population of horses in africa, the middle east, india, pakistan, and, most recently, spain and portugal. although the ahs virus is transmitted primarily by insects (culicoides) to horses, other animals, such as dogs, can be infected by eating infected equine flesh. the pathogenesis of african horse sickness remains unclear, but this equine orbivirus has an obvious tropism for pulmonary and cardiac endothelial cells and, to a lesser extent, mononuclear cells. based on clinical signs (not pathogenesis), african horse sickness is arbitrarily divided into four different forms: pulmonary, cardiac, mixed, and mild. the pulmonary form is characterized by severe respiratory distress and rapid death because of massive pulmonary edema, presumably from viral injury to the pulmonary endothelial cells. grossly, large amounts of froth are present in the airways, lungs fail to collapse, subpleural lymph vessels are distended, and the ventral parts of the lungs are notably edematous (see fig. - ) . in the cardiac form, recurrent fever is detected, and heart failure results in subcutaneous and interfascial edema, most notably in the neck and supraorbital region. the mixed form is a combination of the respiratory and cardiac forms. finally, the mild form, rarely seen in postmortem rooms, is characterized by fever and clinical signs resembling those of equine influenza; it is in most cases transient and followed by a complete recovery. this mild form is most frequently seen in donkeys, mules, and zebras and in horses with some degree of immunity. detection of viral antigen for diagnostic purposes can be done by immunohistochemistry in paraffin-embedded tissues. chapter respiratory system, mediastinum, and pleurae clinically, rhodococcus equi infection can be acute, with rapid death caused by severe bronchopneumonia, or chronic, with depression, cough, weight loss, and respiratory distress. in either form, there may be diarrhea, arthritis, osteomyelitis, or subcutaneous abscess formation. parascaris equorum. parascaris equorum is a large nematode (roundworm) of the small intestine of horses; the larval stages migrate through the lungs as ascarid larvae do in pigs. it is still unclear whether migration of parascaris equorum larvae can cause significant pulmonary lesions under natural conditions. experimentally, migration of larvae results in coughing, anorexia, weight loss, and small necrotic foci and petechial hemorrhages in the liver, hepatic and tracheobronchial lymph nodes, and lungs. microscopically, eosinophils are prominent in the interstitium and airway mucosa during the parasitic migration and in focal granulomas caused by dead larvae in the lung. dictyocaulus arnfieldi. dictyocaulus arnfieldi is not a very pathogenic nematode, but it should be considered if there are signs of coughing in horses that are pastured together with donkeys. donkeys are considered the natural hosts and can tolerate large numbers of parasites without ill effects. dictyocaulus arnfieldi does not usually become patent in horses, so examination of fecal samples is not useful; bal is only occasionally diagnostic because eosinophils (but not parasites) are typically found in the lavage fluid. mature parasites (up to cm in length) cause obstructive bronchitis, edema, and atelectasis, particularly along the dorsocaudal lung. the microscopic lesion is an eosinophilic bronchitis similar to the less acute infestations seen in cattle and sheep with their dictyocaulus species. the results of experimental studies suggest that natural infection likely starts from inhalation of infected dust or aerosols. once in the lung, rhodococcus equi is rapidly phagocytosed by alveolar macrophages, but because of defective phagosome-lysosome fusion and premature lysosomal degranulation, bacteria survive and multiply intracellularly, eventually leading to the destruction of the macrophage. interestingly, rhodococcus equi appears to be easily killed by neutrophils but not macrophages. released cytokines and lysosomal enzymes and bacterial toxins are responsible for extensive caseous necrosis of the lungs and the recruitment of large numbers of neutrophils, macrophages, and giant cells containing intracellular gram-positive organisms in their cytoplasm. depending on the stage of infection and the immune status and age of affected horses, pulmonary lesions induced by rhodococcus equi can vary from pyogranulomatous to granulomatous pneumonia. in young foals, the infection starts as a suppurative cranioventral bronchopneumonia, which progresses within a few days into small variable-size pulmonary abscesses. these abscesses rapidly transform into pyogranulomatous nodules, some of which become confluent and form large masses of caseous exudate ( fig. - ). microscopically, the early lesion starts with neutrophilic infiltration, followed by an intense influx of alveolar macrophages into the bronchoalveolar spaces. this type of histiocytic inflammation persists for a long period of time because rhodococcus equi is a facultative intracellular organism that survives the bactericidal effects of equine alveolar macrophages. in the most chronic cases, the pulmonary lesions culminate with the formation of large caseonecrotic masses with extensive fibrosis of the surrounding pulmonary parenchyma. pcr analysis of tracheobronchial aspirates has successfully been used as an alternative to bacteriologic culture in the diagnosis of rhodococcus equi infection in live foals. b a rhinotracheitis (ibr)/bovine herpes virus (bohv- ), bovine parainfluenza virus (bpiv- ), and bovine respiratory syncytial virus (brsv); and noninfectious interstitial pneumonias, such as bovine pulmonary edema and emphysema, reinfection syndrome, and many others. bovine enzootic pneumonia. enzootic pneumonia, sometimes simply referred to as calf pneumonia, is a multifactorial disease caused by a variety of etiologic agents that produces an assortment of lung lesions in young, intensively housed calves. the hostmicrobial-environmental triad is central in the pathogenesis of this disease. morbidity is often high (up to %), but fatalities are uncommon (> %) unless management is poor or unless new, virulent pathogens are introduced by additions to the herd. enzootic pneumonia is also called viral pneumonia because it often begins with an acute respiratory infection with bpiv- , brsv, or possibly with one or more of several other viruses (adenovirus, bohv- , reovirus, bovine coronavirus [bcov] , and bovine rhinitis virus). mycoplasmas, notably mycoplasma dispar, mycoplasma bovis, ureaplasma, and possibly chlamydophila, may also be primary agents. following infection with any of these agents, opportunistic bacteria, such as pasteurella multocida, trueperella (arcanobacterium) pyogenes, histophilus somni, mannheimia haemolytica, and escherichia coli, can cause a secondary suppurative bronchopneumonia, the most serious stage of enzootic pneumonia. the pathogenesis of the primary invasion and how it predisposes the host to invasion by the opportunists are poorly understood, but it is likely that there is impairment of pulmonary defense mechanisms. environmental factors, including air quality (poor ventilation), high relative humidity, and animal crowding, have been strongly incriminated. the immune status of the calf also plays an important role in the development and severity of enzootic pneumonia. calves with bovine leukocyte adhesion deficiency (blad), which prevents the migration of neutrophils from the capillaries, are highly susceptible to bronchopneumonia. lesions are variable and depend largely on the agents involved and on the duration of the inflammatory process. in the acute phases, lesions caused by viruses are those of bronchointerstitial pneumonia, which are generally mild and transient, and therefore are seen only sporadically at necropsy. microscopically, the lesions are necrotizing bronchiolitis, necrosis of type i pneumonocytes with hyperplasia of type ii pneumonocytes, and mild interstitial and alveolar edema. in the case of bpiv- and brsv infection, intracytoplasmic inclusion bodies and the formation of large multinucleated syncytia, resulting from the fusion of infected bronchiolar and alveolar epithelial cells, can also be observed in the lungs (fig. - ) . airway hyperreactivity has been described in calves after brsv infection; however, the significance of this syndrome in relation to enzootic pneumonia of calves is still under investigation. the mycoplasmas also can cause bronchiolitis, bronchiolar and alveolar necrosis, and an interstitial reaction, but in contrast to viral-induced pneumonias, mycoplasmal lesions tend to progress to a chronic stage characterized by striking peribronchiolar lymphoid hyperplasia (cuffing pneumonia). when complicated by secondary bacterial infections (e.g., pasteurella multocida and trueperella pyogenes), viral or mycoplasmal lesions change from a pure bronchointerstitial to a suppurative bronchopneumonia (fig. - ) . in late stages of bronchopneumonia, the lungs contain a creamy-mucoid exudate in the airways and later often have pulmonary abscesses and bronchiectasis (see fig. - ) . note that the same viruses and mycoplasmas involved in the enzootic pneumonia complex can also predispose cattle to other diseases, such as pneumonic mannheimiosis (mannheimia aspiration pneumonia. aspiration pneumonia is often a devastating sequela to improper gastric tubing of horses, particularly exogenous lipid pneumonia from mineral oil delivered into the trachea in treatment of colic. gross and microscopic lesions are described in detail in the section on aspiration pneumonias of cattle. opportunistic infections. chlamydophila (chlamydia) spp., obligatory intracellular zoonotic pathogens, can cause systemic infection in many mammalian and avian species; in horses, they can also cause keratoconjunctivitis, rhinitis, pneumonia, abortion, polyarthritis, enteritis, hepatitis, and encephalitis. serologic studies suggest that infection without apparent disease is common in horses. horses experimentally infected with chlamydophila psittaci develop mild and transient bronchointerstitial pneumonia. there are unconfirmed reports suggesting a possible association between these organisms and recurrent airway obstruction in horses. detection of chlamydial organisms in affected tissue is not easy and requires special laboratory techniques such as pcr, immunohistochemistry, and fluorescent antibody tests. horses are only sporadically affected with mycobacteriosis (mycobacterium avium complex, mycobacterium tuberculosis, and mycobacterium bovis). the intestinal tract and associated lymph nodes are generally affected, suggesting an oral route of infection with subsequent hematogenous dissemination to the lungs. the tubercles (granulomas) differ from those in ruminants and pigs, being smooth, gray, solid, sarcoma-like nodules without grossly visible caseous necrosis or calcification (e- fig. - ) . microscopically, the tubercles are composed of macrophages, epithelioid cells, and multinucleated giant cells. fibrosis increases with time, accounting in part for the sarcomatous appearance. adenovirus infections occur commonly in arabian foals with combined immunodeficiency (cid), a hereditary lack of b and t lymphocytes. in cases of adenoviral infection, large basophilic or amphophilic inclusions are present in the nuclei of tracheal, bronchial, bronchiolar, alveolar, renal, and intestinal epithelial cells. as it occurs in other species, infection with a unique fungal pathogen known as pneumocystis carinii typically occurs in immunosuppressed or immunoincompetent individuals such as arabian foals with cid (see fig. - ). diagnosis of pneumocystis carinii requires microscopic examination of lungs and special stains. idiopathic interstitial pneumonia. interstitial and bronchointerstitial pneumonias of undetermined cause that can progress to severe pulmonary fibrosis have been reported in foals and young horses. the gross and microscopic lesions are reminiscent of those of bovine pulmonary edema and emphysema or ards. the lungs are notably congested and edematous and microscopically are characterized by necrosis of the bronchiolar epithelium, alveolar edema, hyperplasia of type ii pneumonocytes, and hyaline membranes. the cause of this form of equine interstitial pneumonia is not known, but toxic and particularly viral causes have been proposed. bovine respiratory disease complex (brdc) and acute undifferentiated respiratory disease are general terms often used by clinicians to describe acute and severe bovine respiratory illness of clinically undetermined cause. these terms do not imply any particular type of pneumonia and therefore should not be used in pathology reports. clinically, the brd complex includes bovine enzootic pneumonia (multifactorial etiology); pneumonic mannheimiosis (mannheimia haemolytica); respiratory histophilosis (histophilus somni), previously known as respiratory hemophilosis (haemophilus somnus); mycoplasma bovis; respiratory viral infections, such as infectious bovine .e chapter respiratory system, mediastinum, and pleurae pneumonic mannheimiosis (shipping fever) is the most important respiratory disease of cattle in north america, particularly in feedlot animals that have been through the stressful marketing and assembly processes. mannheimia haemolytica biotype a, serotype is the etiologic agent most commonly responsible for the severe pulmonary lesions. a few investigators still consider that pasteurella multocida and other serotypes of mannheimia haemolytica are also causes of this disease. even after many years of intense investigation, from the gross lesions to the molecular aspects of the disease, the pathogenesis of pneumonic mannheimiosis remains incompletely understood. experiments have established that mannheimia haemolytica a alone is usually incapable of causing disease because it is rapidly cleared by pulmonary defense mechanisms. these findings may explain why mannheimia haemolytica, despite being present in the nasal cavity of healthy animals, only sporadically causes disease. for mannheimia haemolytica to be established as a pulmonary infection, it is first required that stressors impair the defense mechanisms and allow the bacteria to colonize the lung (see section on impairment of defense haemolytica). clinically, enzootic pneumonia is usually mild, but fatal cases are occasionally seen even in farms with optimal health management. pneumonic mannheimiosis (shipping fever). shipping fever (transit fever) is a vague clinical term used to denote acute respiratory diseases that occur in cattle several days or weeks after shipment. the disease is characterized by a severe fibrinous bronchopneumonia, reflecting the fact that death generally occurs early or at an acute stage. because mannheimia haemolytica (formerly pasteurella haemolytica) is most frequently isolated from affected lungs, the names pneumonic mannheimiosis and pneumonic pasteurellosis have been used synonymously. it is known that pneumonic mannheimiosis can occur in animals that have not been shipped and that organisms other than mannheimia haemolytica can cause similar lesions. therefore the term shipping fever should be relinquished in favor of more specific names, such as pneumonic mannheimiosis or respiratory histophilosis. irregular areas of coagulative necrosis are typically bordered by a rim of elongated cells often referred to as oat-shaped cells or oat cells that are degenerating neutrophils mixed with a few alveolar macrophages (see fig. - ). in the early stages of necrosis, there is no evidence of vascular thrombosis, suggesting that necrosis is primarily caused by the cytotoxin of mannheimia haemolytica and is not the result of an ischemic change. the interlobular septa become distended with protein-rich edematous fluid, and the lymphatic vessels contain fibrin thrombi. the trachea and bronchi can have considerable amounts of blood and exudate, which are transported by the mucociliary escalator or coughed up from deep within the lungs, but the walls of the trachea and major bronchi may or may not be involved. because of the necrotizing process, sequelae to pneumonic mannheimiosis can be serious and can include abscesses, encapsulated sequestra (isolated pieces of necrotic lung), chronic pleuritis, fibrous pleural adhesions, and bronchiectasis. clinically, pneumonic mannheimiosis is characterized by a severe toxemia that can kill animals even when considerable parts of the lungs remain functionally and structurally normal. cattle usually become depressed, febrile ( ° to ° f [ ° to ° c]), and anorexic and have a productive cough, encrusted nose, mucopurulent nasal exudate, shallow respiration, or an expiratory grunt. hemorrhagic septicemia. pneumonic mannheimiosis should not be confused with hemorrhagic septicemia (septicemic pasteurellosis) of cattle and water buffalo (bubalus bubalis) caused by inhalation or ingestion of serotypes :b and :e of pasteurella multocida. this oie-notifiable disease does not occur in north america and currently is reported only from some countries in asia, africa, and recently in germany. in contrast to pneumonic mannheimiosis, in which lesions are always confined to the lower respiratory tract, the bacteria of hemorrhagic septicemia always disseminates hematogenously to other organs. at necropsy, typically, generalized petechiae are present on the serosal surfaces of the intestine, heart, and lungs and in skeletal muscles. superficial and visceral lymph nodes are swollen and hemorrhagic. variable lesions include edematous and hemorrhagic lungs with or without consolidation; hemorrhagic enteritis; blood-tinged fluid in the thorax and abdomen; and subcutaneous edema of the head, neck, and ventral abdomen. bacteria can be cultured from blood, and animals have high fever and die rapidly ( % case fatality). respiratory histophilosis (haemophilosis). respiratory histophilosis is part of the histophilus somni (haemophilus somnus) disease complex, which has at least eight different clinicopathologic forms, each one involving different organs. this complex includes septicemia, encephalitis (known as thrombotic meningoencephalitis [tme]), pneumonia (respiratory histophilosis), pleuritis, myocarditis, arthritis, ophthalmitis, conjunctivitis, otitis, and abortion. the portals of entry for the different forms of histophilosis have not been properly established. the respiratory form of bovine histophilosis is the result of the capacity of the bacterium to induce both suppurative and fibrinous bronchopneumonia (e- fig. - ). the latter is in some cases indistinguishable from that of pneumonic mannheimiosis. the pathogenesis of respiratory histophilosis is still poorly understood, and the disease cannot be reproduced consistently by administration of histophilus somni alone. like mannheimia haemolytica, it requires predisposing factors such as stress or a preceding viral infection. histophilus somni is often isolated from the lungs of calves with enzootic pneumonia. the capacity of histophilus somni to cause septicemia and localized infections in the lungs, brain, eyes, ear, heart, mammary gland, male and female genital organs, or placenta is perhaps attributable to specific virulence factors, such as immunoglobulin-binding proteins (igbps) and lipooligosaccharide (los). also, histophilus mechanisms). these stressors include weaning, transport, fatigue, crowding, mixing of cattle from various sources, inclement weather, temporary starvation, and viral infections. horizontal transmission of viruses and mannheimia haemolytica occurs during crowding and transportation of cattle. viruses that most commonly predispose cattle to pneumonic mannheimiosis include bohv- , bpiv- , and brsv. once established in the lungs, mannheimia haemolytica causes lesions by means of different virulence factors, which include endotoxin, lipopolysaccharide, adhesins, and outer membrane proteins; however, the most important is probably the production of a leukotoxin (exotoxin), which binds and kills bovine macrophages and neutrophils. the fact that this toxin exclusively affects ruminant leukocytes probably explains why mannheimia haemolytica is a respiratory pathogen in cattle and sheep but not in other species. during mannheimia haemolytica infection, alveolar macrophages, neutrophils, and mast cells release maximum amounts of proinflammatory cytokines, particularly tnf-α, il- , il- , adhesion molecules, histamine, and leukotrienes. by locally releasing enzymes and free radicals, leukocytes further contribute to the injury and necrosis of bronchiolar and alveolar cells. the gross lesions of acute and subacute pneumonic mannheimiosis are the prototypic fibrinous bronchopneumonia, with prominent fibrinous pleuritis ( fig. - and see fig. - ) and pleural effusion. lesions are always cranioventral and usually ventral to a horizontal line through the tracheal bifurcation. the interlobular septa are distended by yellow, gelatinous edema and fibrin. the "marbling" of lobules is the result of intermixing areas of coagulation necrosis, interlobular interstitial edema, and congestion ( fig. - ) . microscopically, lung lesions are evident hours after experimental infection in which neutrophils fill the bronchial, bronchiolar, and alveolar spaces. within to hours, the cytotoxic effect of mannheimia haemolytica is manifested by necrosis of individual alveolar cells and fibrin begins to exude into the alveoli from increased permeability of the air-blood barrier. these changes are exacerbated by endothelial swelling, altered platelet function, increased procoagulant activity, and diminished profibrinolytic activity in the lungs. by hours, alveolar macrophages start to appear in the bronchoalveolar space. at this time, large and the pulmonary defense mechanisms. lung lesions are typically those of a chronic bronchopneumonia with numerous well-delineated caseonecrotic nodules (fig. - and e-fig. - ) . microscopically, lesions are quite characteristic and consist of distinct areas of pulmonary necrosis centered on bronchi or bronchioles. the lesion is formed by a core of fine eosinophilic granular debris surrounded by a rim of neutrophils, macrophages, and fibroblasts (see fig. - ) . although the origin of the caseonecrotic lesions is under investigation, recent studies incriminate reactive oxygen species (ros) and reactive nitrogen species (rns) as the major contributors for cell injury in the lung. the diagnosis is confirmed by isolation or somni has the ability to undergo structural and antigenic variation, evade phagocytosis by promoting leukocytic apoptosis, inhibit intracellular killing, reduce transferrin concentrations, and induce endothelial apoptosis in the lungs of affected calves. mixed pulmonary infections of histophilus somni, mannheimia haemolytica, pasteurella multocida, trueperella pyogenes, and mycoplasmas are fairly common in calves. mycoplasma bovis pneumonia. mycoplasma bovis is the most common mycoplasma sp. isolated from pneumonic lungs of cattle in europe and north america. pulmonary infection is exacerbated by stress or any other adverse factor (e.g., viral infection) that depresses n control programs for infectious disease. it was eradicated from north america in and from australia in the s, but it is still enzootic in large areas of africa, asia, and eastern europe. the etiologic agent, mycoplasma mycoides ssp. mycoides small colony type, was the first mycoplasma isolated and is one of the most pathogenic of those that infect domestic animals. natural infection occurs in cattle and asian buffalo. the portal of entry is aerogenous, and infections occur when a susceptible animal inhales infected droplets. the pathogenic mechanisms are still inadequately understood but are suspected to involve toxin and galactan production, unregulated production of tnf-α, ciliary dysfunction, immunosuppression, and immune-mediated vasculitis. vasculitis and thrombosis of pulmonary arteries, arterioles, veins, and lymphatic vessels lead to lobular infarction. the name of the disease is a good indication of the gross lesions. it is a severe, fibrinous bronchopneumonia (pleuropneumonia) similar to that of pneumonic mannheimiosis (see figs. - and - ) but having a more pronounced "marbling" of the lobules because of extensive interlobular edema and lymphatic thrombosis. typically, % to % of lesions are in the caudal lobes (not cranioventrally), and pulmonary sequestra (necrotic lung encapsulated by connective tissue) are more frequent and larger than pneumonic mannheimiosis. unilateral lesions are common in this disease. microscopically, the appearance again is like that of pneumonic mannheimiosis, except that vasculitis and thrombosis of pulmonary arteries, arterioles, and capillaries are much more obvious and are clearly the major cause of the infarction and thrombosis of lymphatic vessels in interlobular septa. mycoplasma mycoides ssp. mycoides small colony type remains viable in the sequestra for many years, and under stress (e.g., starvation), the fibrous capsule may break down releasing mycoplasma into the airways, thus becoming a source of infection for other animals. clinical signs are those of severe sepsis, including fever, depression, and anorexia followed by severe respiratory signs such as opened-mouth breathing, dyspnea and coughing, and crepitation and pleural friction on thoracic auscultation. vaccination is highly effective in preventing the disease. bovine tuberculosis. tuberculosis is an ancient, communicable, worldwide, chronic disease of human beings and domestic animals. it continues to be a major problem in human beings in underdeveloped countries, and it is on the rise in some industrialized nations, largely because of the immunosuppressive effects of aids, immigration, and movement of infected animals across borders. the world health organization (who) estimates that more than million people die of tuberculosis and million new cases appear each year, mostly in developing countries. mycobacterium tuberculosis is transmitted between human beings, but where unpasteurized milk is consumed, mycobacterium bovis from the milk of cattle with mammary tuberculosis is also an important cause of human tuberculosis. mycobacterium bovis infections have also been reported in a number of domestic and wild mammalian species; in some countries, wildlife reservoirs exist and may act as a source of infection for cattle. bovine tuberculosis is primarily caused by mycobacterium bovis, but infection with mycobacterium tuberculosis, the pathogen of human tuberculosis, and mycobacterium caprae (formerly mycobacterium bovis ssp. caprae/mycobacterium tuberculosis ssp. caprae) can occur sporadically. tuberculosis can be acquired by several routes, but infection of the lungs by inhalation of mycobacterium bovis is the most common in adult cattle, whereas ingestion of infected milk is more predominant in young animals. organisms belonging to the mycobacterium avium complex can also infect cattle, but for infection caused by these organisms, the term atypical mycobacteriosis (not tuberculosis) is currently preferred. immunohistochemical labeling of tissue sections for mycoplasma antigens. mycoplasma bovis is also incriminated in arthritis, otitis, mastitis, abortion, and keratoconjunctivitis. contagious bovine pleuropneumonia. contagious bovine pleuropneumonia is an oie-notifiable disease of historic interest in veterinary medicine because it was the object of early national a b c than % of bovine cases, a chronic, moist cough can progress to dyspnea. enlarged tracheobronchial lymph nodes can contribute to the dyspnea by impinging on airways, and the enlargement of caudal mediastinal nodes can compress the caudal thoracic esophagus and cause bloating. interstitial pneumonias. atypical interstitial pneumonia (aip) is a vague clinical term well entrenched in veterinary literature but one that has led to enormous confusion among veterinarians. it was first used to describe acute or chronic forms of bovine pneumonia that did not fit in any of the "classic" forms because of the lack of exudate and lack of productive cough. microscopically, the criteria for diagnosis of aip in cattle were based on the absence of obvious exudate and the presence of edema, interstitial emphysema (see the section on pulmonary emphysema), hyaline membranes, hyperplasia of type ii pneumonocytes, and alveolar fibrosis with interstitial cellular infiltrates. at that time, any pulmonary disease or pulmonary syndrome that had a few of the previously mentioned lesions was traditionally diagnosed as aip, and grouping all these different syndromes together was inconsequential because their etiopathogenesis were then unknown. field and laboratory investigations have demonstrated that most of the bovine syndromes previously grouped under aip have rather different causes and pathogeneses ( fig. - ) . furthermore, what was "atypical" in the past has become so common that it is fairly routine nowadays to find "typical cases" of aip. for all these reasons, investigators, largely from britain, proposed that all these syndromes previously clustered into aip should be named according to their specific cause or pathogenesis. the most common bovine syndromes characterized by edema, emphysema, hyaline membranes, and hyperplasia of type ii pneumonocytes include bovine pulmonary edema and emphysema (fog fever), "extrinsic allergic alveolitis" (hypersensitivity pneumonitis), "reinfection syndromes" (hypersensitivity to dictyocaulus sp. or brsv), milk allergy, ingestion of moldy potatoes, paraquat toxicity, toxic silo gases, mycotoxins, and others. acute bovine pulmonary edema and emphysema (fog fever). acute bovine pulmonary edema and emphysema (abpee), known in britain as fog fever (no association with atmospheric conditions), occurs in cattle usually grazing "fog" pastures (i.e., aftermath or foggage, regrowth after a hay or silage has been cut). epidemiologically, abpee usually occurs in adult beef cattle in the fall when there is a change in pasture from a short, dry grass to a lush, green grass. it is generally accepted that l-tryptophan present in the pasture is metabolized in the rumen to -methylindole, which in turn is absorbed into the bloodstream and carried to the lungs. mixed function oxidases present in the nonciliated bronchiolar epithelial (club) cells metabolize -methylindole into a highly pneumotoxic compound that causes extensive and selective necrosis of bronchiolar cells and type i pneumonocytes (fig. - and see fig. - ) and increases alveolar permeability, leading to edema, thickening of the alveolar interstitium, and alveolar and interstitial emphysema. -methylindole also interferes with the lipid metabolism of type ii pneumonocytes. the gross lesions are those of a diffuse interstitial pneumonia with severe alveolar and interstitial edema and interlobular emphysema (see fig. - , a) . the lungs are expanded, pale, and rubbery in texture, and the lesions are most notable in the caudal lobes. microscopically, the lesions are alveolar and interstitial edema and emphysema, formation of characteristic hyaline membranes within alveoli (see fig. - , b) , and in those animals that survive for several days, hyperplasia of type ii pneumonocytes and alveolar interstitial fibrosis. respiratory infection usually starts when inhaled bacilli reach the alveoli and are phagocytosed by pulmonary alveolar macrophages. if these cells are successful in destroying the bacteria, infection is averted. however, mycobacterium bovis, being a facultative pathogen of the monocytic-macrophage system, may multiply intracellularly, kill the macrophage, and initiate infection. from this first nidus of infection, bacilli spread aerogenously via airways within the lungs and eventually via the lymph vessels to tracheobronchial and mediastinal lymph nodes. the initial focus of infection at the portal of entry (lungs) plus the involvement of regional lymph nodes is termed the primary (ghon) complex of tuberculosis. if the infection is not contained within this primary complex, bacilli disseminate via the lymph vessels to distant organs and other lymph nodes by the migration of infected macrophages. hematogenous dissemination occurs sporadically when a granuloma containing mycobacteria erodes the wall of a blood vessel, causes vasculitis, and allows the granuloma to discharge mycobacteria into the alveolar circulation. if dissemination is sudden and massive, mycobacteria are widely disseminated and numerous small foci of infection develop in many tissues and organs and the process is referred to as miliary tuberculosis (like millet seeds). the host becomes hypersensitive to the mycobacterium, which enhances the cell-mediated immune defenses in early or mild infections but can result in host-tissue destruction in the form of caseous necrosis. the evolution and dissemination of the pulmonary infection are closely regulated by cytokines and tnf-α production by alveolar macrophages. unlike abscesses that tend to grow rather fast, granulomas evolve slowly at the site of infection. the lesion starts with few macrophages and neutrophils ingesting the offending organism, but because mycobacterium organisms are resistant to phagocytosis, infected macrophages eventually die, releasing viable bacteria, lipids, and cell debris. cell debris accumulates in the center of the lesion, whereas viable bacteria and bacterial lipids attract additional macrophages and a few lymphocytes at the periphery of the lesion. some of these newly recruited macrophages are activated by local lymphocytes and become large phagocytic cells with abundant cytoplasm resembling epithelial cells, thus the term epithelioid macrophages. multinucleated giant cells (also macrophages) appear at the edges of the lesion, and finally the entire focus of inflammatory process becomes surrounded by fibroblasts and connective tissue (see fig. - ). it may take weeks or months for a granuloma to be grossly visible. bovine tuberculosis, the prototype for granulomatous pneumonia, is characterized by the presence of a few or many caseated granulomas (see fig. - ). the early gross changes are small foci (tubercles) most frequently seen in the dorsocaudal, subpleural areas. with progression, the lesions enlarge and become confluent with the formation of large areas of caseous necrosis. calcification of the granulomas is a typical finding in bovine tuberculosis. single nodules or clusters occur on the pleura and peritoneum, and this presentation has been termed pearl disease. microscopically, the tubercle is composed of mononuclear cells of various types. in young tubercles, which are noncaseous, epithelioid and langhans' giant cells are at the center, surrounded by lymphocytes, plasma cells, and macrophages. later, caseous necrosis develops at the center, secondary to the effects of cell-mediated hypersensitivity and enclosed by fibrosis at the periphery. acid-fast organisms may be numerous but more often are difficult to find in histologic section or smears. clinically, the signs of tuberculosis relate to the dysfunction of a particular organ system or to general debilitation, reduced milk production, and emaciation. in the pulmonary form, which is more grossly, the postmortem lesions vary from subtle, gray, subpleural foci (granulomatous inflammation) to severe lesions, in which the lungs are firm and heavy and have a "meaty appearance" because of interstitial pneumonia (e- fig. - ) with type ii pneumonocyte hyperplasia, lymphocytic infiltration, and interstitial fibrosis. characteristically, discrete noncaseous granulomas formed in response to the deposition of antigen-antibody complexes are scattered throughout the lungs. chronic cases of extrinsic allergic alveolitis can eventually progress to diffuse fibrosing alveolitis. clinically, it can be acute or chronic; the latter has a cyclical pattern of exacerbation during winter months. weight loss, coughing, and poor exercise tolerance are clinical features. full recovery can occur if the disease is recognized and treated early. reinfection syndrome. hypersensitivity to reinfection with larvae of dictyocaulus viviparus is another allergic syndrome manifested in the lungs that causes signs and lesions indistinguishable from abpee, with the exception of eosinophils and possibly larvae in the alveolar exudate. the hypersensitivity reaction in the lung causes diffuse alveolar damage and edema, necrosis of type i pneumonocytes, and hyperplasia of type ii pneumonocytes. in the later stages of the disease, there is formation of small granulomas with interstitial infiltrates of mononuclear cells. it has been suggested but not confirmed that emphysema with diffuse proliferative alveolitis and formation of hyaline membranes can also occur sporadically in the late stages of brsv infection in cattle. presumably, this disease shares many similarities with "atypical" infections occasionally seen in children with respiratory syncytial virus (rsv human strain), in which a hypersensitivity to the virus or virus-induced augmentation of the immune response results in hypersensitivity pneumonitis (see fig. - ). brsv infection is also known to enhance hypersensitivity to environmental allergens in cattle. other forms of bovine interstitial pneumonia. inhalation of manure ("pit") gases, such as nitrogen dioxide (no ), hydrogen interstitial cell infiltrates, fibrosis, emphysema acute proliferation phase hyperplasia of type ii pneumonocytes clinically, severe respiratory distress develops within days of the abrupt pasture change, and cattle develop expiratory dyspnea, oral breathing, and evidence of emphysema within the lungs and even subcutaneously along the back. experimentally, reducing ruminal conversion of l-tryptophan to -methylindole prevents the development of abpee. a number of other agents cause virtually the same clinical and pathologic syndrome as is seen in abpee. the pathogenesis is assumed to be similar, although presumably other toxic factors are specific for each syndrome. one of these pneumotoxic factors is -ipomeanol, which is found in moldy sweet potatoes contaminated with the fungus fusarium solani. mixed function oxidases in the lungs activate -ipomeanol into a potent pneumotoxicant capable of producing irreversible oxidative injury to type i pneumonocytes and bronchiolar epithelial cells, presumably through lipoperoxidation of cell membranes. similarly, purple mint (perilla frutescens), stinkwood (zieria arborescens), and rapeseed and kale (brassica species) also cause pulmonary edema, emphysema, and interstitial pneumonia. extrinsic allergic alveolitis. extrinsic allergic alveolitis (hypersensitivity pneumonitis), one of the most common allergic diseases in cattle, is seen mainly in housed adult dairy cows in the winter. this disease shares many similarities with its human counterpart known as farmer's lung, which results from a type iii hypersensitivity reaction to inhaled organic antigens, most commonly microbial spores, mainly of the thermophilic actinomycete, saccharopolyspora rectivirgula (micropolyspora faeni), commonly found in moldy hay. this is followed by an antibody response to inhaled spores and local deposition of antigen-antibody complexes (arthus reaction) in the lungs (see fig. - ). because it affects only a few animals of the herd or the sporadic person working in a farm, it is presumed that intrinsic host factors, such as dysregulation of dendritic cells, t lymphocytes, igg, interleukins, ifn-γ, and surfactant, are involved in the pathogenesis of the disease. chapter respiratory system, mediastinum, and pleurae e- figure - interstitial pneumonia, adult cow. note meaty appearance of the pulmonary parenchyma and mild edematous distention of the interlobular septa. inset, thick hyaline membranes (arrows) lining hypercellular alveolar walls. hypersensitivity pneumonia was suspected. (courtesy dr. a. lópez, atlantic veterinary college.) gases, inhalation of no (silo gas) also causes bronchiolitis, edema, and interstitial pneumonia and, in survivors, bronchiolitis obliterans ("silo filler's disease"). smoke inhalation resulting from barn or house fires is sporadically seen by veterinarians and pathologists. in addition to skin burns, animals involved in fire accidents suffer extensive thermal injury produced by the heat on the nasal and laryngeal mucosa, and severe chemical irritation caused by inhalation of combustion gases and particles in the lung. animals that survive or are rescued from fires frequently develop nasal, laryngeal, and tracheal edema, and pulmonary hemorrhage and alveolar edema, which are caused by chemical injury to the blood-air barrier or by ards caused by the excessive production of free radicals during the pulmonary inflammatory response (see e- fig. - ) . microscopic examination of the lungs often reveals carbon particles (soot) on mucosal surfaces of the conducting system. verminous pneumonia (dictyocaulus viviparus). pulmonary lesions in parasitic pneumonias vary from interstitial pneumonia caused by migrating larvae to chronic bronchitis from intrabronchial adult parasites, to granulomatous pneumonia, which is caused by dead larvae, aberrant parasites, or eggs of parasites. in many cases, an "eosinophilic syndrome" in the lungs is characterized by infiltrates of eosinophils in the pulmonary interstitium and bronchoalveolar spaces and by blood eosinophilia. atelectasis and emphysema secondary to the obstruction of airways by parasites and mucous secretions are also common findings in parasitic pneumonias. the severity of these lesions relates to the numbers and size of the parasites and the nature of the host reaction, which sometimes includes hypersensitivity reactions (see section on reinfection syndrome). a common general term for all of these diseases is verminous pneumonia, and the adult nematodes are often visible grossly in the airways ( fig. - ) . dictyocaulus viviparus is an important pulmonary nematode (lungworm) responsible for a disease in cattle referred to as verminous pneumonia or verminous bronchitis. adult parasites live in the bronchi of cattle, mainly in the caudal lobes, and cause severe bronchial irritation, bronchitis, and pulmonary edema, which in turn are responsible for lobular atelectasis and interstitial emphysema. atelectasis is confined to the lobules of the lungs ventilated by the obstructed bronchi (dorsocaudal). interstitial emphysema (interlobular) is caused by forced expiratory movements against a partially obstructed single bronchus. in addition to the inflammation of bronchial mucosa, bronchoaspiration of larvae and eggs also causes an influx of leukocytes into the bronchoalveolar space (alveolitis). verminous pneumonia is most commonly seen in calves during their first summer grazing pastures that are repeatedly used from year to year, particularly in regions of europe that have a moist cool climate. the parasite can overwinter in pastures, even in climates as cold as canada's, and older animals may be carriers for a considerable length of time. at necropsy, lesions appear as dark or gray, depressed, wedgeshaped areas of atelectasis involving few or many lobules usually along the dorsocaudal aspect of the lungs. on cut surface, edematous foam and mucus mixed with white, slender (up to -mm long) nematodes are visible in the bronchi (see fig. - ). in the most severe cases, massive numbers of nematodes fill the bronchial tree. microscopically, the bronchial lumens are filled with parasites admixed with mucus because of goblet cell hyperplasia, and there is squamous metaplasia of the bronchial and bronchiolar epithelium because of chronic irritation. there are also inflammatory infiltrates in the bronchial mucosa; alveolar edema; hyperplasia of balt sulfide (h s), and ammonia (nh ), from silos or sewage can be a serious hazard to animals and human beings. at toxic concentrations, these gases cause necrosis of bronchiolar cells and type i pneumonocytes and fulminating pulmonary edema that causes asphyxiation and rapid death (see fig. - ) . like other oxidant secretory granules released by club cells contain several proteins, such as surfactantlike protein, antiinflammatory protein (cc ), and bronchiolar lining proteins. b, ros produced by club cells are also absorbed into capillaries within the lamina propria and are transferred by the circulatory system to pulmonary capillaries where they disrupt the air-blood barrier, causing degeneration and necrosis of type i pneumonocytes. this process leads to leakage of plasma fluid (alveolar edema [pink color]) and extravasation of erythrocytes (alveolar hemorrhage) and neutrophils (inflammation). ingested pneumotoxicants can be metabolized by the liver, leading to release of ros into the circulatory system that then disrupts the air-blood barrier in a similar manner. fig. - ). microscopically, there are focal intraalveolar hemorrhages caused by larvae migrating through the alveolar walls. some larvae admixed with edematous fluid and cellular exudate (including eosinophils) may be visible in bronchioles and alveoli. the alveolar walls are thickened because of edema and a few inflammatory cells. clinical signs include cough and expiratory dyspnea to the point of oral breathing. hydatid cysts, the intermediate stage of echinococcus granulosus, can be found in the lungs and liver and other viscera of sheep and to a lesser extent in cattle, pigs, goats, horses, and human beings. the adult stage is a tapeworm that parasitizes the intestine of canidae. hydatidosis is still an important zoonosis in some countries, and perpetuation of the parasite life cycle results from animals being fed uncooked offal from infected sheep and consumption of uninspected meat. hydatid cysts are generally to cm in diameter, and numerous cysts can be found in the viscera of affected animals ( fig. - ). each parasitic cyst is filled with clear fluid; numerous daughter cysts attach to the wall, each containing several "brood capsules" with protoscolices inside. hydatid cysts have little clinical significance in animals but are economically important because of carcass condemnation. aspiration pneumonias. the inhalation of regurgitated ruminal contents or iatrogenic deposition of medicines or milk into the trachea can cause severe and often fatal aspiration pneumonia. bland substances, such as mineral oil, may incite only a mild suppurative or histiocytic bronchopneumonia, whereas some "home remedies" or ruminal contents are highly irritating and cause a fibrinous, necrotizing bronchopneumonia. the right cranial lung lobe tends to be more severely affected because the right cranial bronchus is the most cranial branch and enters the ventrolateral aspect of the trachea. however, the distribution may vary when animals aspirate while in lateral recumbency. in some severe cases, pulmonary necrosis can be complicated by infection with saprophytic organisms present in ruminal contents, causing fatal gangrenous pneumonia. aspiration pneumonia should always be considered in animals whose swallowing has been compromised-for example, those with cleft palate or hypocalcemia (milk fever). on the other hand, neurological diseases such as encephalitis (e.g., rabies) or encephalopathy (e.g., lead poisoning) should be investigated in animals in which the cause of aspiration pneumonia could not be caused by persistent immunologic stimuli; hypertrophy and hyperplasia of bronchiolar smooth muscle because of increased contraction and decreased muscle relaxation; and a few eosinophilic granulomas around the eggs and dead larvae. these granulomas, grossly, are gray, noncaseated nodules ( to mm in diameter) and may be confused with those seen at the early stages of tuberculosis. the clinical signs (coughing) vary with the severity of infection, and severe cases can be confused clinically with interstitial pneumonias. expiratory dyspnea and death can occur with heavy parasitic infestations when there is massive obstruction of airways. a different form of bovine pneumonia, an acute allergic reaction known as reinfection syndrome, occurs when previously sensitized adult cattle are exposed to large numbers of larvae (dictyocaulus viviparus). lesions in this syndrome are those of a hypersensitivity pneumonia as previously described. other lung parasites. ascaris suum is the common intestinal roundworm of pigs; larvae cannot complete their life cycle in calves, but the larvae can migrate through the lungs and cause severe pneumonia and death of calves within weeks of infection. infection is usually acquired from the soil on which infested pigs were previously kept. the gross lesions are a diffuse interstitial pneumonia with hemorrhagic foci, atelectasis, and interlobular edema and it also occurs in canada, europe, australia, and probably elsewhere. this disease has two major clinicopathologic forms: one involves the central nervous system of goat kids and young goats and is characterized by a nonsuppurative leukoencephalomyelitis; the other form involves the joints of adult goats and is characterized by a chronic, nonsuppurative arthritis-synovitis. in addition, infection with cae virus can cause chronic lymphocytic interstitial pneumonia. the lentivirus of cae, caprine arthritis and encephalitis virus (caev), is closely related to visna/maedi virus and, in fact, cross infection with cae virus in sheep has been achieved experimentally. similar to maedi, cae infection presumably occurs during the first weeks of life when the doe transmits the virus to her offspring through infected colostrum or milk. horizontal transmission between infected and susceptible goats via the respiratory route has also been described. after coming into contact with mucosal cells at the portal of entry, the virus is phagocytized by macrophages, which migrate to the regional lymph nodes. infected macrophages are disseminated hematogenously to the central nervous system, joints, lungs, and mammary glands. like maedi, there is some evidence that the recruitment of lymphocytic cells results from dysregulation of cytokine production by infected macrophages and lymphocytes in affected tissues. it can take several months before serum antibodies can be detected in infected goats. grossly, the interstitial pneumonia is diffuse and tends to be most severe in the caudal lobes. the lungs are gray-pink and firm in texture with numerous, -to -mm, gray-white foci on the cut surface. the tracheobronchial lymph nodes are consistently enlarged. microscopically, the alveolar walls are thickened by lymphocytes and conspicuous hyperplasia of type ii pneumonocytes ( fig. - ). one important difference between the pneumonias of cae and maedi is that in cae the alveoli are filled with proteinaceous eosinophilic material (alveolar proteinosis), which in electron micrographs has structural features of pulmonary surfactant. the pulmonary form of cae can be mistaken for parasitic pneumonia (muellerius capillaris) because these two diseases have lymphocytic interstitial pneumonia and can coexist in the same goat. explained otherwise. depending on the nature of the aspirated material, histopathologic evaluation generally reveals foreign particles such as vegetable cells, milk droplets, and large numbers of bacteria in bronchi, bronchioles, and alveoli (e- fig. - ). vegetable cells and milk typically induce an early neutrophilic response followed by a histiocytic reaction with "foreign body" multinucleated giant cells (see e- fig. - ). special stains are used for the microscopic confirmation of aspirated particles in the lung (e.g., pas for vegetable cells and oil red-o for oil or milk droplets). maedi (visna/maedi). maedi is an important, lifelong, and persistent viral disease of sheep and occurs in most countries, except australia and new zealand. maedi means "shortness of breath" in the icelandic language, and it is known as graaff-reinet disease in south africa, zwoegerziekte in the netherlands, la bouhite in france, and ovine progressive pneumonia (opp) in the united states. more recently, the disease has also been referred to as ovine lentivirusinduced lymphoid interstitial pneumonia or simply lymphoid interstitial pneumonia (lip). maedi is caused by visna/maedi virus (vmv), a nononcogenic small ruminant lentivirus (srlv) of the family retroviridae that is antigenically related to the lentivirus causing caprine arthritisencephalitis (cae). seroepidemiologic studies indicate that infection is widespread in the sheep population, yet the clinical disease seems to be rare. the pathogenesis is incompletely understood, but it is known that transmission occurs largely vertically, through ingestion of infected colostrum, and horizontally, via inhalation of infected respiratory secretions. once in the body, the ovine lentivirus causes lifelong infections within monocytes and macrophages, including alveolar and pulmonary intravascular macrophages; clinical signs do not develop until after a long incubation period of years or more. pulmonary lesions at the time of death are severe interstitial pneumonia and failure of the lungs to collapse when the thorax is opened. notable rib imprints, indicators of uncollapsed lungs, are often present on the pleural surface ( fig. - ). the lungs are pale, mottled, and typically heavy (two or three times normal weight), and the tracheobronchial lymph nodes are enlarged. microscopically, the interstitial pneumonia is characterized by balt hyperplasia and thickening of alveolar walls and peribronchial interstitial tissue by heavy infiltration of lymphocytes, largely t lymphocytes (see fig. - ). recruitment of mononuclear cells into the pulmonary interstitium is presumably the result of sustainable production of cytokines by retrovirus-infected pulmonary macrophages and lymphocytes. hyperplasia of type ii pneumonocytes is not a prominent feature of maedi, likely because in this disease there is no injury to type i pneumonocytes, but there is some alveolar fibrosis and smooth muscle hypertrophy in bronchioles. secondary bacterial infections often cause concomitant bronchopneumonia. enlargement of regional lymph nodes (tracheobronchial) is due to severe lymphoid hyperplasia, primarily of b lymphocytes. the virus can also infect many other tissues, causing nonsuppurative encephalitis (visna), lymphocytic arthritis, lymphofollicular mastitis, and vasculitis. maedi is clinically characterized by dyspnea and an insidious, slowly progressive emaciation despite good appetite. death is inevitable once clinical signs are present, but it may take many months. caprine arthritis-encephalitis. caprine arthritis-encephalitis (cae) is a retroviral disease of goats (small ruminant lentivirus) that has a pathogenesis remarkably similar to that of visna/maedi in sheep. it was first described in the united states in the s, but such as pasteurella multocida, pneumonia may progress to fibrinous or suppurative bronchopneumonia. one might expect some specific evidence pointing to the infectious agents (e.g., large intranuclear inclusion bodies in epithelial cells with adenoviral infection), but this is often not the case, either because examination is seldom done at the acute stage when the lesions are still present or because secondary bacterial infections mask the primary lesions. in the late stages, chronic enzootic pneumonia is characterized by hyperplastic bronchitis, atelectasis, alveolar and peribronchiolar fibrosis, and marked peribronchial lymphoid hyperplasia (cuffing pneumonia). ovine pneumonic mannheimiosis. ovine pneumonic mannheimiosis is one of the most common and economically significant diseases in most areas where sheep are raised. it is caused by mannheimia haemolytica and has a pathogenesis and lesions similar to those of pneumonic mannheimiosis of cattle. colonization and infection of lungs are facilitated by stressors such as changes in weather; handling; deworming; dipping; viral infections such as parainfluenza virus (piv ), respiratory syncytial virus (rsv), and adenovirus; and probably chlamydiae and bordetella parapertussis infections. lesions are characterized by a severe fibrinous bronchopneumonia (cranioventral) with pleuritis ( fig. - and e-fig. - ). subacute to chronic cases progress to purulent bronchopneumonia, and sequelae include abscesses and fibrous pleural adhesions. a similar form of pneumonic mannheimiosis has been reported with increased frequency in bighorn sheep. septicemic pasteurellosis. septicemic pasteurellosis, a common ovine disease, is caused by bibersteinia trehalosi (formerly pasteurella trehalosi or mannheimia haemolytica biotype t) in lambs months of age or older or by mannheimia haemolytica (biotype a) in lambs younger than months of age. both organisms are carried in the tonsils and oropharynx of clinically healthy sheep, and under abnormal circumstances (particularly under stress from dietary or environmental changes) bacteria can invade adjacent tissues, enter the bloodstream, and cause septicemia. gross lesions include a distinctive necrotizing pharyngitis and tonsillitis; ulcerative esophagitis (e- fig. - ) ; severe congestion and edema of the lungs; focal hepatic necrosis; and petechiae in the mucosa of the tongue, esophagus, and intestine and particularly in the lungs and pleura. clinically, goats are active and afebrile but progressively lose weight despite normal appetite. the encephalitic or arthritic signs tend to obscure the respiratory signs, which are only evident on exertion. secondary bacterial bronchopneumonia is common in affected animals. bacterial pneumonias. in the past, pasteurella haemolytica was incriminated in four major ovine diseases known as ( ) acute ovine pneumonic pasteurellosis (shipping fever), ( ) enzootic pneumonia (nonprogressive chronic pneumonia), ( ) fulminating septicemia, and ( ) mastitis. under the new nomenclature, mannheimia haemolytica is responsible for ovine pneumonia resembling shipping fever in cattle (ovine pneumonic mannheimiosis), septicemia in young lambs (younger than months of age), and ovine enzootic pneumonia and sporadic severe gangrenous mastitis in ewes. bibersteinia (pasteurella) trehalosi (formerly pasteurella haemolytica biotype t) is the agent incriminated in septicemia in lambs to months old. chronic enzootic pneumonia. in sheep, this entity is a multifactorial disease complex that, in contrast to ovine pneumonic mannheimiosis, causes only a mild to moderate pneumonia and it is rarely fatal. it generally affects animals younger than year of age. significant costs associated with chronic enzootic pneumonia include reduction of weight gain, labor costs, veterinary fees, and slaughterhouse waste. the modifier "chronic" is used here to avoid any confusion with pneumonic mannheimiosis ("acute enzootic pneumonia"). it is also sometimes called atypical pneumonia, chronic nonprogressive pneumonia, proliferative pneumonia, or other names. chronic enzootic pneumonia is a clinical epidemiologic term and does not imply a single causal agent but is the result of a combination of infectious, environmental, and managerial factors. the list of infectious agents involved in ovine enzootic pneumonia includes mannheimia haemolytica, pasteurella multocida, parainfluenza virus (pi- ), adenovirus, reovirus, respiratory syncytial virus (rsv), chlamydiae, and mycoplasmas (mycoplasma ovipneumoniae). in the early stages of enzootic pneumonia, a cranioventral bronchointerstitial pneumonia is characterized by moderate thickening of alveolar walls because of hyperplasia of type ii pneumonocytes. in some cases, when lungs are infected with secondary pathogens, viviparus of cattle. as seen in cattle with dictyocaulus viviparus, areas of atelectasis secondary to bronchiolar obstruction are present, particularly along the dorsal caudal aspects of the caudal lung lobes. microscopically, affected lungs are characterized by a catarrhal, eosinophilic bronchitis, with peribronchial lymphoid hyperplasia and smooth muscle hyperplasia of bronchi and bronchioles. bronchioles and alveoli can contain edematous fluid, eosinophils, and parasitic larvae and eggs. microscopic granulomas caused by aspirated eggs can be observed in the distal lung. the clinical signs (cough, moderate dyspnea, and loss of condition) and lesions relate mainly to obstruction of the small bronchi by adult worms and filaria. anemia of undetermined pathogenesis and secondary bacterial pneumonia are common in small ruminants with this parasitic disease. muellerius capillaris. muellerius capillaris, also called the nodular lungworm, occurs in sheep and goats in most areas of the world and is the most common lung parasite of sheep in europe and northern africa. it requires slugs or snails as intermediate hosts. the lesions in sheep are typically multifocal, subpleural nodules that tend to be most numerous in the dorsal areas of the caudal lung lobes ( fig. - , a) . these nodules are soft and hemorrhagic in the early stages but later become gray-green and hard or even calcified. microscopically, a focal, eosinophilic, and granulomatous reaction occurs in the microscopically, the hallmark lesion is a disseminated intravascular thrombosis often with bacterial colonies in the capillaries of affected tissues. the alveolar capillaries contain bacteria and microthrombi, and the alveolar lumens have fibrin and red blood cells. mannheimia haemolytica and bibersteinia trehalosi are readily isolated from many organs. affected animals usually die within a few hours of infection, and these animals only rarely have clinical signs such as dullness, recumbency, and dyspnea. contagious caprine pleuropneumonia. a number of mycoplasma spp., often referred to as the "mycoides cluster," can produce respiratory tract infections in goats; however, only mycoplasma capricolum ssp. capripneumoniae is considered to cause contagious caprine pleuropneumonia. this disease is the goat counterpart of contagious bovine pleuropneumonia in cattle; sheep do not have a corresponding disease. this oie-notifiable disease is important in africa, the middle east, and areas of asia, but it is also seen elsewhere. the gross lesions caused by mycoplasma capricolum ssp. capripneumoniae are similar to those of the bovine disease and consist of a severe, often unilateral fibrinous bronchopneumonia and pleuritis; however, distention of the interlobular septa (which are normally not as well developed in goats as in cattle) and formation of pulmonary sequestra are less obvious than in the bovine disease. clinically, contagious caprine pleuropneumonia is similar to contagious bovine pleuropneumonia, with high morbidity and mortality, fever, cough, dyspnea, and increasing distress and weakness. other small ruminant mycoplasmas. pneumonia, fibrinous polyarthritis, septicemia, meningitis, mastitis, peritonitis, and abortion are possible manifestations of disease caused by mycoplasma mycoides ssp. mycoides large colony type and mycoplasma mycoides ssp. capri. the pathogenicity of other mycoplasmas, such as mycoplasma ovipneumoniae, mycoplasma arginini, and mycoplasma capricolum ssp. capricolum, in sheep and goats is still being defined and specific description of the lesions would be premature. these organisms probably cause disease only in circumstances similar to those for enzootic pneumonia, where host, infectious, and environmental factors create a complex interaction in the pathogenesis of the disease. it has been suggested that igg antibodies directed against ovine mycoplasmal antigens cross-react with ciliary proteins, causing inflammation and ciliary dysfunction, a condition in lambs referred to as coughing syndrome. tuberculosis. although tuberculosis has generally been considered uncommon in sheep and goats, caprine tuberculosis has become a significant disease in areas of spain and europe. mycobacterium caprae (formerly mycobacterium bovis ssp. caprae/mycobacterium tuberculosis ssp. caprae) is the most common cause, but infection with mycobacterium bovis or with the mycobacterium avium complex does occur when the disease is prevalent in other species in the locality. the pulmonary form, similar to that seen in cattle, is characterized by a granulomatous pneumonia with multiple, large, caseous, calcified, and well-encapsulated granulomas scattered throughout the lungs. intralesional acid-fast organisms within macrophages are not as abundant as in bovine tuberculosis. staphylococcus aureus. young sheep ( to weeks old) are susceptible to staphylococcus aureus septicemia (tick pyemia). this bacterium causes disseminated inflammation and abscesses in the joints, heart, liver, kidneys, and cns, and in the lung it can also produce bronchopneumonia and pulmonary abscesses (e- fig. - ). dictyocaulus filaria. dictyocaulus filaria, also called the large lungworm, is a serious, worldwide, parasitic disease of the lungs, most commonly of lambs and goat kids but occurring in adults as well. the life cycle and lesions are similar to those of dictyocaulus epithelial cells spreads rapidly throughout the nasal, tracheal, and bronchial mucosa, with the more severe outbreaks reflecting more involvement of intrapulmonary airways and secondary infection with pasteurella multocida, trueperella (arcanobacterium) pyogenes, or haemophilus spp. although uncommon, human beings infected with swine influenza (h n ) can transmit the virus to pigs; therefore it is important that veterinarians or workers with influenza-like illness stay away from pig farms. natural transmission of h n and h n from human beings to ferrets (mustela putorius furo) and from human beings to cats and dogs has also been reported. pulmonary lesions caused by influenza virus alone are rarely seen in the postmortem room because this disease has a very low mortality rate unless complicated with secondary bacterial infections. grossly, a copious catarrhal to mucopurulent inflammation extends from the nasal passages to the bronchioles, with the volume of mucus being sufficient to plug small airways and cause a lobular or multilobular atelectasis in the cranioventral regions of the lungs. the appearance can be similar grossly, although not microscopically, to that of mycoplasma hyopneumoniae. fatal cases have severe alveolar and interstitial pulmonary edema. microscopically, the lesions in uncomplicated cases are typical of a virus-induced, necrotizing bronchitis-bronchiolitis, which in severe cases extends into the alveoli as bronchointerstitial pneumonia. it is characterized by necrosis of the bronchial/bronchiolar epithelium, thickening and infiltration of the alveolar wall with mononuclear cells and aggregates of macrophages, neutrophils, mucus, and some necrotic cells within the alveolar lumen. if these changes are extensive enough, the lumen of bronchioles can be occluded by exudate, causing lobular atelectasis. viral antigen can be demonstrated in infected epithelial cells by immunoperoxidase techniques. in the later stages of alveolar inflammation, neutrophils are progressively replaced by intraalveolar macrophages, unless the pneumonia is complicated by secondary bacterial infections. recent serologic surveys indicate that infection is also prevalent in wild pigs. clinically, a sudden onset of fever, nasal discharge, stiffness, labored breathing, weakness or even prostration, followed by painful and often paroxysmal coughing, is seen in animals of all age groups and may affect most of the herd. the outbreak subsides virtually without mortality within or weeks; the clinical appearance is much more alarming than the pathologic changes, unless the pigs have secondary infection with bacteria. infection can be confirmed using pcr in secretions collected with nasal swabs. the most important effect of most outbreaks of influenza is severe weight loss, but pregnant sows may abort or give birth to weak piglets. porcine reproductive and respiratory syndrome. a disease originally named mystery swine disease was first recognized in the united states in . in , it was seen in europe, and the disease now occurs worldwide in most major pig-raising countries. in , dutch investigators isolated a virus as the etiologic agent; porcine reproductive and respiratory syndrome virus (prrsv) is currently classified in the genus arterivirus of the family arteriviridae. as its name implies, prrs is characterized by late-term abortions and stillbirths and respiratory problems. the respiratory form is generally seen in nursery and grow/finish pigs. the pathogenesis has not been completely elucidated, but it is presumed that there is a mucosal portal of entry with virus replication in macrophages of the lymphoid tissue, followed by viremia and finally dissemination of infected macrophages to the lungs and other organs, such as the thymus, liver (kupffer cells), spleen, lymph nodes, and intestine. the pulmonary alveolar and intravascular macrophages are the major targets for prrs virus, which induces apoptosis of these cells. the virus also downregulates the innate immune response by subpleural alveoli where the adults, eggs, and coiled larvae reside ( fig. - , b) . clinical signs are usually not apparent. goats differ from sheep by having diffuse interstitial rather than focal lesions, and the reaction to the parasites seen microscopically varies from almost no lesions to a severe interstitial pneumonia with heavy infiltrates of mononuclear cells in alveolar walls resembling cae or mycoplasmal infections. secondary effects of muellerius capillaris infection in sheep and goats include decreased weight gain and possibly secondary bacterial infections. protostrongylus rufescens. protostrongylus rufescens is a worldwide parasite of sheep, goats, and wild ruminants. it requires an intermediate snail as a host. infection is usually subclinical, but protostrongylus rufescens can be pathogenic for lambs and goat kids and can cause anorexia, diarrhea, weight loss, and mucopurulent nasal discharge. the adult parasite lives in bronchioles as dictyocaulus spp., but it causes pulmonary nodules similar to those of muellerius capillaris. porcine pneumonias are unequivocally a major obstacle for the contemporary swine industry. the incidence, prevalence, and mortality rates of pneumonias in pigs depend on a series of complex, multifactorial interactions. among the most commonly recognized elements linked to porcine pneumonias are the following: • host (age, genetic makeup, immune status) • infectious agents (viruses, bacteria) • environmental determinants (humidity, temperature, ammonia concentrations) • management practices (crowding, mixing of animals, air quality, nutrition, stress) because of the nature of these multifactorial interactions, it will become obvious in the following paragraphs that more often than not a specific type of pneumonia frequently progresses to or coexists with another. the term porcine respiratory disease complex (prdc) has been introduced in clinical practice to describe pigs with signs of respiratory infection involving combined bacterial and viral infections. commonly implicated microbes include porcine reproductive and respiratory syndrome virus (prrsv), swine influenza virus (siv), porcine circovirus (pcv ), porcine respiratory coronavirus (prcov), mycoplasma hyopneumoniae, and pasteurella multocida. swine influenza (swine flu). swine influenza is a highly contagious acute respiratory viral disease of swine that is caused by swine influenza virus (siv), a type a influenza virus of the family orthomyxoviridae. it is generally accepted that swine influenza resulted from adaptation of the type a influenza virus that caused the human influenza pandemic during world war i. the most common subtypes of siv currently circulating in pigs are h n , h n , and h n . swine influenza is enzootic worldwide and is known to infect human beings who are in close contact with sick pigs. in , an outbreak of swine-human influenza (h n ), presumably transmitted from pigs to human beings, emerged in mexico and rapidly spread to many countries throughout the world. this new "pandemic" was attributed to a triple-reassortant of influenza a virus containing gene segments of swine, eurasian avian, and human strains. human infection with this novel strain affected mainly children and young adults, as well as individuals of any age with an underlying debilitating condition. transmission between influenza-infected and susceptible pigs occurs mainly by aerosol or oral route. siv attaches to and replicates within epithelial cells of the upper respiratory tract; the infection of similar inclusions are occasionally seen in bronchial glandular and renal epithelial cells. the lungs show thickening of the alveolar walls because of hyperplasia of type ii pneumonocytes and interstitial infiltrates of mononuclear cells, peribronchiolar fibrous hyperplasia, and necrotizing bronchitis/bronchiolitis. circovirus can be confirmed in affected tissue by immunohistochemical or pcr techniques. dual infections with pcv and prrsv frequently occur in pigs, and secondary infections with pneumocystis carinii are commonly seen in pigs with this coinfection. characteristically, alveoli are filled with a distinctive foamy exudate that contains the organism, which is not visible in h&e-stained sections but is easily demonstrated with gomori's methenamine silver stain (see fig. - ) . in human beings, pneumocystis (carinii) jirovecii pneumonia (pneumocystosis) is one of the most common and often fatal complications in aids patients. as in aids patients, abnormal populations of cd + and cd + t lymphocytes have been incriminated as the underlying mechanism leading to pneumocystosis in foals and pigs. nipah virus. nipah virus belongs to the paramyxoviridae family and shares a genus (henipavirus) with the closely related hendra virus (see section on pneumonias of horses). another emerging zoonotic disease, nipah virus caused a major epidemic with significant human mortality in southeast asia in and . people handling pigs were primarily affected. similar to hendra virus, fruit bats (flying foxes) act as natural reservoir and are involved in the transmission to pigs by poorly understood mechanisms. in pigs, this virus infects the respiratory system resulting in pneumonia with syncytial cells occurring in the vascular endothelium and in the respiratory epithelium at all levels of the lung. disease is spread to human beings via the respiratory route. human-to-human transmission of this virus has been reported in more recent outbreaks. other viral pneumonias of pigs. porcine respiratory coronavirus (prcov) is sporadically incriminated in pneumonia in pigs. this viral pneumonia is generally mild, and most pigs fully recover if the pneumonia is not complicated with other infections. lesions in the lung are those of bronchointerstitial pneumonia with necrotizing bronchiolitis. interestingly, infections with porcine and other respiratory coronaviruses have been used to investigate the pathogenesis of severe acute respiratory syndrome (sars), an emerging and highly contagious condition in human beings that is attributed to a novel human coronavirus (sars-cov). the relationship between sars-cov and animal coronavirus is still under investigation. other viruses rarely incriminated in porcine respiratory disease complex (prdc) include paramyxovirus, encephalomyocarditis virus, hemagglutinating encephalomyocarditis virus, and adenovirus. petechial hemorrhages in the lung and pulmonary edema may be seen with african swine fever, classical swine fever, and pseudorabies virus infections. porcine enzootic pneumonia. porcine enzootic pneumonia, a highly contagious disease of pigs caused by mycoplasma hyopneumoniae, is grossly characterized by suppurative or catarrhal bronchopneumonia ( fig. - and e- fig. - ). when its worldwide prevalence and deleterious effect on feed conversion are taken into account, this disease is probably the most economically significant respiratory disease of pigs. although an infectious disease, it is very much influenced by immune status and management factors, such as crowding (airspace and floor space), ventilation (air exchange rate), concentrations of noxious gases in the air (ammonia and hydrogen sulfide), relative humidity, temperature fluctuations, and mixing of stock from various sources. it has been demonstrated with inhibiting interferons and deregulates the adaptive immune response, thus interfering with the normal defense mechanisms predisposing pigs to septicemia and bacterial pneumonia. the most common opportunistic organisms are streptococcus suis, salmonella choleraesuis, mycoplasma hyopneumoniae, haemophilus parasuis, bordetella bronchiseptica, pasteurella multocida, and pneumocystis carinii. dual viral infections with prrsv and porcine circovirus (pcv ), siv, and porcine respiratory coronavirus (prcov) are commonly found in pigs, and such coinfections increase the severity of disease. on postmortem examination, pulmonary lesions vary from very mild changes characterized by failure of the lung to collapse when the thorax is opened and the presence of rib imprints (see fig. - ) to severe changes manifested by consolidation of the lung in cases that have been complicated with bacterial pneumonia. tracheobronchial and mediastinal lymph nodes are typically enlarged. microscopically, pulmonary changes are those of interstitial pneumonia characterized by thickening of alveolar walls by infiltrating macrophages and lymphocytes and mild hyperplasia of type ii pneumonocytes. necrotic cells are scattered in the alveolar lumens. unlike some other viral infections, bronchiolar epithelium does not appear to be affected. diagnosis of prrs in tissue collected at necropsy can be confirmed by immunohistochemistry and pcr techniques. infected pigs may become carriers and transmit the infection through body fluids and semen. clinically, prrs in nursery and young growing animals is characterized by sneezing, fever, anorexia, dyspnea, cough, and occasional death. some piglets develop severe cyanosis of the abdomen and ears, which explains why this syndrome was named blue ear disease when first described in europe. porcine circovirus-associated disease. another emerging porcine syndrome, characterized clinically by progressive emaciation in weaned pigs, was originally described in the s in canada, the united states, and europe. since then, it has disseminated to many countries, causing economic devastation in pig farms worldwide. because of the clinical signs and lesions in many organs, this syndrome was named postweaning multisystemic wasting syndrome (pmws). porcine circovirus (pcv ) has been incriminated as the etiologic agent and is a member of the circoviridae family. pcv has been associated with a number of syndromes in pigs, including systemic pcv infection (the preferred term for pmws because it may also affect mature pigs), pcv -associated pneumonia, pcv -associated enteritis, porcine dermatitis and nephropathy syndrome (pdns), pcv -associated reproductive failure, and, most recently, pcv -associated cerebellar vasculitis. the diseases caused by pcv are now collectively known as porcine circovirus-associated disease (pcvad); the most common manifestations are systemic pcv infection (pmws) and pcv -associated pneumonia as part of the porcine respiratory disease complex. all of these manifestations affect more than one organ, and there is substantial overlap between the syndromes. at necropsy, pigs with systemic pcv infection (pmws) and pcv -associated pneumonia are often in poor body condition, and the most remarkable changes, not considering other possible secondary infections, are enlargement of the superficial and visceral lymph nodes and a mild interstitial pneumonia characterized by failure of the lungs to collapse when the thorax is opened. jaundice is occasionally observed. microscopically, the lymphoid tissues show lymphoid depletion, histiocytic replacement of follicles, and notable proliferation of parafollicular histiocytes, some of which fuse and form syncytial cells (granulomatous lymphadenitis); necrosis of the lymphoid follicles is seen less often. in some cases, large basophilic inclusion bodies are present singly or as grapelike clusters (botryoid inclusions) within the cytoplasm of macrophages, particularly in peyer's patches, spleen, and lymph nodes (e- fig. - ). chapter respiratory system, mediastinum, and pleurae peribronchial, bronchiolar, and alveolar interstitium. additional virulence factors include the ability of mycoplasma hyopneumoniae to cause immunosuppression, reduce the phagocytic activity of neutrophils in the lung, and change the chemical composition of mucus. all of these functional alterations can predispose the lung to secondary bacterial infections. the lesions caused by mycoplasma hyopneumoniae start as a bronchointerstitial pneumonia and progress to a suppurative or mucopurulent bronchopneumonia once secondary pathogens are involved (commonly seen at necropsy). in most pigs, gross lesions affect only portions of the cranial lobes, but in more severely affected pigs, lesions involve % or more of the cranioventral portions of the lungs (see fig. - ). the affected lungs are dark red in the early stages but have a homogeneous pale-gray ("fish flesh") appearance in the more chronic stages of the disease. on cut surface, exudate can easily be expressed from airways, and depending on the stage of the lesions and secondary infections, the exudate varies from purulent to mucopurulent to mucoid. microscopic lesions are characterized by an influx of macrophages and neutrophils into the bronchi, bronchioles, and alveoli, and with time there is also notable balt hyperplasia (see fig. - , b) . in some cases, accumulation of exudate can be severe enough to cause occlusion of bronchioles and atelectasis of the corresponding lobules. the suppurative bronchopneumonia may be accompanied by a mild fibrinous pleuritis, which is often more severe if other organisms, such as mycoplasma hyorhinis, pasteurella multocida, or actinobacillus pleuropneumoniae, are also involved. abscesses and fibrous pleural adhesions are sequelae of chronic complicated infections. clinically, enzootic pneumonia occurs as a herd problem in two disease forms. a newly acquired infection of a previously clean herd causes disease in all age groups, resulting in acute respiratory distress and low mortality. in a chronically infected herd, the mature animals are immune and clinical signs are usually apparent only in growing pigs at times of particular stress such as at weaning. in such herds, coughing and reduced rate of weight gain are the most notable signs. porcine pasteurellosis. porcine pasteurellosis is an infectious disease complex with unclear pathogenesis that includes primary infections by pasteurella multocida alone (primary pasteurellosis) or, more frequently, after the defense mechanisms are impaired and a secondary bacterium colonizes the lung (porcine pneumonic pasteurellosis). in rare cases, pasteurella multocida causes acutely fatal septicemias in pigs (primary septicemic pasteurellosis). it is important to remember that pasteurella multocida serotypes a and d are both part of the normal nasal flora and are also causative agents of bronchopneumonia, pleuritis, and atrophic rhinitis in pigs. pasteurella multocida is one of the most common secondary pathogens isolated from the lungs of pigs with swine influenza virus (siv), porcine reproductive and respiratory syndrome virus (prrsv), porcine circovirus (pcv ), pseudorabies (suhv- ), classical swine fever (hog cholera), enzootic pneumonia, and porcine pleuropneumonia. secondary infections with pasteurella multocida notably change the early and mild bronchointerstitial reaction of enzootic and viral pneumonias into a severe suppurative bronchopneumonia with multiple abscesses and sometimes pleuritis. the other important role of pasteurella multocida in porcine pneumonias is as a cause of a fulminating, cranioventral, fibrinous bronchopneumonia (pleuropneumonia) after influenza virus infection or stress from inadequate ventilation resulting in high levels of ammonia in the air. the nature of the lesion and the predisposing factors of poor management or coexisting viral infections suggest that fulminating porcine pasteurellosis has a pathogenesis similar to that of pneumonic mannheimiosis of cattle. pharyngitis with subcutaneous cervical edema, fibrinohemorrhagic polyarthritis, and focal lymphocytic pcr that mycoplasma hyopneumoniae is present in the air of infected farms. the causative agent, mycoplasma hyopneumoniae, is a fastidious organism and very difficult to grow; thus the final diagnosis is frequently based on interpretation of lesions alone or supported by ancillary tests to detect this mycoplasma in affected lungs by immunohistochemistry, immunofluorescence, or pcr. the bronchopneumonic lesions of porcine enzootic pneumonia are in most cases mild to moderate, and thus mortality is low unless complicated with secondary pathogens, such as pasteurella multocida, trueperella (arcanobacterium) pyogenes, bordetella bronchiseptica, haemophilus spp., mycoplasma hyorhinis, and other mycoplasmas and ureaplasmas. although the pathogenesis of porcine enzootic pneumonia is not completely elucidated, it is known that mycoplasma hyopneumoniae first adheres to the cilia of the bronchi by means of a unique adhesive protein, produces ciliostasis, and finally colonizes the respiratory system by firmly attaching to the ciliated epithelial cells of the trachea and the bronchi of the cranioventral regions of the lungs. once attached to the respiratory epithelium, it provokes an influx of neutrophils into the tracheobronchial mucosa; causes extensive loss of cilia (deciliation); stimulates an intense hyperplasia of lymphocytes in the balt; and attracts mononuclear cells into the factors have been identified. these factors allow actinobacillus pleuropneumoniae to attach to cells; produce pores in cell membranes; damage capillaries and alveolar walls, resulting in vascular leakage and thrombosis; impair phagocytic function; and elicit failure of clearance mechanisms. the gross lesions in the acute form consist of a fibrinous bronchopneumonia characterized by severe consolidation and a fibrinous exudate on the pleural surface. although all lobes can be affected, a common site is the dorsal area of the caudal lobes. in fact, a large area of fibrinous pleuropneumonia involving the caudal lobe of a pig's lung is considered almost diagnostic for this disease (fig. - ) . on cut surface, consolidated lungs have notably dilated interlobular septa and irregular but well-circumscribed areas of necrosis caused by potent cytotoxins produced by actinobacillus pleuropneumoniae. except for the distribution, pulmonary lesions of porcine pleuropneumonia are identical to those of pneumonic mannheimiosis of cattle. the microscopic lesions are also very similar and include areas of coagulative necrosis surrounded by a thick cluster of "streaming (oat-shaped/oat cell) leukocytes" and notable distention of the interlobular septa because of severe edema and lymphatic thrombosis. bronchioles and alveoli are filled with edematous fluid, fibrin, neutrophils, and few macrophages (see fig. - ). pigs with the chronic form have multiple pulmonary abscesses and large ( to cm) pieces of necrotic lung encapsulated by connective tissue (sequestra)-changes frequently seen in slaughterhouses. interstitial nephritis are also present in porcine pneumonic pasteurellosis. sequelae of porcine pneumonic pasteurellosis include fibrous pleuritis and pericarditis, pulmonary abscesses, so-called sequestra, and usually death. in contrast to ruminants, mannheimia haemolytica is not a respiratory pathogen for pigs, but in some instances, it can cause abortion in sows. porcine pleuropneumonia. porcine pleuropneumonia is a highly contagious, worldwide disease of pigs caused by actinobacillus (haemophilus) pleuropneumoniae (app), which is characterized by a severe, often fatal, fibrinous bronchopneumonia with extensive pleuritis (pleuropneumonia). survivors generally develop notable residual lesions and become carriers of the organisms. porcine pleuropneumonia is an increasingly important cause of acute and chronic pneumonias, particularly in intensively raised pigs ( to months old). transmission of actinobacillus pleuropneumoniae occurs by the respiratory route, and the disease can be reproduced experimentally by intranasal inoculation of the bacterium. considered a primary pathogen, actinobacillus pleuropneumoniae can sporadically produce septicemia in young pigs and otitis media and otitis interna with vestibular syndrome in weaned pigs. two biovars and serotypes of the organism have been identified; all serotypes can cause the disease, but differences in virulence exist. the pathogenesis is not yet well understood, but specific virulence factors, such as rtx toxins (hemolytic/cytolytic toxins apx i to apx iv), capsular factors, fimbriae and adhesins, lipopolysaccharide, and permeability tuberculosis. tuberculosis is an important disease in domestic and wild pigs that has a much greater prevalence in pigs than in cattle or other domestic mammals in many countries. porcine tuberculosis is attributed to infection with mycobacterium bovis and porcine mycobacteriosis to infection with mycobacterium avium complex. a common scenario in small mixed-farming operations is the diagnosis of avian tuberculosis at the time that pigs are slaughtered, and the source is ingestion of tuberculous chickens or contaminated litter. as would be expected, granulomas are found in the mesenteric, mandibular, and retropharyngeal lymph nodes; to a lesser extent in the intestine, liver, and spleen; and only in rare cases in the lung. the route of infection in pulmonary tuberculosis and mycobacteriosis of pigs is most often hematogenous after oral exposure and intestinal infection. lung lesions are those of a granulomatous pneumonia. the microscopic lesions are basically those of tubercles (granulomas), but the degree of encapsulation, caseation, and calcification varies with the type of mycobacterium, age of the lesion, and host immune response. other bacterial pneumonias of pigs. septicemias in pigs often cause petechial hemorrhages in the lung and pulmonary edema. salmonellae, escherichia coli, and listeria monocytogenes can cause severe interstitial pneumonia in very young animals. salmonella choleraesuis causes a necrotizing fibrinous pneumonia similar to porcine pleuropneumonia, and salmonella typhisuis causes a chronic suppurative bronchopneumonia. in high health herds, actinobacillus suis may cause fibrinohemorrhagic pleuropneumonia and is easily confused with porcine pleuropneumonia. metastrongylosis. metastrongylus apri (elongatus), metastrongylus salmi, and metastrongylus pudendotectus (lungworms) of domestic and feral pigs occur throughout most of the world and require earthworms as intermediate hosts for transmission. the incidence of disease has therefore decreased with development of confinement housing. the importance of pig lungworms is mainly because infection results in growth retardation of the host. clinical signs include coughing because of parasitic bronchitis. the gross lesions, when noticeable, consist of small gray nodules, particularly along the ventral borders of the caudal lobes. the adult worms are grossly visible in bronchi, and microscopically, the parasites cause a catarrhal bronchitis with infiltration of eosinophils and lobular atelectasis ( fig. - ) . ascaris suum. the larvae of ascaris suum can cause edema, focal subpleural hemorrhages, and interstitial inflammation (see fig. - ). along their larval migration tracts, hemorrhages also occur in the liver and, after fibrosis, become the large white "milk spots" seen so frequently as incidental findings at necropsy. it has been reported that ascaris suum may cause immunosuppression in severely affected pigs. pigs can be killed if exposed to an overwhelming larval migration. other causes of pneumonia. foreign body granulomatous pneumonia occurs frequently in pigs after inhalation of vegetable material (starch pneumonia), presumably from dusty (nonpelleted) feed. lesions are clinically silent but are often mistaken for other pneumonic processes during inspection at slaughterhouses. microscopically, pulmonary changes are typical of foreign body granulomatous inflammation in which variably sized feed particles are surrounded by macrophages and neutrophils, and often have been phagocytosed by multinucleated giant cells. feed (vegetable) particles appear as thick-walled polygonal cells that stain positive with pas because of their rich carbohydrate (starch) content (see e- fig. - ) . clinically, porcine pleuropneumonia can vary from an acute form with unexpected death and blood-stained froth at the nostrils and mouth to a subacute form characterized by coughing and dyspnea accompanied by clinical signs of sepsis such as high fever, hypoxemia, anorexia, and lethargy (e- fig. - ) . a chronic form is characterized by decreased growth rate and persistent cough. animals that survive often carry the organism in the tonsils, shed the organism, and infect susceptible pigs. haemophilus pneumonia. in addition to glasser's disease characterized by polyserositis (pericarditis, pleuritis, peritonitis, polyarthritis, and meningitis) (e- fig. - ) , some serotypes of haemophilus parasuis (originally haemophilus influenzae suis) can also cause suppurative bronchopneumonia that in severe cases can be fatal. the causal organism, haemophilus parasuis, is usually carried in the nasopharynx of normal pigs and requires abnormal circumstances such as those following stress (weaning and cold weather) or viral infections (swine influenza or pcv ). specific pathogen-free (spf) pigs seem to be particularly susceptible to glasser's disease (arthritis and serositis) but not to pulmonary infection (bronchopneumonia). streptococcal pneumonia. streptococcus suis is a common cause of porcine disease worldwide and a serious zoonosis capable of causing death by septic shock or meningitis and residual deafness in butchers, veterinarians, and pig farmers. typically, streptococcus suis gains entrance to the susceptible young pig through the oropharyngeal mucosa and is carried in the tonsils, nasal mucosa, and mandibular lymph nodes of healthy animals, particularly in survivors of an outbreak. infected sows can abort or vertically transmit the infection to their offspring. some serotypes of streptococcus suis cause neonatal septicemia, and this can result in suppurative meningitis, otitis, arthritis, polyserositis, myocarditis, valvular endocarditis, and embolic pneumonia ( fig. - ). other serotypes of streptococcus suis can reach the lung by the aerogenous route and cause a suppurative bronchopneumonia, in combination with pasteurella multocida, escherichia coli, or mycoplasma hyopneumoniae, or in combination with actinobacillus pleuropneumoniae, which causes a fibrinous bronchopneumonia. coinfections of streptococcus suis with pcv and prrsv are also frequently seen in some farms. gross lesions in the acute stages include serous to catarrhal to mucopurulent nasopharyngitis and conjunctivitis. the lungs are edematous and have a diffuse interstitial pneumonia ( fig. - ) microscopically characterized by necrotizing bronchiolitis, necrosis and exfoliation of pneumonocytes, mild alveolar edema, and, several hours later, thickening of the alveolar walls because of interstitial mononuclear cell infiltrates and hyperplasia of type ii pneumonocytes. secondary infections with bordetella bronchiseptica and mycoplasmas are common and induce life-threatening suppurative bronchopneumonia. the thymus may be small relative to the age of the animal because of viral-induced lymphocytolysis. microscopically, eosinophilic inclusions are present in the epithelial cells of many tissues, in the nuclei or cytoplasm, or in both (see fig. - ). they appear early in the bronchiolar epithelium but are most prominent in the epithelium of the lung, stomach, renal pelvis, and urinary bladder, making these tissues good choices for diagnostic examination. viral inclusions are rarely seen in the later stages of this disease. the suppurative secondary bronchopneumonias often hinder the detection of viral lesions in the lung, particularly because bronchiolar cells containing inclusion bodies exfoliate and mix with the neutrophils recruited by the bacterial infection. distemper virus antigens can be readily demonstrated in infected cells by the immunoperoxidase technique (see fig. - ), which can also be used in skin biopsies for the antemortem diagnosis of canine distemper. distemper virus also has a tendency to affect developing tooth buds and ameloblasts, causing enamel hypoplasia in dogs that recover from infection. of all distemper lesions, demyelinating encephalomyelitis, which develops late, is the most devastating (see chapter ). sequelae to distemper include the nervous and pneumonic complications mentioned previously and various systemic infections, such as toxoplasmosis and sarcocystosis, because of depressed immunity. persistent viral infection occurs in some dogs that survive the disease, and they may become carriers and the source of infection for other susceptible animals. clinical signs consist of biphasic fever, diarrhea, vomiting, weight loss, mucopurulent oculonasal discharge, coughing, respiratory distress, and possible loss of vision. weeks later, hyperkeratosis of the foot pads ("hard pad") and the nose are observed, along with nervous signs, including ataxia, paralysis, convulsions, or residual myoclonus (muscle twitches, tremors, and "tics"). in general, inflammatory diseases of the lungs are less of a problem in dogs than in food-producing species and can be subdivided in two major groups, infectious and noninfectious pneumonias. "canine infectious respiratory disease" (cird) is the term currently used by clinicians to describe a heterogeneous group of respiratory infections in dogs; these diseases were previously clustered under the name of infectious tracheobronchitis or "kennel cough." cird is the canine counterpart of brd and prd complexes in cattle and pigs, respectively. the most common viruses in cird include canine parainfluenza virus (cpiv), canid herpesvirus (cahv- ), canine adenovirus- (cav- ), canine respiratory coronavirus (crcov), canine distemper virus (cdv), and canine influenza virus (civ). bordetella bronchiseptica, streptococcus equi ssp. zooepidemicus, and mycoplasma spp. are the most frequent bacterial isolates in cird. it has been recently recognized that animal shelters are an important source of viral and bacterial infections for dogs and cats. uremia and paraquat toxicity are perhaps the two most notable noninfectious causes of canine respiratory disease. canine distemper. canine distemper is an important and ubiquitous infectious disease of dogs, other canidae, wild felidae, mustelidae, and marine mammals throughout the world. it is caused by a morbillivirus that is antigenically related to the human measles, rinderpest (officially eradicated in ), "peste de petit ruminants," and phocine distemper viruses. canine distemper virus (cdv) is transmitted to susceptible puppies through infected body fluids. the virus invades through the upper respiratory tract and conjunctiva, proliferates in regional lymph nodes, becomes viremic, and in dogs with an inadequate antibody response, infects nearly all body tissues (pantropic), particularly the epithelial cells. distemper virus hampers the immune response, downregulates cytokine production, and persists for a long time in some tissues. cdv can target the lungs either directly as a viral pneumonia or indirectly by its immunosuppressive effects rendering the lungs susceptible to secondary bacterial and protozoal infections, or as a coinfection with other viruses such as canine adenovirus- and canid herpesvirus . : - , .) inclusion bodies occur within epithelial cells in early lesions. cahv- has also been identified as a cause of ulcerative keratoconjunctivitis in older dogs. canine influenza (canine flu). canine influenza is an emerging contagious respiratory infection of dogs that was first described in the united states and subsequently in other countries. it has a high morbidity (close to %), but the mortality, as with most other influenza infections, is relatively low (less than %). this disease, first diagnosed in greyhounds, is caused by a novel influenza-a virus (canine influenza virus or civ), a mutation from a previously recognized h n strain of equine influenza virus. dog-to-dog transmission does occur and therefore this infection must be distinguished from other viruses of the canine infectious respiratory disease (cird) group. pulmonary lesions are generally mild and transient, but infected dogs are susceptible to secondary bacterial bronchopneumonia. the most relevant lesions in dogs dying unexpectedly from canine influenza are pleural and pulmonary hemorrhages. microscopically, there is necrotizing tracheitis, bronchitis, and bronchiolitis with exudation of neutrophils and macrophages. in severe cases, hemorrhagic interstitial or bronchointerstitial pneumonia may be accompanied by vasculitis and thrombosis. influenza antigen can be demonstrated by immunohistochemistry in airway epithelium and alveolar macrophages. clinically, dogs with canine influenza are lethargic, inappetent, and hyperthermic and frequently cough and show nasal discharge. these signs resemble those seen in dogs with kennel cough or secondary bacterial pneumonia. in addition, there are confirmed cases of canine influenza caused by the porcine h n presumably transmitted from infected pet owners. bacterial pneumonias. dogs generally develop bacterial pneumonias when the pulmonary defense mechanisms have been impaired. pasteurella multocida, streptococcus spp., escherichia coli, klebsiella pneumoniae, and bordetella bronchiseptica can be involved in pneumonia secondary to distemper or after aspiration of gastric contents ( fig. - and e- fig. - ). streptococcus zooepidemicus can cause acute and fatal hemorrhagic pleuropneumonia with canine adenovirus type infection. cav- infection is a common but transient contagious disease of the respiratory tract of dogs, causing mild fever, oculonasal discharge, coughing, and poor weight gain. the portal of entry is generally by inhalation of infected aerosols followed by viral replication in the surface cells of the upper respiratory tract, mucous cells of the trachea and bronchi, nonciliated bronchiolar epithelial cells, and type ii pneumonocytes. pulmonary lesions are initially those of bronchointerstitial pneumonia, with necrosis and exfoliation of bronchiolar and alveolar epithelium, edema, and, a few days later, proliferation of type ii pneumonocytes, mild infiltration of neutrophils and lymphocytes in the alveolar interstitium, and hyperplastic bronchitis and bronchiolitis. large basophilic intranuclear viral inclusions are typically seen in bronchiolar and alveolar cells ( fig. - ) . infection with cav- is clinically mild unless complicated with a secondary bacterial infection or coinfections with other viruses such as distemper virus. experimental work suggests cav- reinfection may lead to hyperreactive airways, a nonspecific condition in which the bronchial mucosa becomes highly "responsive" to irritation such as that caused by cold air, gases, or cigarette smoke. however, it is not clear if this outcome is true in natural infections. canid herpesvirus . canid herpesvirus (cahv- ) can cause fatal systemic disease in newborn puppies and is probably a contributing factor in "fading puppy syndrome." hypothermia has been suggested as a pivotal component in the pathogenesis of fatal infections in puppies. many dogs are seropositive, suggesting that transient or subclinical infections are more common than realized; the virus remains latent in the trigeminal and other ganglia and can be reactivated after stress, resulting in asymptomatic transmission of cahv- virus to offspring via the placenta, thus resulting in abortion or stillbirths. in puppies, cahv- causes ulcerative tracheitis, interstitial pneumonia (e- fig. - ) , and focal necrosis and inflammation in the kidneys, liver, and brain. eosinophilic intranuclear aspiration pneumonia starts as an acute necrotizing bronchitis and bronchiolitis caused by aspiration of irritant materials such as gastric acid or a caustic material administered by mouth. the aspirate also contains potentially pathogenic bacteria, and because the mucociliary apparatus is damaged and these bacteria are not removed, they settle into the ventral portions of the lung (from gravity) and provoke a fibrinosuppurative and necrotizing bronchopneumonia. b, bronchoalveolar spaces are filled with neutrophils, macrophages, and bacteria (arrows). h&e stain. inset, large colonies of bacteria (arrows). h&e stain. (courtesy dr. a. lópez, atlantic veterinary college.) a b infection; thus it most frequently affects outdoor and hunting dogs. from the lung, infection is disseminated hematogenously to other organs, mainly bone, skin, brain, and eyes. pulmonary lesions are characterized by multifocal to coalescing pyogranulomatous pneumonia, generally with firm nodules scattered throughout the lungs (fig. - ) . microscopically, nodules are pyogranulomas with numerous macrophages (epithelioid cells), some neutrophils, multinucleated giant cells, and thick-walled yeasts (see fig. - , c). yeasts are to µm in diameter and are much better visualized when they are stained with pas reaction or gomori's methenamine silver stain. nodules can also be present in other tissues, chiefly lymph nodes, skin, spleen, liver, kidneys, bones, testes, prostate, and eyes. this fungus can be easily identified in properly prepared and stained transtracheal washes or lymph node aspirates. clinical signs can reflect involvement of virtually any body tissue; pulmonary effects include cough, decreased exercise tolerance, and terminal respiratory distress. coccidioidomycosis. coccidioidomycosis (san joaquin valley fever), caused by the dimorphic fungus coccidioides immitis, occurs mainly in animals living in arid regions of the southwestern united states, mexico, and central and south america. it is a primary respiratory tract (aerogenous) infection commonly seen at slaughterhouses in clinically normal feedlot cattle. in dogs, coccidioidomycosis also has an aerogenous portal of entry and then a b hemorrhagic pleural effusion in dogs. death is generally a consequence of severe sepsis and septic shock or from β-hemolytic streptococcal bacteremia causing emboli in the lungs, liver, brain, and lymph nodes. the primary source of the infection cannot be determined in most cases. dental disease in dogs may be a source of systemic and pulmonary infection, a concept wellrecognized in human medicine for many years. the role of mycoplasmas in canine pneumonia is still uncertain because these organisms are frequently isolated from normal nasopharyngeal flora. tuberculosis is uncommon in dogs because these animals appear to be quite resistant to infection; most cases occur in immunocompromised dogs or in dogs living with infected human beings. dogs are susceptible to the infection with mycobacterium tuberculosis, mycobacterium bovis, and mycobacterium avium complex, and therefore canine infection presupposes contact with human or animal tuberculosis. the clinicopathologic manifestation is pulmonary after inhalation or alimentary after oral exposure, but in most cases infection is disseminated to lymph nodes and visceral organs. the gross lesions are multifocal, firm nodules with necrotic centers, most often seen in the lungs, lymph nodes, kidneys, and liver. diffuse granulomatous pleuritis and pericarditis with copious serofibrinous or sanguineous effusion are common. microscopically, granulomas are formed by closely packed macrophages but with very little connective tissue. mycotic pneumonias. mycotic pneumonias are serious diseases seen commonly in animals in some regions. there are two main types: those caused by opportunistic fungi and those caused by a group of fungi associated with systemic "deep" mycoses. all of these fungi affect human beings and most domestic animals but are probably not transmitted between species. aspergillosis. opportunistic fungi, such as aspergillus spp. (particularly aspergillus fumigatus), are important in birds, but in domestic animals, they mainly affect immunosuppressed individuals or those on prolonged antibiotic therapy. the pulmonary lesion is a multifocal, nodular, pyogranulomatous, or granulomatous pneumonia. microscopically, there is necrosis and infiltrates of neutrophils, macrophages, and lymphocytes, with proliferation of fibroblasts eventually leading to encapsulation of the granuloma. fungal hyphae are generally visible in the core of the lesion and in the walls of blood vessels. systemic mycoses (dimorphic fungal infections) . systemic (deep) mycoses are caused by blastomyces dermatitidis, histoplasma capsulatum, coccidioides immitis, and cryptococcus neoformans/ cryptococcus gatti (see fig. - ). blastomycosis mainly affects dogs and is discussed here, whereas cryptococcosis is discussed in the section on pneumonias of cats. in contrast to other fungi, such as aspergillus spp., organisms of the systemic mycosis group are all primary pathogens of human beings and animals and thus do not necessarily require a preceding immunosuppression to cause disease. these fungi have virulence factors that favor hematogenous dissemination and evasion of immune and phagocytic responses. systemic dissemination is often exacerbated by the administration of immunosuppressant drugs such as corticosteroids. these fungi are usually detected by cytological evaluation of affected tissues. blastomycosis. blastomycosis occurs in many countries of the north american continent, africa, the middle east, and occasionally in europe. in the united states, it is most prevalent in the atlantic, st. lawrence, and ohio-mississippi river valley states, compared with the mountain-pacific region. blastomyces dermatitidis is a dimorphic fungus (mycelia-yeast) seen mainly in young dogs and occasionally in cats and horses. this fungus is present in the soil, and inhalation of spores is considered the principal route of from the alveolar interstitium associated with larvae or dead worms because little reaction develops to the live adults. crenosoma vulpis. crenosoma vulpis is a lungworm seen commonly in foxes and sporadically in dogs with access to the intermediate hosts-slugs and snails. the adult lungworms live in small bronchi and bronchioles in the caudal lobes, causing eosinophilic and catarrhal bronchitis manifested grossly as gray areas of inflammation and atelectasis. in some animals, crenosoma vulpis causes bronchiolar goblet cell metaplasia and mucous obstruction, resulting in lobular atelectasis due to the valve effect of the mucous plug. eucoleus aerophilus. eucoleus aerophilus (capillaria aerophila) is a nematode parasite typically found in the trachea and bronchi of wild and domestic carnivores. in some cases, this parasite may also involve the nasal passages and sinuses. although generally asymptomatic, some dogs cough because of the local irritation caused by the parasites on the tracheal or bronchial mucosa. paragonimus spp. paragonimus kellicotti in north america and paragonimus westermani in asia are generally asymptomatic fluke infections in fish-eating species. the life cycle involves two intermediate hosts, the first a freshwater snail and the second a freshwater crab or crayfish; in north america, cats and dogs acquire infection by eating crayfish. gross lesions include pleural hemorrhages where the metacercariae migrate into the lungs. later, multifocal eosinophilic pleuritis, and subpleural cysts up to mm long containing pairs of adult flukes, are found along with eosinophilic granulomas around clusters of eggs. like many other parasitic pneumonias, lesions and scars are more frequent in the caudal lobes. pneumothorax can occur if a cyst that communicates with an airway ruptures to the pleural surface. other parasitic infections. angiostrongylus vasorum and dirofilaria immitis are parasites of the pulmonary arteries and right ventricle and, depending on the stage, can produce different forms of pulmonary lesions. adult parasites can cause chronic arteritis that leads to pulmonary hypertension, pulmonary arterial thrombosis, interstitial (eosinophilic) granulomatous pneumonia, pulmonary interstitial fibrosis, congestive right-sided cardiac failure, and eventually caudal vena caval syndrome. other lesions include pleural petechial hemorrhages and, in later stages, diffuse pulmonary hemosiderosis and multifocal pulmonary infarcts. larvae and eggs also cause alveolar injury, thickening of the alveolar walls with eosinophils and lymphocytes (interstitial pneumonia), and multifocal or coalescing granulomas with giant cells (parasitic granulomas). pneumocystis carinii has been reported as a sporadic cause of chronic interstitial pneumonia in dogs with a compromised immune system (see pneumonias of horses; also see fig. - ). aspiration pneumonia. aspiration pneumonia is an important form of pneumonia that occurs in dogs when vomit or regurgitated materials are aspirated into the lungs, or when drugs or radiographic contrast media are accidentally introduced into the airways (e- fig. - ) . as in other animal species, aspiration pneumonia may be unilateral or may more often affect the right cranial lobe ( fig. - ). the severity of lesions depends very much on the chemical and microbiologic composition of the aspirated material. in general, aspiration in monogastric animals, particularly in dogs and cats, is more severe because of the low ph of the gastric contents (chemical pneumonitis). in severe cases, dogs and cats die rapidly from septic shock and ards (see fig. - ), which is microscopically characterized by diffuse alveolar damage, protein-rich pulmonary edema, neutrophilic alveolitis, and formation of typical hyaline membranes along the alveolar walls (see fig. - ). in animals that survive the acute stages of aspiration, pulmonary lesions progress to bronchopneumonia. aspiration pneumonia is a common sequela to disseminates systemically to other organs. clinical signs relate to the location of lesions, so there can be respiratory distress, lameness, generalized lymphadenopathy, or cutaneous lesions, among others. the lesions caused by coccidioides immitis consist of focal granulomas or pyogranulomas that can have suppurative or caseated centers. the fungal organisms are readily seen in histologic or cytologic preparation as large ( to µm in diameter), double-walled, and highly refractile spherules containing numerous endospores (see fig. - , d) . histoplasmosis. histoplasmosis is a systemic infection that results from inhalation and, in dogs, possibly ingestion of another dimorphic fungus, histoplasma capsulatum. histoplasmosis occurs sporadically in dogs and human beings and, to a lesser extent, in cats and horses. bats often eliminate histoplasma capsulatum in the feces, and droppings from bats and birds, particularly pigeons, heavily promote the growth and survival of this fungus in the soil of enzootic areas. pulmonary lesions are grossly characterized by variably sized, firm, poorly encapsulated granulomas and, sometimes, more diffuse involvement of the lungs. microscopically, granulomatous lesions typically have many macrophages filled with small ( to µm), punctiform, intracytoplasmic, dark oval bodies (yeasts) (see fig. - , a) that are best demonstrated with pas reaction or gomori's methenamine silver stain. similar nodules or diffuse involvement can be present in other tissues, chiefly lymph nodes, spleen, intestine, and liver. toxoplasmosis. toxoplasmosis is a worldwide disease caused by the obligate intracellular, protozoal parasite toxoplasma gondii. cats and other felidae are the definitive hosts in which the mature parasite divides sexually in the intestinal mucosa. human beings, dogs, cats, and many wild mammals can become intermediate hosts after accidental ingestion of fertile oocysts shed in cat feces or ingestion of undercooked or raw meat containing tissue cysts, and fetuses can be infected transplacentally from an infected dam. in most instances, the parasite infects many cells of different tissues and induces an antibody response (seropositive animals) but does not cause clinical disease. toxoplasmosis is often triggered by immunosuppression, such as that caused by canine distemper virus. toxoplasmosis is characterized by focal necrosis around the protozoan. pulmonary lesions are severe, multifocal necrotizing interstitial pneumonia with notable proliferation of type ii pneumonocytes and infiltrates of macrophages and neutrophils. other lesions in disseminated toxoplasmosis include multifocal necrotizing hepatitis, myocarditis, splenitis, myositis, encephalitis, and ophthalmitis. the parasites appear microscopically as small ( to µm) basophilic cysts that can be found free in affected tissues or within the cytoplasm of many epithelial cells and macrophages (see e- fig. - ) . similar findings can be seen sporadically in dogs infected with neospora caninum and sarcocystis canis, and immunohistochemistry would be required to differentiate those protozoal organisms from toxoplasma gondii. filaroides hirthi. filaroides hirthi, a lungworm of the alveoli and bronchioles of dogs, has long been known as a cause of mild subclinical infection in large colonies of beagle dogs in the united states. however, it can on occasion cause severe and even fatal disease in individual pets, presumably as a result of immunosuppression. clinical signs may include coughing and terminal respiratory distress. grossly, the lesions are multifocal subpleural nodules, often with a green hue because of eosinophils, scattered throughout the lungs. microscopically, these nodules are eosinophilic granulomas arising .e chapter respiratory system, mediastinum, and pleurae other pneumonias. idiopathic pulmonary fibrosis is a rare condition of uncertain etiology reported in the west highland white terrier breed that shares similarities with human and feline idiopathic pulmonary fibrosis. microscopically, there is diffuse interstitial pneumonia and progressive alveolar fibrosis with capillary obliteration, hyperplasia of type ii cells, some of which exhibit cellular atypia, and finally hypertrophy and hyperplasia of smooth muscle. the interstitial fibrosis eventually spills over alveolar spaces causing conspicuous intraalveolar fibrosis. although upper respiratory tract infections are common and important in cats, pneumonias are uncommon except when there is immunosuppression or aspiration of gastric contents. viral infections such as feline rhinotracheitis and calicivirus may cause lesions in the lungs, but unless there is secondary invasion by bacteria, they do not usually cause a fatal pneumonia. feline rhinotracheitis. feline rhinotracheitis is an important viral disease of cats caused by the ubiquitous felid herpesvirus (fehv- ). this infection affects primarily young or debilitated cats causing inflammation in the nasal, ocular, and tracheal mucosa and, to a much lesser extent, the lung (see species-specific diseases of the nasal cavity and paranasal sinuses). when lungs are affected, fehv- causes bronchointerstitial pneumonia with necrosis of bronchiolar and alveolar epithelium, thickening of the alveolar walls, and extensive permeability edema. eosinophilic intranuclear inclusion bodies may be seen in infected epithelial cells early in infection. feline calicivirus. feline calicivirus (fcv) causes upper respiratory disease, stomatitis, conjunctivitis, and, to a lesser extent, interstitial pneumonia. microscopically, affected lungs exhibit the typical pattern of bronchointerstitial pneumonia with necrotizing bronchiolitis, thickening of alveolar walls, occasionally hyaline membranes, hyperplasia of type ii pneumonocytes, and macrophages admixed with cellular debris in the alveolar lumens. because pulmonary lesions are similar to those caused by fehv- , isolation or in situ detection is required for final diagnosis. feline infectious peritonitis. feline infectious peritonitis (fip) is caused by fip virus (fipv), a mutated form of feline enteric cleft palate, and in dogs with megaesophagus secondary to either myasthenia gravis or persistent right aortic arch. it is also an important complication of general anesthesia or neurologic diseases affecting laryngeal function. paraquat. paraquat, a broad-spectrum herbicide widely used in gardening and agriculture, can cause severe and often fatal toxic interstitial pneumonia (pneumonitis) in dogs, cats, human beings, and other species. after ingestion or inhalation, this herbicide selectively accumulates in the lung where paraquat toxic metabolites are produced by club (clara) cells. these metabolites promote local release of free radicals in the lung, which causes extensive injury to club cells and to the blood-air barrier, presumably through lipid peroxidation of type i and ii pneumonocytes and alveolar endothelial cells (see fig. - ). paraquat toxicity has been used experimentally as a model of oxidant-induced alveolar injury and pulmonary fibrosis. soon after poisoning, the lungs are heavy, edematous, and hemorrhagic because of extensive necrosis of epithelial and endothelial cells in the alveolar walls. the lungs of animals that survive acute paraquat toxicosis are pale, fail to collapse when the thorax is opened, and have interstitial emphysema, bullous emphysema, and occasionally pneumomediastinum. microscopic findings in the acute and subacute phases include necrosis of type i pneumonocytes, interstitial and alveolar edema, intraalveolar hemorrhages, and proliferation of type ii pneumonocytes. in the chronic stages ( to weeks later), the lesions are typically characterized by severe interstitial and intraalveolar fibrosis. uremic pneumopathy. uremic pneumonopathy (pneumonitis) is one of the many extrarenal lesions seen in dogs with chronic uremia. lesions are characterized by a combination of pulmonary edema and calcification of vascular smooth muscle and alveolar basement membranes. in severe cases, alveolar calcification prevents lung collapse when the thorax is opened. in the more advanced cases, the lungs appear diffusely distended, pale red or brown in color, and show a rough pleural surface with rib imprints (see fig. - ). on palpation, the pulmonary parenchyma has a typical "gritty" texture because of mineralization of the alveolar and vascular walls, which are best visualized microscopically by using special stains such as von kossa (see fig. - ). because this is not primarily an inflammatory lesion, the term pneumonitis should not be used. fig. - ) . a, note that the lungs did not collapse when the thorax was opened (loss of negative pressure) and as a result fill almost the entire thoracic cavity. the cranioventral aspects of the lung are consolidated with hemorrhage. b, alveolar capillary congestion, thick hyaline membranes along the alveolar septa (arrows), and intraalveolar hemorrhage. these microscopic changes are typical of the diffuse alveolar damage seen in lungs with ards. h&e stain. (courtesy dr. a. lópez, atlantic veterinary college.) feline calicivirus has removed chlamydophila felis from its previously overstated importance as a lung pathogen. tuberculosis. cats are susceptible to three types of mycobacterial infections: classic tuberculosis, feline leprosy, and atypical mycobacteriosis. classic tuberculosis in cats is rare and generally caused by mycobacterium bovis and mycobacterium microti but also, to a lesser extent, by mycobacterium tuberculosis. nosocomial tuberculosis (mycobacterium bovis) in cats has been reported with increased frequency. the usual route of infection for feline tuberculosis is oral, through infected rodents/meat or unpasteurized milk, so the granulomatous lesions are mainly in the intestine and mesenteric lymph nodes where they may disseminate through infected phagocytes to other organs. the solid and noncaseated appearance of tuberculous nodules is grossly similar to that of neoplasms, so they must be differentiated from pulmonary neoplasms (e.g., lymphoma). classic tuberculosis with dermal lesions in cats should be differentiated from feline leprosy (localized skin granulomas) caused by mycobacterium lepraemurium and other nonculturable species of acid-fast bacilli. atypical mycobacteriosis is caused by contamination of a skin wound with saprophytic and nonsaprophytic mycobacteria such as those of the mycobacterium avium complex. advances in pcr techniques have notably reduced the time required for etiologic diagnosis of mycobacteriosis in veterinary diagnostic laboratories. cryptococcosis. cryptococcosis (pulmonary cryptococcus neoformans or cryptococcus gatti) is the most frequent systemic mycosis in cats, and lesions are akin to those discussed in the section on mycotic pneumonias of dogs. it occurs worldwide in all species but is diagnosed most frequently in cats, horses, dogs, and human beings. some healthy dogs and cats harbor cryptococcus in the nasal cavity and become asymptomatic carriers. clinical infection may occur in immunocompetent cats and in cats that are immunologically compromised, such as by felv, fiv, malnutrition, or corticosteroid treatment. lesions can occur in nearly any tissue, resulting in a wide c coronavirus (fecv), and is one of a few viral infections of domestic animals that result in pyogranulomatous pneumonia. this disease is microscopically characterized by a vasculitis affecting many tissues and organs ( fig. - ) . other viral pneumonias. other viruses sporadically incriminated in feline interstitial pneumonia are cowpox virus (cpxv) and influenza a h n . pasteurellae. bacteria from the nasal flora such as pasteurella multocida and pasteurella-like organisms are occasionally associated with secondary bronchopneumonia in cats ( fig. - ) . pasteurella multocida also causes otitis media and meningitis, but its role as a respiratory pathogen is mainly associated with pyothorax. interestingly, there are reports of pasteurella multocida pneumonia in older or immunosuppressed human beings acquired through contact with domestic cats. mycoplasmas. mycoplasmas are often isolated from the lungs of cats with pulmonary lesions but are not definitively established as primary pathogens in feline pneumonias. feline pneumonitis. the term feline pneumonitis is a misnomer because the major lesions caused by chlamydophila felis (formerly chlamydia psittaci) are severe conjunctivitis and rhinitis (see species-specific diseases of the nasal cavity and paranasal sinuses). the elucidation of the importance of feline viral rhinotracheitis and organism infects erythrocytes in the erythrocytic stage of disease and multiplies in intravascular macrophages/monocytes, including those in the alveolar capillaries (e- fig. - ) , during the leukocytic stage of disease. aspiration pneumonia. aspiration pneumonias are common in cats as a result of vomiting, regurgitation, dysphagia, or anesthetic complication or after accidental administration of food, oral medicaments, or contrast media into the trachea (iatrogenic). pulmonary lesions are similar to those described for dogs, and the type of lung lesion depends on the chemical and bacterial composition of the aspirated material (see the section on aspiration pneumonia of dogs). feline idiopathic pulmonary fibrosis. feline idiopathic pulmonary fibrosis is a rare, progressive, and fatal disease of cats of uncertain etiology characterized by multifocal fibrotic nodules subpleurally and randomly in the lung making the pleural surface resemble nodular cirrhosis of the liver ( fig. - ) . microscopically, the affected alveolar and peribronchiolar interstitium is thickened by excessive fibrosis, abundant deposition of extracellular matrix, and hypertrophy of smooth muscle. some investigators suggest an intrinsic cellular defect in type ii pneumonocytes as the underlying cause. the alveolar walls are diffusely lined by cuboidal hyperplastic type ii pneumonocytes, and the alveolar lumens often contain exfoliated cells and necrotic debris. this feline condition has morphologic features similar to "equine multinodular pulmonary fibrosis" and "cryptogenic pulmonary fibrosis" in human beings. fetal pneumonias. pneumonia is one of the most frequent lesions found in fetuses submitted for postmortem examination, particularly in foals and food-producing animals. because of autolysis, lack of inflation, and the lungs being at various stages of development, fetal lesions are often missed or misdiagnosed. in the nonaerated fetal lung, the bronchoalveolar spaces are filled with a viscous, locally produced fluid known as lung fluid or lung liquid. it has been estimated that an ovine fetus produces approximately . ml of "lung fluid" per kilogram of body weight per hour. in the variety of clinical signs. however, granulomatous rhinitis, sinusitis, otitis media and interna, pneumonia, ulcerative dermatitis, and meningoencephalitis are most common. the pulmonary lesion in cryptococcosis is a multifocal granulomatous pneumonia and, like those occurring in other internal organs, they are small, gelatinous, white foci. the gelatinous appearance is due to the broad mucous capsule around the yeast (see fig. - , b) . microscopically, lesions contain great numbers of fungal organisms ( to µm in diameter without the capsule) and only a few macrophages, lymphocytes, and multinucleated giant cells. this thick polysaccharide capsule does not stain well with h&e, and thus there is a large empty space or halo around the yeast. feline lungworm. aelurostrongylus abstrusus, known as feline lungworm, is a parasite that occurs in cats wherever the necessary slug and snail intermediate hosts are found. it can cause chronic respiratory disease with coughing and weight loss and, sometimes, severe dyspnea and death, particularly if there are secondary bacterial infections. the gross lesions are multifocal, amber, and subpleural granulomatous nodules up to cm in diameter throughout the lungs. on incision, these nodules may contain viscous exudate. microscopically, the adult parasites, eggs, and coiled larvae are in the bronchioles and alveoli, where they cause catarrhal bronchiolitis, hyperplasia of submucosal glands, and, later, granulomatous alveolitis, alveolar fibrosis, and fibromuscular hyperplasia ( fig. - ) . during routine examination of feline lungs, it is quite common to find fibromuscular hyperplasia in bronchioles and arterioles in otherwise healthy cats. it was alleged in the past that this fibromuscular hyperplasia was a long-term sequela of subclinical infection with aelurostrongylus abstrusus. however, this view has been challenged; thus the pathogenesis and significance of pulmonary fibromuscular hyperplasia in healthy cats remains uncertain. in severe cases, fibromuscular hyperplasia is grossly visible in the lungs as white subpleural nodules. other parasitic pneumonias. toxoplasma gondii, paragonimus kellicotti, and dirofilaria immitis can also affect cats (see the section on parasitic pneumonias of dogs). cytauxzoon felis is an apicomplexan hemoparasite that affects domestic and wild felidae. the diseases that cause fetal pneumonia in farm animals. gross lesions in the lungs are generally undetected, but microscopic lesions include focal necrotizing interstitial pneumonia and focal necrosis in the liver, spleen, or brain. fetal bronchointerstitial pneumonia also occurs in some viral abortions, such as those caused by infectious bovine rhinotracheitis (ibr) virus and bovine parainfluenza virus (bpiv- ) in cattle and equine viral rhinopneumonitis (evr) in horses. fetal pneumonias in dogs and cats are infrequently described, perhaps because aborted puppies and kittens are rarely submitted for postmortem examination. with advancements in molecular biology techniques, the etiologic diagnosis of abortions and their association with pulmonary fetal lesions is rapidly improving. neonatal pneumonias and septicemias. these entities are rather common in newborn animals lacking passive immunity because of the lack of either ingestion or absorption of maternal colostrum (failure of passive transfer or hypogammaglobulinemia). in addition to septicemias causing interstitial pneumonia, farm animals with hypogammaglobulinemia can develop bronchopneumonia by inhalation of bacterial pathogens. these include histophilus somni and pasteurella multocida in calves; streptococcus spp. in foals; and escherichia coli, listeria monocytogenes, and streptococcus suis in pigs. meconium aspiration syndrome. meconium aspiration syndrome (mas) is an important but preventable condition in human babies that originates when amniotic fluid contaminated with meconium is aspirated during labor or immediately after birth. the pathogenesis of mas is basically the same as in those of fetal bronchopneumonia (see fig. - ) . fetal hypoxia, a common event during dystocia or prolonged parturition, causes the fetus to relax the anal sphincter and release meconium into the amniotic fluid. aspiration of meconium can occur directly from aspirating contaminated amniotic fluid before delivery (respiratory movements with an open glottis) or immediately after delivery when the meconium lodged in the nasopharynx is carried into the lung with the first breath of air. this latter form of aspiration is prevented in delivery rooms by routine suction of the nasopharynx in meconium-stained babies. mas is well known in human babies, but the occurrence and significance in animals remains largely unknown. mas has been reported in calves, foals, piglets, and puppies. although pulmonary lesions are generally mild and transient, aspiration of meconium can be life-threatening for newborn babies and animals because it typically occurs in compromised neonates already suffering from intrauterine hypoxia and acidosis. neonatal acidosis is known to impair colostrum absorption in calves. common mas sequelae are lobular atelectasis, pulmonary hypertension, and possibly airway hyperreactivity. in the most severe cases of mas, focal (patchy) atelectasis can be observed grossly in the lung, indicating failure of the lungs to be fully aerated because of the mechanical obstruction and the chemical effect of meconium on pulmonary surfactant (see fig. - ). microscopically, meconium and keratin exfoliated from skin of the fetus into the amniotic fluid are present in bronchi, bronchioles, and alveoli and accompanied by mild alveolitis characterized by infiltration of leukocytes followed by alveolar macrophages and occasional giant cells (e- fig. - ) . lung cancer in animals is rare, unlike in human beings, in which the incidence is alarming and continues to be the number one cause of death due to cancer in canada, the united states, and europe. interestingly, prostatic and breast cancers, so much feared by men fetus, this fluid normally moves along the tracheobronchial tree, reaching the oropharynx, where a fraction is swallowed into the gastrointestinal tract, and a small portion is released into the amniotic fluid. at the time of birth, the lung fluid is rapidly reabsorbed from the lungs by alveolar absorption and lymphatic drainage. aspiration of amniotic fluid contaminated with meconium and bacteria from placentitis is the most common route by which microbial pathogens reach the fetal lungs. this form of pneumonia is secondary to fetal hypoxia and acidosis ("fetal distress"), which cause the fetus to relax the anal sphincter, release meconium into the amniotic fluid, and, in the terminal stages, inspire deeply with open glottis, resulting in the aspiration of contaminated fluid ( fig. - ). gross lesions are only occasionally recognized, but microscopic changes are similar to those of a bronchopneumonia. microscopically, bronchoalveolar spaces contain variable numbers of neutrophils, macrophages, epidermal squames, and pieces of meconium that appear as bright yellow material because of its bile content. in contrast to postnatal bronchopneumonia, lesions in fetuses are not restricted to the cranioventral aspects of the lungs but typically involve all pulmonary lobes. in cattle, brucella abortus and trueperella (arcanobacterium) pyogenes are two of the most common bacteria isolated from the lungs of aborted fetuses. these bacteria are usually present in large numbers in the amniotic fluid of cows with bacterial placentitis. inflammation of the placenta interferes with oxygen exchange between fetal and maternal tissue, and the resultant fetal hypoxia induces the fetus to "breathe" with an open glottis and aspirate the amniotic fluid. aspergillus spp. (mycotic abortion) and ureaplasma diversum cause sporadic cases of placentitis, which results in fetal pneumonia and abortion. in addition to the respiratory route (aspiration), pathogens, such as bacteria and viruses, can also reach the lungs via fetal blood and cause interstitial pneumonia. listeriosis (listeria monocytogenes), salmonellosis (salmonella spp.), and chlamydiosis (chlamydophila abortus [c. psittaci]) are the best known examples of blood-borne primary benign neoplasms of the lungs, such as pulmonary adenomas, are highly unusual in domestic animals. most primary neoplasms are malignant and appear as solitary masses of variable size that, with time, can metastasize to other areas of the lungs and to distant organs. it is sometimes difficult on gross and microscopic examination to differentiate primary lung cancer from pulmonary metastasis resulting from malignant neoplasms elsewhere in the body. it is often difficult to determine the precise topographic origin of a neoplasm within the lungs-for example, whether it originates in the conducting system (bronchogenic carcinoma), transitional system (bronchiolar carcinoma), exchange system (alveolar carcinoma), or bronchial glands (bronchial gland carcinoma). according to the literature, pulmonary carcinomas in animals arise generally from club (clara) cells or type ii pneumonocytes of the bronchioloalveolar region, in contrast to those in human beings, which are mostly bronchogenic. tumors located at the hilus generally arise from major bronchi and tend to be a solitary large mass with occasional small metastasis to the periphery of the lung. in contrast, tumors arising from the bronchioloalveolar region are often multicentric with numerous peripheral metastases in the lung parenchyma. because of histologic architecture and irrespective of the site of origin, many malignant epithelial neoplasms are classified by the all-encompassing term of pulmonary adenocarcinomas. dogs and cats are the species most frequently affected with primary pulmonary neoplasms, largely carcinomas, generally in older animals. the mean age for primary lung tumors is years for dogs and years for cats. pulmonary carcinomas in other domestic animals, except for retrovirus-induced pulmonary carcinoma in sheep, are less common, possibly because fewer farm animals are allowed to reach their natural life span. these neoplasms can be invasive or expansive, vary in color (white, tan, or gray) and texture (soft or firm), and often have areas of necrosis and hemorrhage, which result in a "craterous" or "umbilicate" appearance. this umbilicate appearance is frequently seen in rapidly growing carcinomas in which the center of the tumoral mass undergoes necrosis as a result of ischemia. some lung neoplasms resemble pulmonary consolidation or large granulomas. cats with moderately differentiated neoplasms had significantly longer survival time (median, days) than cats with poorly differentiated neoplasms (median, days). dogs with primary lung neoplasms, grades i, ii, and iii, had survival times of , , and days, respectively. ovine pulmonary adenocarcinoma (ovine pulmonary carcinoma). ovine pulmonary adenocarcinoma, also known as pulmonary adenomatosis and jaagsiekte (from the south african afrikaans word for "driving sickness"), is a transmissible, retrovirus-induced neoplasia of ovine lungs caused by jaagsiekte sheep retrovirus (jsrv). it occurs in sheep throughout the world, with the notable exception of australia and new zealand; its incidence is high in scotland, south africa, and peru and unknown but probably low in north america. this pulmonary carcinoma behaves very much like a chronic pneumonia, and jsrv shares many epidemiologic similarities with the ovine lentivirus responsible for maedi and the retrovirus responsible for enzootic nasal carcinoma in small ruminants. pulmonary adenomatosis has been transmitted to goats experimentally but is not known to be a spontaneous disease in that species. ovine pulmonary adenocarcinoma affects mainly mature sheep but can occasionally affect young stock. intensive husbandry probably facilitates horizontal transmission by the copious nasal discharge and explains why the disease occurs as devastating epizootics with % to % mortality when first introduced into a flock. differential diagnosis between maedi and pulmonary adenomatosis can prove difficult because both diseases often coexist in the same flock and women, are a distant second. to say that cigarette smoking is responsible for this epidemic of lung cancer is unnecessary. although dogs have been proposed as valuable "sentinels" for environmental hazards, such as exposure to passive smoking, asbestos, dyes, and insecticides, it is not known if the prevalence of canine lung tumors has increased in geographical areas with high contamination. alterations in genes (oncogenes) and chromosomes and changes in biologically active molecules have been linked to lung cancer in recent years. as with many other forms of cancer, epidemiologic studies indicate that the incidence of pulmonary neoplasms increases with age, but there are still insufficient data to confirm that particular canine or feline breeds have a higher predisposition to spontaneous lung neoplasms. a standard nomenclature of pulmonary neoplasms in domestic animals is lacking, and as a consequence, multiplicity of names and synonyms occur in the veterinary literature. some classifications are based on the primary site, whereas others emphasize more the histomorphologic type. the most common types of benign and malignant pulmonary neoplasms in domestic mammals are listed in box - . clinically, the signs of pulmonary neoplasia vary with the degree of invasiveness, the amount of parenchyma involved, and locations of metastases. signs may be vague, such as cough, lethargy, anorexia, weight loss, and perhaps dyspnea. in addition, paraneoplastic syndromes, such as hypercalcemia, endocrinopathies, and pulmonary hypertrophic osteoarthropathy, have been associated with pulmonary neoplasms. primary neoplasms of the lungs. primary neoplasms of the lungs arise from cells normally present in the pulmonary tissue and can be epithelial or mesenchymal, although the latter are rare. any malignant tumor metastatic from another body location (e.g., osteosarcoma in dogs, uterine carcinoma in cows, and malignant melanoma in horses) box - classification of pulmonary neoplasms .e chapter respiratory system, mediastinum, and pleurae abundant cytoplasm containing numerous acidophilic granules, which are positive for pas and for s- protein using immunohistochemistry. although this tumor can cause bronchial obstruction and respiratory signs, in most cases, it is an incidental finding in older horses submitted for postmortem examination. lymphomatoid granulomatosis. lymphomatoid granulomatosis is a rare but interesting pulmonary disease of human beings, dogs, cats, and possibly horses and donkeys characterized by nodules or large solid masses in one or more lung lobes. these frequently metastasize to lymph nodes, kidneys, and liver. microscopically, tumors are formed by large pleomorphic mononuclear (lymphomatoid) cells with a high mitotic rate and frequent formation of binucleated or multinucleated cells. tumor cells have a distinct tendency to grow around blood vessels and invade and destroy the vascular walls. lymphomatoid granulomatosis has some resemblance to lymphoma and is therefore also referred to as angiocentric lymphoma; phenotypic marking confirms that neoplastic cells are a mixed population of plasma cells, b and t lymphocytes, and histiocytes. cerebral and cutaneous forms of lymphomatoid granulomatosis have also reported in human beings, dogs, and cats. secondary neoplasms of the lungs. secondary neoplasms of the lungs are all malignant by definition because they are the result of metastasis to the lungs from malignant neoplasms elsewhere. because the pulmonary capillaries are the first filter met by tumor emboli released into the vena cava or pulmonary arteries, secondary neoplasms in the lung are relatively common in comparison to primary ones. also, secondary tumors can be epithelial or mesenchymal in origin. common metastatic tumors of epithelial origin are mammary, thyroid ( fig. - ) , and uterine carcinomas. tumors of mesenchymal origin are osteosarcoma ( fig. - , a) ; hemangiosarcoma ( fig. - , b) ; malignant melanoma in dogs; lymphoma in cows, pigs, dogs, and cats ( fig. - ) ; and vaccineassociated sarcoma in cats. usually, secondary pulmonary neoplasms are multiple; scattered throughout all pulmonary lobes (hematogenous dissemination); of variable size; and, according to the growth pattern, can be nodular, diffuse, or radiating (e- fig. - ) . the appearance of metastatic neoplasms differs according to the type of neoplasm. for example, dark red cystic nodules containing blood indicate hemangiosarcoma, dark black solid nodules indicate melanoma, and hard solid nodules (white, yellow, or tan color) with bone spicules indicate osteosarcoma. the gross appearances of or in the same animal. death is inevitable after several months of the initial onset of respiratory signs, and a specific humoral immune response to jsrv is undetectable in affected sheep. during the early stages of ovine pulmonary carcinoma, the lungs are enlarged, heavy, and wet and have several firm, gray, variably sized nodules that in some cases can be located in the cranioventral lobes mimicking a bronchopneumonic lesion ( fig. - , a) . in the later stages, the nodules become confluent, and large segments of both lungs are diffusely, but not symmetrically, infiltrated by neoplastic cells. on cross section, edematous fluid and a copious mucoid secretion are present in the trachea and bronchi ( fig. - , b) . microscopically, the nodules consist of cuboidal or columnar epithelial cells lining airways and alveoli and forming papillary or acinar (glandlike) structures (see fig. - , a) . because the cells have been identified ultrastructurally as originating from both type ii alveolar epithelial cells and club (clara) cells, the neoplasm is considered a "bronchioloalveolar" carcinoma. sequelae often include secondary bronchopneumonia, abscesses, and fibrous pleural adhesions. metastases occur to tracheobronchial and mediastinal lymph nodes and, to a lesser extent, to other tissues such as pleura, muscle, liver, and kidneys. neoplastic cells stain strongly positive for jsrv using immunohistochemistry. clinically, ovine pulmonary adenocarcinoma is characterized by a gradual loss of condition, coughing, and respiratory distress, especially after exercise (e.g., herding or "driving"). appetite and temperature are normal, unless there are secondary bacterial infections. an important differentiating feature from maedi (interstitial pneumonia) can be observed if animals with pulmonary adenomatosis are raised by their hind limbs; copious, thin, mucoid fluid, produced by neoplastic cells in the lungs, pours from the nostrils of some animals. carcinoid (neuroendocrine) tumor of the lungs. carcinoid tumor of the lungs is a neoplasm presumably arising from neuroendocrine cells and is sporadically seen in dogs as multiple, large, firm pulmonary masses close to the mainstem bronchi. it has also been reported in the nasal cavity of horses. tumor cells are generally polygonal with finely granular, pale, or slightly eosinophilic cytoplasm. nuclei are small, and mitotic figures are absent or rare. granular cell tumor. granular cell tumor is a rare and locally invasive tumor that has been reported mainly in human beings and older horses. the cell origin of this tumor was thought to be the myoblast, but it is currently presumed to be schwann cells, which are normally present in the bronchovascular bundles of the lung. microscopically, neoplastic cells are large, polyhedron-shaped with metastatic carcinomas are generally similar to the primary neoplasm and sometimes have umbilicated centers. proper diagnoses of pulmonary neoplasms in live animals require history, clinical signs, radiographs, cytologic analysis of bal fluid, and, when necessary, a lung biopsy. identification of a specific lineage of neoplastic cells in biopsy or postmortem specimens is often difficult and requires electron microscopy or immunohistochemical techniques. electron microscopy allows identification of distinctive cellular components such as osmiophilic lamellar phospholipid nephritic bodies in alveolar type ii epithelial cells or melanosomes in melanomas. immunohistochemical staining is also helpful in identifying tumor cells. the thoracic wall, diaphragm, and mediastinum are lined by the parietal pleura, which reflects onto the lungs at the hilum and continues as the visceral pleura, covering the entire surface of the lungs, except at the hilus where the bronchi and blood vessels enter. the space between the parietal and visceral pleura (pleural space) is only minimal and under normal conditions contains only traces of clear fluid, which is a lubricant, and a few exfoliated cells. samples of this fluid are obtained by thoracocentesis, a simple procedure in which a needle is passed into the pleural cavity. volumetric, biochemical, and cytologic changes in this fluid are routinely used in veterinary diagnostics. anomalies congenital defects are rare and generally of little clinical significance. cysts within the mediastinum of dogs and, less often, cats in severe cases, the amount of fluid present in the thoracic cavity can be considerable. for instance, a medium-size dog can have l of fluid, and a cow may accumulate l or more. excessive fluid in the thorax causes compressive atelectasis resulting in respiratory distress (see fig. - ). hydrothorax is most commonly seen in cattle with right-sided heart failure or cor pulmonale (hydrostatic) (e- fig. - ); dogs with congestive heart failure (hydrostatic), chronic hepatic disease (hepatic hydrothorax) ( fig. - ) , or nephrotic syndrome (hypoproteinemia); pigs with mulberry heart disease (increased vascular permeability); and horses with african horse sickness (increased vascular permeability). hemothorax. blood in the thoracic cavity is called hemothorax, but the term has been used for exudate with a sanguineous component. causes include rupture of a major blood vessel as a result of severe thoracic trauma (e.g., hit by car); erosion of a vascular wall by malignant cells or inflammation (e.g., aortitis caused by spirocerca lupi); ruptured aortic aneurysms; clotting defects, including coagulopathies; warfarin toxicity; disseminated intravascular coagulation (consumption coagulopathy); and thrombocytopenia. hemothorax is generally acute and fatal. on gross examination, the thoracic cavity can be filled with blood, and the lungs are partially or completely atelectatic ( fig. - ). chylothorax. the accumulation of chyle (lymph rich in triglycerides) in the thoracic cavity ( fig. - ) is a result of the rupture of major lymph vessels, usually the thoracic duct or the right lymphatic duct. the clinical and pathologic effects of chylothorax are similar to those of the other pleural effusions. causes include thoracic neoplasia (the most common cause in human beings but a distant second to idiopathic cases in dogs), trauma, congenital lymph vessel anomalies, lymphangitis, dirofilariasis, and iatrogenic rupture of the thoracic duct during surgery. the source of the leakage of chyle is rarely found at necropsy. when the leakage of chyle occurs in the abdominal cavity, the condition is referred to as chyloabdomen. cytologic and biochemical examination of fluid collected by thoracocentesis typically reveals large numbers of lymphocytes, lipid droplets, few neutrophils in chronic cases, and high triglyceride content. can be large enough to compromise pulmonary function or mimic neoplasia in thoracic radiographs. these cysts may arise from the thymus (thymic branchial cysts), bronchi (bronchogenic cysts), ectopic thyroid tissue (thyroglossal duct cysts), or from remnants of the branchial pouches, and they are generally lined by epithelium and surrounded by a capsule of stromal tissue. anomalies of the thoracic duct cause some cases of chylothorax. pleural calcification. pleural calcification is commonly found in dogs and less often in cats with chronic uremia. lesions appear as linear white streaks in parietal pleura, mainly over the intercostal muscles of the cranial part of the thoracic cavity. the lesions are not functionally significant but indicate a severe underlying renal problem. vitamin d toxicity (hypervitaminosis d) and ingestion of hypercalcemic substances, such as vitamin d analogs, can also cause calcification of the pleura and other organs. pneumothorax. pneumothorax is the presence of air in the thoracic cavity where there should normally be negative pressure to facilitate inspiration. human beings have a complete and strong mediastinum so that pneumothorax is generally unilateral and thus not a serious problem. in dogs, the barrier varies, but in general it is not complete, so often some communication exists between left and right sides. there are two main forms of pneumothorax. in spontaneous (idiopathic) pneumothorax, air leaking into the pleural cavity from the lungs occurs without any known underlying disease or trauma. in secondary pneumothorax, movement of air into the pleural cavity results from underlying pulmonary or thoracic wall disease. the most common causes of secondary pneumothorax in veterinary medicine are penetrating wounds to the thoracic wall, perforated esophagus, iatrogenic trauma to the thorax and lung during a transthoracic lung biopsy or thoracoscopy, tracheal rupture from improper intubation, and rupture of emphysematous bullae or parasitic pulmonary cysts (paragonimus spp.) that communicate with the thoracic cavity. pneumothorax and pneumomediastinum caused by high air pressure (barotrauma) are also well documented in cats after equipment failure during anesthesia. clinical signs of pneumothorax include respiratory distress, and the lesion is simply a collapsed, atelectatic lung. the air is readily reabsorbed from the cavity if the site of entry is sealed. pleural effusion. pleural effusion is a general term used to describe accumulation of any fluid (transudate, modified transudate, exudate, blood, lymph, or chyle) in the thoracic cavity. cytologic and biochemical evaluations of pleural effusions taken by thoracocentesis are helpful in determining the type of effusion and possible pathogenesis. based on protein concentration and total numbers of nucleated cells, pleural effusions are cytologically divided into transudates, modified transudates, and exudates. hydrothorax. when the fluid is serous, clear, and odorless and fails to coagulate when exposed to air, the condition is referred to as hydrothorax (transudate). causes of hydrothorax are the same as those involved in edema formation in other organs: increased hydrostatic pressure (heart failure), decreased oncotic pressure (hypoproteinemia, as in liver disease), alterations in vascular permeability (inflammation), or obstruction of lymph drainage (neoplasia). in cases in which the leakage is corrected, if the fluid is a transudate, it is rapidly reabsorbed. if the fluid persists, it irritates the pleura and causes mesothelial hyperplasia and fibrosis, which thickens the pleura. from a perforated esophagus. chronic injury typically results in serosal fibrosis and tight adhesions between visceral and parietal pleurae (see fig. - ). when extensive, these adhesions can obliterate the pleural space. pleuritis or pleurisy. inflammation of the visceral or parietal pleurae is called pleuritis, and according to the type of exudate, it can be fibrinous, suppurative, granulomatous, hemorrhagic, or a combination of exudates. acute fibrinous pleuritis can progress with time to pleural fibrosis ( fig. - ). when suppurative pleuritis results in accumulation of purulent exudate in the cavity, the lesion is called pyothorax or thoracic empyema ( fig. - ) . clinically, pleuritis causes considerable pain, and in addition, empyema can result in severe toxemia. pleural fibrous adhesions (between parietal and visceral pleura) and fibrosis are the most common sequelae of chronic pleuritis and can significantly interfere with inflation of the lungs. pleuritis can occur as an extension of pneumonia, particularly in fibrinous bronchopneumonias (pleuropneumonia), or it can occur alone, without pulmonary involvement ( fig. - ). bovine and ovine pneumonic mannheimiosis and porcine and bovine pleuropneumonia are good examples of pleuritis associated with fibrinous bronchopneumonias. polyserositis in pigs and pleural empyema, particularly in cats and horses, are examples of pleural inflammation in pleural tissue is readily susceptible to injury caused by direct implantation of an organism through a penetrating thoracic or diaphragmatic wound; by hematogenous dissemination of infectious organisms in septicemias; or by direct extension from an adjacent inflammatory process, such as in fibrinous bronchopneumonia or in contrast to those with the effusive ("wet") form, in which thoracic involvement is primarily that of a pleural effusion. cytologic evaluation of the effusion typically shows a low to moderate cellularity with degenerated leukocytes, lymphocytes, macrophages, and mesothelial cells, and a pink granular background as a result of the high protein content. pleuritis is also an important problem in horses. nocardia spp. can cause fibrinopurulent pneumonia and pyothorax with characteristic sulfur granules. although mycoplasma felis can be isolated from the respiratory tract of normal horses, it is also isolated from horses with pleuritis and pleural effusion, particularly during the early stages of infection. the portal of entry of this infection is presumably aerogenous, first to the lung and subsequently to the pleura. the pleural surface of the lung is often involved in neoplasms that have metastasized from other organs to the pulmonary parenchyma and ruptured the visceral pleura to seed the pleural cavity. mesothelioma is the only primary neoplasm of the pleura. which involvement of the lungs may not accompany the pleuritis. pleural inflammation is most frequently caused by bacteria, which cause polyserositis reaching the pleura hematogenously. these bacteria include haemophilus parasuis (glasser's disease) (see , streptococcus suis, and some strains of pasteurella multocida in pigs; streptococcus equi ssp. equi and streptococcus equi ssp. zooepidemicus in horses; escherichia coli in calves; and mycoplasma spp. and haemophilus spp. in sheep and goats. contamination of pleural surfaces can be the result of extension of a septic process (e.g., puncture wounds of the thoracic wall and, in cattle, traumatic reticulopericarditis) and ruptured pulmonary abscesses (e.g., trueperella pyogenes). in dogs and cats, bacteria (e.g., nocardia, actinomyces, and bacteroides) can cause pyogranulomatous pleuritis, characterized by accumulation of blood-stained pus ("tomato soup") in the thoracic cavity. this exudate usually contains yellowish flecks called sulfur granules ( fig. - ), although these are less common in nocardial empyema in cats. many species of bacteria, such as escherichia coli, trueperella pyogenes, pasteurella multocida, and fusobacterium necrophorum, can be present in pyothorax of dogs and cats. these bacteria occur alone or in mixed infections. the pathogenesis of pleural empyema in cats is still debatable, but bite wounds or penetration of foreign material (migrating grass awns) are likely. pyogranulomatous pleuritis with empyema occurs occasionally in dogs, presumably associated with inhaled small plant material and penetrating (migrating) grass awns. because of their physical shape (barbed) and assisted by the respiratory movement, aspirated grass awns can penetrate airways, move through the pulmonary parenchyma, and eventually perforate the visceral pleura causing pyogranulomatous pleuritis. cats with the noneffusive ("dry") form of feline infectious peritonitis (fip) frequently have focal pyogranulomatous pleuritis, mesothelioma is a rare neoplasm of the thoracic, pericardial, and peritoneal mesothelium of human beings that is seen most commonly in calves, in which it can be congenital. in human beings, it has long been associated with inhalation of certain types of asbestos fibers (asbestos mining and ship building) alone or with cigarette smoking as a probable cocarcinogen; no convincing association between the incidence of mesothelioma and exposure to asbestos has been made in domestic animals. in animals, there may be pleural effusion with resulting respiratory distress, cough, and weight loss. mesothelioma initially causes a thoracic effusion, but cytologic diagnosis can be difficult because of the morphologic resemblance of malignant and reactive mesothelial cells. during inflammation, mesothelial cells become reactive and not only increase in number but also become pleomorphic and form multinucleated cells that may be cytologically mistaken for those of a carcinoma. grossly, mesothelioma appears as multiple, discrete nodules or arborescent, spreading growths on the pleural surface ( fig. - ) . microscopically, either the mesothelial covering cells or the supporting tissue can be the predominant malignant component, so the neoplasm can microscopically resemble a carcinoma or a sarcoma. figure - nocardiosis. a, chronic pleuritis (nocardia asteroides), pleural cavity, cat. the pleural cavity is covered with abundant red-brown ("tomato soup") exudate" (syringe). once considered to be pathognomonic of nocardia spp. infection, it is no longer regarded as being diagnostic of nocardiosis. the fluid contains abundant protein, erythrocytes, granulomatous inflammatory cells, and sulfur granules. b, chronic pleuritis (nocardia asteroides), visceral pleura, dog. the thickened pleura has a granular pink-gray appearance because of granulomatous inflammation and the proliferation of fibrovascular tissue of the pleura. c, chronic pleuritis (nocardia asteroides), dog. the pleura has been thrown up into villous-like projections composed of abundant fibrovascular tissue and granulomatous inflammation. leakage from the neocapillaries of the fibrovascular tissue is responsible for the hemorrhagic appearance of the pleural exudate. h&e stain. d, chronic pleuritis (nocardia asteroides), thoracic cage, parietal pleura, cat. large pieces of exudate, which contain yellow sulfur granules, are present on the thickened pleura. although considered malignant, mesotheliomas rarely metastasize to distant organs. secondary neoplasms of the pleura. secondary tumors may also spread into the visceral and parietal pleura. thymomas are rare neoplasms that grow in the cranial mediastinum of adult or aged dogs, cats, pigs, cattle, and sheep. thymomas are composed of thymic epithelium and lymphocytes (see chapter ). old age, both in human beings and in animals, is known to be a risk factor for pulmonary infections, but the precise mechanisms involved in this increased susceptibility are still under investigation. some studies have shown that in aged individuals the antibacterial properties provided by surfactant proteins, proinflammatory cytokines, and complement are altered. pulmonary hyperinflation (often referred to as senile emphysema) has been reported as an age-related change in human and canine lungs. other age-related changes described in canine lungs include mineralization of bronchial cartilage, pleural and alveolar fibrosis, and heterotopic bone formation (so-called "pulmonary osteomas"). we thank all pathologists at the atlantic veterinary college, university of prince edward island for providing case material. suggested readings are available at www.expertconsult.com. lung section showing a distended and partially occluded blood vessel (center of figure) containing large granular cells. these large cells are macrophages, and their cytoplasm is filled with myriad merozoites isolation of porcine circoviruslike viruses from pigs with a wasting disease in the usa and europe exercise-induced pulmonary hemorrhage effect of mucociliary transport relies on efficient regulation of ciliary beating epidemiology, diagnosis, and treatment of blastomycosis in dogs and cats canine h n influenza virus infection in dogs and mice failure of respiratory defenses in the pathogenesis of bacterial pneumonia in cattle the respiratory system advances in diagnosis of respiratory diseases of small ruminants canine nasal disease transmission of equine influenza virus to dogs dear jd: bacterial pneumonia in dogs and cats acute respiratory distress syndrome in dogs and cats: a review of clinical findings and pathophysiology inflammatory response to infectious pulmonary injury laryngeal paralysis: a study of cases in a mixed-breed population of horses stem cells of the respiratory tract exudative pleural disease in small animals bovine respiratory disease research pulmonary thromboembolism coccidioidomycosis in dogs and cats: a review cousens c: pathology and pathogenesis of ovine pulmonary adenocarcinoma prognosis factors for survival in cats after removal of a primary lung tumor: cases ( - ) the acute respiratory distress syndrome: from mechanism to translation endogenous lipid pneumonia in cats: cases ( - ) retroviral infections in sheep and goats: small ruminant lentiviruses and host interaction canine and feline nasal neoplasia the acute respiratory distress syndrome equine respiratory medicine and surgery canine pleural and mediastinal effusions: a retrospective study of cases a review of histiocytic diseases of dogs and cats estimation of nasal shedding and seroprevalence of organisms known to be associated with bovine respiratory disease in australian live export cattle polymicrobial respiratory disease in pigs current state of knowledge on porcine circovirus type -associated lesions common and emerging infectious diseases in the animal shelter chronic rhinitis in the cat advances in the understanding of pathogenesis, and diagnosis and therapeutics of feline allergic asthma mannheimia haemolytica and bovine respiratory disease detection of respiratory viruses and bordetella bronchiseptica in dogs with acute respiratory tract infections current perspectives on the diagnosis and epidemiology of mycoplasma hyopneumoniae infection mannheimia haemolytica: bacterialhost interactions in bovine pneumonia acute lung injury review rhodococcus equi: the many facets of a pathogenic actinomycete tumors of the respiratory system key: cord- -tvqpv fp authors: corrin, bryan; nicholson, andrew g. title: occupational, environmental and iatrogenic lung disease date: - - journal: pathology of the lungs doi: . /b - - - - . - sha: doc_id: cord_uid: tvqpv fp nan in practice the term is confined to the effects of mineral dust on the lungs. diseases caused by organic dusts are not included among the pneumoconioses and, in medicolegal practice at least, the presence of dust alone is insufficient to indicate pneumoconiosis: for compensation to be considered, the mineral dust must alter the structure of the lung and cause disability. the british industrial injuries advisory council defined pneumoconiosis as 'permanent alteration of lung structure due to the inhalation of mineral dust and the tissue reactions of the lung to its presence, excluding bronchitis and emphysema' . parkes recommends that cancer and asthma caused by mineral dust should also be excluded from the definition, an opinion with which we concur. to reach the lung, dust particles have to be very small. particle density and shape also affect the aerodynamic properties of dust. host factors such as airflow characteristics, airway branching patterns and airway disease also affect dust deposition. three deposition mechanisms are recognised ( fig. . . ): . inertial impaction: when air streams change direction or velocity, the inertia of the entrained particles causes them to maintain their original direction for a distance that depends upon their density and the square of their diameter. the same rules govern a car approaching a bend too fast: the car crashes into the outside of the bend. . sedimentation (gravitational settlement): under the influence of gravity, particles settle with a speed that is proportional to their density and the square of their diameter. . diffusion: very small airborne particles acquire a random motion as a result of bombardment by the surrounding gas molecules. inhaled dust particles are liable to sediment out in the alveoli if they have a diameter in the range of - µm, are roughly spherical in shape, and in density approximate to that of water. larger or denser particles impact or precipitate on the walls of the conductive airways and are rapidly removed by ciliary action. smaller particles may reach the alveoli but do not sediment so readily and many are therefore exhaled. very small particles are deposited on the walls of alveoli by diffusion but because they are so small the total amount of dust deposited in this way is insignificant compared with that deposited by sedimentation ( fig. . . ). direct measurement shows that most lung dust ( %) has a particle diameter less than . µm. fibrous dust particles behave differently. fibres over µm in length may reach the alveoli if they are very thin and remain aligned with the air stream. fibre penetration is inversely related to path length and the number of bifurcations. tall people have longer conductive airways and experience more deposition in these sites than short people who have greater alveolar deposition for the same level of exposure. slightly more dust is deposited in the right lung than the left, probably because the right main bronchus is more in line with the trachea, and is broader and shorter than the left, and carries % of the inhaled air. , dust clearance from the lung inhaled dust that settles in the conductive airways is removed within a day or two by ciliary action. only dust that reaches the alveoli is liable to cause pneumoconiosis and much of this is also removed, but the clearance rate here is much slower: many coalminers continue to expectorate mine dust years after retirement. alveolar clearance is gravity largely effected by macrophages, principally via the airways to the pharynx but also via lymphatics to the regional lymph nodes. the airway and interstitial routes interconnect at the bronchiolar level where some dust-laden macrophages leave the interstitium for the air space. this interconnection is probably the route utilised by circulating macrophages clearing other parts of the body of endogenous or exogenous particulate matter via the lung. long asbestos fibres present a particular problem to macrophage clearance. some minerals, notably chrysotile asbestos, undergo slow physicochemical dissolution in the lungs. only a small fraction of the inhaled dust gains access to the interstitium, a necessary step if it is to cause pneumoconiosis. some free dust enters through the bronchus-associated lymphoid tissue , and some is taken up by, or pierces, the alveolar epithelium ( fig. . , p. ). [ ] [ ] [ ] some of this is transported within hours to the hilar lymph nodes. so rapid is this translocation that it is thought not to involve most, the lesions are more numerous and better developed in the upper lobes than the bases but the reverse is true of asbestosis. the reasons for this are complex but undoubtedly involve the dust deposition:clearance ratio for the effect of the dust will depend upon both its amount and the duration of its stay in the lungs. there are well-recognised regional differences in the distribution and clearance of inhaled material, which in turn are dependent upon man's upright posture, the consequent gravitational forces being maximal at the apices. when standing at rest, the apices of the lungs are hardly perfused, so that lymph formation and clearance are much better at the bases. [ ] [ ] [ ] similarly, the apices are relatively less well aerated; alveoli in the lower lobes receive more air than those in the upper lobes. , the greater respiratory excursions at the bases are thought to promote macrophage mobility there. it is to be expected therefore that the bases would both receive and clear more dust than the apices, rendering it difficult to predict on theoretical grounds which parts of the lungs carry the heaviest dust burden. in fact, more dust of all types is found in the upper lobes, the part most severely affected by every type of pneumoconiosis except asbestosis. , the predilection of asbestos to affect the periphery of the lower lobes is attributed to the dangerous long asbestos fibres preponderating there. , pulmonary reactions to mineral dust the main tissue reaction to mineral dust is fibrosis. silica is highly fibrogenic and is therefore very likely to cause pneumoconiosis. carbon is non-fibrogenic and therefore, unless there are complications, coal pneumoconiosis causes little disability. tin too is harmless, and stannosis therefore unimportant, although the chest radiograph is highly abnormal because tin is very radiopaque. stannosis is one of several terms that specify pneumoconiosis due to a particular mineral, the best known being silicosis, asbestosis and anthracosis. the blackness of carbon and red-brown colour of iron give ample evidence, both naked-eye and microscopically, of the type and amount of these dusts when they are present in the lung ( fig. . . ), but other inorganic dusts may be more difficult to identify. however, a flick-out substage condenser and polaroid filters to test for refractility and birefringence respectively are useful adjuncts that are too often neglected by the histopathologist. crystalline silica is traditionally regarded as being only weakly birefringent, in contrast to silicates which generally show up brightly with simple crossed polaroid filters. however, with modern microscope lamps, if the light source is set at high intensity when using polaroid filters, both silica and silicates are birefringent. mineralogists use polarising microscopy for analysis, but only by studying large polished crystals with controlled orientation of the light. the small dust particles found in tissue sections are too small to permit analysis by this technique but it is nevertheless very useful for detecting their presence ( fig. . . ) . particle shape gives a useful indication of mineral type but appearances are sometimes deceptive: the plate-like crystals of talc are seldom observed as such, usually being viewed edge-on, when they appear to be needle-shaped. occasionally, stains can be used to identify minerals, e.g. a modified perls' reaction for inhaled iron, and irwin's aluminon stain for aluminium, but these too have largely been replaced by modern analytical techniques. ultrafine dust particles are particularly liable to be transported across the alveolar epithelium. the integrity of the alveolar epithelium is very important to dust translocation from the air spaces to the interstitium. much more dust reaches the interstitium if the epithelium is damaged. , it is widely thought that macrophages that have left the interstitium for the alveolar space never return, , but this is probably untrue. heavily laden macrophages accumulate in alveoli bordering the terminal and respiratory bronchioles, eventually filling them completely. erosion of the alveolar epithelium permits re-entry of these macrophages into the interstitium, very close to foci of bronchial mucosaassociated lymphoid tissue (malt), which are found near the terminal bronchioles. these aggregates guard the mouths of lymphatics, which commence at this point; alveoli are devoid of lymphatics. dustladen interstitial macrophages accumulate in and around the bronchial malt, which macklin therefore referred to as dust sumps. most pneumoconiotic lesions are found in the region of the dust sumps and are therefore focal. asbestosis is diffuse rather than focal because the long asbestos fibres are not readily mobilised and cannot be concentrated in the centriacinar dust sumps. this is also seen on occasion with platy non-fibrous dusts such as talc, mica, kaolinite and feldspar. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] within the dust sumps the dust particles are not static. they are constantly being freed and reingested by interstitial macrophages and, because these cells are mobile, successively inhaled dusts soon become intimately mixed. macrophages play an important role in pneumoconiosis and if the dust is fibrogenic the repeated phagocytosis of indestructible mineral particles results in constant fibroblast stimulation. the zonal distribution of pneumoconiosis pneumoconiosis affects both lungs but seldom evenly and some pneumoconioses show characteristic patterns of lung involvement. in microincineration combined with dark-field microscopy can also be used to demonstrate small particles. incombustible mineral particles that cannot be seen with bright-field or polarising microscopy are rendered visible by this technique and their position on the slide can be compared with tissue reactions evident in a serial section that has not been incinerated. microincineration has, however, also been largely replaced by modern analytical techniques that will now be considered. analytical electron microscopy is very helpful in identifying minerals, whether applied to lung digests or tissue sections. [ ] [ ] [ ] [ ] scanning electron microscopy permits the examination of thicker sections than transmission electron microscopy but does not detect very small particles. however, scanning electron microscopy allows more tissue to be examined and avoids the difficulty of cutting mineral particles with an ultramicrotome. mineral particles in a -µm thick deparaffinised section can be recognised in a scanning electron microscope set to collect the back-scattered electrons. the instrument can then be focused on points of potential interest and switched to x-ray diffraction, which provides information on crystal structure (fig. . . ) . alternatively, elemental analysis may be undertaken with either energy-dispersive or wavelength-dispersive x-ray spectroscopy. with energy-dispersive x-ray spectroscopy, all elements of atomic number above are identified, whilst with wavelength-dispersive x-ray spectroscopy the section can be scanned for one particular element. with the former technique different elements are shown graphically as individual peaks, the heights of which are proportional to the amounts of the different elements within the particle studied, thereby giving information on probable molecular formula ( fig. . . ) . thus, different silicates can be distinguished from each other and also from silica, which registers as pure silicon, oxygen (atomic number ) not being detected. the fact that the elements of low atomic number that constitute organic chemicals are not detected means that any minerals present (except beryllium, atomic number ) can be recognised easily in tissue sections. only particles can be analysed however: elements present in only molecular amounts cannot be detected by x-ray analysis. the detection of trace amounts of substances such as beryllium requires bulk chemical analysis or techniques that are not widely available such as atomic absorption spectrometry, neutron activation analysis and microprobe mass spectrometry. , the last of these techniques can also provide molecular (as opposed to elemental) analysis of organic as well as inorganic particles. another analytical technique of interest is microscopic infrared spectroscopy which provides data on the compound nature of microscopic particles in tissue sections ( fig. . . ) . micro-raman spectroscopy is also useful in this respect. some metals cause hypersensitivity, which can be identified by exposing the patient's lymphocytes to metals and measuring their reaction in vitro. radiological grading of pneumoconiosis a scheme for grading pneumoconiosis radiologically by comparison with standard radiographs has been adopted by the international labour organisation (ilo) and is widely used. small opacities (up to cm diameter) are graded by their profusion, , and indicating increasing numbers, and by their size, increasing through p, q and r if rounded and s, t and u if irregular. type p opacities are described as punctiform and measure up to . mm in diameter; larger lesions up to mm in diameter (type q) are described as micronodular or miliary; and those over mm and up to cm in diameter (type r) are described as nodular. irregular opacities cannot be sized so accurately, s, t and u indicating fine, medium and coarse respectively. large opacities (over cm diameter) are graded by their combined size, increasing through a, an opacity measuring between and cm in diameter; b, one or more opacities whose combined area does not exceed the equivalent of one-third of the area of the right lung field (when they are regrouped in the mind's eye or measured with a transparent ruler); and c, one or more opacities whose combined area exceeds one-third of the area of the right lung field (when similarly regrouped). in coalworkers, small opacities (up to cm diameter) correspond to simple coalworker's pneumoconiosis and large opacities (over cm diameter) to complicated coalworker's pneumoconiosis, which is also known as progressive massive fibrosis. silicotic lesions have been identified in the lungs of egyptian mummies, and the injurious effects on the lungs of inhaling mine dust have been recognised for more than years. as long ago as the sixteenth century in joachimsthal, bohemia (now jachymov, czech republic), diseases of miners' lungs were attributed to the dust the miners breathed. silicosis, tuberculosis and lung cancer are all now known to have been prevalent among the miners in this region, the cancer being largely attributable to the high level of radioactivity in the mines. silicosis was recognised in the uk soon after the discovery in that the addition of calcined flint to the clay from which china is made produced a finer, whiter and tougher ware. the preparation and use of this flint powder were highly dangerous, causing the condition known as potter's rot, one of the first of the many trade names by which silicosis has since been known. aluminium oxide (alumina) now provides a safe, effective substitute for flint in this industry. in it was noted that sheffield fork grinders who used a dry grindstone died early, and amongst other preventive measures it was recommended that the occupation should be confined to criminals: fortunately for them, the substitution of carborundum (silicon carbide) for sandstone was effective enough. however, silicosis still occurs in some miners, tunnellers, quarrymen, stone dressers and metal workers. silica in one form or another is used in many trades -in the manufacture of glass and pottery, in the moulds used in iron foundries, as an abrasive in grinding and sandblasting, and as a furnace lining that is refractory to high temperatures. rocks such as granite and sandstone are siliceous and their dusts are encountered in many mining and quarrying operations. in coal mining in the uk the highest incidence of the disease was in pits where the thinness of the coal seams required the removal of a large amount of siliceous rock, a process known as 'hard heading' . in south africa, silicosis causes a high mortality among the gold miners on the witwatersrand, where the metallic ore is embedded in quartz. slate is a metamorphic rock that contains both silica and silicates, and slateworkers develop both silicosis and mixed-dust pneumoconiosis. , nor are rural industries immune from the disease, particularly if ventilation is inadequate, as it is in certain african huts where stone implements are used to pound meal and the occupants develop mixed-dust pneumoconiosis. silicosis and mixed-dust pneumoconiosis have also been reported in dental technicians. desert sand is practically pure silica but the particles are generally too large to reach the lungs. however, silicosis has been reported in inhabitants of the sahara, libyan and negev deserts and those living in windy valleys high in the himalayan mountains, [ ] [ ] [ ] [ ] [ ] [ ] [ ] whilst in california the inhalation of dust raised from earth has led to silicate pneumoconiosis in farm workers, horses and a variety of zoo animals. the silica in rocks such as granite, slate and sandstone is largely in the form of quartz and this is therefore the type of silica encountered in most of the industries considered above. cristobalite and tridymite, which are possibly even more fibrogenic than quartz, are more likely to be encountered in the ceramic, refractory and diatomaceous earth industries where processing involves high temperatures. many workers with silicosis are asymptomatic. as a general rule, exposure to silica dust extends over many years, often or more, before the symptoms of silicosis first appear: by the time the disease becomes overt clinically, much irreparable damage has been inflicted on the lungs. the initial symptoms are cough and breathlessness. from then onwards, respiratory disability progresses, even if the patient is no longer exposed to silica dust. ultimately, there may be distressing dyspnoea with even the slightest exercise. silicosis sometimes develops more rapidly, perhaps within a year or so of first exposure. such 'acute silicosis' was observed in the scouring powder industry in the s when these cleansing agents consisted of ground sandstone mixed with a little soap and washing soda. , the additives were considered to have rendered the silica in the sandstone more dangerous but it is possible that the rapidity of onset of the disease merely reflected the intensity of the dust cloud to which the packers were exposed. confusingly, the term 'acute silicosis' has since been applied to a further effect of heavy dust exposure in tunnellers, sand blasters and silica flour workers, namely pulmonary alveolar lipoproteinosis (see below), , whilst the terms 'accelerated silicosis' or 'cellular phase silicosis' have been substituted for 'acute silicosis' in referring to the rapid development of early cellular lesions. , the time from first exposure to the development of symptoms (the latency period) is inversely proportional to the exposure level. however, it is evident that a certain amount of silica can be tolerated in the lungs without fibrosis developing, indicating either a time factor in the pathogenetic process or a threshold dust load that has to be reached before fibrosis develops. silica particles that are roughly spherical in shape and of a diameter in the range of - µm sediment out in the alveoli and are concentrated within macrophages at macklin's dust sumps, as explained previously (see p. ). early lesions, as seen in so-called accelerated or cellular phase silicosis, consist of collections of macrophages separated by only an occasional wisp of collagen. the early lesions have been likened to granulomas and on occasion have been mistaken for langerhans cell histiocytosis or a storage disorder, but langerhans cells are scanty and the histiocytes contain dust particles rather than accumulated lipid or polysaccharide. the macrophages of the early lesion are gradually replaced by fibroblasts and collagen is laid down in a characteristic pattern. the mature silicotic nodule is largely acellular and consists of hyaline collagen arranged in a whorled pattern, the whole lesion being well demarcated ( fig. . . ) and sometimes calcified. small numbers of birefringent crystals are generally evident within the nodules when polarising filters are used, but these mainly represent silicates such as mica and talc, inhaled with the silica. silica particles are generally considered to be only weakly birefringent, but fairly strong birefringence is evident in strong light (see above). silicotic nodules develop first in the hilar lymph nodes and are generally better developed there than in the lungs. [ ] [ ] [ ] indeed, silicotic nodules are occasionally found in the hilar lymph nodes of persons who have no occupational history of exposure to silica and whose lungs are free of such lesions, the silica in the nodes being presumed to represent inhaled particles derived from quartz-rich soil. severely affected lymph nodes often calcify peripherally, giving a characteristic eggshell-like radiographic pattern. this is sometimes the only radiological abnormality. such enlarged lymph nodes may occasionally press upon and obstruct adjacent large bronchi or result in a left recurrent laryngeal nerve palsy, so simulating malignancy. sometimes the nodules develop within the walls of major bronchi, occasionally causing a middle-lobe syndrome (see p. ). silicotic nodules are also found along the lines of the pleural lymphatics , where they have been likened to drops of candle wax on the visceral pleura. very rarely, silica-induced fibrosis is more pronounced in the pleura than in the lungs. lung tissue between the nodules is often quite normal and not until the process is very advanced is there any disability ( fig. . . b). in severe cases large masses of fibrous tissue are formed, which may undergo central necrosis and cavitation ( fig. . . ). on close inspection it is evident that these consist of conglomerations of many silicotic nodules closely packed together. in such severe cases cor pulmonale develops. occasionally, silicotic nodules develop in the abdominal as well as the thoracic lymph nodes, and in the liver, spleen, peritoneum and bone marrow. [ ] [ ] [ ] [ ] [ ] in about % of cases, the typical pulmonary nodules that predominantly affect the upper lobes are accompanied by diffuse fibrosis that is maximal in the lower lobes. , , [ ] [ ] [ ] the latter may show 'honeycombing' and closely resemble idiopathic pulmonary fibrosis. the association is too common to be explained by chance and the diffuse fibrosis is therefore regarded as a further manifestation of the pneumoconiosis, possibly due to an interaction between the dust and the immunological factors discussed below. the pathogenesis of silicosis has excited much interest and many different theories have been advanced over the years. an early theory held that the hardness of the silica was responsible, but this was discounted by the observation that silicon carbide (carborundum) is harder than silica but is non-fibrogenic. theories based on the piezoelectric property and on the solubility of silica were successively abandoned although the latter had a long period of popularity. it gained support from kettle's experiments which showed that fibrosis developed about chambers placed in an animal's peritoneal cavity if the chambers contained silica powder sealed in by a collodion membrane through which solutes such as silicic acid could pass. however, it was later shown that the pores in a collodion membrane are quite irregular in size and when the experiments were repeated using chambers guarded by millipore membranes, no fibrosis developed, despite solutes being able to diffuse out. the solubility theory also fails to take account of the differing fibrogenicity of the various forms of silica despite them being of similar solubility. furthermore, if the outer, more soluble layer of the particles is removed by etching, fibrogenicity is increased although solubility is decreased. in line with this, freshly fractured crystalline silica is more pathogenic in every respect than its aged equivalent, which may partly explain the severity of silicosis in trades such as sandblasting. these observations suggest that the fibrogenicity of silica is connected with its surface configuration. it is now known that uptake of the silica by macrophages is necessary for silicosis to develop. if silica and macrophages are enclosed together in peritoneal millipore chambers, a soluble product of the macrophages diffuses out and causes fibrosis. this observation led to the realisation that the fibrogenicity of the various crystalline forms of silica correlated well with their toxicity to macrophages and for a time macrophage death was thought to be necessary. it is now considered that before the macrophages are killed by the ingested silica, they are stimulated to secrete factors that both damage other con stituents of the lung and promote fibrosis. [ ] [ ] [ ] [ ] [ ] [ ] [ ] transforming growth factor-β is one fibrogenic factor that has been implicated in the pathogenesis of silicosis. [ ] [ ] [ ] toxic damage to macrophages is due to silica particles injuring the phagolysosomal membranes, so releasing acid hydrolases into the cytoplasm. it is important in the pathogenesis of the disease indirectly because when the macrophage crumbles, the silica particles are taken up by fresh macrophages and the fibrogenic process continues. it has been suggested that early involvement of the hilar lymph nodes in the fibrogenic process promotes the development of the disease in the lung by delaying dust clearance. immunological factors have been implicated in the pathogenesis of silicosis because many patients with silicosis have polyclonal hypergammaglobulinaemia, rheumatoid factor or antinuclear antibodies, and because there is a well-recognised association between autoimmune diseases such as systemic sclerosis and rheumatoid disease and exposure to silica. , [ ] [ ] [ ] [ ] the relation of immunity to dust exposure appears to be a reciprocal one: on the one hand, the presence of dust results in rheumatoid lesions in the lungs being more florid (see caplan's syndrome, p. ), whilst on the other, non-specific immunisation of rabbits with horse serum results in experimental silicotic lesions being larger and more collagenous. it is doubtful whether pneumoconiosis and autoimmune disease play a causative role in each other but one seems to aggravate the other and may lead to its earlier development. one of the commonest and most feared complications of silicosis is chronic respiratory tuberculosis. once this infection has been added to the silicosis, the prognosis rapidly worsens. it is thought that in the presence of silica, the tubercle bacilli proliferate more rapidly because the ingested silica particles damage phagolysosomal membranes and thereby interfere with the defensive activity of the macrophages. the synergistic action of silica dust has long been held responsible for the inordinately high incidence of respiratory tuberculosis in mining communities. many former south african gold miners now have acquired immunodeficiency syndrome (aids) as well as silicosis and tuberculosis has consequently reached almost epidemic proportions amongst these men. phagocyte damage by ingested dust particles may also cause some cases of chronic necrotising aspergillosis complicating pneumoconiosis. a series of studies suggesting that there might be a link between silica inhalation and lung cancer was reviewed by the international agency for research on cancer in , leading to the conclusion that the evidence for carcinogenicity of crystalline silica in experimental animals was sufficient, while in humans it was limited. subsequent epidemiological publications were reviewed in , when it was concluded that the epidemiological evidence linking exposure to silica to the risk of lung cancer had become somewhat stronger but that in the absence of lung fibrosis remained scanty. the pathological evidence in humans is also weak in that premalignant changes around silicotic nodules are seldom evident. nevertheless, on this rather insubstantial evidence, lung cancer in the presence of silicosis (but not coal or mixed-dust pneumoconiosis) has been accepted as a prescribed industrial disease in the uk since . some subsequent studies have provided support for this decision. in contrast to the sparse data on classic silicosis, the evidence linking carcinoma of the lung to the rare diffuse pattern of fibrosis attributed to silica and mixed dusts is much stronger and appears incontrovertible. , alveolar lipoproteinosis in response to heavy dust exposure a further complication of exposure to silica is the development of alveolar lipoproteinosis (see p. ). , , , very heavy experimental exposure to silica, and indeed other dusts, stimulates hypersecretion of alveolar surfactant to such an extent that the normal clearance mechanism is overwhelmed. [ ] [ ] [ ] [ ] [ ] [ ] [ ] alveolar macrophages are enlarged by numerous phagolysosomes distended by lamellar bodies that represent ingested surfactant. the alveoli are filled by such cells and, having a foamy cytoplasm, they produce the appearances of endogenous lipid pneumonia, similar to that more usually encountered as part of an obstructive pneumonitis distal to a bronchial tumour. the macrophages gradually disintegrate and the free denatured surfactant slowly becomes compacted, during which time its staining with both eosin and the periodic acid-schiff reagents intensifies until the appearances are finally those of alveolar lipoproteinosis. this process prevents the aggregation and concentration of the dust in the usual foci and thereby hinders the development of silicosis. lipoproteinosis and silicosis may be seen in conjunction but, more often, different areas of the lung show one or the other. the lipoproteinosis has its own severe impact on lung function, but, unlike silicosis, is potentially reversible (by massive alveolar lavage). occasional patients exposed to silica develop renal disease. [ ] [ ] [ ] [ ] two mechanisms appear to operate. first, translocation of silica particles from the lungs leads to their deposition in the renal interstitium with resultant nephrotoxity. second, silica stimulates an autoimmune response characterised by the formation of various antibodies, notably rheumatoid factor and antinuclear antibodies, which leads to the development of immune complex-mediated glomerulonephritis. , amorphous silica manmade submicron forms of silica, variously known as amorphous, vitreous, colloidal, synthetic or precipitated silica, are widely used in industry. they consist of pure non-crystalline silicon dioxide. particle size ranges from to nm but aggregates of the particles measure from to µm. industrial surveys suggest that inhalation of such dust is harmless, observations that are in accord with the results of animal experiments. an amorphous silica is the principal component of the fossilised remains of diatoms that constitute the sedimentary rock, diatomite ( fig. . . ). this is generally obtained by open-cast mining, following which the rock is crushed and calcined. the calcined product is used in filters, insulation material and as a filler. being amorphous, the silica in diatomite is harmless, but calcining (> °c) results in its conversion to crystalline forms of silica. diatomaceous earth pneumoconiosis is unusual and its risk appears to be related to the amount of cristobalite and tridymite (two forms of crystalline silica) produced in the calcining process. the silicates are complex compounds in which silicon and oxygen form an anion combined with cations such as aluminium and magnesium: talc, for example, is a hydrated magnesium silicate with the formula mg si o (oh) . silicates include fibrous forms (asbestos and the zeolites), plate-like forms (talc and mica) and clays (kaolinite and fuller's earth). in histological sections, the platy talc and mica particles are generally cut tangentially and therefore appear needleshaped (see fig. . . ). they are strongly birefringent whereas the clays are only weakly so. talc particles in the lung exceeding µm in length should arouse suspicion of intravenous drug abuse. of the fibrous silicates, zeolite is used as a building material in certain communities, notably in central turkey. pneumoconiosis is not a problem but zeolites are of medical interest because, like asbestos, they present a mesothelioma risk. asbestos is dealt with separately (see below). pneumoconiosis has been described with various non-fibrous silicates, notably in the rubber industry, which uses talc and, less commonly, mica as lubricants. other occupations posing a risk include the extraction of kaolinite from china clay (kaolin), , , and in the open-cast and underground mining of fuller's earth (montmorillonite, bentonite and attapulgite clays, which were originally used in 'fulling' (degreasing) wool). , however, all these substances are commonly contaminated with silica, asbestos or both, and it has been questioned whether in pure state they are at all fibrogenic. the modifying effect of inert substances such as iron on that of silica is well known (see mixed-dust pneumoconiosis, below) and it has been suggested that talc, mica and fuller's earth act in a similar way in regard to their more fibrogenic contaminants, the pneumoconioses attributed to them in reality representing mixed-dust pneumoconiosis or asbestosis. contrary evidence comes from reports of pulmonary fibrosis in persons heavily exposed to pure talc, mica or kaolin. all these silicates are evident in the tissues as plate-like birefringent crystals which often provoke a foreign-body giant cell reaction (see fig. . . ) and may result in fibrotic nodules. large focal lesions resembling the progressive massive fibrosis of coalworkers may be produced, and also a diffuse 'asbestosis-like' form of pneumoconiosis, the latter attributed to poor macrophage mobilisation of the plate-like particles. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] it would appear therefore that silicates are indeed fibrogenic if enough is inhaled; they appear to vary in fibrogenicity but in all cases they are less fibrogenic than silica. inert dusts are non-fibrogenic and therefore of little clinical consequence, although elements of high atomic number can give rise to a striking chest radiograph. it should be noted however that inert or lowly fibrogenic materials may be associated with substances of medical importance, for example, kaolin, bentonite and barytes (barite) may all be contaminated with silica , , and talc may be contaminated with asbestos. the best known of the inhaled inert mineral dusts is carbon while, of the remainder, iron is the most widespread. others include tin and barium. with all these dusts, particles retained in the lung are gathered at macklin's dust sumps by heavily laden macrophages which are lightly bound together there by a few reticulin fibres. collagen is not formed and the worker suffers no ill-effects. the lungs take on the colour of the dust and in siderosis assume a deep brick-red hue. carbon deposition is commonly found in the lungs, particularly those of city dwellers and tobacco smokers. it is also the principal constituent of coal, which is dealt with separately below, and large amounts of pure carbon may be inhaled by workers involved in the manufacture of carbon black, carbon electrodes and charcoal. [ ] [ ] [ ] [ ] although carbon is regarded as being non-fibrogenic, the very heavy lung burdens encountered in industries such as these may lead to the complicated form of pneumonconiosis known as progressive massive fibrosis that is more commonly encountered in coal workers (see p. ). heavy pure carbon deposition may also be acquired domestically when wood is burnt in buildings devoid of a chimney, so-called 'hut lung', a term that is also applied to the domestic acquisition of carbon mixed with silica or silicates, resulting in forms of mixeddust pneumoconiosis. , , anthracofibrosis is a term introduced by chinese bronchoscopists for bronchial stenosis or obliteration associated with carbon pigmentation of the mucosa. although the original description incriminated tuberculosis, mixtures of various mineral dusts acquired at work or domestically are a more likely cause. [ ] [ ] [ ] [ ] iron dust in the lungs was first described by zenker in , when he also introduced the terms siderosis and pneumonokoniosis. zenker was describing a woman who coloured paper with iron oxide powder ('rouge'), a substance which is still encountered by some workers engaged in polishing silver, glass, stone and cutlery. siderosis is also found in welders, iron foundry fettlers, steel workers, boiler scalers and haematite miners and crushers. iron dust particles are reddish-brown but in the lung may be masked by carbon : when evident, or revealed by microincineration, they resemble haemosiderin and generally give a positive perls' reaction, but particularly with haematite, heat ( - o c) and concentrated ( n) hydrochloric acid may be necessary. haematite miners in both the uk (cumbria) and france (lorraine) have an increased risk of bronchial carcinoma, but radon gas rather than haematite is the suspected carcinogen. radon is a decay product of uranium. minute amounts are present in all rocks but local concentrations occur and these are liable to build up in mines if ventilation is limited. silver, as well as iron, is found in the lungs of silver polishers, where it stains elastin in alveolar walls and pulmonary vessels grey. such argyrosiderosis is as harmless as siderosis. tin miners are subject to silicosis but not stannosis because the ore, which is found in association with siliceous rocks, contains only low concentrations of the metal. tin smelters, on the other hand, and factory workers exposed to high concentrations of tin dust or fume, are liable to inhale large amounts of this inert metal and develop the striking chest radiograph of stannosis. they remain in good health however for tin is completely non-fibrogenic. tin particles in the lung resemble carbon but are strongly birefringent and remain after microincineration: microprobe analysis provides positive identification. other inert dusts include barium, which also has a high atomic number and is therefore radiopaque, and minerals of low radiodensity such as limestone, marble and cement (all chiefly composed of calcium carbonate) and gypsum (hydrated calcium sulphate). however, the extraction of barium ore (almost entirely in the form of barium sulphate, which is known as barytes in europe and barite in the usa) may entail exposure to silica and silicates. pure baritosis resembles stannosis and siderosis. the term 'mixed-dust pneumoconiosis' refers to the changes brought about by inhaling a mixture of silica and some other less fibrogenic substance such as iron, carbon, kaolin or mica. , , [ ] [ ] [ ] the proportion of silica is usually less than %. typical occupations include foundry work and welding and the mining of coal, haematite, slate, shale and china clay. the action of the silica is modified and, although fibrotic nodules are formed, they lack the well-demarcated outline and concentric pattern of classic silicosis. the lesions are found in a centriacinar position and are stellate in outline with adjacent scar emphysema. they are firm and generally measure no more than mm in diameter. they closely resemble the fibrotic nodules of simple coal pneumoconiosis (see below). confluent lesions also occur on occasions. these resemble the progressive massive fibrosis of coalworkers and appear to represent a single large lesion rather than a conglomeration of individual nodules, as in advanced silicosis. abundant dust is generally evident in lesions of all sizes; this consists of black carbon or brown iron mixed with crystals of varying degrees of birefringence, silicates generally being strongly birefringent and silica weakly so. calcification is unusual. mixed-dust pneumoconiosis carries an increased risk of pulmonary tuberculosis, but not to the same degree as silicosis. in some cases the stellate nodules are accompanied by diffuse fibrosis, as in silicosis and again possibly involving interactions between the dust and immunological factors. involvement of the bronchi with consequent stenosis (so-called anthracofibrosis) is described above. the term 'anthracosis' was initially applied to changes observed in a coalminer's lung but is now often extended to include the common carbon pigmentation of city dwellers' lungs, and the term 'coal pneumoconiosis' is more appropriate to a special form of pneumoconiosis to which coalworkers are subject, particularly those who work underground. the principal constituent of coal, carbon, is non-fibrogenic, so suspicion has naturally fallen on the ash content of mine dust, some of which derives from the coal, some from adjacent rock strata and some from stone dust laid in the roadways to minimise the risk of coal dust explosions. coal itself appears to be the responsible agent because coal-trimmers, working in the docks and not exposed to rock dust, also develop the disease. coalminers encountering siliceous rock are, of course, also liable to develop silicosis like other underground workers. coal consists largely of elemental carbon, oxygen and hydrogen with traces of iron ore and clays such kaolinite, muscovite and illite, but no silica. the mineral content varies with the type and rank (calorific value) of the coal. all coal derives from peat, the youngest type being lignite and the oldest anthracite, with bituminous (house) coal in between. as it ages, the oxygen and mineral constituents diminish and the coal hardens. lignite is soft and said to be of low rank, anthracite hard and of high rank, with bituminous coal intermediate. although high-rank coal is of low mineral content, its dust is more toxic to macrophages in vitro and is cleared more slowly in vivo. this observation may explain why, in the uk, high-rank coal is associated with a higher prevalence of coal pneumoconiosis. the low mineral content of high-rank coal is reflected in the mineral content of the lungs of those who hew such coal in the uk, but in the ruhr, in germany, and in pennsylvania, in the usa, anthracite miners' lungs contain more silica than those who hew bituminous coal, the silica presumably deriving from other sources. not surprisingly, the presence of silica is reflected in the tissue reaction to the inhaled dust, resulting in a more fibrotic reaction very analogous to mixed-dust pneumoconiosis. a spectrum of changes is therefore encountered in coalminers' lungs, ranging from coal pneumoconiosis through mixeddust pneumoconiosis to silicosis; the findings in any individual depend upon the nature of the coal being mined and the type of work undertaken. in high-rank british collieries the development of coal pneumoconiosis appears to depend on the total mass of dust inhaled, whereas in low-rank british collieries the mineral content of the lung dust appears to be more important. this may explain apparently contrary data drawn from different coalfields -data based on coals of different composition that are not strictly comparable. some workers have stressed the importance of silica in the dust whereas others, particularly in the high-rank coalfields of south wales, have been unable to detect any association between silica and the level of pneumoconiosis. both findings may be correct, but only for the particular group of miners examined in each case. the lesions of coal pneumoconiosis are generally focal and fall into one or other of two major types, simple and complicated, depending upon whether the lesions measure up to or over cm; simple corresponds to categories - of the ilo grading system (see p. ) and complicated, which is also known as progressive massive fibrosis, to ilo categories a-c. more diffuse interstitial fibrosis has been reported in about % of welsh and west virginian coalminers, usually involving those carrying a particularly heavy dust burden; it runs a more benign course than non-occupational interstitial fibrosis (idiopathic pulmonary fibrosis). similar findings have been reported from france. simple coal pneumoconiosis consists of focal dust pigmentation of the lungs, which may be associated with a little fibrosis and varying degrees of emphysema. its clinical effects are relatively minor. some degree of black pigmentation (anthracosis) of the lungs is common in the general urban population, especially in industrial areas, but much denser pigmentation is seen in coalminers, whose lungs at necropsy are black or slate-grey. black pigment is evident in the visceral pleura along the lines of the lymphatics and on the cut surface where it outlines the interlobular septa and is concentrated in macklin's centriacinar dust sumps ( fig. . . ). the dust is generally more plentiful in the upper parts of the lungs and in the hilar lymph nodes, possibly due to poorer perfusion and consequently poorer lymphatic drainage there (see p. ). two forms of coal dust foci are recognised, macules and nodules, the former being soft and impalpable and the latter hard due to substantial amounts of collagen. both lesions are typically stellate but the more fibrotic the nodules, the more rounded they become, until it is difficult to distinguish them macroscopically from those of silicosis. in these circumstances reliance has to be placed on the whorled pattern of the collagen that is evident microscopically in silicosis. the stellate nodules are analogous to those seen in mixed-dust pneumoconiosis caused by mixtures of silica and inert dusts other than carbon (see above). with polarising filters, small numbers of birefringent crystals may be seen in both macules and nodules, usually representing mica or kaolinite derived from rock that bordered the coal. macules consist of closely packed dust particles, free or within heavily laden macrophages, so that the lesion appears black throughout ( fig. . . ). appropriate stains show that the dust-laden macrophages and free dust are lightly bound by reticulin. very little collagen is evident. although striking in their appearance, dust macules are thought to have little effect on lung function. nodules contain substantial amounts of collagen and are thought to have an adverse, but limited, effect on respiration. they vary from a heavily pigmented, stellate lesion, which apart from its collagen content resembles the dust macule ( fig. . . ), to one that is less pigmented and more circumscribed. the stellate, heavily pigmented type of nodule is seen in lungs that have a relatively low ash content whilst the more rounded and less pigmented nodule is seen in lungs with relatively high ash loads. radiologically (see p. ), p-type opacities correspond to macules, q-type opacities to the stellate nodules that resemble those of mixeddust pneumoconiosis and r-type opacities to the rounded nodules that resemble those of silicosis. , thus, the radiological changes of simple coalworker's pneumoconiosis are due to the dust and the small amount of collagen present and do not reflect any emphysema that may also be present. however, pulmonary dust foci are often associated with emphysema ( fig. . . ) and the severity of the emphysema appears to correlate with the dust load. the prevalence of chronic bronchitis and emphysema is high in the coal industry and it has long been debated whether occupation or cigarette smoking is the major factor contributing to emphysema in coalminers. [ ] [ ] [ ] [ ] as well as mineral dust, nitrous fumes from shot-firing form another occupational hazard of coal mining. heppleston made a special study of the emphysema found in coalminers, claiming that it differs from centriacinar emphysema, as seen in smokers in the general population, and attributing it to the dust. he introduced the term 'focal emphysema of coalworkers' to describe this special process. others find it very difficult to identify any convincing difference between the emphysema of coalworkers and that encountered outside the industry but heppleston based his claims on the study of serial sections. by this means he showed that, although both forms affect respiratory bronchioles, the focal emphysema of coalworkers affects more proximal orders of these airways and is not associated with the bronchiolitis seen with centriacinar emphysema. furthermore, focal emphysema is a dilatation lesion whereas coniosis, also known as progressive massive fibrosis, can have very serious consequences. particularly when the lesions are large, it is associated with productive cough, breathlessness, significant impairment of lung function and premature death. the major factor accounting for the development of progressive massive fibrosis appears to be the sheer bulk of coal dust in the lung, rather than coal rank or the silica content of the mine dust. progressive massive fibrosis has occasionally been recorded in dockers loading silica-free coal into the holds of ships and in workers exposed to pure carbon in the manufacture of carbon black and carbon electrodes. [ ] [ ] [ ] progressive massive fibrosis is characterised by large (over cm) black masses, situated anywhere in the lungs but most common in the upper lobes. the lesions may be solitary or multiple and very large, occupying most of the lobe and even crossing an interlobar fissure to involve an adjacent lobe (figs . . b, . . ). they cut fairly easily, often with the release from a central cavity of black fluid flecked by cholesterol crystals. for many years it was believed that the condition was the result of synergism between mycobacterial infection and dust but the failure of the attack rate to decrease as tuberculosis declined negated this view. today, more emphasis is placed on total dust load for the lesions tend to affect lungs that carry an unduly heavy dust burden. if the remainder of the lung shows little evidence of dust accumulation, the possibility of the masses representing caplantype lesions (see below) should be considered. centriacinar emphysema involves destruction of adjacent alveolar walls. by definition, therefore, focal emphysema is not a true emphysema at all (see p. ). however, it has been shown that mineral dusts cause elastin and collagen breakdown in the rat lung. focal emphysema may progress to the destructive centriacinar form and this has strengthened claims that mine dust plays a causal role in centriacinar emphysema. , [ ] [ ] [ ] [ ] [ ] [ ] in the uk, these claims have been accepted and chronic bronchitis and emphysema in coalminers and metal production workers have been accepted as prescribed industrial diseases since . in germany too, chronic obstructive pulmonary disease is now compensatable as an occupational disease. the conditions for compensation in the uk were initially: • underground coal mining for a minimum of years in aggregate • forced expiratory volume in second at least litre below that expected or less than litre in total • radiological category of at least / . however the last of these criteria has now been dropped. the inclusion of a time element and the omission of some estimate of dust load (such as radiological category) have been criticised, with some justification. as with lung cancer caused by chromates benefit is paid irrespective of smoking habits. whereas simple coal pneumoconiosis, particularly the macular variety, has little effect on lung function, complicated coal pneumo- microscopically, the lesions consist of dust and connective tissue intermixed in a random fashion. central necrosis and cavitation commonly occur. the necrosis is thought to be ischaemic. it is amorphous or finely granular, and eosinophilic apart from abundant dust particles and cholesterol crystal clefts. the fibrotic component in a complicated pneumoconiotic lesion is rich in fibronectin, with collagen only more abundant at the periphery. two types of progressive massive fibrosis are recognisable, corresponding to the two types of nodule described in simple coal pneumoconiosis. the first appears to have arisen by enlargement of a single nodule, whereas the second is a conglomeration of individual lesions, each of which corresponds to the more circumscribed type of nodule seen in simple coal pneumoconiosis. the ash content of the lungs bearing these two types of progressive massive fibrosis varies in the same way as with the two types of simple pneumoconiotic nodules, the enlarged single lesion being found in lungs with a relatively low ash content, and the conglomerate lesion in lungs with a relatively high ash content. the second type resembles the conglomerate nodules of large silicotic lesions but lacks the characteristic whorled pattern of the latter. the diffuse interstitial fibrosis found in a minority of coalworkers is associated with heavy dust deposition. it may progress to honeycombing but, as with the focal forms and unlike idiopathic interstitial fibrosis, it is better developed in the upper zones, the reasons for which are discussed above (see the zonal distribution of pneumoconiosis, p. ). the pathogenesis of coal pneumoconiosis has much in common with that of silicosis, and indeed many other pneumoconioses. it involves the promotion of fibrogenic factor synthesis and release by cells phagocytosing the inhaled dust. several such factors have now been identified, the degree of fibrosis produced varying with the amount of dust inhaled and the ability of its constituents to promote the production of the responsible cytokines. these include plateletderived growth factor, insulin-like growth factors and , transforming growth factor-β and tumour necrosis factor-α. , , as with other minerals, the indestructability of the dust perpetuates the process. as in silicosis, immunological factors appear to be involved, for there is an increased prevalence of rheumatoid arthritis and of circulating autoantibodies [ ] [ ] [ ] in miners with coal pneumoconiosis. rheumatoid factor has also been demonstrated within the lung lesions. these abnormalities are generally more pronounced in miners with complicated pneumoconiosis but are also found in those with the simple variety. it is also possibly pertinent to the immunological basis of coal pneumoconiosis that some of the pulmonary manifestations of rheumatoid disease are more pronounced in coalminers. this was first pointed out by caplan and will be considered next. caplan described distinctive radiographic opacities in the lungs of coalminers with rheumatoid disease, and it is now recognised that similar lesions may develop in rheumatoid patients exposed to siliceous dusts. the development of such rheumatoid pneumoconiosis does not correlate with the extrapulmonary or serological activity of the rheumatoid process. nor is there a strong relation to dust burden: caplan lesions are characteristically seen in chest radiographs that show little evidence of simple coal pneumoconiosis. pathologists recognise the lesions as particularly large necrobiotic nodules similar to those seen in rheumatoid patients who are not exposed to dust (fig. . . ) . however, because of their large size (up to cm diameter) they may be confused with progressive massive fibrosis undergoing central ischaemic necrosis (see above) or silicosis complicated by caseating tuberculosis. such errors will be less likely if the radiological evolution of the lesions is considered for they tend to cavitate and undergo rapid remission, only to be succeeded by others. they are also well demarcated radiologically. pathologically, they resemble rheumatoid nodules in showing peripheral palisading but differ in their large size and the presence of dust. the dust accumulates in circumferential bands or arcs within the necrotic centres of the lesion (fig. . . ), an arrangement that suggests periodic episodes of inflammatory activity. caplan lesions differ from tuberculosis in lacking satellite lesions and tubercle bacilli, and from progressive massive fibrosis in showing characteristic bands of dust pigmentation (table . asbestosis is defined as diffuse interstitial fibrosis of the lung caused by exposure to asbestos dust. , it does not cover asbestos-induced carcinoma of the lung or asbestos-induced pleural disease. the development of asbestosis depends on the presence of fairly large dust burdens: this is in contrast to mesothelioma and other forms of asbestos-induced pleural disease, which, although also dose-related, occur following the inhalation of far smaller amounts of asbestos dust. asbestos is a generic term for more than naturally occurring fibrous silicates, fibre being defined as an elongated particle with a length-tobreadth (aspect) ratio of at least . asbestos fibres have a high aspect ratio, generally over . based on their physical configuration they can be divided into two major groups, serpentine and amphibole. the physical dimensions and configuration of asbestos fibres are strongly linked to their pathogenicity. chrysotile (white asbestos) is the only important serpentine form. it accounts for most of the world production of asbestos of all types ( being a serpentine mineral, chrysotile consists of long, curly fibres that can be carded, spun and woven like cotton ( fig. . . ). the curly chrysotile fibres are carried into the lungs less readily than the straight amphibole asbestos fibres, and once there undergo physicochemical dissolution and are cleared more readily. they readily fragment into short particles that are easily ingested by macrophages and in the acidic environment of the macrophage phagolysosome they are particularly unstable. the half-life of chrysotile in the lungs is estimated to be in the order of only a few months. , not surprisingly therefore chrysotile is the least harmful type of asbestos in respect of all forms of asbestos-induced pleuropulmonary disease. [ ] [ ] [ ] it may nevertheless cause pulmonary fibrosis if sufficient is inhaled. , in contrast to chrysotile, amphibole forms of asbestos consist of straight rigid fibres that are stable within the lung. they do not fragment, they are insensitive to chemical attack and their clearance halflives are in the order of decades rather than months. the main amphibole forms of asbestos of commercial importance are crocidolite (blue asbestos) and amosite (brown asbestos). crocidolite, reputedly the most dangerous in regard to all forms of asbestos-related disease, was formerly mined in western australia (wittenoom) and south africa (cape province and the transvaal); it was the principal amphibole used in the uk. amosite, the name of which derives from the acronym for the former asbestos mines of south africa company in the transvaal, was the principal amphibole used in north america. amphiboles are no longer imported by the developed countries but much remains in old lagging and presents a considerable dust hazard when this is removed. tremolite, a further amphibole asbestos, contaminates quebec chrysotile deposits, montana vermiculite and many forms of commercial (non-cosmetic) talc and is responsible for much of the asbestos-related disease in chrysotile miners and millers. another amphibole asbestos, anthophyllite, was formerly mined in finland. it causes pleural plaques (see p. ) but not lung disease, possibly because its fibres are relatively thick ( fig. . . ) . erionite is a zeolite rather than a type of asbestos but is comparable in form to amphibole asbestos and is also biopersistent. it is found . these coated structures are termed 'asbestos bodies' . because other fibres may gain a similar coat, the non-specific term 'ferruginous body' has been advocated. however, coated carbon fibres (so-called coal bodies) are easily recognised as such by their black core. in practice, ferruginous bodies with the appearance of asbestos bodies almost always prove to have an asbestos core. , long fibres are more likely to be coated than short ones, which are cleared more quickly: in one study few fibres less than µm in length were coated and few fibres over µm in length were uncoated. amphiboles form bodies more readily than chrysotile. a comparison of light and electron microscopic fibre counts found that . % of chrysotile, % of crocidolite and . % of amosite formed bodies. nevertheless, sufficient chrysotile fibres are coated to permit recognition of asbestosis by standard histological criteria (diffuse fibrosis and asbestos bodies), even if chrysotile is the only asbestos present. despite the biodegradability of chrysotile, asbestos body numbers do not materially diminish with time. very occasionally however a patient with diffuse pulmonary fibrosis and a history of asbestos exposure has no evident asbestos bodies but analysis shows a fibre burden within the range found in asbestosis, justifying fibre analysis in such cases. a there is evidence that alveolar macrophages are involved in the coating of asbestos fibres to form asbestos bodies and that the bodies are less harmful to the macrophages than uncoated fibres. asbestos bodies give a prussian blue reaction for iron when stained by perls' method and their yellow-brown colour makes them easily recognisable in unstained films of sputum or in unstained histological sections. sections may be cut µm thick to increase the yield and help identify bodies that lie at an angle to the microtome blade. there is a good correlation between the numbers of asbestos bodies seen in lung sections and those in tissue digests. , the bodies may be found singly or in irregular clumps or stellate clusters. they are unevenly distributed but in well-established asbestosis they are easily found. if they are not evident, asbestos burden may be assessed quantitatively in tissue digests (see below). their presence in lung tissue, sputum or bronchoalveolar lavage fluid merely confirms exposure, not the presence of disease. however, the number of asbestos bodies in lavage fluid correlates well with lung asbestos burden , and the number in sputum correlates with the duration and intensity of exposure. [ ] [ ] [ ] fibre counts , , [ ] [ ] [ ] [ ] [ ] quantitation is desirable in certain circumstances (box . . ), in which case it is best effected on -cm blocks of fixed or fresh lung tissue obtained from three different sites, avoiding tumour and thickened pleura. the tissue blocks are digested with caustic soda or bleach, following which the fibres may be collected on a millipore membrane or viewed in suspension in a red blood cell-counting chamber. if phase contrast optics are used both coated and uncoated fibres can be assessed. alternatively, dark ground illumination can be used to demonstrate uncoated fibres. however, electron microscopy is to be preferred as it detects far more fibres than are visible by light microscopy and can also provide information on fibre type. it is important that the laboratory is well practised in fibre analysis and has established its own control range for the general population as well as asbestosis as most lungs contain some asbestos. ambient fibres are generally shorter than µm and some workers therefore confine their counts to fibres that are at least as long as this. justification for this comes from animal experiments demonstrating that long fibres cause more inflammation, chromosomal damage, fibrosis, lung tumours and mesotheliomas than short fibres, [ ] [ ] [ ] [ ] and from studies in humans suggesting that long fibres in parts of central turkey where it causes both mesothelioma and a pattern of interstitial pulmonary fibrosis that is comparable to asbestosis. , asbestos use and exposure exposure to asbestos occurs in countries where it is extracted ( asbestos is used particularly for fireproofing, in heat and sound insulation and for strengthening plastics and cement. thus, unless adequate precautions are taken, exposure is experienced by dockers unloading asbestos in the close confines of a ship's hold, by thermal insulation workers (laggers and strippers) in shipyards, power stations, train maintenance depots, factories and other large buildings, by construction workers such as carpenters cutting asbestos building panels, and by workers making asbestos products such as fireproof textiles, brake and clutch linings, and specialised cement. as well as such direct exposure, exposure may also be: • indirect, as experienced by the families of asbestos workers • paraoccupational, as experienced by those working alongside an asbestos worker • neighbourhood, as experienced by those living downwind of an asbestos works or mine • ambient, as experienced by those living or working in a building containing asbestos. exposure to asbestos incorporated in the structure of a building carries a negligible health risk if the asbestos material is well maintained to prevent shedding of dust. stripping asbestos out is more dangerous than maintaining it in situ, but maintenance is sometimes neglected. the near indestructibility of asbestos accentuates the health problems that its ubiquity poses. because of their aerodynamic properties, fibres of µm or more in length may reach the finer bronchioles and alveoli. once impacted, the sharp asbestos fibres become coated with a film of protein that is rich in iron. the coating is thickest at the ends of the fibres, giving a other human studies have shown that, although asbestos load is maximal in the upper lobes, more long fibres are found at the bases, where fibrosis is most marked. , a further reason for limiting attention to the longer fibres is that the shorter ones are cleared more easily and their number therefore varies with the time lapsed since last exposure. for these reasons asbestos regulations in many countries now limit attention to fibres that are over µm in length and have a length-to-diameter (aspect) ratio greater than : such fibres have become known as regulatory or world health organization (who) fibres. values are best expressed as fibres/g dry lung. by light microscopy, normal values range up to : over is seen with mesotheliomas, and over in asbestosis (table . . ). , , , however, compared with electron microscopy, light microscopy is relatively insensitive, showing only . % of the amosite, % of the crocidolite and . % of the chrysotile. light microscopic counts correlate poorly with severity of asbestosis and electron microscopy non-asbestos fibres commonly found in the lung include mullite, which derives from fly ash. this may constitute up to % of the total fibre burden (see table . . ) and is thought to be harmless. there is no firm evidence that manmade fibres present a health hazard but in certain localities natural non-asbestos mineral fibres, zeolites for example, are important causes of mesothelioma (see p. ) and also cause interstitial pulmonary fibrosis. in contrast to the first half of the twentieth century, much of the asbestosis encountered today is asymptomatic, identified radiologically or histologically in lungs resected for carcinoma or removed at autopsy. symptomatic cases are characterised by an insidious onset of breathlessness, a dry cough and crackles over the lower lung fields. finger clubbing is a variable feature. lung function tests show a restrictive respiratory defect. radiology initially shows small irregular basal opacities that gradually coalesce to become linear, coarsen and eventually progress to a honeycomb pattern of small cysts. the principal differential diagnosis, both clinically and pathologically, is from idiopathic pulmonary fibrosis. this is aided by the slow progression of asbestosis, which often extends over years, as opposed to an average course of - years from presentation to death for the idiopathic condition. most cases of asbestosis are diagnosed solely on the occupational history and these clinicoradiological features. recourse to histology is unusual but biopsy (preferably as a wedge of lung) may be undertaken if the clinical features are atypical. histology also arises when the pathologist samples lung parenchyma remote from a resected carcinoma (the universal importance of which cannot be overemphasised). asbestosis (established) over over the light microscopic counts include total fibres (coated and uncoated). the electron microscopic counts include only amphibole asbestos. results from different laboratories vary and these figures, derived from several sources, , , provide only a general guide. reliable results depend upon counts being made regularly and the normal range from that laboratory being ascertained. ratios of counts obtained by electron and light microscopy vary greatly but approximate to . is better in this respect. [ ] [ ] [ ] by transmission electron microscopy, values may range up to in controls, with asbestosis generally above and mesotheliomas found at any level down to , all these figures representing amphibole fibres/g dried lung (see table . . ). , , it should be noted that counts from different parts of the same lung may vary widely; , - caution should therefore be exercised in interpreting a count obtained on a single sample. there is also wide discrepancy between laboratories, even when analysing the same sample. results obtained in an individual case therefore have to be evaluated against a standard set of values unique to that laboratory. electron microscopy also provides valuable information on the type of fibre. chrysotile differs physically from the amphiboles in two respects: its fibres are both curved and hollow (figs . . and . . ). with an electron microscope equipped for microprobe analysis, the various forms of asbestos may also be distinguished from other fibres and from each other (box . . ), , an important point as the amphibole forms of asbestos are far more dangerous than chrysotile (table . . ). [ ] [ ] [ ] coroners require autopsy verification of the diagnosis in all suspected cases and this also necessitates hystology. when the lungs from a patient with asbestosis are seen at autopsy, pleural fibrosis is often found, and although this may also be attributable to asbestos exposure it is to be regarded as an independent process and not part of the asbestosis: it is dealt with separately on page . slicing the lung affected by asbestosis shows a fine subpleural fibrosis, especially of the lower lobes ( fig. . . ). in severe cases the fibrosis often extends upwards to involve the middle lobe and lingula, and sometimes the upper lobes also. microcystic change associated with the fibrosis develops in advanced cases and in severe disease there may be cysts over cm in diameter. however, these classic changes are seldom seen in developed countries today. following decades of dust suppression in asbestos factories, current patients have mild to moderate asbestosis and are dying of related cancer or of non-pulmonary disease. in some of these cases the asbestosis is only detectable microscopically. fixation of the lungs through the bronchi and the use of heard's barium sulphate impregnation technique facilitate demonstration of the fibrosis (see p. and fig. . . ). the mild degree of asbestosis currently encountered is of little functional significance but is often critical in determining whether an associated carcinoma of the lung should be attributed to asbestos exposure (see below). the histological diagnosis of asbestosis requires an appropriate pattern of interstitial fibrosis associated with the presence of asbestos bodies. both components must be present. the fibrosis is paucicellular, lacking any significant degree of inflammation and being collagenous rather than fibroblastic. it is generally considered that asbestosis begins about the respiratory bronchioles and alveolar ducts where most of the asbestos fibres impact. alveolar walls attached to these bronchioles show fine interstitial fibrosis. however, this early lesion has to be interpreted with caution because it is not specific to asbestos, being found with other inhaled mineral dusts , and even in many cigarette smokers who have not been so exposed. it more likely represents a non-specific reaction to a variety of inhaled particles. it may cause mild airflow obstruction but is not associated with the radiographic, clinical or restrictive changes of classic asbestosis. as the disease progresses, the focal changes join up so that the basal subpleural regions show widespread interstitial fibrosis and eventually complete destruction of the alveolar architecture. in severe cases there may be honeycombing and metaplastic changes in the alveolar and bronchiolar epithelium. apart from the presence of asbestos bodies the changes resemble those of non-specific interstitial pneumonia, or more rarely usual interstitial pneumonia. fibroblastic foci may be found but they are uncommon. there is often an increase in alveolar macrophages but the desquamative interstitial pneumonia that has been reported in association with asbestos , is not to be regarded as a variant of asbestosis ; concomitant smoking is a more likely cause. a variety of other non-specific inflammatory processes such as organising pneumonia have been reported in asbestos workers and if localised some have been suspected of representing malignancy until biopsied. several schemes have been proposed for grading the extent and severity of asbestosis. these are of value in epidemiological studies but should only be applied to cases meeting the histopathological criteria for a diagnosis of asbestosis. one such scheme is shown in box . . . , , in well-established asbestosis asbestos bodies are numerous and easy to find, aggregates of them sometimes forming clumps ( fig. . . ) . in earlier lesions a detailed search may be necessary, in which fibrosis confined to the walls of respiratory bronchioles and the first tier of adjacent alveoli b extension of fibrosis to involve alveolar ducts and/or two or more tiers of alveoli adjacent to the respiratory bronchiole, with sparing of at least some alveoli between adjacent bronchioles fibrotic thickening of the walls of all alveoli between at least two adjacent respiratory bronchioles honeycomb change a an average score is obtained for an individual case by adding the scores for each slide ( - ), then dividing by the number of slides examined b grade and, to a lesser extent, grade need to be distinguished from smoking-induced peribronchiolar fibrosis and mixed-dust pneumoconiosis. case the examination of unstained or perls-stained sections facilitates their identification. minimum criteria for the diagnosis of asbestosis require the identification of diffuse interstitial fibrosis in well-inflated lung tissue remote from a lung cancer or other mass lesion and the presence of either two or more asbestos bodies in tissue with a section area of cm or a count of uncoated asbestos fibres that falls in the range recorded for asbestosis by the same laboratory. , there are marked variations in the concentration of asbestos fibres between samples from the same lung , and it is therefore recommended that at least three areas be sampled, the apices of the upper and lower lobes and the base of the lower lobe. the equivalent of mallory's alcoholic hyalin of the liver has been described in the lungs in asbestosis, , and subsequently in other [ ] [ ] [ ] [ ] it is seen as small eosinophilic cytoplasmic inclusions within hyperplastic type ii alveolar epithelial cells (fig. . . a ). electron microscopy shows that the inclusions consist of a tangle of tonofilaments ( fig. . . b ) and by immunocytochemistry a positive reaction is obtained with antibodies to cytokeratin, both these features being typical of mallory's hyalin in the liver. the inclusions also react for ubiquitin, the accumulation of which is indicative of cellular damage, in particular faulty proteinolysis. the differential diagnosis of asbestosis includes pulmonary fibrosis due to many other causes, any of which may of course affect an asbes-tos worker as much as members of the general population. the proportion of diffuse pulmonary fibrosis in asbestos workers that is not attributable to asbestos has been estimated to be as high as % and likely to rise as the risk of asbestosis diminishes with better industrial hygiene. the principal differential diagnosis of asbestosis is from idiopathic pulmonary fibrosis. both diseases affect the bases and periphery of the lungs predominantly. in the late stages, cystic change is more evident in idiopathic pulmonary fibrosis but this criterion is not totally reliable. nor is the presence of pleural fibrosis, although it is usually present in asbestosis and is seldom found in idiopathic pulmonary fibrosis. asbestosis seldom progresses or does so very slowly after exposure ceases , whereas idiopathic pulmonary fibrosis typically proves fatal within - years from onset. the fibrosis of asbestosis is generally paucicellular: inflammation is not a feature and the fibroblastic foci that characterise the usual interstitial pneumonia pattern of fibrosing alveolitis are seldom observed in asbestosis. very often the distinction from idiopathic pulmonary fibrosis has to be based on the amount of asbestos in the lung and, if asbestos bodies are not readily identifiable, this has to depend on fibre counts. errors are made both by overlooking substantial numbers of asbestos bodies completely and by ascribing undue importance to scanty bodies. if considering the possibility of minimal asbestosis (to justify attributing carcinoma of the lung to asbestos, for example) it should be remembered that a little peribronchiolar fibrosis is also characteristic of smokers' lungs, centriacinar emphysema and early mixeddust pneumoconiosis. [ ] [ ] [ ] as described above, at least two asbestos bodies/cm in the presence of interstitial fibrosis distant from any lung cancer or other mass lesion is required for a diagnosis of asbestosis. although the causes of asbestosis and idiopathic pulmonary fibrosis are very different, they resemble each other in several ways, suggesting that similar pathogenetic mechanisms may operate. , [ ] [ ] [ ] in both these diseases there is degeneration of the alveolar epithelium and capillary endothelium, with patchy loss of the former, and bronchoalveolar lavage shows an increase in macrophages that might perpetuate the damage by releasing lysosomal enzymes, nitric oxide and hydroxyl radicals. , [ ] [ ] [ ] both diseases are also characterised by an increased prevalence of circulating non-organ-specific autoantibodies. experimentally, asbestos exposure leads to the activation of a variety of fibrogenic cytokines at sites of lung injury. , [ ] [ ] [ ] [ ] [ ] [ ] inhaled asbestos activates a complement-dependent chemoattractant for macrophages and macrophage stimulation involves the secretion of fibroblast stimulating factors, [ ] [ ] [ ] asbestos being intermediate between haematite and silica in regard to macrophage-mediated fibrogenicity. the epithelial damage could be mediated directly by the needle-like asbestos fibres or indirectly through enhanced phagocyte generation of free radicals (which is much greater with amphibole asbestos than with either chrysotile or silica). , fibrogenic cytokines released by activated pulmonary phagocytes and regenerating alveolar epithelial cells in asbestosis include tumour necrosis factor-α and transforming growth factor-β, as in idiopathic pulmonary fibrosis. as a result of better industrial hygiene, asbestosis is less severe today than in earlier years when it followed much heavier exposure, with the consequence that death from respiratory failure and cor pulmonale is less common and sufferers are surviving longer. there is therefore now a greater risk of asbestos-related cancer eventually developing. asbestos exposure predisposes to two varieties of malignant neoplasm, carcinoma of the lung and mesothelioma of the pleura and peritoneum. the risk of malignancy increases with dose but the relative risk of carcinoma is much smaller than that of mesothelioma. for example, with heavy exposure, as in lagging, the risk of mesothelioma is increased -fold whereas it is increased only fivefold for lung cancer. hence, with light exposure there is a substantial risk of mesothelioma but only a small risk of lung cancer. asbestosis requires heavy exposure and in one group of patients with asbestosis, % died of pulmonary carcinoma, % of mesothelioma and % of other respiratory diseases. although there were many earlier reports, the link with carcinoma of the lung may be considered to have been firmly established by , that between crocidolite asbestos and mesothelioma by , and that between amosite asbestos and mesothelioma by . mesothelioma is considered on page . in regard to carcinoma of the lung, asbestos is not such a potent pulmonary carcinogen as cigarette smoke but together their effects are multiplicative rather than additive (table . . ). , however, the risk attributable to asbestos is the same regardless of smoking history, being increased fivefold in both smokers and non-smokers. there is usually a latent period in excess of years between first exposure to asbestos and the development of lung cancer and the risk increases the greater the cumulative exposure. the increased risk involves carcinomas of all the histological types encountered in the lung, although adenocarcinoma has been disproportionately overrepresented. , [ ] [ ] [ ] [ ] [ ] [ ] it is uncertain whether the increased risk of carcinoma is caused by the asbestos , [ ] [ ] [ ] [ ] [ ] [ ] or the asbestosis. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the latter view envisages the carcinoma arising in the foci of alveolar epithelial hyperplasia and dysplasia that commonly accompany any interstitial fibrosis (see carcinoma complicating idiopathic pulmonary fibrosis, p. ). however, most carcinomas complicating asbestosis arise in the bronchi rather than the alveolar tissue. on the other hand, more arise in the sites worst affected by asbestosis, the lower lobes and the periphery of the lung, than in the general population ( fig. . . ) . , , [ ] [ ] [ ] [ ] [ ] the majority view has been that asbestosis is a necessary precursor of the carcinoma but evidence to the contrary is finding increasing support (table . . ). in the uk, industrial compensation was formerly only awarded to an asbestos worker for carcinoma of the lung if there was also asbestosis or diffuse pleural fibrosis but new rules were introduced in . asbestosis remains a sufficient criterion but diffuse pleural thickening is not and asbestosis is no longer a necessary criterion: asbestos is deemed to have been responsible if the patient worked in asbestos textile manufacture, spraying, lagging or gas mask manufacture for at least years before or years after . the basis for these changes is the premise that heavy asbestos exposure is sufficient in itself to account for carcinoma of the lung. together, these factors have a multiplicative rather than additive effect mortality ratio non-smoking controls non-smoking asbestos workers cigarette-smoking controls cigarette-smoking asbestos workers asbestosis associated with carcinoma of the lung. the asbestosis has been highlighted by barium sulphate impregnation and is seen as a grey subpleural band to the right of the picture. although the carcinoma has arisen in the same lobe as the asbestosis it has not obviously arisen in an area affected by asbestosis. . asbestosis diagnosed clinically, radiologically or histologically or a minimum count of asbestos bodies per gram dry lung tissue (/g dry), or an uncoated asbestos fibre burden of million amphibole fibres more than µm in length/g dry, or million amphibole fibres more than µm in length/g dry or estimated cumulative exposure to asbestos of at least fibres/ ml-years or an occupational history of year of heavy exposure to asbestos (e.g. manufacture of asbestos products, asbestos spraying) or - years of moderate exposure (e.g. construction or ship-building) and . a minimum lag time of years lung fibre counts in the asbestosis range (see table . . ) provide valuable evidence of such exposure. compensation standards for asbestos-associated lung cancer in different countries are shown in box . . . , asbestos-induced airway disease although asbestosis causes a restrictive respiratory defect, airflow limitation is also seen in this disease. much of the airflow limitation is attributable to cigarette smoking but it is also seen in non-smoking asbestos workers and is worse in those with asbestosis. the pathological basis of this appears to be small-airways disease (see p. ). it is possibly a non-specific reaction to inhaled dust or cigarette smoke. because it is not established that this lesion progresses to interstitial alveolar fibrosis (asbestosis) the term 'asbestos airways disease' is suggested. fibrosis limited to the bronchioles is specifically excluded from the definition of asbestosis in the latest guidelines (although these retain grade for fibrosis limited to the bronchiolar walls). it should also be noted that, although emphysema is considered to be a destructive rather than fibrotic condition, a little focal the presence of asbestos-related bilateral pleural plaques or asbestos-related bilateral pleural thickening and occupational exposure and a lag time of at least years the presence of asbestosis or pleural plaques or diffuse pleural thickening or fibre-years of exposure only fibre-years of exposure are taken into account exposure, at least years' latency and asbestos-related pleural or parenchymal changes asbestosis is not required but smoking is taken into consideration attempts are made to quantify separately the attributability to asbestos, smoking and other factors (e.g. radon) fibrosis is generally evident in this common condition and does not necessarily indicate early asbestosis. aluminium has been implicated in the development of respiratory disease during the refining of its principal ore, bauxite, to yield various aluminium oxides (aluminas), in the preparation of the metal by smelting alumina, in the production of corundum abrasive and in the production of special aluminium powders used in explosives. bauxite is a mixture of various aluminium oxides, hydroxides and silicates, iron oxide and titanium dioxide. the oxides of aluminium are obtained by differential heating of the ore and the respiratory effects of this work appear to be no more than mild airway irritation. it is generally accepted that aluminium oxide is inert. aluminium is prepared by the electrolytic reduction of its oxide dissolved in sodium aluminium fluoride (cryolite), a process releasing a considerable amount of fluoride-rich effluent. exposed workers have complained of what is termed pot-room asthma. the pathology of this condition is not well described but the pathogenesis is thought to involve irritation rather than allergy. the abrasive corundum is formed from bauxite mixed with coke and iron heated in an electric arc furnace, a process in which workers may be exposed to the fumes of alumina and free silica. in the past some of these workers developed diffuse pulmonary fibrosis (shaver's disease) and, although this was initially attributed to the aluminium, it is now agreed that the free silica was the responsible agent. the exposure to free silica has been reduced and the disease is now regarded as historic. aluminium powder holds a paradoxical position in regard to lung disease. in certain industries it has caused very severe pulmonary fibrosis, yet in others it has proved harmless. indeed, at one time canadian miners breathed aluminium dust before work, in the belief that this would reduce the danger of silica in the mine dust and more recently silicosis has been treated by such means in france. it is questionable whether this practice is effective but it at least appears to cause no harm. the explanation for these contradictory observations probably lies in differing methods of manufacture of aluminium powder. aluminium metal appears to be an inert substance but this is only because it has a high affinity for oxygen and the surface layer of aluminium oxide so formed is firmly bound to the underlying metal, unlike ferric oxide which permits further rusting of iron. granular aluminium powders, produced in a ball mill or from a jet of molten aluminium, therefore acquire a protective coat of surface oxide and are inert. with stamped aluminium powders, however, surface oxidation is prevented by lubricants added to aid the separation of these flake-like particles. the usual lubricant (stearin) contains stearic acid and this polar compound combines with the underlying metal, which is thereby protected from both atmospheric oxidation and the action of body fluids when such dust is inhaled. in certain circumstances, however, non-polar lubricants in the form of mineral oils have been substituted for stearin. this happened in germany during the second world war when munition production was stepped up but stearin was difficult to obtain, , and in the uk in the s to make the powder darker for purely commercial reasons. in vitro, oil-coated stamped aluminium powder reacts with water to produce aluminium hydroxide, which affords the underlying metal no protection against further attack, so that aluminium hydroxide continues to be formed. this substance is a protein denaturant, once used in the tanning industry, and it is believed that this property underlies the very ex ceptional cases of severe pulmonary fibrosis that have occurred in connection with stamped aluminium powder produced with mineral oil rather than stearin. , the fibrosis has a very characteristic pattern, affecting the upper lobes and progressing rapidly, the interval from onset of symptoms to death being as short as years. there is marked shrinkage of the lungs with gross elevation of the diaphragm and buckling of the trachea (fig. . . ). the lungs are grey ( fig. . . ) and microscopically, numerous small black jagged particles are seen. these can be shown to contain aluminium with irwin's aluminon stain or by microprobe analysis. what appears to be a different pathological effect of aluminium dust on the lungs is the rare development of granulomatous disease resembling sarcoidosis and berylliosis. , this represents hypersensitivity to the metal, amenable to confirmation with a lymphocyte transformation test similar to that used to diagnosis berylliosis (see below). rare cases of desquamative interstitial pneumonia and pulmonary fibrosis have been reported in aluminium welders. , elements with atomic numbers from (lanthanum) to (lutetium) are known as the lanthanides or rare earth metals. they are used in many manufacturing processes, including the production of hightemperature ceramics and the grinding of optical lenses. carbon arc lamps used in reproduction photography emit appreciable quantities of oxidised lanthanides, particularly cerium oxide, and there are reports of pneumoconiosis in exposed individuals. the pathological changes reported have varied from granulomatous nodules to diffuse interstitial fibrosis indistinguishable from the idiopathic variety except for the presence of rare earth elements (usually cerium) detected by polarising light microscopy and electron microprobe analysis. hard metal is a tungsten alloy containing small amounts of cobalt, titanium, molybdenum and nickel. it is exceptionally tough and once formed can only be worked with diamond. it is used in the tips of drill bits, on abrasive wheels and discs, and in armaments. interstitial lung disease is liable to arise in its manufacture or in those using hard metal as an abrasive. experimental work suggests that cobalt is the dangerous constituent but this element is soluble and, unless industrial contact has been recent, analysis of lung tissue usually shows tungsten and titanium but no cobalt. the role of cobalt is also indicated by the development of similar interstitial lung disease in diamond polishers using high-speed polishing discs made with a diamond-cobalt surface that lacked tungsten carbide and the other constituents of hard metal. , hard-metal lung disease and cobalt lung take two forms, an industrial asthma and interstitial fibrosis. the latter has a diffuse lower zonal distribution and the appearances mimic idiopathic pulmonary fibrosis. however, an unusual feature is the presence of moderate, or perhaps only small numbers, of giant cells (fig. . . a, b) . , not only are there multinucleate alveolar macrophages but syncytial cell forms develop in the alveolar epithelium. electron microscopy confirms that these are multinucleate type ii pneumocytes (fig. . . c ). such epithelial changes are well known in measles pneumonia but the viral inclusion bodies that characterise this infection are not found in hard-metal pneumoconiosis. the changes are those initially described as a particular pattern of idiopathic interstitial pneumonia termed giant cell interstitial pneumonia or gip (see p. ). elemental analysis shows that many, but not all, cases of gip represent hardmetal disease. the exceptions seldom give a history of cobalt exposure and must be presumed to represent true idiopathic cases. conversely, epithelial giant cells are not always found in hard-metal pneumoconiosis and so their presence, although highly characteristic, is neither totally specific nor totally sensitive. beryllium is the lightest of metals. it has an atomic weight of and special properties that make it especially useful in many applications. it is more rigid than steel, has a high melting point and is an excellent conductor of heat and elecricity. unfortunately, the inhalation of beryllium dust or fume is exceedingly dangerous. , those who worked with beryllium compounds before precautionary measures were taken suffered a high morbidity and mortality. sometimes, the escape of dangerous fumes from the factories was on such a scale that people living in nearby houses, downwind from the places in which these materials were being worked, contracted and occasionally died from berylliosis ('neighbourhood cases'). alternatively, contamination of a beryllium worker's clothes might lead to berylliosis in a temperatures. the alloys of beryllium are also now widely used, especially those with copper, on which it confers elasticity and resistance to fatigue. alloy manufacture and the machining of beryllium alloys are therefore further activities that entail a risk of berylliosis, as is the recovery of the metal in the recycling of scrapped electronic and computer parts. seemingly innocuous occupations such as dental laboratory technician are not without risk of chronic berylliosis. there are good grounds for regarding chronic berylliosis as being an allergic condition. many of those affected react strongly to skin tests with dilute solutions of beryllium salts, although these must be undertaken with care: occasionally in a highly sensitised person even so small an exposure may evoke a systemic reaction. the skin reaction is of the delayed type, occurs in only % of exposed individuals, is not associated with a clear-cut dose-response curve and represents a granulomatous response. further evidence for the disease having an allergic basis derives from bronchoalveolar lavage, which demonstrates an excess of t-helper lymphocytes that proliferate in vitro on exposure to beryllium salts. a positive transformation test given by these lymphocytes is a more reliable indicator of disease than in vitro blood lymphocyte transformation testing, which is safe but not wholly reliable and indicates only sensitization, rather than berylliosis. susceptibility to berylliosis varies widely from person to person and it is notable that chronic pulmonary disease is strongly associated with the hla antigen dpβ and the glu gene. , the importance of genetic factors is supported by a report of the disease in identical twins. chronic berylliosis is thought to be initiated by the metal binding to tissue proteins and acting as a hapten to initiate a delayed hypersensitivity response characterised by a proliferation of t-helper lymphocytes. these sensitised cells in turn secrete a variety of cytokines (e.g. interleukin- , tumour necrosis factor-α and interferon-γ) that recruit and activate macrophages, which mature into epithelioid cells. the resultant epithelioid cell granulomas destroy the lung tissue and lead to pulmonary fibrosis. if beryllium enters the subcutaneous tissues through a cut or abrasion, as often happened in the earlier days of fluorescent lamp manufacture, a sarcoid-like granuloma soon appears at the site; in time, the overlying epidermis may break down to form an ulcer. even more serious are the lesions produced by the inhalation of beryllium. chronic pulmonary berylliosis takes the form of a widespread granulomatous pneumonia with a histological picture identical to that of sarcoidosis (fig. . . a ). both berylliosis and sarcoidosis affect the upper lobes more than the lower (fig. . . b ) and in both diseases the granulomas are preferentially distributed along lymphatics and may involve adjacent blood vessels. in neither condition is there widespread necrosis but in both diseases the granulomas occasionally display a little central necrosis or hyalinisation. as in sarcoidosis, the hilar lymph nodes may be involved but, unlike sarcoidosis, not in isolation. over a period of many years, the sarcoid-like granulomas gradually undergo progressive fibrosis, with consequent impairment of pulmonary function. in the later stages, when the disease has become chronic, dispersal of beryllium from its site of initial absorption may lead to generalisation of the disease and to the appearance of similar granulomas elsewhere, particularly in the liver, kidneys, spleen and skin, but this is unusual. relative. beryllium compounds may also cause contact dermatitis and conjunctivitis. beryllium is also classified as a probable pulmonary carcinogen, but this is controversial. two forms of berylliosis are recognised, acute and chronic. acute berylliosis was first reported in germany in and is now largely of historical interest, being only encountered as a result of rare accidental or unexpected exposure. it follows the inhalation of a soluble beryllium salt and represents chemical injury, the pathology being that of diffuse alveolar damage (see p. ). further consideration will be confined to chronic berylliosis, which is allergic in nature. chronic berylliosis was first reported in in the fluorescent lamp industry. beryllium has now been replaced in this application but it has since proved to be of great value in the nuclear, electronic, computer and aerospace industries and the production of refractory materials and crucibles that are to be subjected to particularly high and there is a lifelong risk of disease. progression often entails alternating exacerbations and remissions, long after exposure has ceased. in keeping with the view that berylliosis is a hypersensitivity reaction, very little beryllium is necessary to cause the disease. particulate beryllium is so scanty in the affected tissues and the atomic number of beryllium so low that electron microprobe analysis is generally unsuitable for its detection. furthermore conventional detectors are protected by a beryllium window. however, the substitution of a polymeric window has enabled beryllium to be detected by electron microprobe analysis, presumably in a patient with fairly heavy exposure. ion or laser microprobe mass spectroscopy can also detect very small amounts of beryllium in tissue sections but these techniques are not widely available. the differential diagnosis of chronic berylliosis is from sarcoidosis, to which it is identical morphologically. [ ] [ ] [ ] however, as noted above, it is unusual for berylliosis to cause significant hilar lymphadenopathy in the absence of pulmonary disease, which is a common feature of sarcoidosis. extrathoracic granulomas, erythema nodosum and uveitis, which are all common in sarcoidosis, are unusual in berylliosis. however, one group found that % of patients initially diagnosed as having sarcoidosis actually had chronic berylliosis. similar findings have been reported by others. , any patient thought to have sarcoidosis who has worked with or near metals should be offered a beryllium lymphocyte transformation test. a list of laboratories performing this test can be found at www.dimensional. com/~mhj/medical_testing.html. although polyvinyl is not a mineral and the reaction of the lungs to its presence is therefore not a true pneumoconiosis, it is generally so termed and is dealt with here for convenience. workers are exposed to polyvinyl chloride dust in the milling and bagging of this plastic and micronodular opacities may be detected in their lungs radiologically. however, the material is non-fibrogenic and histology merely shows a foreign-body reaction to the dust particles. the radiological opacities may abate when exposure ceases. nevertheless, one polyvinyl chloride worker developed systemic sclerosis, which is a recognised complication of silicosis (see p. ). polyvinyl chloride is produced from vinyl chloride monomer, which has a causal association with angiosarcoma of the liver and probably other forms of cancer, including carcinoma of the lung (see p. ). in the late s a characteristic lung disease was identified in workers at several factories producing plush material by spraying nylon flock on to an adhesive backing material. [ ] [ ] [ ] [ ] the flock fibres are too large to be inspired but may be mixed with smaller nylon shards of respirable size. the workers complained of cough and breathlessness and were found to have a restrictive ventilatory defect with interstitial markings on radiography. their symptoms improved on removal from the workplace but relapsed on return to work. pathologically, there was lymphocytic bronchiolitis and peribronchiolitis with widespread lymphoid hyperplasia represented by lymphoid aggregates. chronic berylliosis is characterised by the gradual onset of cough, shortness of breath, chest pain, night sweats and fatigue. these symptoms may develop within a few weeks of exposure or many years later. once the worker is exposed, the beryllium is retained in the tissues granulomas were not identified. the histological appearances suggest a severe immunological reaction and raise possibilities such as rheumatoid disease and sjögren's syndrome but consideration of the clinical and serological setting and the occupation should permit recognition of the cause. the industrial production of popcorn and other foodstuffs appears to carry a risk of obstructive airway disease. [ ] [ ] [ ] [ ] biopsy of affected workers has shown peribronchiolar fibrosis and granulomas and air sampling has identified many volatile organic compounds, of which the flavouring agent diacetyl ( , -butanedione) is suspected of being responsible for the bronchiolitis. it is difficult to continue paint spraying (air brushing, aerographics) without adequate respiratory protection but in the early s several small aerographic factories operated in the neighbourhood of alicante, southeastern spain without any concern for the workers' health. the workers were required to paint patterns on textiles using a hand-held spray gun. the atmospheric pollution was intense but complaints of respiratory difficulties were met with reassurances and the workers urged to continue. this they did because of the otherwise poor economy, often returning to work when disabling breathlessness had settled down. a change of paint (to acramin f) may have contributed because the worst-affected workers were employed at two plants that had made this switch. their illness has been described as the 'ardystil syndrome' after the name of one of these factories. some workers were left with permanent respiratory disability. one required a lung transplant and others died. [ ] [ ] [ ] [ ] transbronchial biopsy showed organising pneumonia, which in the fatal cases had progressed to irreversible interstitial fibrosis. a similar outbreak of respiratory disease was subsequently reported in algerian textile factories where acromin f was applied by the same technique. , acromin f is marketed as a paste and used as such without ill-effect. its use in heavy spray form appears to be responsible for the 'ardystil syndrome' . workers in engineering workshops may be exposed to the prolonged inhalation of fine sprays or mists of the longer-chain hydrocarbons that constitute many mineral oils. this may result in exogenous lipid pneumonia, which is described on page , or extrinsic allergic alveolitis. [ ] [ ] [ ] the vapour of shorter-chain hydrocarbons such as paraffin oil (kerosene: c - ) and petrol (gasoline: c - ) and gaseous hydrocarbons such as propane may act as acute asphyxiants or central nervous system depressants but have negligible pulmonary toxicity. however, if they are ingested or aspirated in their liquid form they are acutely toxic to the lungs, producing a chemical pneumonitis with the features of diffuse alveolar damage. ingestion may be accidental or deliberate (see fig. . , p. ) whereas aspiration is generally inadvertent, occurring in siphoning accidents, such as those experienced by fairground operatives who 'breath or eat fire' ('fire-eater's lung'). , animal experiments involving the intratracheal injection of kerosene resulted in acute pulmonary exudates, which cleared except for residual bronchiolitis. welder's pneumoconiosis, first recognised in , essentially represents the fairly harmless deposition of iron in the lungs (siderosis -see p. ). however, welders may suffer various ill-effects from the inhalation of substances other than iron (table . . ). some of these are para-occupational risks, that is, encountered by welders because they work near another process and are inadvertently exposed: thus, shipyard welders may be exposed to asbestos, and those in foundries to silica. welders may therefore develop a mixed-dust pneumoconiosis (see p. ), rather than just siderosis. however, one analytical investigation identified excess amounts of iron alone in association with pulmonary fibrosis; the silicon content did not differ from that in controls. more directly, welders may be exposed to asbestos insulation that they themselves use, while welders of special steel alloys run the risk of metal-induced asthma, metal fume fever, polymer fume fever and the consequences of toxic metal fume inhalation, all of which are described separately in this chapter, as is lung disease in aluminium welders. chronic bronchitis has been attributed to the inhalation of low concentrations of irritants such as ozone and nitrogen dioxide by welders but this risk is unproven and the subject of much controversy. welders may also inhale carcinogenic hexavalent chromium compounds in the course of their work and therefore develop lung cancer. the term 'welder's lung' is often applied indiscriminately to any of these diseases and, as it has no specific meaning, is best avoided. dust, fume and gas are some of the terms used to describe different physical forms of respirable agents. they are defined in table . . on the finely divided fume of several metals is highly toxic to the lungs and capable of producing severe acute and chronic damage to both the conductive airways and the alveoli, resulting in acute tracheobronchitis and bronchiolitis, diffuse alveolar damage, obliterative bronchiolitis and pulmonary fibrosis. important metal fumes in this respect include aluminium, which is released together with silica fume in bauxite smelting (see shaver's disease, above), cadmium from welding or cutting special steels, chromium from cutting its alloys or in the manufacture of chromates, cobalt released in the production and use of its alloys (see hard-metal disease, above), mercury released in various industries and in the home, nickel carbonyl released during the purification of metallic nickel or the manufacture of nickel alloys and beryllium (see above). many irritant gases cause severe acute and chronic damage to both the conductive airways and alveoli. the changes are non-specific and similar to those wrought by toxic metal fumes (see above) and viruses amongst other agents. they consist of acute tracheobronchitis and bronchiolitis, obliterative bronchiolitis, diffuse alveolar damage and pulmonary fibrosis. the gases liable to produce such damage include oxides of nitrogen, sulphur dioxide, ozone, phosgene, chlorine, ammonia and various constituents of smoke, notably acrolein. some of these are also touched upon in chapter . because they are of general as well as occupational importance, although there is no rigid difference between general and occupational pollution. ozone, sulphur dioxide and nitrogen dioxide are oxidising gases that may be found together as industrial atmospheric pollutants. each is capable of producing diffuse alveolar damage by means of its oxidising properties and the release of free active radicals. in addition, they cause damage to distal airways, particularly terminal and respiratory bronchioles, with resulting bronchiolitis. oxides of nitrogen may be encountered with fatal consequences by farmhands seeking to free a blockage in a silo when they encounter pockets of this gas that have accumulated on top of the fermenting silage: the term 'silo-filler's disease' is generally applied to the initial haemorrhagic oedema or the obliterative bronchiolitis that develops in those who survive the initial chemical injury. [ ] [ ] [ ] [ ] asphyxia due to the farmhand encountering pockets of carbon dioxide is a further hazard within agricultural silos. other farmhands have suffered from the inhalation of toxic gases or bacteria when handling liquid manure. [ ] [ ] [ ] [ ] welding, which is considered below, may also involve exposure to toxic gases such as oxides of nitrogen. ozone, the principal oxidant gas of photochemical smog, produces pulmonary changes at relatively low levels and may be encountered at higher concentrations in various industries. potentially dangerous levels of ozone are produced from atmospheric oxygen by ultraviolet radiation given off in welding while ozone is used in industry to sterilise water, bleach paper, flour and oils, and mask the odour of organic effluents. the damage wrought by ozone is predominantly centriacinar in distribution, affecting terminal and respiratory bronchiolar epithelium and proximal alveolar epithelium. [ ] [ ] [ ] there is loss of cilia and necrosis of centriacinar alveolar type i epithelial cells. the changes are dose-dependent and, in one study, the youngest animals were most sensitive. in long-term experiments, hyperplastic bronchiolar clara and ciliated cells extended peripherally to line alveolar ducts. the role of granulocytes is stressed in some experimental studies and it is notable that neutrophil migration is prominent when the human lungs are damaged by ozone. aldehydes such as acetaldehyde, formaldehyde and acrylic aldehyde (acrolein) are widely used in the plastics and chemical industries. the first is a liquid and the others are water-soluble gases. pathologists are of course familiar with formaldehyde solution from its use as a disinfectant and histological fixative. all these aldehydes are intensely irritant and their acute effects generally prevent prolonged exposure to high concentrations. chronic effects include skin sensitivity and asthma, and in rats nasal carcinoma. however, the doses to which these experimental animals were exposed far exceed any that are likely to be encountered by humans, in whom there is no convincing evidence of aldehyde-induced cancer. ammonia gas is extensively used in industry as a raw material, notably in the manufacture of nitrogenous products such as fertilisers and plastics. it is highly soluble and its acute irritative effects are mainly felt in the eyes, nose and throat, but high levels affect the major airways, possibly leading to them being blocked by exudates. survival usually brings full recovery but bronchiectasis and obliterative bronchiolitis have been described. chlorine gas is widely used in the chemical industry. it is transported and stored under pressure in liquid form. heavy exposure through its accidental release or use as a war gas has proved fatal through its acute toxicity causing exudative airway occlusion and pulmonary oedema. survivors usually recover completely but, as with nitrogen dioxide and ammonia, there is a risk of obliterative bronchiolitis. phosgene (carbonyl chloride, cocl ) is a poisonous, colourless gas that was responsible for thousands of deaths during world war i, when it was used in chemical warfare. it is used industrially in the preparation of some organic chemical compounds and is formed, perhaps inadvertently, by the combustion of methylene chloride in products such as paint strippers. phosgene causes injury to terminal bronchioles and alveoli, with resulting oedema and hyaline membrane formation. the mechanism of cell damage is uncertain but it may depend on inactivation of intracellular enzymes by the gas. longterm problems are rare but chronic bronchitis and emphysema have been described in survivors. mustard gas (bichloroethyl sulphide, c h cl s) is a further agent that has been used in chemical warfare. it is primarily a skin vesicant but when inhaled it results in widespread epithelial destruction and pulmonary oedema. survivors may be left with irritant-induced asthma (reactive airways dysfunction), chronic bronchitis, tracheobronchomalacia, bronchiectasis and bronchiolitis obliterans. [ ] [ ] [ ] thionyl chloride is used in the manufacture of lithium batteries where it is liable to result in the release of sulphur dioxide and hydrochloric acid fumes. workers in such factories have developed lung injury varying from mild, reversible interstitial disease to severe obliterative bronchiolitis. hydrogen sulphide is the principal chemical hazard of natural gas production. high levels of the gas also buid up in sheds housing large numbers of pigs, the source here being the pig manure. once inhaled the gas is rapidly absorbed into the blood stream. the effects are therefore widespread but include the usual respiratory effects of irritant gases, varying from sneezing to pulmonary oedema and acute respiratory distress, depending upon the exposure. in alberta cases were identified over a -year period. the overall mortality was %; % of victims were dead on arrival at hospital. most required admission to hospital but the survivors experienced no long-term adverse effects. a the danger of asphyxia from the inhalation of gases devoid of oxygen is fairly widespread in industry. it generally arises from the use of inert gases, which, being non-toxic, give a false sense of security. pockets of these gases tend to form in confined spaces. anoxic death from the accumulation of methane is well known in mines and has also occurred in slurry pits and sewers. anoxic asphyxia in diving (and anaesthesia) has resulted from the incorrect connection of gas cylinders or failure to notice that a mixed gas contains insufficient oxygen. deaths have occurred in welding when argon or carbon dioxide has been used to shield the weld and prevent oxidation of the metals at the high temperatures employed. deaths have also resulted from inadvertent entry to discharged oil tanks filled with nitrogen to reduce the risk of explosions, or from the formation of pockets of nitrogen gas applied in liquid form to freeze the contents of damaged pipes so that they can be repaired without the necessity to drain down. the respiration of a gas devoid of oxygen causes loss of consciousness within seconds because it not only fails to provide oxygen but removes that present in the pulmonary arterial blood. the changes at autopsy are those common to cellular hypoxia. they include cerebral and serosal petechiae and pulmonary congestion and haemorrhage but these features are not specific and are not always present. the cause of death can generally only be surmised from the circumstances surrounding the death. occupational asthma is the commonest cause of work-related respiratory disease in many western countries (table . . ). [ ] [ ] [ ] the reported incidence ranges from per million workers in south africa to per million workers in finland. , it occurs in many industries (table . . ) and occupational factors can be identified as contributing to asthma in about % of adult cases. over aetio- in the uk a third are organic, a third chemical, % metallic and the rest miscellaneous. the commonest, in descending order, are isocyanates, flour and grain, laboratory animals, glutaraldehyde, solder or colophony and hardening agents. atopy appears to predispose to occupational asthma when the allergen is of high molecular weight but not when it is of low molecular weight. for example, atopic individuals are particularly prone to develop asthma if employed in the manufacture of biological detergents, whereas atopy does not increase the risk of asthma from sensitisation to toluene di-isocyanate, which is a serious health problem in the manufacture of polyurethane. similarly, platinum salts are such potent sensitising agents that nearly all those exposed to them develop asthma. asthma-provoking metals other than platinum include chromium, cobalt, nickel and vanadium, all of which are used in steel alloys, and possibly aluminium (see pot-room asthma, p. ). other asthma-inducing factors encountered in industry include grain and flour dust, certain wood dusts, soldering fluxes containing colophony (pine resin), epoxy resin hardeners such as phthallic anhydride, isocyanate-containing foams and paints, formaldehyde and the excreta of laboratory animals. contaminated humidifiers may cause occupational asthma as well as humidifier fever and extrinsic allergic alveolitis. pathologically, occupational asthma is identical to nonoccupational asthma (see p. ). byssinosis is a further form of occupational asthma, one encountered in the cotton industry. the sensitising agent is a component of the cotton bract, which is the part of the cotton harvest other than the cotton fibre. bract consists of dried leaf, other plant debris and soil particles and contains a variety of fungal and bacterial residues, including lipopolysaccharide endotoxin, but the exact nature of the sensitising agent remains unknown. the endotoxin is unlikely to be responsible for byssinosis but may be the cause of so-called mill fever, a self-limiting illness characterised by malaise, fever and leukocytosis that is experienced by many people on first visiting a cotton mill. dust levels and the risk of byssinosis are particularly high in the carding rooms where the raw cotton is teased out before it is spun. affected workers are worse when they return to work after the weekend break, a feature attributed to antibody levels having built up during this brief respite from the cotton dust. there is no link with atopy and the fluctuating antibodies are precipitins of the immunoglobulin g class. complement activation by both arms of the complement cascade has been reported. , when the lancashire economy was largely cotton-based, necropsies on workers suffering from byssinosis generally showed gross emphysema, and this came to be accepted as evidence of byssinosis. however, it is now realised that in this heavily industrialised part of the uk, emphysema is as common in the general population as in cotton workers and it can no longer be considered a component of byssinosis. other findings in byssinosis are more commensurate with asthma, namely an increase in bronchial muscle and mucous cells. no granulomas or other evidence of extrinsic allergic alveolitis are found. fever may be the predominant feature in a variety of occupational illnesses and the unifying term 'inhalation fever' has been proposed. however, the individual occupations are of interest and these conditions will therefore be considered separately. mill fever has been mentioned above under byssinosis. humidifier fever is an acute illness characterised by malaise, fever, myalgia, cough, tightness in the chest and breathlessness, all of which are worse on monday mornings if the humidifier responsible is at work rather than home. the chest complaints, and their aggravation on return to work after the weekend, are features shared with byssinosis (see above) but the general complaints fit better with extrinsic allergic alveolitis (see p. ). humidifier fever develops in circum-stances that also lead to the development of a form of extrinsic allergic alveolitis, and not surprisingly the same name has been extended to this latter condition, with inevitable confusion. both diseases are caused by microbiological contamination of humidifiers or air conditioners so that a fine spray of microorganisms is emitted into the office, factory or home. investigations have generally shown the baffle plates of the air conditioner to be covered with a slime of bacteria, fungi or protozoa (mainly amoeba and ciliates), and extracts of this have been used to identify precipitins in the patient's sera, as in extrinsic allergic alveolitis. however, unlike extrinsic allergic alveolitis, humidifier fever resolves within a day and leaves no permanent injury. for this reason there is seldom the opportunity to study the tissue changes, and partly for this reason it remains unclear whether the disease is mediated by immune complexes, as in extrinsic allergic alveolitis, or by endotoxins derived from the contaminants. a febrile illness occurring in precipitin-negative farm-workers after heavy exposure to fungi in their silos was attributed to inhaled fungal toxins and named pulmonary mycotoxicosis. it is also known as precipitin test-negative farmer's lung and organic dust toxic syndrome. the condition is generally self-limiting and is seldom biopsied but desquamative interstitial pneumonia and diffuse alveolar damage have been reported. , metal fume fever this is a self-limiting acute illness characterised by fever, sweating, myalgia, chest pain, headache and nausea, that comes on monday mornings when occupational exposure is experienced after a weekend's respite, as with bysinnosis and humidifier fever; during the week tolerance develops. , the disease involves the release of cytokines such as tumour necrosis factor and is presumed to have an allergic basis. the metals involved are chiefly zinc, copper and magnesium, and, to a lesser extent, aluminium, antimony, iron, manganese and nickel. occupations at risk include any that generate such metal fumes, but particularly welding. it is most commonly associated with welding zinc-coated surfaces. if the symptoms persist, alternative diagnoses, such as acute cadmium poisoning and other specific toxic metal fume diseases, should be suspected: these are not self-limiting and may cause severe bronchiolitis or diffuse alveolar damage (see above). this illness resembles metal fume fever except that it occurs without regard to previous exposure: no tolerance develops and there is therefore no particular susceptibility on mondays. the polymers concerned are quite inert, except when heated to produce fume: polytetrafluorethylene (ptfe, teflon, fluon, halon) is a notable example. as with other self-limiting diseases, little is known of the tissue changes. environmental irradiation chiefly affects the skin but in some parts of the world rocks near the surface release significant amounts of radon gas. this carcinogen is liable to accumulate in buildings and be inhaled, so subjecting the occupants to an increased risk of lung cancer. the installation of underfloor ventilation is therefore advocated in such areas. this subject is explored more fully on page . the body is vulnerable to both increases and decreases in pressure and it is the lungs that often bear the brunt of the damage. increased pressure may result in blast injury or crushing of the chest while decreased pressure may result in the lungs literally bursting or dissolved gases being released within the blood (caisson disease), or the vascular alterations that underlie mountain sickness developing. some of these pressure changes entail a risk of pneumothorax and it is essential that this is properly investigated postmortem by the chest being opened under a water seal. loud music has been incriminated as a specific form of air pressure change causing pneumothorax and metereologists have shown that 'spontaneous' pneumothoraces tend to occur in clusters associated with natural drops in atmospheric pressure. , explosions may cause injury by the body being violently thrown against a less moveable object, by objects being thrown against the body or by the blast wave hitting the body. these mechanisms often act together but sometimes there is only blast injury, to which the lungs are particularly vulnerable. for a time it was considered that the damage was direct, the blast wave travelling down the airways to injure the lungs. however, at the start of the second world war, experiments conducted in the uk showed that the lungs were injured indirectly, the blast wave being transmitted to them through the chest wall: pulmonary blast injury is worst on the side of the body towards the explosion, and can be reduced by protective clothing. underwater explosions are particularly dangerous because water is incompressible. there may be severe internal injury but no external evidence of damage other than a trickle of blood from the mouth or nose. this is because the injury is rate-dependent. quite small thoracic deform-ation may produce severe pulmonary damage if peak compression is attained very quickly, typically in less than ms. conversely, severe chest wall distortion may produce only minor pulmonary contusion if this time is extended beyond ms. at necropsy, the lungs are contused, with blood evident in the airways and parenchyma. depending on the force of the blast, the haemorrhage may be pinpoint, patchy or confluent. it tends to follow the lines of the ribs and may be accompanied by pleuropulmonary lacerations having the same distribution. in this case there will also be haemothorax, pneumothorax and possibly air embolism. patchy pulmonary haemorrhages cuff the blood vessels. , in patients who survive for a few days, the lungs resemble the liver macroscopically and histologically show chronic interstitial inflammation and fibrosis as well as haemorrhage. other injuries are often present and fat embolism, aspiration pneumonia, fluid overload and infection may all be added to the effects of the blast wave. 'chest squeeze' is another form of barotrauma caused by high pressure but here the body is compressed rather than subject to a sudden wave of pressure as in blast injury. it is experienced by divers who descend very deeply, thereby subjecting their bodies to such high pressure that their chest walls are literally crushed, so that their ribs break and their lungs are severely compressed. more common mishaps experienced by divers include drowning and decompression sickness, both of which are dealt with below, and neurological syndromes such as nitrogen narcosis, which will not be considered further. 'burst lung' is the most acute form of decompression sickness. it is experienced by divers and submariners making rapid ascents from depth and by aviators who ascend too rapidly in unpressurised aeroplanes, experience failure of a plane's pressure system or have to eject at high altitudes. injury to the lung is caused by trapped alveolar gas expanding so rapidly that it exceeds total lung capacity before it can escape through the trachea. the lungs literally burst: the alveolar walls rupture and blood mixes directly with alveolar air. the victim experiences chest pain and there may be blood-stained froth at the mouth or frank haemoptysis. air may enter the alveolar walls to cause interstitial emphysema or air embolism. asthmatics may be at particular risk because of regional air-trapping. . diving mammals such as porpoises and whales are protected from such dangers of peripheral air-trapping by cartilage extending far out into the finest conductive airways so that these passages never close, even at the end of full expiration (fig. . . ) . , patients requiring positive-pressure artificial respiration are also at risk of burst lung, but the complications of the resultant interstitial emphysema differ from those experienced by divers. in divers, the chest wall is buttressed by the surrounding water and air in the interstitium is liable to track towards the hilum of the lungs and enter pulmonary veins, with resultant cerebral and coronary air embolism, either of which may prove fatal. iatrogenic burst lung, on the other hand, takes place in patients whose chest wall is not so buttressed, and then outward rupture of the interstitial air is more likely, resulting in pneumothorax. extension of the interstitial emphysema to the mediastinum, neck and chest wall is also more likely in such patients, resulting in surgical emphysema at these sites. however, there are exceptional cases marked by both cerebral embolism and extensive air tracking. the same circumstances that lead to burst lung may also cause decompression sickness, which is also known as caisson disease. in this condition there is a sudden release of nitrogen gas that has gone into solution in the lipids of adipose tissue and of myelinated nervous tissue at the higher pressure: the released nitrogen gains access to the blood stream in which it forms bubbles. doppler ultrasound techniques show that this is quite customary when divers ascend from depth, but the lungs generally provide an effective filter so that there are no untoward systemic effects, although there may be sudden chest pain on deep inspiration ('the chokes'). gradual decompression permits the nitrogen to diffuse across the alveolar membranes and be exhaled. if, however, substantial amounts of nitrogen are released from solution, sufficient pulmonary arteries may be blocked to cause pulmonary hypertension, with resultant opening of arteriovenous communications or a patent foraman ovale, so permitting the gas to enter the systemic circulation. this is often followed by limb pains ('the bends') and perhaps cerebral symptoms ('the staggers'). fatal cases are characterised by gas bubbles within blood vessels throughout the body and froth in the heart chambers. delayed effects include ischaemic necrosis of bones and other tissues. deep-diving mammals are protected by the same mechanism that prevents them suffering from burst lung. they exhale before diving and during the dive the chest is compressed to the extent that virtually all the gas in the lungs passes into the cartilage-buttressed nonrespiratory airways (see fig. . . ) , resulting in very little to be absorbed by the blood. the pulmonary collapse also serves to reduce buoyancy. the distribution of the little gas that is absorbed is minimised by bradycardia. many viscera experience anaerobic respiration but hypoxia is minimised in the heart and musculature by high levels of haemoglobin and myoglobin. the brain is further protected by the supplying arteries drawing on oxygen stored in an unusual spongelike cervical organ known as the rete mirabilis. mountain sickness is due to reduced atmospheric pressure brought about more slowly than that responsible for decompression sickness . , it may be acute or chronic. acute mountain sickness is likely to be experienced by anyone who ascends above - m without a period of acclimatisation at intermediate levels. symptoms are as liable to occur in people born at high altitude who return after a few weeks spent at sea level as in those who go to the mountains for the first time: acclimatisation is obviously short-lived and is therefore necessary whenever an ascent is to be made. the ill-effects are commonly precipitated by exercise. in the susceptible, acute mountain sickness commonly appears within days of ascent. the basis of acute mountain sickness is tissue hypoxia. it results in deteriorating intellectual and psychological function, headache, nausea, vomiting, and more rarely pulmonary and cerebral oedema. high-altitude pulmonary oedema is characterised by increasing dyspnoea, cyanosis and a dry cough, and later the production of copious, frothy sputum, which sometimes becomes blood-stained. the pulmonary artery pressure is markedly raised but wedge pressures are normal, indicating that the left side of the heart is unaffected and that pulmonary venous constriction is unlikely to be an important contributory factor. the pulmonary oedema fluid has a high protein content and the condition has been characterised as a non-cardiogenic high-permeability oedema associated with excessive pulmonary hypertension. , hypoxia is a well-known cause of pulmonary arteriolar constriction but in acute mountain sickness the vascular response appears to be exaggerated for the pulmonary artery pressure is considerably higher than is usual for the altitude. an association with certain hla complexes (hla-dr and hla-dq ) suggests that this has a genetic basis. although arteriolar constriction only tends to protect the pulmonary capillaries, it could explain the oedema if the process was patchy -as is the resultant oedema -for patchy arteriolar constriction would subject the rest of the lung to abnormally high pressures and lead to capillary stress failure in these areas (see pp. and ). , measurements of capillary pressure suggest that this is indeed the case. furthermore, vasodilators such as calcium channel blocking agents and inhaled nitric oxide gas , , have been used with success to counter acute mountain sickness, supporting the idea that hypoxic vasoconstriction plays a central role. autopsy shows the lungs to be heavy and firm. the cut surface weeps oedema fluid, which is often blood-stained, but a striking feature is the patchy distribution of the changes. areas of haemorrhagic oedema alternate with others that contain clear oedema fluid and others that are normal apart from overinflation. pulmonary arterial thrombi are commonly found. microscopy confirms the presence of haemorrhagic oedema and may show neutrophils and hyaline membranes in the alveoli. the alveolar capillaries are congested and may contain thrombi. there may also be an increase in mast cells and rarely pulmonary infarction. the right ventricle is commonly dilated whereas the left ventricle is normal. highlanders generally show right ventricular hypertrophy and increased muscle in their pulmonary arteriesm, changes that are not apparent in lowlanders. , chronic mountain sickness prolonged residence at high altitude leads to hypoxic pulmonary hypertension (see p. ), an increase in red cell mass and cor pulmonale. livestock taken from lowland plains to high-altitude pastures suffer similarly but the natural stock of the himalayas and ethiopian highlands are apparently immune. so too are other species long established at high altitude such as the llama and yak. these species are said to have adapted to their climate, that is, the forces of natural selection have bred out the pulmonary vasoconstrictive response to hypoxia. cattle of european origin and humans acclimatise to high altitude by processes such as increasing their red cell mass but generally they are not adapted like native species and suffer hypoxic pulmonary hypertension at altitudes in excess of m. certain himalayan highlanders may be an exception to this in that their small pulmonary arteries are reported not to show the muscularisation that characterises hypoxic pulmonary hypertension. in cattle of european origin, the dependent oedema of right-sided cardiac failure caused by hypoxic pulmonary hypertension affects the breast (brisket) particularly and in the rocky mountains of north america such cattle are said to have 'brisket disease' . a human counterpart of this has been described in children of chinese ancestry who have been taken to reside in tibet and who have developed a fatal form of subacute infantile mountain sickness. a small minority of permanent residents in the andes develop the changes of chronic mountain sickness to a marked degree and are said to suffer from monge's disease. the basis of this is alveolar hypoventilation, which leads to a progressive fall in systemic arterial oxygen saturation and elevation of haemoglobin concentration to an unusually severe degree. the latter averages about g/dl, which exceeds even the g/dl found in healthy high-altitude residents. patients with monge's disease are so deeply cyanosed that their lips are virtually black. their pulmonary artery resistance is also markedly raised. the cause of the alveolar hypoventilation is uncertain but the only cases of monge's disease that have come to necropsy had conditions such as kyphoscoliosis that predispose to alveolar hypoxia. drowning is defined as suffocation by submersion, and usually occurs in water. it is the commonest cause of accidental death among divers but % of drowning accidents do not involve deep descents. falling into quite shallow water is a particularly common cause of drowning in young children. in adults, men outnumber women by to . more die in fresh water than the sea, not because it is more hazardous to the lungs than sea water, but because unguarded inland waters and swimming pools are visited more frequently. alcohol consumption contributes to many deaths by drowning. drowning is not simply a matter of being unable to keep one's head above water. this may be merely a secondary event. for example, the entry dive may result in underwater head injury, or the exertion of swimming may precipitate a heart attack. furthermore, the struggling swimmer going down for the third time ('drowning not waving') is the exception: most drowning is characterised by the swimmer failing to surface or quietly dropping beneath the surface without anyone noticing. swimming underwater can be extremely hazardous if it is preceded by hyperventilation, a danger that needs to be more widely appreciated. hyperventilation results in undue loss of carbon dioxide so that instead of hypercapnia forcing the swimmer to surface to breathe, progress under water may be continued until hypoxia causes sudden loss of consciousness. panic contributes to many swimming accidents and is often precipitated by the inadvertent aspiration of just a little water. most people are naturally buoyant, but only slightly so. with the lungs fully expanded the average adult has a positive buoyancy of about . kg, which is sufficient to keep the head out of the water if the rest of the body is submerged. if an arm (weight about kg) is raised to wave for help, the head will go down. if the swimmer shouts, exhalation reduces buoyancy to neutral at normal end-expiration and to negative at residual volume. buoyancy cannot be regained when the head is submerged and unless able to swim to the surface, the person will continue to sink. autopsy generally shows that the lungs are full of water, but some victims die of 'dry drowning' due to laryngospasm. events may also be modified by the temperature of the water. sudden immersion in cold water may result in tachycardia, hypertension and hyperventilation, making it difficult for the victim to keep the airways free of water. it may also result in sudden death due to ventricular fibrillation. even a good swimmer loses consciousness within an hour of immersion in very cold water. drowning is then inevitable unless a correctly fitted life jacket is worn, in which case there is a danger of death from hypothermia. however, as in open heart surgery, cold prolongs the interval before there is irreversible brain damage. if the person is rescued, water in the lungs is quickly absorbed, even if it is saline, and therefore hyperosmolar:aspirated sea water is quickly equilibrated by pure water joining it from the blood but the alveolar epithelial barrier remains impermeable to protein and once osmotic equilibrium is reached, all is quickly reabsorbed. [ ] [ ] [ ] fresh water is absorbed even more quickly. it is unnecessary to tip the patient to hasten this process. any water recovered in this way comes from the stomach and time that should be devoted to mouth-to-mouth breathing and cardiac massage is lost. these resuscitative efforts may need to be prolonged as fresh water in particular inactivates alveolar surfactant, leading to alveolar collapse which persists until the surfactant is replenished. very few victims who are resuscitated on site fail to survive, and very few who cannot be resuscitated on site recover later. interchange of fluid between the blood and air spaces may cause major fluctuations in plasma volume with consequent changes in ionic concentrations and haemolysis. hypervolaemia may cause circulatory problems but hyperkalaemia consequent upon the haemolysis is not thought to be as important as was formerly believed: ventricular fibrillation following submersion is more likely to be a complication of hypothermia than of electrolyte imbalance. circulatory collapse may ensue shortly after rescue. this is due to loss of the circulatory support provided by the pressure the water exerts on the body, which results in a considerable increase in cardiac output while the body is immersed. on leaving the water the loss of this support results in a tendency to venous pooling. although this is countered by baroreceptor responses, these are reduced by prolonged immersion in cold water. circulatory collapse is believed to be the cause of death in many persons who perish within minutes of rescue. to counter this effect, patients should be lifted out of the water in the prone position. it can be seen that, in fatal cases, the pathologist is faced with several possibilities. thus, death may have been due to: • natural causes before the body entered the water • unnatural causes before entry, the body merely being disposed of in the water • natural causes in the water • injuries received in the water from impact with rocks, a boat or a ship's propeller, or in tropical waters from predators such as a crocodile or a shark (any of which may also be incurred after death, as may disfigurement by fish and rats) • 'dry drowning' • true drowning • hypothermia • circulatory failure after rescue. true drowning is indicated by froth in the airways and heavy waterfilled lungs. both fresh and salt water contain numerous microscopic algae known as diatoms and those representative of the water in which the drowning occurred are found in the lungs. unless death occurred before submersion, diatoms are also found in other viscera because these tiny life forms easily enter the circulation. thus, the presence of diatoms in digests of organs such as the kidneys, liver, brain and bone marrow suggests that death was due to drowning. because they have a siliceous capsule, diatoms are resistant to putrefaction as well as digestion and can be identified in the body long after death. however, a positive test is not always accepted as proof of drowning and a negative test does not exclude drowning. the various physical forms in which respirable environmental agents may be encountered are defined in table . . . some effects of inhalant lung injury are recognised as distinct disease entities and are dealt with elsewhere: for example, the pneumoconioses on page , extrinsic allergic alveolitis on page , chronic bronchitis on page and lung cancer on page . other respirable agents, such as lead fume and carbon monoxide gas, exert their harmful effects elsewhere in the body and will not be considered further. this section is concerned with toxic substances that may be inhaled by the general public. those that are more likely to be encountered in the workplace or in war zones are considered on page . the lungs have a rather stereotyped pattern of response to inhaled toxins, displaying degenerative changes and inflammation of varying degree, the former sometimes amounting to necrosis. in general, the site of maximal absorption or injury is related to solubility (for gases and vapours) and particle size (for aerosols such as dusts, fog, fumes, mists, smog and smoke): the less water-soluble and the smaller the particle size, the further down the respiratory tract the agent will penetrate ( fig. [ ] [ ] [ ] thus, ammonia produces intense congestion of the upper respiratory passages and laryngeal oedema whereas phosgene has little effect on these sites but causes pulmonary oedema. air pollution [ ] [ ] [ ] [ ] [ ] the toxic (as opposed to allergenic) air pollutants thought to pose the greatest threat to the lungs comprise smoke particles, sulphur dioxide, oxides of nitrogen, various aldehydes and ozone. smoke and sulphur dioxide derive particularly from the combustion of fossil fuels in domestic fires and power stations, nitrogen dioxide is an important car exhaust and domestic gas appliance pollutant and ozone is the principal photochemical product of smog. aldehydes such as formaldehyde and acrylic aldehyde (acrolein) also contribute to general air pollution because they are released in the combustion of diesel oil and petrol. collectively, these pollutants have been incriminated in the exacerbation (rather than causation) of asthma. they also predispose to respiratory infection and result in airway inflammation and hypersecretion. , their effect on children is of particular concern because development of the lungs is known to continue well into childhood and damage to the lungs before their growth is complete is likely to be irreparable. at the other extreme of life episodes of severe air pollution are known to hasten the deaths of many patients with chronic airway disease. particularly high concentrations of the agents responsible for air pollution may be encountered in industry and their effects are therefore also considered in chapter . , on occupational diseases of the lung. many of the polycyclic hydrocarbons found in polluted air are carcinogenic (see p. ) and it is therefore not surprising that urban air pollution has been found to be associated with excess mortality from lung cancer. domestic air pollution is rife in many of the poorer parts of the world due to the burning of biomass (wood, dried cow dung, bagasse, straw) in unventilated living rooms for heating and cooking. the women are particularly at risk of developing chronic bronchitis while their children have an increased incidence of acute respiratory infections. , , a volcanic ash (tephra) irritates the eyes, skin and respiratory tract and in some eruptions may contain much free silica (e.g. montserrat in and mount st helens, washington state, usa in ) or be associated with the release of radon gas (e.g. the azores in ). the destruction of the world trade center in caused massive air pollution of new york city that had lasting respiratory effects on survivors, rescue workers and local residents. [ ] [ ] [ ] at the time of the disaster there was much smoke from combustion of aeroplane fuel and flammable materials in the building while the collapse of the twin towers released dust from cement and dry-wall partitions that was highly alkaline. [ ] [ ] [ ] this caused considerable irritation of the eyes and the conductive airways. a year later many victims were still suffering from bronchial hyperreactivity and poor ventilatory function, in a so-called reactive airways dysfunction syndrome , and there was continuing spirometric decline years later. the respirable portion of the dust formed only a small fraction of the whole but given the level of exposure its future effects cannot be discounted, particularly as it contained substances such as asbestos. unusual effects attributed to the disaster include acute eosinophilic pneumonia and granulomatous pneumonitis. , allergenic air pollutants are dealt with in detail in the sections on asthma (see p. ) and extrinsic allergic alveolitis (see p. ). allergenic air pollution is generally occupational or domestic but periodic widespread air pollution was responsible for the epidemics of asthma seen in barcelona in the s, which were eventually traced to ships discharging cargoes of soya flour (see p. ). smoking-related diseases figure large throughout this book and in this section they are merely summarised collectively. of the greatest importance, both in the number of patients they affect and in their clinical effects on the individual, are the various forms of chronic obstructive lung disease and lung cancer, but there are many other respiratory diseases associated with smoking, and a few that are less common in smokers (box . . ). not surprisingly, these diseases are often encountered in combination and sometimes one may obscure another. for example, a cigarette smoker may have emphysema in the upper lobes and idiopathic pulmonary fibrosis in the lower lobes. , alternatively, langerhans cell histiocytosis and desquamative interstitial pneumonia may affect the same parts of the lungs, in which case the focal lesions of the former may be masked by the latter condition. the term 'smoking-related interstitial lung disease' has been introduced to cover a spectrum of interstitial diseases related to smoking , , as well as being used in a more restricted sense to describe a combination of air space enlargement and interstitial fibrosis predominantly affecting the lower lobes. , , a quite advanced interstitial fibrosis has been reported in smokers with no clinical evidence of interstitial lung disease. b early changes detectable in smokers include chronic bronchiolitis, fibrosis of the bronchiolar wall and mild peribronchiolar interstitial fibrosis. , even earlier changes are detectable at the molecular level: as many as smoking-responsive genes that are significantly up-regulated or down-regulated have been identified in normal cigarette smokers. there is marked individual variation, which may explain why many lifelong heavy smokers experience no respiratory problems. histological evidence that a patient smokes is provided by an increase in the number of alveolar macrophages and a characteristic brown discoloration of cytoplasm due to the phagocytosis of tar and other particulate matter derived from tobacco smoke (fig. . . ) . cigarette smokers are at greater risk of lung disease than cigar and pipe smokers, probably because they inhale more deeply. they do this because cigarette smoke is more acid than cigar and pipe smoke and its nicotine content is therefore absorbed more easily through the lungs than the buccal mucosa. smokers obviously put their own health at greatest risk but the lesser hazards of passive smoking are now well recognized (see p. ). passive smoking involves both the smoke exhaled by others and that coming from smouldering tobacco between puffs, the latter being known as sidestream smoke. the harmful effects of maternal smoking on the unborn child also come in this category. they include increased airway responsiveness and reduced lung function during the neonatal period and an increased risk of sudden infant death syndrome. reduced numbers of alveolar attachments to the bronchioles have been demonstrated in such infants. smoking is also associated with disease of other organs (e.g. carcinoma of the oesophagus and bladder) but these are outwith the remit of this text. tobacco smoking by waterpipe (shisha, hubble-bubble) is enjoying a rise in popularity, both in its heartland, the middle east, and western countries, and wherever it is practised it is widely perceived as being less dangerous than smoking cigarettes. this is probably a mis conception. what evidence there is suggests that waterpipe tobacco smoking is just as harmful as cigarette smoking, if not more so. the lungs may be injured in burned patients in many ways (box . . ) , but an important consideration when a body is recovered from a fire is whether death was due to the fire or took place beforehand, the latter raising the possibility of foul play. a vital reaction to the skin burns and the presence of soot in the lower airways provide evidence that death occurred in the fire but an absence of soot from the airways may be due to death occurring rapidly, from asphyxia or poisoning by gases released in the conflagration. soot is cleared rapidly and if the patient survives a few days an absence of soot from the airways is to be expected. lung injury may result directly from heat and smoke inhalation or indirectly from the release of mediators associated with blast injury or shock. although air temperature in a fire may reach very high temperatures thermal injury seldom extends beyond the carina but more extensive injury from heat alone was seen in men exposed to steam escaping from a fractured boiler pipe. those dying immediately showed coagulative necrosis of the respiratory mucosa down to the level of the alveolar ducts and alveolar congestion and oedema, while those surviving a little longer exhibited diffuse alveolar damage. the diffuse alveolar damage probably represented a manifestation of shock from their extensive cutaneous scalding whereas the mucosal necrosis is directly attributable to heat. diffuse alveolar damage is extrinsic allergic alveolitis sarcoidosis blast injury asphyxia poisoning by combustion products (e.g. carbon monoxide, cyanide) direct thermal injury (largely limited to the trachea) irritant smoke, fume and gas (e.g. oxides of nitrogen, ammonia, acrolein, sulphur dioxide) hypovolaemic shock secondary to skin loss septicaemic shock from: infected skin burns infected central lines secondary viral and bacterial pneumonia fluid overload tracheostomy complications, including tracheobronchitis, pneumonia and barotrauma oxygen toxicity absorption of toxic topical disinfectants thromboembolism uraemia usually part of systemic multiorgan failure in these patients, and is the leading cause of death in burns. the ubiquity of plastics today means that smoke contains numerous irritants, including isocyanates, aldehydes and fluorinated organic chemicals. irritant smoke products have two principal effects. firstly, they cause an immediate painful stimulation of the eyes and respiratory tract which at low concentrations may prevent escape and at high concentrations may cause laryngeal spasm and death. secondly, they cause bronchopulmonary injury some hours after exposure. burned patients dying within - days often show tracheobronchial necrosis and diffuse alveolar damage with prominent hyaline membranes. , , secondary herpesvirus infection is often present. , the respiratory changes caused by heat and smoke are non-specific and careful consideration of the many causes of lung injury in burned patients listed in box . . and of the clinical circumstances and management is generally required. often it will be concluded that the cause of the lung injury is multifactorial. long-term consequences of smoke inhalation include bronchiectasis and obliterative bronchiolitis. methyl isocyanate, the chemical released at bhopal the bhopal catastrophe of was caused by the accidental release of tons of methyl isocyanate gas (ch -n=c=o) from a pesticide plant. over people were exposed, of whom died, mostly within hours of exposure, and were seriously injured. the victims complained of intense ocular and respiratory irritation. some survivors were left with persistent respiratory impairment, which was thought to be due to obliterative bronchiolitis. , methyl isocyanate is an extremely potent respiratory irritant, destroying the epithelium throughout the conducting airways, with comparatively less parenchymal injury. in survivors, epithelial regeneration, often involving squamous metaplasia, quickly commences, but not before endobronchial granulation tissue projections have developed, resulting in obliterative bronchiolitis. tear gases are chemical irritants delivered as an aerosol for the purpose of riot control. they react with mucocutaneous sensory nerve receptors causing intense irritation of the eyes, mucous membranes and skin. the respiratory effects are mainly concentrated on the upper tract so that there is violent sneezing, severe rhinorrhoea and cough but there may also be tracheobronchitis and rarely pulmonary oedema. patients with pre-existent asthma or chronic obstructive pulmonary disease are most severely affected while others may be left with reactive airways dysfunction. toxins reaching the lungs via the blood stream may be drugs, food contaminants, metabolites produced elsewhere in the body, or chemicals ingested intentionally or accidentally, either in the home or the workplace. the lungs are selectively damaged by certain blood-borne toxins for a variety of reasons. for example, the herbicide paraquat is preferentially taken up by the lungs because of its molecular homology with certain endogenous substances. as detailed below, the type i alveolar epithelial cells are the cells that bear the brunt of the damage in paraquat poisoning. on the other hand, the alveolar capillary endothelium has its own selective uptake mechanisms (see metabolic functions of the pulmonary endothelium, p. ) which may be responsible for it being selectively damaged by other chemicals. the bronchiolar clara cells are selectively injured by some ingested chemicals because they are equipped to deal with inhaled xenobiotics, but occasionally this activity results in metabolites that are extremely toxic. an example of this from veterinary medicine is provided by the furan-derivative -ipomeanol, which is found in mouldy sweet potatoes and results in acute pulmonary oedema in cattle fed such a diet. when this chemical is injected into mice, the bronchioles are denuded of clara cells whereas the intervening ciliated cells are completely unaffected. the selective damage to the bronchiolar clara cells appears to stem from the oxidative efficiency of their p- cytochromes, which is much higher than those of the liver. chemicals having a similarly selective effect on bronchiolar clara cells include -methylfuran, carbon tetrachloride, naphthalene and , -dichloroethylene, the last of which is a volatile compound that is widely used in the plastics industry. procarcinogens may be activated in the airways by similar mechanisms. paraquat is a dipyridylium compound that is widely used in agriculture as a herbicide. it kills all green plants but is inactivated on contact with the soil. it is applied as a spray and if the manufacturer's instructions are followed there is no danger to health. most fatal cases of paraquat poisoning, both accidental and suicidal, have been due to ingestion of the % aqueous solution gramoxone. the less concentrated granular form weedol is unlikely to be ingested accidentally but may be taken suicidally. paraquat is not absorbed by the intact skin but repeated or prolonged application damages the epidermis so that absorption into the blood stream with consequent systemic effects is possible, but rare. although paraquat has toxic effects on the liver, kidneys and myocardium, these are transient and attention has centred on the pulmonary changes, which are usually fatal. following suicidal ingestion of large amounts of paraquat, death from multiorgan failure and pulmonary haemorrhage occurs within a few days, whereas most victims of accidental paraquat poisoning die from progressive pulmonary fibrosis between and days after ingestion. in those who survive longer, a honeycomb pattern of pulmonary fibrosis may be apparent. paraquat is a powerful oxidant and owes its toxicity to the production of active oxygen radicals. the lungs are particularly susceptible because paraquat is concentrated there by an active uptake mechanism in the alveolar epithelium. the inadvertent uptake of paraquat probably stems from a similarity between the molecular arrangement of its quaternary nitrogen atoms and the amine groups of endogenous oligoamines such as putrescine, spermidine and spermine, which are concerned in alveolar epithelial cell division and differentiation (fig. . . ) . this results in paraquat levels being - times higher in the lung than in the plasma. once taken up by the lung, paraquat is not metabolised but participates in redox cycling so that superoxide radicals are constantly produced. epithelial injury is proportional to the concentration of paraquat, while it is lessened by hypoxia and antioxidants such as superoxide dismutase, and potentiated by increased concentrations of oxygen. [ ] [ ] [ ] [ ] the high concentration of oxygen in the alveoli is a further reason why the lungs are particularly vulnerable to paraquat. knowledge of the toxic effects of paraquat comes from observations on autopsy series , , and from experimental studies that have enabled the sequence of pulmonary changes to be observed. [ ] [ ] [ ] [ ] in accordance with paraquat being taken up by the alveolar epithelium, electron microscopy shows that these cells suffer more profound damage than the endothelium. type i epithelial cells swell and undergo necrosis (fig. . . ), whilst type ii cells, although remaining capable of proliferation, show ultrastructural evidence of damage with derangement of cell organelles. , histological changes in the lungs follow the pattern of diffuse alveolar damage, with a characteristic feature of the early exudative phase being intense vascular congestion and alveolar haemorrhage. , , hyaline membranes are most clearly seen by about days (fig. . . ) and epithelial proliferation and fibrosis are conspicuous by about days. the pattern of pulmonary fibrosis in paraquat poisoning has been disputed. some authors have stressed its interstitial position, whereas others have clearly demonstrated that it is intra-alveolar. , , [ ] [ ] [ ] [ ] however, as described on page , it generally assumes an obliterative pattern of intra-alveolar fibrosis in which the lumina of several adjacent alveoli are totally effaced, rendering them completely airless (see fig. . , p. ). a new multisystem disease appeared abruptly in the environs of madrid in . [ ] [ ] [ ] over people were affected and about in died. the disease was initially thought to be mycoplasma pneumonia but was soon found to be associated with the use of adulterated oil sold illicitly by door-to-door salesmen. although it was sold for culinary purposes the oil had been produced for industrial use in steel manufacture. it consisted of rapeseed and olive oil mixed with liquified animal fat, aniline and other organic chemicals. it has not been possible to identify the exact chemical responsible for the disease or to reproduce the changes in other species but the later induction of similar pathological changes by another substance contaminated with an aniline derivative is possibly relevant (see l-tryptophan-induced eosinophilia-myalgia syndrome, p. ). some clinical and pathological features of the disease suggest that immune mechanisms may also be involved. the initial clinical features included fever, respiratory distress, cough, haemoptysis, skin eruptions and marked eosinophilia. radiographs suggested pulmonary oedema and sometimes showed pleural effusion. about % of patients died at this stage but most recovered quickly. however, within a few weeks many were readmitted to hospital with nausea, vomiting, diarrhoea and abdominal pain. about a quarter then proceeded to develop weakness, myalgia, weight loss, scleroderma-like skin signs and pulmonary hypertension. , many of these patients died after a long, wasting illness or are permanently disabled with neurological and hepatic disorders. in the early phase the lungs showed the most severe changes, which consisted of a combination of diffuse alveolar damage, eosinophilic infiltrates and arterial luminal narrowing by endothelial swelling and vacuolation, intimal foam cell infiltration and a non-necrotising vasculitis. , , there was also capillary thrombosis, which later extended into arteries and veins, culminating in fibrosing obliteration of these blood vessels. in some patients dying of haemoptysis, dilated thin-walled blood vessels were identified in the mucosa of major blood-filled airways. late features in the lungs included plexogenic arteriopathy (see p. ), possibly secondary to changes in the liver. similar inflammatory and vascular changes were seen in many other tissues. notable extrapulmonary features included fasciitis, vasculitis, neuronal degeneration, perineuritis, hepatic injury and tissue eosinophilia. sauropus androgynus is a vegetable that is widely cultivated for the table in many south-eastern asian countries. it is apparently harmless when cooked but recently there has been a vogue in taiwan for consuming large amounts of its unprocessed juice, blended with that of guavas or pineapple, because of its supposed efficacy as a slimming aid and in blood pressure control. coincident with this fad there has been an upsurge in patients with symptoms of obstructive lung disease. within a -month period more than such patients were seen at one hospital. [ ] [ ] [ ] they had four features in common: recent consumption of uncooked s. androgynus juice, fixed ventilatory obstruction, radiological evidence of bilateral bronchiectasis and an absence of any previous chronic respiratory disease. four patients agreed to undergo open-lung biopsy. this showed chronic bronchiolitis or obliterative bronchiolitis of constrictive pattern. the lymphocytes were mainly t cells but immunofluorescent and electron microscopy showed no evidence of an immune process. four patients underwent single-lung transplantation. the excised lungs showed sclerotic obliteration of bronchial arteries in the walls of bronchi - mm in diameter with segmental necrosis of bronchi - mm in diameter. the changes were considered to fit best with segmental ischaemic necrosis of bronchi at the watershed zone of the bronchial and pulmonary vasculature. further patients have required lung transplantation but public education of the dangers of this herbal medicine now appears to have been successful. alcohol and nicotine outstrip all other recreational drugs in popularity and their effects are of course well known. those of tobacco smoking are summarised above and dealt with in detail in the chapters on obstructive lung disease (chapter ) and carcinoma of the lung (chapter . ). less well known is the lung disease that results from smoking blackfat tobacco, a practice popular with guyanese indians. blackfat is the trade name of a type of tobacco that is flavoured with mineral oil, some of which vaporises and is inhaled when the tobacco is smoked, to cause exogenous lipid pneumonia (see p. [ch ] ). in recent years the smoking of two other substances, marijuana and cocaine, has gained in popularity. it would not be surprising if the long-term effects of smoking these substances were similar to those of cigarette smoking but as yet it is too early to judge. however, the short-term effects are similar to those of tobacco smoking and this bodes badly for their ultimate effects. marijuana consists of the dried leaves of the cannabis plant, also known as hemp, as opposed to hashish, which is the plant's resin, and a further extract known as 'weed oil' . all these substances are smoked because they contain cannabis alkaloids which have psychoactive effects. however, this habit also exposes the lungs to many of the same respiratory irritants that are found in tobacco smoke. initial exposure to marijuana smoke often results in coughing while habitual smokers produce black sputum. bronchial biopsy shows inflammation and squamous metaplasia and bronchoalveolar lavage demonstrates increased numbers of cells, which are predominantly macrophages but also include neutrophils. [ ] [ ] [ ] [ ] [ ] these changes are virtually identical to the short-term effects of tobacco smoke and are therefore likely to be similarly followed by the development of chronic obstructive lung disease and lung cancer. indeed, the dangers of smoking marijuana are probably greater than those of smoking tobacco as compared with tobacco smoking it is associated with a fivefold greater increase in blood carboxyhaemoglobin and a threefold increase in the amount of tar inhaled. it is estimated that three cannabis cigarettes result in the same degree of bronchial damage as tobacco cigarettes. there is also evidence that the effects of smoking marijuana and tobacco are additive. not surprisingly therefore, epidemiological studies report a doserelated impairment of large-airway function in marijuana smokers. there are also several reports attributing pneumothorax to marijuana smoking ( fig. . . ) . , the pneumothorax may be spontaneous or develop during the deep, sustained inspiratory effort involved in smoking marijuana (or cocaine), which may be enhanced by a partner applying positive ventilatory pressure by mouth-to-mouth contact. thoracoscopy in such cases has shown predominantly apical, irregular bullous emphysema, while lung biopsy has demonstrated widespread alveolar filling by heavily pigmented macrophages. , evidence is also beginning to accumulate that long-term cannabis use increases the risk of lung cancer. smoking cannabis in the form of weed oil is also reported to result in exogenous lipid pneumonia. cocaine cocaine hydrochloride is a fine white powder derived from the leaves of the plant erythroxolon coca by a complex chemical process. it is heat-labile and therefore cannot be smoked. users inject it intravenously or inhale it unheated through the nose, the latter practice being known as 'snorting' . however, a heat-stable free-base form that can be smoked is easily prepared from the hydrochloride with baking powder and a solvent such as ether. this process results in a crystalline deposit that is known as 'rock' because of its appearance or 'crack' because of the crackling sound it emits when heated. when smoked, the cocaine is readily absorbed and an intense surge of euphoria is experienced within seconds. the intravenous route takes twice as long and 'snorting' several minutes. the hard addict therefore prefers to smoke 'crack' . a variety of pulmonary complications of smoking free-base cocaine has been reported. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] acute effects include cough, shortness of breath, chest pain and haemoptysis. asthma may be aggravated, black sputum is produced, and pneumothorax and interstitial emphysema have resulted from valsalva manoeuvres undertaken in the belief that they promote even more rapid absorption. biopsy has shown pulmonary congestion and oedema, organising pneumonia, haemorrhage, haemosiderosis, diffuse alveolar damage and interstitial pneumonia or fibrosis. less common effects include eosinophilic pneumonia, extrapulmonary eosinophilic angiitis, medial thickening of pulmonary arteries and the barotrauma described above (see fig. . . ) . severe burning of the airways has also been seen due to 'crack' being smoked before all the ether used in its preparation has evaporated. 'snorting' unheated cocaine has its own complications: substances such as cellulose or talc with which the drug is 'cut' (mixed as a diluent) are liable to provoke a foreign-body giant cell reaction in the lungs (fig. . . ). however, particles of foreign material larger than those in the usual respirable range (allowing for the fibrous shape of substances such as cellulose) should suggest intravenous use (see 'filler embolism', below). heroin is usually injected, but it may be smoked, when, as with marijuana, it is liable to lead to a very pronounced macrophage response. intravenous heroin abuse sometimes causes the sudden onset of a potentially fatal high-permeability pulmonary oedema (fig. . . ). intravenous abuse of heroin and other drugs is also liable to cause 'filler embolism', which will now be considered. 'filler embolism' is the result of illicit drug usage in which compounds designed for oral use are injected intravenously to heighten their effects. oral preparations consist largely of fillers such as talc or starch and this insoluble particulate matter accumulates in the pulmonary capillaries. it provokes a foreign-body giant cell reaction, thrombosis and fibrosis and may cause pulmonary hypertension ( fig. this 'designer' drug, taken for its central stimulant activity (street names 'ice' or 'u- -e-uh', pronounced euphoria), is related to the appetite suppressor aminorex, discussed on page , and has similarly been associated with pulmonary hypertension. assessing whether a particular clinical manifestation represents an adverse drug reaction considers previous experience with the drug, alternative aetiological agents, the timing of events, drug levels, and the effect of withdrawing the drug and rechallenge with the drug. it is worth bearing in mind that: • one drug may cause several patterns of disease. • one pattern of disease may be produced by a variety of drugs. • a drug reaction may develop long after the drug has been withdrawn. • a drug reaction may develop suddenly even though the dose of the drug has not been altered. • drug effects may be augmented by factors such as age, previous radiotherapy and elevated oxygen levels. • drug reactions may be localised. • many drugs cross the placenta to affect the fetus. an alternative classification of adverse drug reactions, which is more appropriate to pathology practice and which will be followed here, is one based on the pattern of disease. some pathological patterns of drug-induced lung disease are shown in table central depression of respiration occurs as a side-effect of barbiturates, morphine and its derivatives, and even mild sedatives, and may be particularly troublesome in patients suffering from chronic obstructive lung disease. ventilation in such patients may be largely dependent on hypoxic respiratory drive and treatment with oxygen may therefore also have an adverse effect on respiration by lowering the degree of hypoxia and so diminishing the stimulation of the respiratory centre. peripheral impairment of the respiratory drive may be brought about by aminosides and other antibiotics, while corticosteroids may result in a myopathy affecting the respiratory muscles. other iatrogenic hazards affecting the peripheral nerves controlling respiration include nerve root disease complicating immunisation and surgical damage to the spinal and phrenic nerves. asthmatic patients are particularly susceptible to exacerbations of their disease by drugs (box . . ). this effect may occur either as a predictable pharmacological side-effect of the drug or as an idiosyncratic response. examples of the former include β-adrenergicic antagonists and cholinergic agents while examples of the latter include sensitivity to the colouring agent tartrazine, for which reason many manufacturers have eliminated tartrazine from their red, orange and yellow tablets. allergic bronchoconstriction also forms part of generalised anaphylactic reactions induced by vaccines and antisera and occurs as a localised response to penicillin, iodine-containing contrast media, iron dextran and other medicaments. bronchospasm may also be initiated by the non-specific irritant effect of inhaling nebulised drugs if they are prepared as a hypotonic solution, a side-effect that is prevented by using isotonic solutions. aspirin and other non-steroidal anti-inflammatory agents aspirin-induced asthma has been recognised for many years and more recently several of the newer anti-inflammatory drugs have been found to exacerbate asthma in certain sensitive individuals. the basis for this is uncertain but the likelihood of an individual antiinflammatory drug provoking an asthmatic response is related to its potency as an inhibitor of prostaglandin cyclooxygenase pathway, resulting in the production of leukotrienes. [ ] [ ] [ ] as well as asthma being exacerbated by drugs, the disease has been caused by occupational exposure in the pharmaceutical industry to certain drugs which can be inhaled during manufacture, notably penicillin, cephalosporin, methyldopa, cimetidine and piperazine. obliterative bronchiolitis of the constrictive type has been reported with penicillamine , and gold , but in many cases it is possibly the underlying condition rather than the drug that is res ponsible (see p. ). this is often rheumatoid disease, which is sometimes complicated by bronchiolitis obliterans whether the patient is under treatment or not. organising pneumonia extending into peripheral bronchioles (see p. ) may be seen with a variety of drugs but results in a restrictive rather than obstructive lung defect and is to be regarded as a cytotoxic effect of the drug acting primarily at the alveolar level (see below). raw sancropus androgyns taken as a slimming aid causes severe obliterative bronchiolitis (see p. ). the cytotoxic effects of drugs may be acute or chronic, leading to changes as varied as pulmonary oedema, diffuse alveolar damage, pulmonary haemorrhage and haemosiderosis, organising pneumonia, interstitial pneumonitis and interstitial fibrosis. , some of the most severe acute effects are seen with the chemotherapeutic agents used in malignant disease but they are also recorded with drugs that are not traditionally thought to be cytotoxic, e.g. desferrioxamine administered as a prolonged intravenous infusion in acute iron poisoning. pulmonary toxicity due to busulphan was first described in , and has been the subject of several subsequent studies. [ ] [ ] [ ] [ ] it remains the mainstay of treatment for chronic myeloid leukaemia. like other alkylating agents, it acts by cross-linking dna strands. clinical estimates of the incidence of pulmonary toxicity vary around % but subclinical damage is thought to be much more common. although not strictly dose-dependent, toxicity is rarely seen with a total cumulative dose of less than mg. synergy with radiation and other cytotoxic drugs occurs. similar effects have been reported for most cytotoxic agents, particularly bleomycin. pulmonary toxicity is seen less commonly with other alkylating agents, such as cyclophosphamide and melphalan. [ ] [ ] [ ] [ ] bleomycin is a cytotoxic antibiotic derived from streptomyces species. it is widely used in the treatment of neoplasms such as lymphomas and germ cell tumours, and is thought to produce its therapeutic and toxic effects by altering the normal balance between oxidants (active oxygen radicals) and antioxidant systems. bleomycin produces superoxide radicals when incubated with oxygen and iron in vitro. oxygen enhances its effects, a fact well known to anaesthetists who accordingly take care to limit concentrations of inspired oxygen to % in patients on bleomycin who are undergoing surgery. [ ] [ ] [ ] radiotherapy and cytotoxic agents such as bleomycin are also synergistic. bleomycin is preferentially concentrated in the lungs and pulmonary fibrosis can be produced in animals when it is administered intravenously, intraperitoneally or by intratracheal instillation. electron microscopy shows that the early changes consist of swelling and vesiculation of endothelial cells, interstitial oedema and type i epithelial cell necrosis. , the reported incidence of bleomycin toxicity varies from to % depending on the type of patient being treated and on dosage. in general, toxic effects increase with age and cumulative dose: above a total dose of about units they rise significantly. the acute morphological changes attributable to drugs include pulmonary oedema and diffuse alveolar damage. acute pulmonary oedema is seen in heroin addicts who die while injecting themselves intravenously but it is also seen in patients administered a variety of drugs therapeutically, for example hydrochlorothiazide, salicylate, opiates, vinorelbine,and desferrioxamine. the oedema is of the high permeability type (see p. ), rich in protein, and is occasionally haemorrhagic or accompanied by the hyaline membranes of diffuse alveolar damage. diffuse alveolar damage has alveolar epithelial necrosis as its basis (figs . . and . . ). however, the continuing action of many cytotoxic drugs affects the regeneration process so that atypical type ii epithelial cells develop, a characteristic feature that was first described with busulphan and subsequently with bleomycin. , these two drugs differ chemically but both act (by different mechanisms) on dna. the atypical cells have abundant deeply eosinophilic or amphophilic cytoplasm and large nuclei, which may be multiple but are usually single. the nuclei measure up to µm and are densely stained throughout or contain either large homogeneous deeply eosinophilic inclusions or clear vacuoles (fig. . . ) . electron microscopy distinguishes the inclusions from nucleoli and shows them to consist of tubular aggregates derived from the internal nuclear membrane. airway epithelium shows similar nuclear changes and often undergoes squamous metaplasia. the presence of such cells in sputum specimens submitted for cytology can lead to a misdiagnosis of malignancy. fibrosis may follow diffuse alveolar damage or develop insidiously, perhaps many years after drug therapy ceased (fig. . . ) . it may be both interstitial and intra-alveolar. the interstitial component is often accompanied by a non-specific chronic inflammatory infiltrate. the proportions of inflammation, which is potentially reversible, and fibrosis, which when collagenous is irreversible, obviously bear on the prognosis. however, most case reports antedate the recent classification of interstitial pneumonia described in chapter and it is uncertain how their pathological appearances would now be classified. the majority lack the classic features of usual interstitial pneumonia and fibrotic non-specific interstitial pneumonia. many show overlapping patterns of intersitital pneumonia and this alone should arouse suspicion that a drug may have been responsible. however, some cytotoxic drugs result in pulmonary changes by more than one mechanism: for example, methotrexate may produce hypersensitivity reactions with granuloma formation [ ] [ ] [ ] [ ] or pulmonary eosinophilia as well as diffuse alveolar damage. pulmonary toxicity is also occasionally seen in patients undergoing treatment with gold salts for rheumatoid disease: in addition to diffuse alveolar damage, there may be eosinophilia and dermatitis in these cases, again indicating possible hypersensitivity. nitrofurantoin is another example of a drug resulting in a variety of patterns of alveolar injury: diffuse alveolar damage, desquamative interstitial pneumonia, giant cell interstitial pneumonia, organising pneumonia and eosinophilic pneumonia have all been recorded in association with this drug. [ ] [ ] [ ] it should also be noted that in patients with neoplastic disease, clinical features suggestive of a pulmonary drug reaction may be due to factors other than drugs. in leukaemic patients, for example, these include direct infiltration of the lungs by leukaemic cells, opportunist infection and, if bone marrow transplantation has been undertaken, the effects of irradiation and possibly graft-versus-host disease. phospholipidosis is encountered with drugs such as the antidysrhythmic agent amiodarone, which block lysosomal enzymes involved in the breakdown of complex lipids. this leads to their accumulation throughout the body but the effect is most marked in tissues that take up the drug and contain cells rich in lysosomes. the lung fulfils both these requirements through its rich complement of alveolar macrophages. these cells accumulate the enzyme substrate (phospholipid) in their cytoplasm with the result that large foam cells fill the alveoli (fig. . . ). the appearances are those of endogenous lipid pneumonia, similar to that seen in obstructive pneumonitis. however, with amiodarone cytoplasmic vacuolation is also seen in epithelial and interstitial cells. the phospholipid inclusions contained within the vacuoles are particularly well seen in unstained frozen sections viewed by polarised light. identical changes to those induced by amiodarone were seen in the lungs of rats exposed to very high levels of the antidepressant drug iprindole and the anorectic drug chlorphentermine. these three compounds, iprindole, chlorphentermine and amiodarone, all belong to the amphiphilic group of drugs which block lysosomal phospholipase and sphingomyelinase. although their pharmacological actions are very different, a molecular homology is apparent (fig. . . ) . it is likely that all patients receiving substantial amounts of amiodarone develop phospholipidosis throughout the body, but this is generally well tolerated. only a minority experience respiratory impairment and in these there is also evidence of pulmonary inflammation and fibrosis, which is possibly mediated immunologically. these patients generally have a restrictive lung deficit, the onset of which may be acute or chronic. bronchoalveolar lavage shows foamy macrophages but these cells indicate exposure to the drug rather than drug toxicity; nor are they specific to amiodarone, being observed on occasion with other drugs. lymphocytes of suppressor type may also be detected on lavage. histologically, amiodarone toxicity is diagnosed on a combination of phospholipidosis and interstitial pneumonia and fibrosis. occasionally the hyaline membranes of diffuse alveolar damage are superimposed on the interstitial changes (see fig. . . ) . [ ] [ ] [ ] in some patients the fibrosis is intraalveolar rather than interstitial and the appearances are those of organising pneumonia. the process may be localised and mimic a neoplasm radiologically. , amiodarone toxicity is probably dose-dependent but there is considerable individual variation in the amount required, , which appears to be under genetic control. amiodarone toxicity is uncommon in patients taking daily doses of mg or less whereas the there are drugs that undoubtedly cause a usual interstitial pneumonia pattern, for example the chemotherapeutic agents and nitrofurantoin (fig. . . ), while others, for example the statins, are recorded as having induced a non-specific interstitial pneumonia pattern. a drug history is therefore imperative when assessing any patient with diffuse parenchymal lung disease. organising pneumonia similar to the cryptogenic condition described on page , and probably similarly reversible with steroids, has been encountered with a variety of drugs, including amiodarone, sulphasalazine and pencillamine. penicillamine has also been incriminated in the development of both diffuse alveolitis and bronchiolitis obliterans, but both these changes could well be due to the underlying rheumatoid disease for which the pencillamine is administered. in busulphan lung there may be an organising intraalveolar fibrinous exudate, which at its most extreme results in irreversible effacement of the alveolar architecture by sheets of loose connective tissue (see p. ). with continued experimental administration of the drug iprindole mentioned above, the phospholipidosis it produced gradually evolved into alveolar proteinosis (more properly called lipoproteinosis; see p. ), but this has not been reported as a drug effect in humans. alveolar proteinosis has however been recognised in a number of patients receiving chemotherapy for conditions such as leukaemia. the mechanism here is probably based on the cytotoxic action of the drug and the material filling the alveoli may represent the detritus of degenerate alveolar cells rather than excess pulmonary surfactant, as in the primary auto-immune form of alveolar proteinosis. eosinophilic pneumonia, the pathology of which is described on page , may be caused by several drugs, including nitrofurantoin, para-aminosalicylic acid, sulphasalazine, phenylbutazone, gold compounds, aspirin and penicillin (see box . , p. ). , it may also follow radiation to the chest. the tissue eosinophilia is generally accompanied by a rise in the number of eosinophils in the blood. the clinical picture varies from transient asymptomatic opacities on a chest radiograph to a life-threatening illness with severe respiratory distress and hypoxaemia, so-called acute eosinophilic pneumonia (see p. ). the reaction is often associated with a florid rash. withdrawal of the drug may be all that is required to effect resolution but corticosteroids are usually given as they produce a marked improvement. this syndrome of necrotising granulomatosis, vasculitis and eosinophilia in asthmatic patients, which is described more fully on page , has been reported when leukotriene receptor antagonists have been used to treat asthma. however, it is likely that the syndrome has been merely unmasked by the antileukotriene permitting a reduction in corticosteroid dose rather than representing a direct effect of the antileukotriene. , mesalazine has also been implicated in inducing a vasculitis during treatment for inflammatory bowel disease. the eosinophilia-myalgia syndrome was identified in the usa in and quickly identified as being due to the ingestion of ltryptophan from one particular japanese supplier. withdrawal of this substance led to the virtual elimination of the disease, but not before patients had been affected, in fatally. [ ] [ ] [ ] [ ] [ ] cases were subsequently described in europe where there were further fatalities. l-tryptophan is an essential amino acid that is freely available to the public: its purchase does not require a medical prescription. it has been promoted as a dietary supplement and as an agent against insomnia and premenstrual tension. women in the reproductive years preponderated in the patients affected by the resultant eosinophiliamyalgia. the clinicopathological features of the syndrome are similar to those of the spanish toxic oil syndrome (see p. ) and differ more in degree than type. the discovery of an aniline-derived contaminant in the tryptophan-induced condition is a further link connecting these two syndromes. an immune basis is suggested by the identification of t lymphocytes activated against fibroblasts in the eosinophilia-myalgia syndrome. the illness is a multisystem disorder and besides blood eosinophilia and myalgia there may be arthralgia, fever, rash and involvement of the lungs, liver and central nervous system. as in the toxic oil syndrome, there is fasciitis, wasting and muscle pain associated with blood and tissue eosinophilia. the lungs are affected in % of cases. pulmonary symptoms have included cough, dyspnoea and chest pain. radiographs have shown diffuse bilateral infiltrates and pulmonary hypertension has been documented in a few cases. histology of the lungs shows an oedematous myxoid intimal thickening affecting small pulmonary blood vessels and a diffuse interstitial lymphocytic and eosinophilic infiltrate. , , , , these cells may also be seen within the walls of the thickened blood vessels (fig. . . ) . , massive ingestion of l-tryptophan has resulted in the appearances of an organising pneumonia. as an adverse drug reaction, granulomatous alveolitis is best exemplified by the extrinsic allergic alveolitis of pituitary snuff-takers, but it is also encountered on rare occasions with cytotoxic and other drugs, including methotrexate, bacille calmette-guérin (bcg) immunisation, interferons, ciprofloxacin, antiviral therapy and tumour necrosis factor antagonists. [ ] [ ] [ ] , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the histological appearances may suggest extrinsic allergic alveolitis or sarcoidosis but the centri-acinar or lymphangitic concentration of these conditions is usually lacking. however, unless an infective agent can be demonstrated the diagnosis generally requires consideration of the clinical and environmental details, including any drug regimen. exogenous lipid pneumonia may result from the unintentional aspiration of various fat-based medicaments such as liquid paraffin, oily nose drops and petroleum jelly or of fat-rich dietary supplements in the form of ghee. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the consumption of liquid paraffin as an aperient is common in some countries and may be taking place without the knowledge of the patient's medical practitioner. regurgitation and aspiration of ingested oil are especially likely to happen during sleep in the presence of a hiatus hernia or when the oesophagus fails to empty completely into the stomach because of achalasia of the cardia. the aspiration of vegetable oil occurred in the past from the use of menthol in olive oil for the treatment of tuberculous laryngitis, and occasionally from the use of iodinated vegetable oils for bronchography. [ ] [ ] [ ] [ ] more recently exogenous lipid pneumonia has developed from the constant sucking of lollipops formulated for the administration of the analgesic fentanyl but also containing a stearate component. the treatment of epistaxis by nasal packing with paraffin gauze has also led to exogenous lipid pneumonia. the pathology of exogenous lipid pneumonia is described on page . other medicines may also be aspirated unwittingly, for example a ferrous sulphate tablet may cause brown iron staining and necrosis of the bronchus at the point of impact, progressing to bronchial stenosis. [ ] [ ] [ ] distal infection is then likely, as with any foreign body. barium sulphate aspiration may complicate gastrointestinal radiography. large amounts may impair ventilation but being inert there is no permanent injury to the lungs, although the striking changes are evident on the chest radiograph. an outbreak of pulmonary hypertension affecting many swiss, austrian and german patients in the period - was probably due to the anorectic drug aminorex, which was accordingly withdrawn with regression in the number of new cases. the pathology in these patients was identical to that of primary pulmonary hypertension (see p. ) and it proved impossible to reproduce the condition in laboratory animals but the epidemiological evidence that aminorex was to blame is very strong. fenfluramine and phentermine, further anorectic drugs that are chemically similar to aminorex, have also been associated with such plexogenic pulmonary hypertension, [ ] [ ] [ ] [ ] [ ] and with fibroproliferative plaque on the tricuspid valve and pulmonary arteries. pulmonary hypertension due to pulmonary veno-occlusive disease has sometimes complicated the use of cytotoxic chemotherapeutic agents or followed bone marrow transplantation. non-steroidal anti-inflammatory agents such as indomethacin and diclofenac cross the placenta and, if given in late pregnancy, may cause premature closure of the ductus arteriosus, resulting in severe neonatal pulmonary hypertension. , pulmonary hypertension is a well-recognised association of human immunodeficiency virus (hiv) infection but until recently has been unexplained. now, however, evidence is emerging that the highly active antiretroviral therapy administered to hiv-positive patients might be responsible for the pulmonary hypertension. the older high-oestrogen contraceptive drugs carried a slight risk of thromboembolism but this is not seen with the newer preparations. pulmonary thromboembolism has also occurred with a drug-induced lupus syndrome associated with anticardiolipin antibodies. chemotherapeutic drugs such as mitomycin may cause widespread smallvessel thrombosis resulting in the haemolytic-uraemic (thrombotic microangiopathic) syndrome. there is prominent involvement of pulmonary vessels and patients often suffer from respiratory as well as renal insufficiency, and pulmonary hypertension. the syndrome can develop during treatment or up to several months after the drug has been withdrawn. pulmonary thromboembolism is also recorded as a complication of immunoglobulin infusion. non-traumatic fat embolism has resulted from the agglutination or 'creaming' of fat emulsions administered intravenously as a source of calories to debilitated patients. [ ] [ ] [ ] [ ] [ ] [ ] the agglutinated liposomes occlude fine blood vessels throughout the body, causing effects such as priapism, osteonecrosis and pancreatitis. they may be demonstrated in the pulmonary capillaries but the lungs have considerable vascular reserve and it is uncertain what effect the vascular occlusion has on pulmonary function. agglutination of these fat emulsions is particularly common in severely ill patients and this has been attributed to the elevated blood levels of acute-phase proteins, especially c-reactive protein, that are found in the very ill. the agglutination is also induced by calcium and may be brought about by administering calcium and other mineral supplements through the same venous line as the fat. once agglutinated, the fat is less soluble and may be demonstrated in paraffin sections. sudan black is especially useful for this purpose (fig. . . ). microvascular crystal embolism is a further risk of parenteral nutrition, the crystals representing various calcium salts that may precipitate in the circulation. transient diffusion abnormalities attributed to oil embolism are very common in patients undergoing lymphangiography but serious respiratory impairment is limited to those patients with pre-existing lung disease or in whom substantial amounts of contrast medium are injected rapidly. [ ] [ ] [ ] [ ] other emboli of an iatrogenic nature described in pulmonary arteries include the broken-off ends of intravenous catheters and cannulas, particles from dialysis tubing, prosthetic implants of substances such as teflon and silicone , [ ] [ ] [ ] [ ] and various materials injected to occlude abnormal blood vessels. , diffuse pulmonary haemorrhage diffuse pulmonary haemorrhage may result from interference with the clotting mechanism by anticoagulants or from widespread pulmonary capillaritis, the latter reported in leukaemic patients treated with retinoic acid. pulmonary haemorrhage has also been reported as an idiosyncratic reaction to lymphangiography media and as a complication of immunoglobulin infusion, while the development of anti-basement membrane antibodies resulting in goodpasture's syndrome has been attributed to penicillamine. a infection is a common pulmonary hazard in any patient receiving corticosteroids, chemotherapy or any other immunosuppressant drug. viral, bacterial, fungal and protozoal infections, often in combination, may all develop in the lungs of such patients and tissue reactions may be atypical. pneumocystis jiroveci, for example, may elicit a granulomatous reaction or cause diffuse alveolar damage rather than the usual foamy alveolar exudate (see p. ). metastatic calcification, described on page , may result from any drug causing hypercalcaemia, e.g. high doses of vitamin d, calcium and inorganic phosphate or excessive alkali intake in the treatment of peptic ulceration. carcinoma of the lung may be promoted by drugs. arsenicals cause squamous metaplasia of the bronchi and occasionally squamous carcinoma, while peripheral scar cancers, usually adenocarcinomas, have developed in lungs showing fibrosis due to drugs such as busulphan. drugs may result in a variety of pleural diseases. common examples include effusions, chronic inflammation and fibrosis. these are usually encountered in isolation but may be associated with chronic interstitial pneumonia or fibrosis. sometimes there is also serological evidence of systemic lupus erythematosus: many drugs, including hydantoin, practolol, procainamide, hydralazine and sulphonamides, are associated with the development of a syndrome resembling systemic lupus erythematosus that includes pleural disease. whether the drugs are directly responsible for the syndrome or merely promote the development of latent natural disease is uncertain. ergotamine derivatives such as methysergide and bromocriptine are notable for the production of pleural fibrosis, which is sometimes associated with mediastinal and retroperitoneal fibrosis large amounts or prolonged treatment are generally required to produce this effect. [ ] [ ] [ ] in patients given practolol, pleural thickening has become evident several years after the drug was discontinued. this shows the need for a careful drug history in any patient with unexplained pleural fibrosis. reports of radiation-induced lung damage began to appear soon after ionising radiation became widely used in the treatment of malignant disease. [ ] [ ] [ ] despite refinements in radiotherapy techniques it is often impossible to avoid irradiating small areas of lung when treating cancer of the lung, breast, spine, thymus and oesophagus. parts of the lungs are also included in 'mantle' irradiation of mediastinal lymph nodes affected by lymphoma. occasionally, the whole of both lungs is irradiated, as in the treatment of widespread pulmonary metastases or as part of whole-body irradiation prior to marrow transplantation for the treatment of leukaemia. radiation pneumonitis, usually localised, is estimated to affect about % of patients. therapeutic irradiation is given as divided doses over several weeks in order to minimise damage to adjacent tissue. the effects of such fractionated treatment are cumulative. in the lungs an early exudative phase soon passes and progressive damage becomes apparent only after months or even years. , the changes are generally confined to the area of lung that is irradiated but are widespread when the whole body is irradiated prior to bone marrow transplantation or there is accidental whole-body irradiation. however, localised irradiation of the lung has been followed by abnormalities in non-irradiated areas. these include bilateral alveolar exudates, migratory organising pneumonia affecting both lungs , and fulminant bilateral interstitial pneumonia. the likelihood of lung injury is increased by the simultaneous use of cytotoxic drugs and oxygen therapy. furthermore, chemotherapy following irradiation may result in exacerbation of the injury in areas previously irradiated, a phenomenon termed 'recall pneumonitis' . , in the long term, irradiation also results in an increased incidence of lung carcinoma. this was seen in patients given therapeutic irradiation to the spine for ankylosing spondylitis and is still encountered on occasion following irra diation for breast cancer. the pathogenesis of radiation injury is described on page . radiation damage to the lung is traditionally separated into fulminant acute injury coming on within days, subacute pneumonitis developing within several weeks (typically - months) and interstitial fibrosis slowly evolving from the subacute stage or making itself apparent years later. the migratory organising pneumonia referred to above is an unusual further effect, as is chronic eosinophilic pneumonia. in the pleura, radiation causes fibrinous effusions and adhesions. pleural effusion and pulmonary oedema may be augmented by the long-term effects of radiation on the heart. fulminant acute injury is an unusual and unexpected effect of therapeutic radiation but one that is likely to come to the attention of the pathologist as an autopsy is often requested. the clinical features are those of acute lung injury and the pathological changes are those of diffuse alveolar damage. the cause is likely to be accidental overdosage, augmentation of the radiation damage by accompanying oxygen therapy or treatment with cytotoxic drugs. occasionally however these factors can be excluded, in which case the damage has to be ascribed to 'hypersensitivity' . subacute radiation pneumonitis is encountered more commonly. after an interval of about - months the patient complains of shortness of breath and a non-productive cough. the chest radiograph shows hazy opacification proceeding to more dense consolidation. lung biopsy shows alveolar and interstitial oedema, possibly with residual hyaline membranes, proliferation of atypical alveolar epithelial cells and interstitial fibroblasts and organising thrombosis. later, as the process advances, there is widespread fibrosis comparable to that illustrated in figure . on page and ultimately dense scarring (fig. . . ) . tracheal and aortic injury may complicate radiation treatment of tracheal lesions, sometimes resulting in an aortotracheal fistula. patients requiring mechanical ventilation are liable to suffer lung injury in a number of ways. in addition to effects of barotrauma such as pneumothorax and surgical emphysema, they often develop diffuse alveolar damage. the high oxygen tension that is often combined with mechanical ventilation is a major factor - but mechanical forces other than the high pressures responsible for barotrauma can also contribute to this form of lung injury, notably by resulting in excessive end-expiratory stretch and repeated collapse/recruitment of the alveolar walls. , low tidal volume ventilation is therefore a fundamental part of the management of diffuse alveolar damage. although oxygen is necessary to life, it is cytotoxic in high concentrations. severe hyperoxia damages dna, inhibits cellular proliferation and ultimately kills cells. its toxicity is thought to be due to the intracellular production of active oxygen radicals, some of which derive from activated neutrophils attracted to the site of injury. [ ] [ ] [ ] [ ] under normal conditions most of the oxygen is reduced to water by cytochrome oxidase, and any active radicals produced are eliminated by superoxide dismutase, catalase and other antioxidants. however, these defence mechanisms may prove inadequate when active radicals are produced in excess. problems are likely to arise in clinical practice when lung disease necessitates the concentration of oxygen in the inspired air being raised in order to maintain normal blood levels of oxygen and prevent cerebral hypoxia. [ ] [ ] [ ] a 'safe' level for oxygen administration is not firmly established and, because of species differences in susceptibility to oxygen, caution is needed in extrapolating from animal studies. however, animal experiments have shown that previous damage to the lungs renders them unduly sensitive to oxygen , and conversely that prior exposure to high levels of oxygen confers some resistance to subsequent oxygen exposure. clinical studies suggest that less than % oxygen (at atmospheric pressure) can be tolerated for long periods without ill effect. little, if any, serious lung damage results from administration of % oxygen for up to hours but concentrations between % and % carry a risk of damage if this period is exceeded. , extracorporeal oxygenation of the blood circumvents the problem but if it is to be prolonged it becomes a major undertaking that poses its own hazards; it is therefore generally reserved for patients who remain hypoxaemic despite other measures. intravenous blood oxygenators are employed to minimise the supplementation of inspired oxygen and partial liquid ventilation utilising perfluorocarbon has also been used. experimentally, disruption of cd binding to reduce the release of proinflammatory cytokines has shown promising results in blunting oxygen-induced lung injury. none of the morphological changes attributable to oxygen toxicity is specific. the earliest ultrastructural change in experimental oxygen poisoning is swelling of endothelial cells, the cytoplasm of which becomes grossly oedematous and vacuolated. swelling and fragmentation of type i epithelial cells follow and these cells become separated from their basement membrane, which is then coated by thin strands of protein. this coating is replaced by proliferating type ii cells by the th day. with recovery in room air the lungs practically return to normal. the full clinical picture of oxygen poisoning is the acute respiratory distress syndrome and the corresponding pathological changes are those of diffuse alveolar damage, as described on page . patients with hypovolaemic shock or undergoing major surgery often require massive blood transfusions and this provides another possible cause of pulmonary damage. although hypervolaemia is the commonest cause of pulmonary oedema after blood transfusion, transfusion-related acute lung injury is more often fatal. platelet and white cell aggregates are known to develop in stored blood, but a relationship between the number of microaggregates transfused and the degree of respiratory impairment has not been convincingly demonstrated. leukocyte antibodies are a more likely cause of lung injury in these patients. such antibodies are often found in multiparous female donors as a result of sensitisation by fetal white cells during pregnancy. alternatively, the recipient may have developed them during pregnancy or as a result of previous blood transfusions. the implicated antibodies are thought to initiate alveolar capillary damage within hours of transfusion by stimulating granulocyte aggregation. , electron microscopy has shown capillary endothelial damage with activated granulocytes in contact with alveolar basement membranes. cardiopulmonary bypass entails oxygenation and circulation of the blood by extracorporeal devices, so permitting major heart surgery. in the early days of such surgery it was not unusual for patients to develop fatal respiratory insufficiency in the postoperative period. this led to the term 'postperfusion lung' . electron microscopic studies showed alveolar damage with degranulation of neutrophils in pulmonary capillaries. , the syndrome is now less common but infants remain susceptible. the most likely explanation is that the synthetic materials with which blood comes into contact during the bypass procedure are able to activate complement. this is mediated by hageman factor (factor xii) and the alternative pathway. aggregation of neutrophils leads to their sequestration in the lungs and damage results from their release of lysosomal enzymes and active radicals. [ ] [ ] [ ] the process is delayed by hypothermia. a postcardiac injury syndrome develops after a variety of myocardial or pericardial injuries: it has been described after cardiac surgery (postpericardiotomy syndrome), myocardial infarction (dressler's syndrome), blunt trauma to the chest, percutaneous puncture of the heart and implantation of a pacemaker. there is a delay of anything between a few days and a few months between the cardiac injury and the onset of symptoms, which comprise chest pain, breathlessness, dyspnoea and fever. examination usually reveals haemorrhagic pleural or pericardial effusions and pulmonary infiltrates. the syndrome usually resolves spontaneously and few pathological studies have therefore been conducted. however, the changes of diffuse alveolar damage have been reported, principally hyaline membrane formation and type ii pneumocyte hyperplasia. the pathogenesis is obscure. antibodies reacting with myocardial antigens often develop after cardiac surgery but there is no relationship between these and the development of the syndrome. [ ] [ ] [ ] this minimally invasive technique is used to destroy lesions as varied as pulmonary metastases and the connection between the left atrium and ectopic foci in the muscular sleeves that surround the terminations of the pulmonary veins (see p. ). the former may be complicated by pneumothorax and the latter by pulmonary vein stenosis. , central venous cannulation (synonym: catheterisation) is widely used in treating seriously ill patients and may give rise to serious complications. the commonest early complications related to the respiratory tract are caused by local trauma: they include pneumothorax, subcutaneous emphysema, haemothorax and air embolism. infection occurs later, causing endocarditis, septic emboli and lung abscesses. thrombosis is another common late complication: one autopsy study of patients with central venous lines showed that % had major pulmonary emboli and % had microscopic emboli in their pulmonary arteries. pulmonary artery cannulation, for example with a swan-ganz catheter, may result in pulmonary infarction or any of the traumatic complications of central venous catheterisation mentioned above. , tracheotomy entails a small immediate risk of haemorrhage from damaged subthyroidal arteries, while an endotracheal tube predisposes to infection, as with all foreign bodies. infection is also promoted by the filtering action of the upper respiratory air passages being bypassed. the latter factor also necessitates humidification of the inspired air and on occasion the humidifier or ventilator has become contaminated so that an aerosol of bacteria is introduced directly into the lower respiratory tract. high-pressure ventilation may also lead to interstitial emphysema, pneumothorax and surgical emphysema. asphyxia may follow an endotracheal tube becoming blocked by secretions or through it being badly positioned. secretions need to be constantly removed yet repeated suctioning to achieve this has led to cardiac dysrrythmia and even cardiac arrest. if the balloon on the endotracheal tube is too near the tracheostomy it may act as a fulcrum, causing the tip of the tube to press into the tracheal wall. pressure necrosis and perforation may follow, leading to mediastinitis, tracheo-oesophageal fistula or erosion of a large blood vessel. these are also complications of tracheobronchial laser therapy. pressure from the balloon may lead to a tracheal diverticulum and after the tube is withdrawn the trachea may become narrowed at either the site of the incision or further down where the balloon on the tracheal tube causes pressure. small, shallow ulcers generally heal quickly but deeper ulcers cause necrosis of the tracheal cartilage, and healing is then often accompanied by fibrous stenosis (fig. . . ) or web formation. this results in wheezing and dyspnoea but not before the trachea has narrowed to % of its original size, which may take months. earlier narrowing may be caused by oedema or a fibrinous pseudomembrane. , sometimes the stenosis takes the form of a large mass of granulation tissue at the tracheostomy site, a so-called granuloma ball. in children especially, intubation may lead to tracheomalacia so that after the tube is removed the airway collapses. necrotising sialometaplasia is a further complication of prolonged intubation. the incidence of such posttracheostomy complications can be minimised by careful placement of the stoma and tube, avoidance of large apertures and high cuff pressures, elimination of heavy connecting equipment and meticulous care of the tracheostomy. nasogastric feeding tubes may of course lead to aspiration lesions in the lungs and even fatal asphyxia if they are inadvertently allowed to enter the trachea rather than the oesophagus. bronchoscopy is generally a safe, almost routine procedure. a review of patients who underwent bronchoscopy identified severe complications in ( . %), of whom three died. the fatal cases comprised a -year-old with coronary heart disease who developed cardiac arrest and two patients who had had tracheal transplantation for oesophageal cancer and required bronchoscopic laser treatment but died of airway obstruction. the pleural cavity is intubated in the treatment of pneumothorax and pleural effusions the tube being placed anteriorly to drain air and posteriorly to drain fluid. complications include laceration of an intercostal artery or vein, the lung, the diaphragm and the heart. pneumonectomy has been practised since the s, since when the mortality associated with this operation has dropped from over % to near zero in the best hospitals. risk factors include underlying lung disease, other medical conditions and more extensive procedures such as pleuropneumonectomy and pneumonectomy combined with chest wall resection. the anatomical changes that take place soon after pneumonectomy have been extensively studied by radiologists who describe the air-filled postpneumonectomy space gradually filling with fluid and contracting as the mediastinum shifts and the ipsilateral dome of the diaphragm rises. much of the space is filled by fluid within weeks but complete opacification may take up to months. rapid filling in the immediate postoperative period suggests haemorrhage or chylothorax. however, fluid accumulation is normally rapid after pleuro-pneumonectomy and may compromise the function of the other lung. pathologists conducting autopsies long after the operation may find complete fibrous obliteration of the postpneumonectomy space, coupled with mediastinal shift and elevation of the hemidiaphragm, but often there is persistent brown fluid, which may be clear, cloudy or occasionally purulent. the remaining lung is generally enlarged, with its volume greater than predicted. animal studies have shown that if one lung is excised early in life the enlargement is partly due to enhanced growth but later it represents only dilatation of existing air spaces. hepatocyte growth factor is thought to be involved in the proliferation of residual lung cells following pneumonectomy. pulmonary complications include those typically seen after other thoracic procedures, such as haemorrhage and infection, and those unique to the postpneumonectomy state, namely anastomotic dehiscence and postpneumonectomy pulmonary oedema. the latter presents as the acute respiratory distress syndrome and represents the early stages of diffuse alveolar damage. it follows severe shift of the heart and mediastinum, which is commoner in children and young adults, in whom the tissues are more compliant. [ ] [ ] [ ] [ ] the condition complicates up to % of lung resections , and is commoner following excision of the right lung when severe herniation of the left lung into the postpneumonectomy space stretches the trachea and left main bronchus and the latter is compressed between the left pulmonary artery in front and the arch of the aorta behind. in the long term the compression can result in bronchomalacia and postobstructive bronchiectasis. if postpneumonectomy oedema develops the immediate postoperative mortality is high - % following pneumonectomy, % following lobectomy and % following sublobar resections. , the pathogenesis is probably multifactorial but apart from factors such as fluid overload and high inspired oxygen concentrations there is probably an element of alveolar wall injury, induced by oxidant generation secondary to lung stretching and general surgical trauma. , occupational dust exposure and chronic obstructive pulmonary disease -a systematic overview of the evidence 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factors influencing its obliteration hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice severe airway obstruction caused by mediastinal displacement after right pneumonectomy in a child. a case report postpneumonectomy syndrome: diagnosis, management, and results treatment of left pneumonectomy syndrome with an expandable endobronchial prosthesis postpneumonectomy syndrome: another twist acute lung injury and acute respiratory distress syndrome after pulmonary resection the mortality from acute respiratory distress syndrome after pulmonary resection is reducing: a -year single institutional experience prevalence and mortality of acute lung injury and ards after lung resection lung injury following pulmonary resection in the isolated, blood-perfused rat lung the pathogenesis of lung injury following pulmonary resection it is estimated that % of all hospital admissions are due to effects of therapeutic drugs, that - % of inpatients experience a drug reaction and that % of deaths in hospital may be related to drug therapy. [ ] [ ] [ ] [ ] the lungs are often involved in these adverse reactions. the mechanism of an adverse drug reaction may be based on:• overdosage: toxicity linked to excess dose, or impaired excretion, one classification of adverse drug reactions is that based upon the type of drug (box . . ). this is not adopted here but in passing it is worth noting that pharmacists are generally very helpful in supplying details of adverse reactions to specific drugs. alternatively, information on the long list of potentially pneumotoxic drugs may be obtained at http://www.pneumotox.com. a useful scheme for chapter key: cord- -nqj ctk authors: ogger, patricia p.; byrne, adam j. title: macrophage metabolic reprogramming during chronic lung disease date: - - journal: mucosal immunol doi: . /s - - - sha: doc_id: cord_uid: nqj ctk airway macrophages (ams) play key roles in the maintenance of lung immune tolerance. tissue tailored, highly specialised and strategically positioned, ams are critical sentinels of lung homoeostasis. in the last decade, there has been a revolution in our understanding of how metabolism underlies key macrophage functions. while these initial observations were made during steady state or using in vitro polarised macrophages, recent studies have indicated that during many chronic lung diseases (clds), ams adapt their metabolic profile to fit their local niche. by generating reactive oxygen species (ros) for pathogen defence, utilising aerobic glycolysis to rapidly generate cytokines, and employing mitochondrial respiration to fuel inflammatory responses, ams utilise metabolic reprogramming for host defence, although these changes may also support chronic pathology. this review focuses on how metabolic alterations underlie am phenotype and function during clds. particular emphasis is given to how our new understanding of am metabolic plasticity may be exploited to develop am-focused therapies. the respiratory mucosa is a unique site, as our airways are continually exposed to particulates, viruses, bacteria, and fungi, which challenge the pulmonary immune system . to maintain pulmonary homoeostasis and ensure efficient gas exchange, a complex regulatory system is in place, of which airway macrophages (ams) are a core component. ams are the most numerous immune cell type present in healthy lungs, are strategically positioned at the interface of airways and environment , and critical sentinels of barrier immunity. ams form the first line of defence against inhaled particles, pathogens and antigens . although inherently suppressive, ams exhibit significant functional and phenotypical specialisation, allowing efficient responses to environmental signals and rapid alterations in phenotype. increasing evidence suggests that metabolic alterations provide an additional layer of functional plasticity to am populations. activation of macrophages in vitro with a range of inflammatory stimuli, induce profound metabolic adaptations, such as the switch from oxidative phosphorylation (oxphos) to glycolysis in oxygen-sufficient conditions, similar to the "warburg effect" seen in some cancers . it is now clear that how macrophages utilise energy dictates immune responses, and that manipulating cellular metabolism can alter the inflammatory response . however in vivo, the unique oxygen rich environment of the airways coupled with specific local nutrient availabilities, shapes am phenotype and function. indeed, many recent studies have indicated that in chronic lung diseases (clds), such as asthma, chronic obstructive pulmonary disease (copd), cystic fibrosis (cf), idiopathic pulmonary fibrosis (ipf), and during infection such as with mycobacterium tuberculosis (mtb), there are significant alterations in am metabolic processes and that targeting these pathways could represent an exciting therapeutic approach , . this review focuses on how metabolic adaptations underlie am phenotype and function during clds. particular emphasis is given to how our new understanding of am metabolic plasticity may be exploited to develop am-focused therapies. airway macrophages: guardians of the lung environment to maintain gas exchange, it is critical that ams sustain a naturally hyporesponsive state whilst also reserving the ability to rapidly mount effective inflammatory responses. this balance is achieved through complex am-airway epithelial cell (aec) interactions via cell surface-expressed receptors and secreted products. ams express transforming growth factor beta receptor (tgf-βr), interleukin (il)- receptor (il- r), cd receptor (cd r) and signal regulatory protein-α, key components mediating am: aec crosstalk and in turn, regulating am activation . for example, am-aec contact decreases am phagocytosis and cytokine production in a tgf-β-dependent manner . conversely, loss of the integrin αvβ such as through loss of contact of ams with aec upon toll-like receptor (tlr) activation leads to initiation of the am pro-inflammatory phenotype and inflammatory response . ams are characterised by a distinct cellular phenotype. human ams highly express the lectin-binding transmembrane glycoprotein cd , the adhesion molecule cd , the integrin cd c and mannose receptor cd (fig. ). in mice, expression of the cd + cd + cd c hi cd b lo cell surface phenotype is conserved at steady state [ ] [ ] [ ] , while murine ams also express the mer tyrosine kinase (mertk), sialic acid dependent adhesion molecule siglecf, hormone receptor f / , glycoprotein cd and the cd receptor (fig. ) . recent work in mice has indicated that many tissue resident macrophages, including those in the airways, are foetally derived and self-maintain locally with minimal contribution from circulating monocytes, during steady state conditions [ ] [ ] [ ] [ ] [ ] . during murine prenatal development, foetal liver or yolk sac macrophages are the major contributing pool to am populations and am colonization of the lung occurs in sequential waves in the first week of life . furthermore, post birth and during maturation, circulating monocytes do not significantly contribute to lung macrophage populations at homoeostasis . during pulmonary inflammatory responses however, monocytes are recruited to the lung , and subsequently develop into am-like cells , . thus, post-injury murine airways contain at least two ontologically distinct am populations, tissue resident ams (tr-am) which are prenatally derived and monocytederived ams (mo-ams). several groups have studied samples from lung transplant patients to investigate the origins of ams in the human lung [ ] [ ] [ ] [ ] [ ] . utilizing bronchoalveolar lavage (bal) from sexmismatched lung transplant patients our group recently demonstrated that the majority of ams in human lung post-transplant are derived from peripheral classical monocytes . thus, the unique airway niche combined with distinct ontological origins, age and environmental exposures results in remarkable am plasticity and adaptability [ ] [ ] [ ] . while the recruitment of monocytes to the lungs to replenish the tr-am pool is relatively well understood in mice, the origins of ams in the human lung during healthy aging or clds requires further investigation; in particular clear markers which distinguish mo-ams and tr-am are not well established. airway macrophage metabolic phenotype at homoeostasis beyond delineation of macrophage populations based on anatomical location or ontological origin, macrophage populations are also classified according to their activation status. analogous to the th /th paradigm, in vitro cultured human monocyte derived macrophages (mdms) or murine bone marrow derived macrophages (bmdms) are categorised as m or m macrophages, respectively. seminal studies have demonstrated that pro-wound healing m (il- stimulated) macrophages in vitro rely on fatty acid oxidation (fao), an intact tricarboxylic acid cycle (tca) cycle, high rates of oxphos and increased expression of arginase (arg ), which catalyses the production of ornithine from arginine as precursor for collagen to facilitate wound healing , [ ] [ ] [ ] . conversely, pro-inflammatory m -macrophages rely on glycolysis and breaks in the tca cycle lead to accumulation of metabolites, many of which have signalling functions such as citrate, succinate, fumarate and α-ketoglutarate , , . however, although useful in defining the range of potential macrophage responses, in vitro derived cells do not recapitulate the core aspects of am phenotypes which are shaped by the local niche . as ams are highly adapted to the unique environment of the airway lumen, it is perhaps unsurprising that the metabolic state of ams is also distinct. glucose concentrations in the alveolar lumen are less than % of blood glucose concentrations and ams exhibit extremely low levels of glycolysis ; in stark contrast to bmdms, ams do not undergo glycolytic reprogramming in response to lps . consequently, ams readily engage oxphos and highly express the peroxisome proliferator-activated receptor gamma (pparγ) , which regulates lipid accumulation and promotes fao to sustain oxphos. ams also play a major role in the catabolism of pulmonary surfactant, a monolayer composed mainly of phosphocholinebased lipids, phospholipids and cholesterol which lines the alveoli, lowers surface tension and prevents alveolar collapse during expiration . mice lacking gm-csf and thus the am compartment, develop pulmonary alveolar proteinosis (pap), an inflammatory lung syndrome caused by the defective clearance of surfactant [ ] [ ] [ ] . in humans, mutations in genes encoding for gm-csf receptors, result in hereditary pap as a result of progressive alveolar surfactant accumulation [ ] [ ] [ ] [ ] . am phenotype and behaviour are influenced by surfactant exposure, which has major implications for am-mediated immune responses in pulmonary tissue. there are four principle surfactant proteins (sp-a-d) and sp-a and sp-d have been shown to directly influence am functions such as cell migration, phagocytosis and activation phenotypes . both sp-a and sp-d bind carbohydrates, lipids, and nucleic acids and initiate phagocytosis of inhaled pathogens and apoptotic cells . furthermore, sp-a blocks the binding of tlr ligands to tlr , tlr and tlr co-receptors and furthermore inhibits complement activation , . whilst the alveoli are covered with a monolayer of surfactant, a thin layer of mucus produced by goblet cells and ciliated epithelium protects the airways. mucus serves as a barrier and facilitates clearance of microbes and pollutants. a major component of mucus are mucin glycoproteins, which may be categorized as polymerizing, nonpolymerizing and cell-surface associated. of the cell-surface associated mucins, muc is expressed in ams and contributes to the resolution of inflammation by decreasing phagocytic potential and pro-inflammatory cytokine production . the polymerizing mucins include muc ac and muc b; in particular, muc b deficiency has been linked to particle accumulation in the lung, mucus obstruction and impaired macrophage phagocytosis . pro-inflammatory macrophages induce muc b expression to aid mucociliary clearance . furthermore, a single nucleotide polymorphism in the muc b promotor has been strongly associated with the risk of developing ipf, highlighting the importance of mucins for the pulmonary environment . in addition to low glucose and a lipid rich environment, the airways also have a unique distribution of amino acids and central carbon metabolites. surowiec et al. showed that whilst several glucogenic and ketogenic amino acids were present in the bronchial wash, only alanine is present in bal (fig. ). in addition, the central airways contained key glycolytic and oxphos metabolites such as fructose, glucose- -phosphate, fumarate and malate as well as oxidised gluthathione (gssg, indicating oxidative stress, fig. ) ; interestingly, these could not be detected murine ams express the lectin-binding transmembrane glycoprotein cd , the mer tyrosine kinase (mertk), the integrin alpha x chain protein cd c, the type i membrane glycoprotein cd receptor, the mannose receptor cd , the egf-like module-containing mucin-like hormone receptor-like (f / ), the sialic acid binding lectin siglec-f and the fc receptor cd . human ams express cd , the adhesion molecule cd , cd c, cd as well as mhc class ii receptor hla-dr. in the periphery, suggesting either minimal secretion, high utilisation or as a result of anatomical location (i.e. close proximity to nutrient rich pulmonary capillaries) . recently the lung microbiome has gained attention as a factor which modifies the pulmonary environment and directs immune responses by producing short chain fatty acids (scfa). whilst the airways and alveoli are colonised mainly by proteobacteria, bacteroidetes and firmicutes , , the nasal mucosa additionally hosts actinobacteria , (fig. ) . proteobacteria, bacteroidetes and firmicutes produce large amounts of scfa, including acetate, propionate and butyrate, which influence barrier function by regulating epithelial tight junctions and anti-inflammatory immune responses . recent advances in understanding the pulmonary microbiome during homoeostasis and clds are described in detail elsewhere , , . thus, at homoeostasis ams are exposed to a unique environment, with minimal glucose availability and a distinct distribution of nutrients and scfa, which depend on anatomical location (fig. ) . however, despite the profound influence that local substrate availabilities may exert on macrophage development, activation and function, this is an understudied area. new knowledge, which further defines especially human am substrate dependencies at homoeostasis is required in order to fully understand how local metabolic perturbations during clds may contribute to pathology. this is particularly relevant as already slight changes in nutrient availability during inflammation, such as succinate or citrate, can alter macrophage phenotypes through stabilization of hif α, post-translational modification of proteins and production of no and ros , thereby contributing to a pathological development. am metabolism during clds chronic lung diseases affect a significant proportion of the world's population, killing more than , people in the uk alone, each year . persistent inflammation, impaired repair processes and pulmonary remodelling are cardinal features of clds [ ] [ ] [ ] . there are multiple overlaps in environmental exposures driving clds, such as smoking, pollution and environmental exposures; viral infection can also exacerbate symptoms in each disease , , . interestingly, am metabolic adaptation may play a central role in dictating pathology during clds and present novel therapeutic opportunities (fig. ) . asthma. asthma is a heterogeneous disease of the airways characterized by airway remodelling, mucus production, airway hyperresponsiveness (ahr), and inflammation . although most patients have good control with standard medication, a proportion experience life-threatening, severe disease . ams are central to mediating type- inflammation against allergens and parasitic worms . in vitro, macrophages respond to type- cytokines such as il- that drive an 'alternative' m activation phenotype, linked to wound repair and type- pathology , . manipulation of am phenotype via genetic deletion of the transcription factor interferon regulatory factor (irf ), a master regulator of macrophage activation , promoted pulmonary remodelling, ahr and mucus secretion in mice, in an il- dependent manner . indeed, a recent study has shown that both cd + am (activated by il- and il- ) and pro-inflammatory irf + am are increased in asthmatic patients , highlighting the plasticity of macrophages and heterogeneity of human asthma. roles of ams during antigen induced airway inflammation include phagocytosis of apoptotic cells and eosinophils as well as triggering anti-inflammatory pathways to regulate airway hyper responsiveness, mucus secretion and matrix deposition . in severe asthma however, this protective function is impaired, resulting in the loss of phagocytic ability and anti-inflammatory programme , which can contribute to airway remodelling . thus, ams are uniquely involved in responses to allergen and type- inflammation, and aberrant amphenotypes can directly influence respiratory pathology. numerous lines of evidence suggest that metabolic stress leading to the production of reactive oxygen species (ros) plays a role in asthma. increased ros have been detected in ams of asthmatic patients , and contributes to lung injury and proinflammatory tumour necrosis factor-alpha (tnf-α) and il- β secretion by macrophages . furthermore, heme-oxygenase- (ho- ), which mediates ros production in response to chemical and physical agents, is increased in ams in asthmatics . in addition to these pro-inflammatory characteristics, ams show key features of a more anti-inflammatory phenotype in studies using ovalbumin to model allergic asthma. using this model, al-khami et al. show that expression of carnitine palmitoyltransferase (cpt) is increased in ams, shuttling fatty acids into the mitochondria, as well as increased gene expression of fao related genes . another functional pathway that is altered in asthmatic ams and links to the underlying metabolic phenotype is the eicosanoid pathway, which is induced by th cytokines il- and il- . eicosanoids, including prostaglandins and leukotrienes, are produced from the poly-unsaturated fatty acid arachidonic acid, which is released during asthma . increased production of the eicosanoid -hete and leukotrienes b (ltb ) and e (lte ) has been detected in ams from asthmatic patients stimulated ex vivo . this contributed to bronchial constriction and pro-inflammatory phenotype and failure to generate the anti-inflammatory eicosanoid -hete and prostaglandin e (pge ), which is associated with reduced am phagocytosis . lte has been shown to cause ahr in subjects with aspirin-induced asthma and can be produced in ams by γ-glutamyl transpeptidase , . il- furthermore induces arg , which may further contribute to the asthmatic phenotype via metabolism of collagen precursors ornithine and proline to collagen and airway remodelling , . several of these observed alterations have been targeted therapeutically, attempting to rewire am phenotype. these include the eicosanoid pathway, ros, glycolysis and fao. administration of the anti-inflammatory eicosanoid -hete inhibited leukotriene synthesis and reduced ahr in asthmatics . ex vivo, the corticosteroid dexamethasone decreased levels of thromboxane b and ltb in macrophages and asthmatic ams , while prednisone decreased ltb production in ams . treatment with the antioxidant ad improved ahr and airway inflammation by decreasing ros in the ova-sensitised mouse model of allergic airway disease (aad) , . together, these studies indicate that there is significant disruption of am metabolism during asthma and aad, notably via dysfunction in eicosanoid, glycolysis and fatty acid pathways. in fig. altered metabolic pathways in ams drive key features of chronic lung disease. several metabolic pathways are rewired during chronic lung disease. while this response exists to clear invading pathogens and launch an inflammatory response, long-term activation of these pathways has negative implications. the glycolysis pathway supports inflammatory responses of am, while iron and metabolites produced in the tca cycle can function as bacterial substrates and contribute to pathogen survival. while fatty acid synthesis and oxidation is useful as a way of storing energy and alternative energy source during times of macrophage activation, fatty acid synthesis can also contribute to mucus production. leukotrienes contribute to the am pro-inflammatory phenotype but also cause bronchial constriction and contribute to airway remodelling in asthmatics by causing smooth muscle thickening. the amino acid arginine is a proliferator for collagen via ornithine and proline and can thereby contribute to extracellular matrix deposition. order to evaluate candidate therapies, it is crucial that studies utilise relevant preclinical models and ex vivo patient samples to understand disease. models which more closely recapitulate the complex immune response to allergens, are more likely to reveal viable targets for intervention; in particular the ovalbumin model of aad, which requires an adjuvant and a sensitization phase , is a poor murine model of asthma. furthermore, our new understanding of asthma heterogeneity has allowed the development of biologics which target "type- high" asthma ; delineation of how metabolic changes underlie distinct asthma phenotypes could lead to new treatments for other phenotypes, such as neutrophilic and paucigranulocytic asthma. copd. copd is the th leading cause of death in high income countries , affecting over million people worldwide . copd is a heterogeneous disease, characterised by destruction of the parenchyma and emphysema, narrowing of the airways, remodelling and chronic inflammation driven by chronic exposure to cigarette smoke and particular matter . am numbers are increased in copd bal and contribute to copd pathology through numerous pathways. during copd, ams are found in areas of lung destruction and produce pro-inflammatory cytokines , chemokines and matrix metalloproteases (mmps) with elastolytic properties , . at the same time, tissue inhibitor of metalloproteases (timp)- is decreased in ams in copd and furthermore, decreased phagocytic capacity and impaired bacterial killing have been described in copd-ams [ ] [ ] [ ] . ams of copd patients experience a high level of oxidant burden induced through cigarette smoke and subsequent increased ros production is a key feature . compared to controls, copd-ams secrete increased levels of mitochondrial ros (mtros) , superoxide and hydrogen peroxide , whilst glutamyl cysteine ligase for gsh synthesis is downregulated . cigarette smoking also alters iron homoeostasis and ams in copd show increased sequestering of iron , which can furthermore contribute to ros production. bewley et al. showed recently that increased generation of mtros in copd ams results in impaired bacterial clearance . this study also reported a decrease in the mitochondrial membrane potential , which has recently been linked to am exposure to particulate matter . this may explain the impaired phagocytic capacity of ams in copd as decreased mitochondrial membrane potential results in energy failure in the cell, proton leakage and increased mtros . another study by o'beirne et al. further investigated the metabolic profile of ams from healthy smokers, non-smokers and copd patients. while all groups had similar baseline glycolysis rates, there was a decrease in coupling efficiency, maximal respiration and spare respiratory capacity in copd-ams, while proton leak was significantly increased . in addition, expression of genes related to glutathione metabolism, mitochondrial transport, pyruvate metabolism, tca cycle and electron transport chain were altered in smokers and copd patients, compared to nonsmoking healthy controls . other metabolic alterations in copd ams include increased expression of inducible nitric oxide synthase (inos) contributing to increased levels of nitric oxide (no) and increased levels of the adenosine receptor a br , suggesting increased adenosine metabolism, which might be linked to the increased levels of hif α in copd ams . while excessive ros production through oxidant burden and iron accumulation has been identified as an important regulator of am phenotype in copd, it has only recently been linked to mitochondrial dysfunction and metabolic reprogramming. it would be interesting to follow up on these transcriptomic and metabolic alterations to understand their underlying disease driving role and to identify ways to rewire am metabolism. as corticosteroids have been found to be particularly ineffective in copd, more specific pathways involved in am function and metabolism have been investigated recently, such as the ros pathway and iron accumulation. a study by harvey et al. showed that treatment with sulforaphane in copd ams ex vivo improved bacterial clearance by activating the antioxidant and antiinflammatory nrf pathway , while cloonan et al. found that treatment with an iron chelator or a low iron diet protected mice from cigarette smoke induced copd . furthermore, procysteine, a precursor of gsh, increased am efferocytosis in a mouse model of copd . overall, copd is marked by distinct iron sequestration, ros, no production and energetic dysfunction in ams; further delineation of how mitochondrial phenotype links to inflammatory processes and pathology in copd will allow the identification of molecular targets for modulating mitochondria during the disease. cystic fibrosis. cystic fibrosis (cf) is caused by mutation of the cf transmembrane conductance regulator (cftr), a chloride channel, which regulates fluid homoeostasis in mucosal surfaces. in the lung, cftr mutation and subsequent loss of function results in a reduced aqueous film covering the epithelium and mucus thickening, leading to impaired mucociliary clearance and frequent bacterial infection . cf is furthermore characterised by hyper-inflammation of the lungs, airway obstruction, structural damage and progressive reduction of lung function . during recurring airway inflammation, large numbers of neutrophils, macrophages and t lymphocytes infiltrate the lungs and secrete pro-inflammatory cytokines, while anti-inflammatory il- is reduced , . although am numbers are increased in cf patients , , pathogen clearance is attenuated, leading to colonisation of the airways and chronic inflammation , . meyer et al. report a more pro-inflammatory phenotype of ams in a murine model of cf, even in the absence of infection and mdms differentiated from cf patients show an increased inflammatory profile , while others have shown that monocytes from cf patients had an impairment in activation upon il- stimulation . cf-am phenotype can be heterogenous, depending on infection status and local environment. while ams from p. aeruginosa infected cf patients showed increased expression of mannose receptor cd and augmented arginase activity , in cf sputum ams a decrease in expression of cd and scavenger receptor marco was detected . furthermore, ams are involved in the structural damage in cf airways by secreting serine-and metalloproteases, which subsequently degrade connective tissue components . the lower volume of airway surface liquid in cf airways activates ams to increase their release of mmp , resulting in the cleavage of elastin and degradation of the airway and parenchyma . in cf airways, gsh is depleted , , while levels of iron, transferrin, haem and haemoglobin are increased , resulting in high oxidative stress and ros production. ros in turn can induce tgf-β , which has recently been shown to be increased in cf-bal and ams and inhibits cftr biogenesis and cellular trafficking to the surface of epithelial cells , while also contributing to airway remodelling by recruitment and differentiation of myofibroblasts . however, during infection with bacteria from the burkholderia family, both mdms and ams from cf patients showed reduced superoxide production as well as decreased phosphorylation of nadph oxidase (nox) components p phox and p phox , suggesting an inherent deficit in cf-ams generating oxidative bursts for pathogen defence . p. aeruginosa is one of the most common pathogens to cause recurrent pulmonary infection in cf patients and exploits the host to maintain infection by inducing production of the tca cycle metabolite itaconate in ams. itaconate exerts antimicrobial properties via inhibition of bacterial isocitrate lyase in the glyoxylate shunt and to evade this mechanism p. aeruginosa has developed a way to use itaconate as an energy source . similarly succinate, which is secreted in high levels during cf and especially during bacterial infection , can be utilised by p. aeruginosa and s. aureus as a substrate to generate oxidative stress. changes in lipid metabolism are a hallmark of cf and increased fao, lipid turnover in cell membranes and eicosanoid production in ams have been reported. furthermore, sterol regulatoryelement binding protein (srebp), a regulator of lipid homoeostasis, has been linked to cftr loss of function . this results in altered plasma and tissue fatty acid profiles, and while levels of the omega- fatty acid docosahexaenoic acid (dha) were unchanged in ams upon loss of cftr , ex vivo treatment with dha decreased tnf-α levels . furthermore, in cf ams the antiinflammatory lipoxin a (lxa ), which is synthesised from the fatty acid arachidonic acid, is reduced and the lxa /ltb ratio in cf bal is decreased , while the fatty acid metabolite resolvin d (rvd ) has been suggested as a biomarker . increased energy demand by ams in cf, either by manipulation through bacterial pathogens or to fight sustained infection, results in increased utilization of all available metabolic pathways. recently, lara-reyna et al. reported increased glycolysis, mitochondrial function, and production of tnf-α in cf macrophages is due to an alteration in the serine/threonine-protein kinase/ endoribonuclease ire α pathway and this supports exacerbated inflammation . while this study used pbmcs and monocytederived m macrophages from cf patients, it would be important to detect such a mechanism in ams and to target this pathway specifically. several of the above described pathways have been identified as potential drug targets in cf, however yet there are no treatments targeting ams. delivery of gsh to the lower respiratory tract improves the antioxidant barrier of cf epithelium , while treatment with cysteamine and restoration of microrna (mir ) and mir expression improves disease by restoring autophagy , . several studies administered omega- fatty acids (dha/epa) to cf patients [ ] [ ] [ ] [ ] , although only one trial reported improved fev after months treatment with dha . treatment with dha in a murine model of cf decreased liver inflammation but did not improve lung morphology . in conclusion, am metabolic phenotype during cf is marked by increased energy expenditure to support exacerbated inflammation and is readily exploited by bacterial pathogens, leaving ams deficient of oxidative burst capability during infection. it will be important to clarify the role of fatty acids in cf and furthermore, to target metabolic changes in ams such as increased glycolysis, oxphos and fao specifically to rewire am phenotype and prevent exploitation through bacterial pathogens. idiopathic pulmonary fibrosis (ipf). ipf is a chronic interstitial lung disease characterised by excessive extracellular matrix deposition in the lung parenchyma and has a particularly poor prognosis . repetitive alveolar injury in genetically susceptible individuals causes activation of mesenchymal cells, recruitment of fibroblasts and differentiation into myofibroblasts to replace damaged alveolar epithelial cells and provide a matrix for wound healing and tissue repair . during ipf, the wound healing process is dysregulated, leading to fibrotic plaque formation and excessive build-up of extracellular matrix, resulting in impaired gas exchange. ams have been identified as key contributors to the dysregulated wound healing process, by secreting large amounts of ros and tgf-β . furthermore, ams can shape the extracellular matrix by secreting factors contributing to the matrix (proline, collagen) and breaking down the matrix (plasmin, mmps) [ ] [ ] [ ] . several changes to the central carbon metabolism pathways have been identified recently in ams of ipf patients, including dysmorphic mitochondria . in murine models of pulmonary fibrosis, increased glucose consumption, glycolysis and enhanced expression of key glycolytic mediators was detected , while in ipf ams, expression of the pulmonary glucose transporter glut was increased , which enabled augmented glucose uptake . the increased glucose uptake via glut can furthermore sustain nadph production in the pentose phosphate pathway and tca cycle and is therefore a key substrate for ros production via nox . activation of macrophages results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles such as succinate and itaconate [ ] [ ] [ ] . recently, our laboratory identified itaconate as an endogenous anti-fibrotic in the human and murine lung. in patients with ipf, there were reduced levels of airway itaconate, and decreased expression of acod (which controls the synthesis of itaconate) in ams compared to healthy controls. acod deficiency in mice leads to more severe disease pathology and exogenous itaconate limits fibroblast activity . these data indicate that am metabolites may play a key role in the pathogenesis of lung fibrosis and may be exploited for the development of anti-fibrotic therapies. ros production is a key feature of ams in ipf and can occur during oxphos, by the membrane bound nox or by reaction of hydrogen peroxide with intracellular iron . nox, and subsequent superoxide production, is activated by binding gtp-bound rac , which is secreted from ams in ipf and can also activate the mtor signalling hub . superoxide produced by nox can further react with no to form peroxynitrite (oono -), another type of ros. at the expense of nadph, no is produced in the mitochondria by inos, which is upregulated in proinflammatory macrophages and in ipf-ams leading to increased levels of the cytotoxic oonoin ipf ams . in the bleomycin mouse model of pulmonary fibrosis, increased levels of superoxide, no and oonowere measured in ams . mtros is furthermore linked to expression of ppar-γ coactivator -alpha (pgc- α), which induces metabolic reprogramming to fao and is regulated by the mitochondrial calcium uniporter (mcu), which is increased in ipf ams . mcu has furthermore been shown to regulate expression of the fatty acid transporter cpt- , which is increased in ams from ipf patients and bleomycin exposed mice . while human ipf-ams have increased levels of mcu, mitochondrial calcium and expression of pgc- a, bleomycin exposed mice utilise increased fao , which is reduced in mice expressing dominant-negative mcu . furthermore, these mice were protected from bleomycin induced pulmonary fibrosis. these findings highlight calcium transport and fao as pathways to target in ipf ams; however, a better understanding of the linking mechanism will be necessary. ipf ams have also been shown to be iron laden , which further induces oxidative stress and ros production . using rna-sequencing, lee et al. show furthermore, that macrophage activation is increased in iron laden ams in ipf, suggesting that iron accumulation plays a role in macrophage activation . the proportion of ams expressing transferrin receptor (cd ), importing transferrin bound iron into the cell, are decreased in ipf ams, leading to an extracellular accumulation of transferrin. furthermore, numbers of cd -negative macrophages are an independent predictor of survival in ipf . iron metabolism is therefore likely a key pathway in ipf-ams and targeting it would be a viable option to decrease ros, oxidative stress and macrophage activation. recently, therapies targeting metabolic processes in ipf are of considerable interest. while antioxidant therapy in ipf was promising in vivo, the double-blind placebo controlled panther trial, administering either n-acetylcysteine or placebo to ipf patients for weeks did not show a change in lung function parameters . another arm of this study investigated the combined potential of corticosteroid prednisone, immunosuppressant azathioprine and n-acetylcysteine but was stopped prematurely due to increased mortality and adverse effects without evidence of benefit . another randomized, double-blind clinical trial assessed the safety and tolerability of n-acetylcysteine in patients already receiving pirfenidone anti-fibrotic therapy. while this trial showed that n-acetylcysteine in combination with pirfenidone was safe, no change in fvc, -minute walk test or occurrence of adverse effects was detected . another promising therapeutic avenue was the use of metformin, a potent metabolic remodelling drug often prescribed for type ii diabetes. while on a global level metformin lowers the amount of blood sugar in diabetic patients, on a cellular level metformin activates ampactivated protein kinase (ampk) leading to inhibition of tgf-β induced nox activity . sato et al., have shown that metformin inhibited tgf-β induced nox activity via ampk leading to inhibition of myo-fibroblast differentiation in vitro and reduced bleomycin induced collagen deposition in vivo . consistent with this, rangarajan et al. showed that metformin treatment reversed bleomycin induced pulmonary fibrosis via ampk activation, while in ipf patients ampk phosphorylation was decreased . a posthoc analysis study of the effect of metformin in ipf patients however showed no change in clinically outcomes , once again showing the difficulty of translating in vitro and in vivo findings into the clinic. another study investigating the nox-nrf imbalance as a therapeutic target showed that in vivo knockdown of nox and nox / inhibition restored the capacity of fibrosis resolution in aged mice . furthermore, treatment with nitrated fatty acids, reversed pulmonary fibrosis in a mouse model by promoting collagen uptake by ams and dedifferentiating myofibroblasts . while these treatment approaches targeted metabolic changes during pulmonary fibrosis, none was specific to ams. targeting macrophage specific metabolic reprogramming, which sustains ros and tgf-β production and contributes to dysregulated wound healing in ipf would therefore be a promising approach. during respiratory tract infections, activation of pattern recognition receptors expressed by am can elicit a variety of proinflammatory host responses . for example, severe coronavirus disease- (covid- ) associated pneumonia patients may exhibit features of systemic hyper-inflammation also known as macrophage activation syndrome or "cytokine storm" which is associated with sustained elevation of macrophage/monocytederived pro-inflammatory cytokines (e.g., il- , il- , tnf-α, il- β) leading to acute respiratory distress syndrome (ards) [ ] [ ] [ ] . using single cell approaches a recent study demonstrated that highly inflammatory, monocyte recruited ams, rather than quiescent pulmonary resident ams, predominate in the bal in covid- patients with severe pathology, implicating these cells in covid- -associated ards . rather than direct infection of ams, am:aec cross-talk has been identified as a major mechanism for control of many respiratory viral infections and aec have been shown to be a key source of pro-inflammatory cytokines, modulating am phenotype , . for example, rhinovirus (rv), the causative agent of the common cold, primarily infects the upper airways, however prior infection with rv attenuates subsequent am antibacterial responses . although ams are susceptible to influenza a viral infection (iav), replication within ams has been shown to be minimal with the exception of several highly virulent strains [ ] [ ] [ ] . here, we will focus on mycobacterium tuberculosis (mtb) infection, as ams are the primary infected cell type and metabolic changes in response to mtb infection are well studied. tuberculosis. tuberculosis (tb) is a contagious, chronic disease and one-third of the world's population is infected with mtb, the causative agent of tb, resulting in~ million deaths per year ( world health organization report) . during infection, mtb colonises ams intracellularly and disables innate intracellular defence mechanisms such as the phagolysosome and inflammasome and accesses macrophage intracellular nutrients . am host defence mechanisms against mtb include production of ros and reactive nitrogen species (rns) for bacterial killing and fusing mycobacteria-containing phagosomes with lysosomes as well as autophagy and apoptosis . however, virulent or multi-drug resistant strains can evade these host responses e.g. by preventing phagolysosome fusion and surviving ros/rns . during mtb infection, ams shift their metabolic programme from oxphos to aerobic glycolysis, which is regulated by hif α and interferon-gamma (ifn-γ). this metabolic shift and subsequent enhanced glycolytic flux in infected ams is crucial to control infection. mice lacking hif α in the myeloid lineage are more susceptible to infection and show decreased cytokine and antimicrobial effector production . to support this metabolic reprogramming, key glycolysis genes are upregulated in the early stages of granuloma formation in mice, supporting the shift towards aerobic glycolysis . mtb furthermore induce ferroptosis, associated with reduced levels of gsh, superoxide and increased free iron. the ferroptosis inhibitor ferrostatin- (fer- ) as well as iron chelation decreased necrotic cell death of mtb-infected macrophages in vitro, while in vivo treatment with fer- reduced bacterial load . mtb can cope in low iron environments however macrophage metabolic reprogramming during chronic lung disease pp ogger and aj byrne by downregulating their non-essential protein content via specific srna . several changes in fatty acid metabolism of mtb infected ams were identified recently. compared to interstitial macrophages during mtb infection, which are reliant on glycolysis, ams utilise fa, which is induced by ppar-α and have a lower burden of mtb infection . to escape host defence, mtb has developed a mechanism inhibiting pathways related to autophagy, lysosomal function and fao in support of replication by inducing microrna- (mir- ) in the host cell. silencing of mir- however induced am lipid catabolism and autophagy and rescued host defence . furthermore, amino acid metabolism is altered during mtb infection. in mice and macaque lungs, indoleamine , -dioxygenase (ido), which is involved in tryptophan catabolism, was increased during mtb infection, while inhibition of ido in a macaque model of tb decreased bacterial burden and pathology, as tryptophan metabolites suppress host immunity . while mtb relies on host lipids as energy source, existing therapies such as targeting ppar transcription factors or cholesterol synthesis have been successful mainly in animal models [ ] [ ] [ ] [ ] , whereas retrospective human studies, which investigated the effect of statins in diabetic tb patients did not show any results . as mtb can also utilise iron as a substrate, another approach is to prevent iron accumulation. treatment of mtb infected human mdms and primary am with iron chelator desferrioxamine (dfx) ex vivo induced the expression of glycolytic enzymes and enhanced glycolysis, as well as il- βα, thereby supporting host defence and offers a novel therapeutic approach, which will need to be investigated in clinical trials. together, these findings highlight the distinct phenotype of ams during mtb infection, which counteracts intracellular infection through aerobic glycolysis, but is also heavily exploited by mtb bacteria feeding on host lipids and iron. targeting metabolism during chronic lung disease many potential targets have been identified recently that could rewire macrophage metabolic and phenotypic changes driving chronic lung disease. since all cells depend on oxidative phosphorylation or cytoplasmic glycolysis to synthesize atp, there is the potential for unwanted side effects by targeting specific metabolic processes. however, it is becoming increasingly apparent that it is possible to safely target metabolic pathways in patients. for example, dimethyl fumarate, a known regulator of macrophage phenotype, is a first-line-treatment for relapsingremitting multiple sclerosis . indeed, metabolic processes are highly plastic with significant redundancy, modulation of these processes may have the added benefit of selectively targeting cells with high metabolic demands . targeted delivery to ams may add another layer of selectivity, improving efficacy, sustained drug release and evading capture by mucus . systems for inhaled am targeted drug delivery include the use of micro-and nanocarriers, including liposomes, which are phagocytosed by ams. rifampicin-loaded microspheres as a therapeutic approach for mtb have been described , and have been further refined to allow a one-step assembly for rifampicin containing microspheres . recently, aerosolised delivery of sirna, which posttranslationally downregulates gene expression, has been developed to target ams specifically , whilst mannose coated microspheres have been developed which exploit the phagocytotic activity of ams . many of these delivery vehicles have been developed to transport antibiotics targeting intracellular am bacterial infections, which are helpful for treating tb, however other drugs could be incorporated into aerosolised micro-or nano delivery systems. specifically, treatment with iron chelators, antioxidants and nitrated fatty acids has shown to rewire am phenotype and improve diverse chronic lung disease; these may be ideal candidates to develop novel, aerosolised vehicle-assisted drug delivery to ams during chronic lung disease. in the last decade enormous strides have been made regarding our understanding of how adaptations in metabolic pathways underlie macrophage phenotype and function. ams are remarkably plastic cells, orchestrating not only pathogen defence and efferocytosis, but also pulmonary tolerance and resolution. it has become increasingly clear that ams tailor their metabolic profile to fit their local niche generating ros for pathogen defence, utilising aerobic glycolysis to rapidly generate cytokines, employing the tca cycle to fuel inflammatory responses and generating metabolites with secondary signalling functions such as citrate, itaconate, succinate and fumarate. work elucidating the complexities of am metabolic alterations in the context of clds has highlighted many potential therapeutic targets (summarized in table ). indeed, a lack of understanding of shared cellular mechanisms, which underlie clds has been a major obstacle in respiratory biology; identification of common am-metabolic pathways/metabolites which directly influence core features of clds would be a significant advance on the route to devising new am-directed strategies to treat pulmonary diseases which affect millions worldwide. lung homeostasis: influence of age, microbes, and the immune system pulmonary macrophages: key players in the innate defence of the airways monocytes and macrophages: developmental pathways and tissue homeostasis metabolic reprograming in macrophage polarization macrophage immunometabolism: where are we (going)? metabolic disorders in chronic lung diseases alveolar macrophage immunometabolism and lung function impairment in smoking and chronic obstructive pulmonary disease alveolar macrophages: plasticity in a tissue-specific context alveolar macrophage in the driver's seat integrin αvβ : structure, function and role in health and disease pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease? flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung identification of myeloid cell subsets in murine lungs using flow cytometry lung environment determines unique phenotype of alveolar macrophages a critical function for cd in lung immune homeostasis and the severity of influenza infection a lineage of myeloid cells independent of myb and hematopoietic stem cells alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via gm-csf tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages the lung environment controls alveolar macrophage metabolism and responsiveness in type inflammation tissue-resident macrophage ontogeny and homeostasis developmental origin of lung macrophage diversity the fate and lifespan of human monocyte subsets in steady state and systemic inflammation monocyte recruitment during infection and inflammation transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages cellular chimerism of the lung after transplantation: an interphase cytogenetic study long-term persistence of human donor alveolar macrophages in lung transplant recipients long-term persistence of donor alveolar macrophages in human lung transplant recipients that influences donor specific immune responses the human alveolar macrophage direct evidence for a bone marrow origin of the alveolar macrophage in man dynamics of human monocytes and airway macrophages during healthy aging and after transplant human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function agedependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults succinate is an inflammatory signal that induces il- β through hif- α succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization metabolic reprogramming in macrophages and dendritic cells in innate immunity tissue-resident alveolar macrophages do not rely on glycolysis for lps-induced inflammation induction of the nuclear receptor ppar-γ by the cytokine gm-csf is critical for the differentiation of fetal monocytes into alveolar macrophages pulmonary surfactant protein a modulates the cellular response to smooth and rough lipopolysaccharides by interaction with cd gm-csf regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense gm-csf regulates alveolar macrophage differentiation and innate immunity in the lung through targeted pparγ deficiency in alveolar macrophages disrupts surfactant catabolism familial pulmonary alveolar proteinosis caused by mutations in csf ra adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in csf rb hereditary pulmonary alveolar proteinosis caused by recessive csf rb mutations pulmonary alveolar proteinosis caused by deletion of the gm-csfrα gene in the x chromosome pseudoautosomal region protective role of the lung collectins surfactant protein a and surfactant protein d in airway inflammation surfactant protein a regulates complement activation surfactant protein a directly interacts with tlr and md- and regulates inflammatory cellular response: importance of supratrimeric oligomerization membrane-tethered muc mucin counter-regulates the phagocytic activity of macrophages muc b is required for airway defence macrophages are related to goblet cell hyperplasia and induce muc b but not muc ac in human bronchus epithelial cells a common muc b promoter polymorphism and pulmonary fibrosis multi-platform metabolomics assays for human lung lavage fluids in an air pollution exposure study the respiratory tract microbiome and lung inflammation: a two-way street respiratory microbiome and epithelial interactions shape immunity in the lungs the microbiome of the upper respiratory tract in health and disease the nasal cavity microbiota of healthy adults butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of ampactivated protein kinase in caco- cell monolayers understanding the holobiont: how microbial metabolites affect human health and shape the immune system the microbiota of the respiratory tract: gatekeeper to respiratory health immunometabolism: cellular metabolism turns immune regulator the european respiratory society. the burden of lung disease asthma-copd overlap syndrome: pathogenesis, clinical features, and therapeutic targets. - integrated genomics reveals convergent transcriptomic networks underlying chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis the pathogenesis of copd and ipf: distinct horns of the same devil? virus-induced 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macrophages: its implications in il- -inhibited nitric oxide production the effect of inhaled -(s)-hydroxyeicosatetraenoic acid ( -hete) on airway calibre and non-specific responsiveness in normal and asthmatic human subjects corticosteroid suppression of lipoxin a and leukotriene b from alveolar macrophages in severe asthma single oral dose of prednisone decreases leukotriene b production by alveolar macrophages from patients with nocturnal asthma but not control subjects: relationship to changes in cellular influx and fev a novel thiol compound, n-acetylcysteine amide, attenuates allergic airway disease by regulating activation of nf-κb and hypoxia-inducible factor- α a potential new therapy for asthma? orchestrating house dust mite-associated allergy in the lung benralizumab: an updated treatment of eosinophilic asthma global burden of copd: risk factors, prevalence, and future trends chronic obstructive pulmonary disease: current burden and future projections new insights into the 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particulate matter (pm) and their toxic components: implications for pminduced cardiovascular and lung disease diminished immunoreactivity of γ-glutamylcysteine synthetase in the airways of smokers' lung the iron-y of iron overload and iron deficiency in chronic obstructive pulmonary disease increased iron sequestration in alveolar macrophages in chronic obtructive pulmonary disease defective bacterial phagocytosis is associated with dysfunctional mitochondria in copd macrophages mitochondrial dysfunction in macrophages: a key to defective bacterial phagocytosis in copd alveolar macrophage immunometabolism and lung function impairment in smoking and chronic obstructive pulmonary disease increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis the mif antagonist iso- attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of copd targeting nrf signaling improves bacterial clearance by alveolar macrophages in patients with copd and in a mouse model mitochondrial iron chelation ameliorates cigarette smokeinduced bronchitis and emphysema in mice cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine progress in understanding mucus abnormalities in cystic fibrosis airways lung inflammation in cystic fibrosis: pathogenesis and novel therapies inflammation in cystic fibrosis: an update inflammation and its genesis in cystic fibrosis alveolar macrophages and cc chemokines are increased in children with cystic fibrosis inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis azithromycin reduces exaggerated cytokine production by m alveolar macrophages in cystic fibrosis macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator-/-mice cftr-dependent defect in alternatively-activated macrophages in cystic fibrosis characterization of macrophage activation states in patients with cystic fibrosis pivotal advance: expansion of small sputum macrophages in cf: failure to express marco and mannose receptors tgf-β inhibits cftr biogenesis and prevents functional rescue of Δf -cftr in primary differentiated human bronchial epithelial cells series 'matrix metalloproteinases in lung health and disease': the role of matrix metalloproteinases in cystic fibrosis lung disease glutathione and infection systemic deficiency of glutathione in cystic fibrosis iron accumulates in the lavage and explanted lungs of cystic fibrosis patients transforming growth factorβ activation in the lung: focus on fibrosis and reactive oxygen species impaired defenses of neonatal mouse alveolar macrophage with cftr deletion are modulated by glutathione and tgfβ human cystic fibrosis macrophages have defective calciumdependent protein kinase c activation of the nadph oxidase, an effect augmented by burkholderia cenocepacia irg expression in myeloid cells prevents immunopathology during m. tuberculosis infection pseudomonas aeruginosa utilizes host-derived itaconate to redirect its metabolism to promote biofilm formation pulmonary pathogens adapt to immune signaling metabolites in the airway lipid metabolism in cystic fibrosis alterations in immune response and ppar/lxr regulation in cystic fibrosis macrophages reduced -lipoxygenase and lipoxin a /leukotriene b ratio in children with cystic fibrosis pro-resolving lipid mediator resolvin d serves as a marker of lung disease in cystic fibrosis metabolic reprograming of cystic fibrosis macrophages via the ire α arm of the unfolded protein response results in exacerbated inflammation glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis elevated mirc /mir - cluster expression negatively regulates autophagy and cftr (cystic fibrosis transmembrane conductance regulator) function in cf macrophages cysteamine re-establishes the clearance of pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant f del-cftr mutation an overview of monitoring and supplementation of omega fatty acids in cystic fibrosis fatty acid alterations and n- fatty acid supplementation in cystic fibrosis oral dha supplementation in Δf homozygous cystic fibrosis patients bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic fibrosis patients: a randomized, controlled study effect of an -month treatment with ω- fatty acids (eicosapentaenoic and docosahexaenoic) in patients with cystic fibrosis long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in to evidence-based 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macrophages in the bleomycin-induced interstitial pneumonia mice model mitochondrial calcium uniporter regulates pgc- α expression to mediate metabolic reprogramming in pulmonary fibrosis iron laden macrophages in idiopathic pulmonary fibrosis: the telltale of occult alveolar hemorrhage? bronchoalveolar lavage (bal) cells in idiopathic pulmonary fibrosis express a complex pro-inflammatory, pro-repair, angiogenic activation pattern, likely associated with macrophage iron accumulation the transferrin receptor cd delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis tollip, muc b, and the response to n-acetylcysteine among individuals with idiopathic pulmonary fibrosis prednisone, azathioprine, and n-acetylcysteine for pulmonary fibrosis safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase trial metformin: an old dog with a new trick? metformin attenuates lung fibrosis development via nox suppression metformin reverses established lung fibrosis in a bleomycin model metformin does not affect clinically relevant outcomes in patients with idiopathic pulmonary fibrosis reversal of persistent fibrosis in aging by targeting nox -nrf redox imbalance nitrated fatty acids reverse pulmonary fibrosis by dedifferentiating myofibroblasts and promoting collagen uptake by alveolar macrophages sars-cov- and viral sepsis: observations and hypotheses complex immune dysregulation in covid- patients with severe respiratory failure covid- : consider cytokine storm syndromes and immunosuppression the landscape of lung bronchoalveolar immune cells in covid- revealed by single-cell rna sequencing severe acute respiratory syndrome (sars) coronavirus-induced lung epithelial cytokines exacerbate sars pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells the role of cytokines including interleukin- 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by combined exploratory and targeted metabolomics competing interests: the authors declare no competing interests.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -a t u authors: nan title: alphabetic listing of diseases and conditions date: - - journal: handbook of autopsy practice doi: . / - - - - _ sha: doc_id: cord_uid: a t u part ii begins with a list of special histologic stains, their for use and their corresponding references. at the end of this list is a procedure for removal of formalin precipitate from tissue sections. diseases. there may also be a list of possible associated conditions. these entities are generally linked pathogenetically to the main disease entry. any asterisk after a related disease indicates that that disorder is also listed as a disease entry. many disease entries will be followed by a three-column table that provides the reader with a listing of the pathologic findings to be expected with the disease as well as the prosection and dissection procedures necessary to demonstrate those findings. it is expected that routine hematoxylin-eosin stains will be done on all sections submitted for histologic examination. special stains will be recommended in the procedures column of the tables, when indicated. any table immediately following the two columns of disease entries always refers to the disease in the right column. prepare smears of undiluted blood. obtain blood for molecular studies for preservation of small intestinal mucosa and for preparation for study under dissecting microscope, see part i, chapter . submit sample for histologic study. submit stool for chemical analysis. record weight and submit sample for histologic study. freeze liver for molecular studies record appearance of spine (see also chest roentgenogram). for removal and specimen preparation, see chapter . request luxol fast blue stain. for removal and specimen preparation, see chapter . below-normal weight in infants. kyphoscoliosis. very low concentrations of cholesterol and decreased triglycerides; serum~-lipoprotein or absent; a.-lipoproteins present. acanthocytosis (spiny red cells). gene mutations ( ) . abnormal shape of villi; vacuolation of epithelial cells. fatty stools fatty changes. gene mutations ( ) systemic manifestations of malabsorption syndrome* and of vitamin a deficiency. * kyphoscoliosis. axonal degeneration of the spinocerebellar tracts; demyelination of the fasciculus cuneatus and gracilis ( ) . possible involvement of posterior columns, pyramidal tracts, and peripheral nerves. atypical retinitis pigmentosa ( ) with involvement of macula. angioid streaks ( ) . synonym: cerebral abscess. note: for microbiologic study of tissues and abscesses, see part i, chapter . include samples for anaerobic culture. it is best to study the brain after fixation but if specimen is examined fresh, aspirate and prepare smears of abscess content. photograph surface and coronal slices of brain. request giemsa stain, gram stain, pas stain, and grocott's methenamine silver stain for fungi. external examination if there is evidence of trauma, see also under "injury, head." prepare roentgenograms of chest and skull. submit for microbiologic study. for removal and specimen preparation, see chapter . for microbiologic study, photography, and special stains, see under "note." for exposure of venous sinuses, see chapter . sample walls of sinuses for histologic study. for exposure of paranasal sinuses, mastoid cells, and middle ears, see chapter . for removal and specimen preparation, see chapter . procedures depend on suspected lesions as listed in right-hand column. skin infections in upper half of face. edema of forehead, eyelids, and base of nose, proptosis, and chemosis indicate cerebral venous sinus thrombosis. * trauma; craniotomy wounds. skull fracture and other traumatic lesions. for possible intrathoracic lesions, see below under "other organs." the national transportation safety board (ntsb)* has authority over aircraft wreckage and the legal authority to investigate and to determine the cause of air crashes. ( ) the dead are the responsibility of the medical examiner or coroner. local police will seal off the area of the crash. other than for the purpose of determining that death has occurred, no one should be allowed to approach the bodies or any objects until the identification teams and the medical examiner or coroner have taken charge. the sudden influx of bodies after a commercial air carrier accident and the request for speedy identification of the victims would overburden almost any institution. managing such a disaster is eased by writing a contingency plan beforehand. temporary morgue facilities may have to be established near the scene of the crash. refrigerated trucks may serve as storage space. a practical approach is to deal first with those bodies that seem to be the easiest to identify, in order to narrow the field for the more difficult cases. if bodies are scattered, their locations can be referenced to stakes in the ground or spray paint on pavement; only then should these bodies (or parts) and personal effects be collected. for large-scale crashes a locations can be referenced to a string-line grid benchmarked to gps coordinates. records and diagrams of the relative positions of victims are prepared during this phase. if bodies are still within the airplane, their positions are recorded, and photographed. the personnel of the medical examiner or coroner can augmented by d-mort team staffed by forensic pathologists, anthropologists, dentists, morgue technicians, and investigators supplied by the national disaster medical system. ** the airline will provide a list of the passengers and the federal bureau of investigation (fbi) disaster team will make itself available to take and identify fingerprints and aid in the acquisition of other identifying data such as age, race, weight, height, and hair color and style. if dental records can be obtained, this provides one of the most certain methods of identification. a medical history indicating amputations, internal prostheses, or other characteristic surgical interventions or the presence of nephrolithiasis, gallstones, and the like will be helpful. fingerprints (and footprints of babies) should be taken in all instances. wallets with identification cards,jewelry, name tags in clothing, or other personal belongings may provide the fastest tentative identification. the medical examiner may elect to autopsy only the flight crew but not the passengers of an aircraft crash. however, the grossly identifiable fatal injuries should be described, photographed, and x-rayed. this may reveal identifying body changes. if comparison of somatic radiographs, dental records, fingerprints, or photographs do not identify the victim, dna comparison must be considered. burned or fragmented bodies of passengers and the bodies ofcrew members, and particularly the pilots, must have a complete autopsy, including roentgenographic and toxicologic examinations, which must always include alcohol and carbon monoxide determinations. internal examination might reveal a coronary occlusion, or roentgenograms may disclose a bullet as evidence that violence preceded the crash. in some airplane crashes, particularly in light airplane accidents, suicide must be considered. in such cases police investigation is required to determine if the pilot exhibited suicidal ideation in the recent past.. when resources permit, autopsies should be performed on all deceased occupants of aircraft crashes, including passengers, in order to distinguish among blunt impact trauma, smoke inhalation, and flash fires as causes ofdeath, and to answer future questions concerning pain and suffering, intoxication, and sequence of survivorship. after a crash victim has been identified, the coroner or medical examiner will issue a death certificate. if remains of a decedent cannot be found, a judge can, upon petition, declare a passenger dead and sign a death certificate prepared by a medical examiner. *phone # ofntsb command center: - - **phone # of dmort: - - . entry should be followed. usually, the circumstances that led to drowning are not apparent from the autopsy findings but can be reconstructed from reports of witnesses and the police. because the reflex drive to seek air is triggered by hypercarbia, not hypoxia, loss of consciousness and drowning can ensue after hyperventilation and breath-holding by experienced swimmers who then drown without a struggle. there are no specific autopsy findings. a search for trauma, including a posterior neck dissection, should be made in all instances. head and cervical injuries may be responsible for loss of consciousness and drowning, usually in individuals diving into shallow water. toxicologic examination as described below for scuba diving accidents is always indicated. with scuba diving fatalities, investigation of the equipment and circumstances is usually more important than the autopsy. scuba fatalities should be studied by or with the aid of diving experts-for instance, members of a diving club or shop (not the one providing the gear used by the decedent) or the u.s. navy. ( ) careful investigation of the scene and study of reports of witnesses and the police are essential. the investigation should ascertain the site of diving (currents and other underwater hazards), the estimated depth, the water temperature (exposure to cold), and a description of water clarity. electrocution should be considered if the site has electric underwater cables (see "injury, electric"). cerebral concussion should be considered if explosives were used in the vicinity. knowledge of the method of recovery of the body and the type of resuscitation efforts can aid in the interpretation of apparent wounds. the medical history of the diving victim should be sought, as it may lead to a diagnosis for which the autopsy is typically silent, such as seizure disorder, or may reveal asthma, emphysema, or chronic bronchitis, all of which increase the risk of air trapping and arterial air embolism. although drowning may be the terminal event in some scuba deaths, the investigation should be focused on the adverse environmental and equipment factors that place a capable swimmer at risk of drowning (see "embolism, air" and "sickness, decompression"). because scuba divers risk arterial air embolism if they ascend with a closed glottis, on can attempt to document gas bubbles at autopsy, but their interpretation is problematic: bodies recovered immediately are subjected to resuscitation efforts, which can by themselves produce extra-alveolar air artifacts, and bodies not recovered immediately tend to be found in a putrefied condition, full of postmortem gas. in the remaining cases, the pathologist must consider the potential of introducing artifactual gas bubbles by the forcible retraction of the chest plate and by sawing the calvarium. the following procedures apply primarily to scuba diving accidents. interrogation of witnesses is important; the behavior and complaints of the decedent, if any, might help distinguish between a natural death by heart disease and an unnatural death by air embolism. external examination eyes and ears head (skull and brain) chest blood (from heart and peripheral vessels) heart tracheobronchial tree and lungs a procedures photograph victim as recovered and after removal of wet suit and other diving gear. record condition of clothing and gear. impound all diving equipment for study by experts, particularly scuba tank, breathing hoses, and regulators. residual air in tank should be analyzed. record color of skin (including face, back, soles, palms, and scalp). palpate skin and record presence or absence of crepitation. record extent and character of wounds. prepare histologic specimens. record appearance of face (including oral and nasal cavities) and of ears. prepare roentgenograms. if air embolism must be expected, as in the presence of pneumomediastinum, follow procedures described under "embolism, air." for evaluation of findings, see also above under "note." if decompression sickness (caisson disease) is suspected, also prepare roentgenograms of the elbows, hips, and knees. otoscopic examination. funduscopic examination. save vitreous for possible toxicologic and other studies. for removal of brain, see chapter . record contents of arteries of the circle of willis and its major branches and basilar artery. strip dura from base of skull and from calvarium. for removal and specimen preparation, see chapter . for demonstration of pneumothorax, see under "pneumothorax". if gas is visible in coronary arteries, photograph. photograph and aspirate gas in heart chambers. submit samples of heart blood and peripheral blood for toxicologic study and drug screen. examine lungs in situ. save bronchial washings for analysis of debris. fresh dissection is recommended. if decompression sickness is suspected, prepare sudan stains from fresh-frozen lung sections. complete toxicologic sampling should be carried out (see chapter ). record nature of gastric contents. remove neck organs toward end of autopsy. for posterior neck dissection, see chapter . incise tongue. for removal, see chapter . for removal, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . consult roentgenograms. in decompression sickness, fatty change of liver, and ischemic infarctions of many organs. interstitial emphysema. aspiration (see above). trauma to cervical spine. mottled pallor of tongue after air embolism. contusion of tongue after convulsive chewing. nitrogen bubbles in spinal cord arteries may occur after rapid ascent. air embolism;' cerebral edema in decompression sickness. aseptic necroses (infarcts, "dysbaric osteonecrosis"), most often in head of femur, distal femur, and proximal tibia. infarcts indicate repeated hyperbaric exposures. nitrogen bubbles in and about joints and in periosteal vessels ("bends") occur during rapid ascent. related terms: automobile accident; motorcycle accident. note: a visit to the scene can make the interpretation of the autopsy findings easier. the vehicle can also be inspected in a more leisurely fashion at the impound lot. this is particularly useful for correlating patterned injuries with objects in the vehicle. most vehicular crashes occur as intersection crashes or because a vehicle with excessive speed left a curved road. the medical examiner or coroner should gain a basic understanding of the crash mechanism so that informed descriptions can be rendered, e.g., "impact to the b pillar of the decedent's automobile by the front of a pickup truck which failed to stop for a stop sign at an intersection, resulting in a -feet intrusion into the cabin; restraint belts not employed; air bag deployed; extrication required which took minutes." police are responsible for determining mechanical and environmental risk factors for the crash and for determining some human risk factors such as suicidal or homicidal intent. the pathologist determines other risk factors for crashes such as heart disease, a history of epilepsy, and intoxication by carbon monoxide, drugs, and alcohol. suicide as a manner of death should be considered when a single-occupant vehicle strikes a bridge abutment or a large tree head-on, with no evidence of evasive action or braking. in such a situation, the standard police traffic investigation should be supplemented of interviews of the victim's family and friends. the ambulance run sheet is an invaluable source of observations that often are not available from the police. this document should be acquired in all instances, even if the paramedics determined that death occurred and did not transport. the basic autopsy procedures are listed below. most traffic victims who die at the scene or who are dead on arrival at the hospital died from neurogenic shock caused by wounds of the head or vertebral column, or from exsanguination from a tom vessel or heart. as such, they have little lividity, and little blood is found in the vehicles. presence ofintense lividity may indicate suffocation or heart disease as a cause of death. if postural asphyxia is suspected, the first responders to the scene should be interviewed to determine the position of the decedent in the vehicle, and the vital signs, ifany, ofthe decedent from the time of the crash to the time of extrication. posterior neck dissection is indicated in these instances. if manifestations of heart disease, intense lividity, and absence oflethal wounds suggest that a crash occurred because the driver was dead, other drivers on the road may have observed that the victim was slumped at the wheel before the crash. the determination of heart attack at the wheel is usually simple, because most such victims realize that something is wrong, and bring the vehicle to a stop at the side of the road, or coast gently into a fixed object. in such instances, damage to the vehicle is minor, and wounds to the decedent are usually trivial. while pattemed wounds can often be matched to objects (see below), patternless wounds usually cannot be visually matched to specific objects, although an opinion can sometimes be given as to what object was struck, based on the direction of motion and position ofthe body with respect to the vehicle. impacts with the a-pillar produce narrow vertical zones of facial laceration and fractures extending from forehead to jaw. tempered glass shatters into small cubes on impact, and leaves so-called "dicing" wounds, which are abraded cuts arranged in a somewhat rectilinear pattern. windshield glass leaves shallow, abraded, vertically oriented cuts on the face or scalp. with pedestrians, the lower extremities are of particular forensic interest, to determine the height and direction of impact from vehicles that left the scene. scalp hair and blood should be collected from such "hit and run" victims and from occupants of a suspect car if police have a question as to which occupant was the driver; these exemplars can be compared to fibers and tissue recovered from the vehicle in question. likewise, foreign material in wounds can sometimes be matched to suspect vehicles, and should be sought and retained as evidence. for pedestrians, the distance between the impact point on the lower extremities and the soles of the feet should be recorded. the legs should be opened to inspect tibial fractures; cortical fractures initiate propagation opposite to the side of impact, where they usually have a pulled-apart appearance, and then splinter the cortex at the side of impact. abrasions are better impact markers than contusions, because subcutaneous blood extravasation can be caused not only by impact to the skin, but also from blood extravasating from underlying fractures. if no cutaneous abrasions or fractures of the leg bones are found, the skin of the legs should be incised to expose contusions. fracture descriptions should include location in the bone (e.g., proximal metaphysis or shaft), whether the fracture is complete or incomplete, and whether the fracture is displaced or distracted. lacerations of intervertebral disks, facet joint capsules, and ligamenta flava should not be loosely termed "fractures." the presence or absence of blood extravasation in soft tissue adjacent to the fractures should be recorded, and its volume estimated if it appears severe enough. venous air embolism from tom dural sinuses cannot be diagnosed without a pre-autopsy chest radiograph or an in situ bubble test. if an x-ray machine is readily available, an anterior-posterior chest radiograph should be obtained in every traffic victim who dies at the scene or after a failed resuscitation attempt. if a hemothorax is suspected, the rib cuts should be placed further lateral and the chest plate reflected so that the internal mammary vessels can be inspected before the chest plate is removed. after measuring and removing the bloody effusion, the underlying serosal surfaces should be inspected for defects. lacerations of the heart and aorta will be obvious. tamponaded lacerations of the aorta, around which the adventitia still holds, must be noted as such. if no lacerations are found at the usual sites, lacerations of the azygous veins must be considered, especially in association with fracture dislocations of the thoracic vertebral column; other sites are the internal mammary arteries, especially with fractures of ribs i and or of the sternum, and intercostal arteries with displaced rib fractures. only after the serosal defect is identified should the organs be removed, because that procedure creates many more holes in the serosa. for that reason, as much information as possible should be gained by in situ observation. the only evidence of concussion of the heart may be a cardiac contusion or a sternal fracture. the usual clinical history suggests cardiovascular instability that is not associated with craniocerebral trauma and which does not respond to the infusion of intravenous volume agents. the autopsy assistant may saw but should not retract the skull cap and remove the brain. the pathologist should observe in situ whether shallow lacerations of the pontomedullary junction with stretching of the midbrain are present. these lesions cannot be distinguished from artifact by examining the brain later. thus, only after appropriate in situ inspection should the pathologist remove the brain. a posterior neck dissection is required if no lethal craniocerebral or cardiovascular trauma is found, or if suffocation is suspected; neck trauma must be ruled out to diagnose suffocation in a traffic fatality. sudden death in a patient with seemingly trivial wounds may be caused by undiagnosed trauma of the craniocervical articulation. a posterior neck dissection is required in these instances. the diagnosis of diffuse axonal injury of the brain in victims with no appreciable survival interval requires that suffocation be ruled out and that no resuscitation from a cardiac arrest has been attempted. clinicians are quick to apply the label "closed head injury" when a victim of a traffic crash has cerebral edema on a computerized axial tomogram of the head, even if no cerebral contusions, scalp contusions, or skull fractures are evident. this may be a misinterpretation, because cerebral edema can be caused by hypoxic encephalopathy made evident after resuscitation from a cardiac arrest, or from hypoxia caused by suffocation. procedures possible or expected findings record presence of lividity. photograph all external wounds; measure all lacerations and any abrasions or contusions with a pattern. collect scalp hair and blood (see below) from victims of hit and run accidents. collect foreign material in wounds. intense lividity and absence of lethal wounds may indicate that the crash occurred because the driver was dead from heart disease or suffocation. wound documentation. patterned injuries often sometimes be matched to objects in or about the vehicle (the most common patterned wound is that from tempered glass; see above under "note"). impact patterns in pedestrians may help to reconstruct the accident. hair and blood of the victim may be matched to transfer evidence on a vehicle suspected of having left the scene. part ii / diseases and conditions internal examination of body cavities heart and great vessels abdomen skull and brain; neck soft tissue compartments at any location prepare roentgenograms of chest is cases with head impact and skull fractures. collect samples for toxicologic study from all victims, including passengers. create pleural window to detect pneumothorax. if blood is seen, examine internal mammary vessels (see under "note"). measure volume of blood in cavity bleeds, and note whether chambers of heart and great vessels are collapsed or filled. record evidence of cardiac contusion, sprain of intracardiac inferior vena cava, laceration of pericardial sac, and fracture of sternum. laceration of heart or great vessels (measure volume of blood). follow routine procedures for dissection of heart and great vessels (see chapter ) . in situ bubble test to confirm venous air embolism. record evidence of trauma and volume of blood in peritoneal cavity; estimated volume of blood in retroperitoneal soft tissues. autopsy assistant may saw the skull but pathologist should inspect brain in situ and remove it personally. for removal and specimen preparation of brain, see chapter . record brain weight. posterior neck dissection is indicated if there is no craniocerebral or cardio-vascular trauma, or if suffocation is suspected. record evidence of trauma and estimate volume of blood. venous air embolism.' evidence of alcohol or drug intoxication. pneumothorax, hemothorax, e.g., after laceration of internal mammary vessels. evidence of significant hemorrhage. indirect evidence of cardiac concussion. evidence of exsanguinating wounds. evidence of cardiovascular disease that may have felled the driver before the crash. in european countries, the concentration is expressed in promille (grams per liter). in the united states, it has become customary to refer to concentration by percentage (grams per deciliter), and values in these units have been written into legislation and included in the uniform vehicle codes. unless qualified, the use of promille or percentage does not indicate whether the result of the analysis is weight/weight, weight/ volume, orvolume/volume. another common way ofexpressing concentration, milligrams per deciliter, has also been used to indicate alcohol concentrations. the method ofexpressing concentration must be clearly specified whenever the alcohol level is mentioned. the desired expression canbe derived from the toxicologic report by using the following equation: i, ~g/ml = mg/dl = . g/dl = . mmolll = . promille = . % what is the legal interpretation of alcohol (ethanol) intoxication? objective impairment of driving ability is observed at threshold blood alcohol concentrations of . -. g/dl. as of august all states and the district of columbia have adopted laws that make it criminal offense for a driver to operate a motor vehicle with a blood alcohol concentration of . g/ dl or greater. many states have an enhanced penalty for high concentrations such as . g/dl or above. several states have zero tolerance laws, under which drivers who are minors are legally operating only if their blood alcohol concentration is . g/dl or less, and in some states, not detectable at all. blood alcohol concentrations obtained at autopsy are valid until putrefaction begins. specimen tubes with sodium fluoride should be used, and the specimen should be stored in the refrigerator. if the air space above the blood samples in the container is large, alcohol can evaporate and a falsely low blood alcohol level can result. putrefactive changes before autopsy or during storage may cause a falsely high blood alcohol concentration. ethanol can be produced in the specimen container; this is more likely in the absence of a preservative. because fluoride inhibits bacteria far more than fungi, higher fluoride concentrations are required for the inhibition of fungal growth ( ) . although there is no major difference in the alcohol concentrations ofblood samples from the intact heart chambers and the femoral vessels ( ), autopsy samples from pooled blood in the pericardial sac or pleural cavity are unsatisfactory. we therefore recommend that blood be withdrawn from peripheral vessels. is there normal "endogenous" blood alcohol (ethanol) in a living person? blood alcohol concentrations are generally believed to be negligible in the absence of ingested alcohol. "endogenous" ethanol in human blood exists at a concentration of about . g/dl, which is below the limit of detection for most methods ( ) . first in such a list would be postural asphyxia, for example, in drunks who fall asleep face down. also, depressant drugs in the tricyclic, analgesic, barbiturate, and benzodiazepine classes all potentiate the effect of alcohol ( ) . also included in such a list would be infancy and childhood; ischemic heart disease;' chronic bronchitis and emphysema;' other chronic debilitating diseases; poisoning with carbon tetrachloride' or carbon monoxide;' and other causes of hypoxia.' how can one estimate blood alcohol (ethanol) concentrations from vitreous, urine, or tissue alcohol levels and from alcohol in stomach contents? the ratio of serum, plasma, urine, vitreous, and various tissues has been compiled by garriot ( ) . the values may vary considerably. for vitreous, the ratios varied from . - . . these variations may depend on whether blood alcohol concentrations were increasing or decreasing at the time of death. most other body fluids and tissues showed ranges closer to . most urine values were above the blood alcohol concentrations. in another study ( ) , the blood/vitreous (bn) ratio in the early absorption phase was . (range, . - . ; sd . ) and in the late absorption and elimination phase, the bn ratio was . (range, . - . ; sd . ). blood ethanol concentrations probably can be estimated using b = . v for early absorption and b = . v for later phases. a urinelblood ethanol ratio of . or less indicates that the deceased was in the early absorption phase. how can one use alcohol (ethanol) concentrations in postmortem specimens to estimate the blood alcohol concentration at various times before death? with certain limitations, one can base calculations of this kind on the assumption that the blood alcohol level decreases from its peak at a fairly constant rate of . -q. g/dl/h until death ( ) . if blood is not available, conversion factors (see above) must be used. alcoholics have been reported to metabolize at a rate of up to . g/dl/h ( ) . example: the driver of an automobile drinks at a party until midnight. he leaves his host at about : a.m. and is involved in a head-on collision at : a.m. he dies in the emergency room at : a.m. there are multiple injuries and the patient exsanguinates. the autopsy is done at : p.m. although this appears quite unlikely, let us assume that no satisfactory blood sample was obtained before death and that no blood or plasma expanders were given. if under such circumstances the alcohol concentration in the vitreous was found to be . g/dl, what was the alcohol concentration in the blood at the time of the accident? vitreous and blood alcohol concentrations may be assumed to have remained unchanged after death. therefore, the blood alcohol level at the time of death must have been approx . (vitreous humor alcohol) x . (conversion factor, see above) = . g/dl. the time interval between the accident ( : a.m.) and death ( : a.m.) is hand min or / h. if we assume that the decedent was not an alcoholic and that the blood alcohol concentration was decreasing from its peak at a constant rate of . g/dl/h, then the concentration at the time ofthe accident is estimated to have been . (concentration at time of death) + ( / x . ) = . + . = . g/dl or . %. the blood alcohol concentration at the time of the accident could have been lower if the victim stopped drinking later than h or / h before the accident. in the latter case, the peak alcohol level would have occurred after the accident, reflecting the time to absorb the latest drink. the blood alcohol concentration at the time of the accident could have been lower or higher if the time when the patient stopped drinking, the time of the accident, or the time of the death is uncertain. the blood alcohol concentration at the time of the accident could have been higher if the victim was a chronic alcoholic. the elimination rate in such persons may be as high as . mg/dl, which would change the figures in our example above to . + ( / x . ) = . + . = . g/d or . %. only rough estimates are possible. first, the peak blood alcohol level must be determined or calculated, as described in the previous paragraphs. tables (see below) are available that relate blood alcohol level to the minimal amounts of whiskey, wine, or beer that must have been consumed ( ) . however, tables of this type are often based on the minimum amount of alcohol circulating in the body after specific numbers of drinks; such tables do not yield reliable results if used conversely. furthermore, inasmuch as drinking and elimination of alcohol may take place concomitantly, over a longer period the total amount of alcohol consumed may have been much greater than the tables would indicate. it cannot be lower. according to these tables, pints of ordinary beer or fl oz of whiskey would be the minimal amounts needed to produce a blood alcohol level of about mg/dl in a person weighing - pounds. the total body alcohol can be calculated from the blood alcohol level by using widmark's formula: average concentration of alcohol in entire body = . concentration of alcohol in the blood in a person weighing kg, the blood alcohol concentration would be increased mg/dl ( . %) by the absorption of oz of ethanol ( z of -proof whiskey). strength of alcohol is measured in "proof'; absolute alcohol is proof. therefore, in the united states, alcohol content as volume percent is half the proof (for example, -proof whiskey contains % alcohol by volume). the alcohol content of various beverages is shown in the following table. approximate alcohol content in various beverages t toata from glaister, rentoul e. medical jurisprudence and toxicology, th ed. e & s livingstone, edinburgh, with permission. twithin h after consumption of diluted alcohol (approx %) on an empty stomach, assuming body weight of - pounds ( . - . kg) reproduced from ( ) with permission. *one ounce (about ml) of whiskey or z (about ml) of beer. what is the toxicity of alcohol other than ethanol? in general, the toxicity increases as the number of carbon atoms in the alcohol increases. thus, butyl alcohol is two times as toxic as ethyl alcohol: but isopropyl alcohol is only twothirds as toxic as isobutyl alcohol and one-half as toxic as amyl alcohol. primary alcohols are more toxic than the corresponding secondary isomers ( ) . anemia, hemolytic synonyms and related terms: acquired hemolytic anemia; extracorpuscular hemolytic anemia; hereditary hemolytic anemia (hereditary elliptocytosis, pyropoikilocytosis, stomatocytosis. spherocytosis); immunohemolytic anemia; intracor-puscular hemolytic anemia; microangiopathic hemolytic anemia; spur cell anemia. possible associated conditions: disseminated intravascular coagulation;* eclampsia;* glucose- -phosphatase deficiency (g pd); hemolytic uremic syndrome;* malignant hypertension; lymphoma* and other malignancies; paroxysmal nocturnal hemo-globinuria; sickle cell disease;*thalassemia;* thrombotic thrombocytopenic purpura.* (see also below under "note.") note: hemolysis also may be caused by conditions such as poisoning with chemicals or drugs, heat injury, snake bite,* or infections or may develop as a transfusion reaction* or be secondary to adenocarcinoma, heart valve prostheses (see below), liver disease (see below), renal disease, or congenital erythropoietic porphyria. * procedures prepare skeletal roentgenograms. jaundice; skin ulcers over malleoli. in young patients: thickening of frontal and parietal bones with loss of outer table ("hairon-end" appearance); paravertebral masses caused by extramedullary hematopoiesis; deformities of metacarpals, metatarsals, and phalanges. osteonecrosis* of femoral heads. remove and place in fixative as early as possible in order to minimize autolysis (alternatively, formalin can be injected in situ; see below). samples should include oxyntic corpus and fundus mucosa. record weights. submit tissue samples for histologic study. record weight of thyroid gland. for removal and specimen preparation, see chapter . request luxol fast blue stain. for removal and specimen preparation, see chapter . if there is a clinical diagnosis of anemia-related amblyopia, follow procedures described under "amblyopia, nutritional." jaundice. manifestations of malnutrition. * stomatitis with cheilosis and perianal ulcerations due to folic acid deficiency. chronic exfoliative skin disorders. vitiligo. macrocytosis; poikilocytosis; macroovalocytes; hypersegmentation of leukocytes; abnormal platelets. atrophic glossitis with ulcers. pharyngoesophagitis (folic acid deficiency). previous total or subtotal gastrectomy. carcinoma of stomach. autoimmune gastritis (diffuse corporal atrophic gastritis) with intestinal metaplasia. crohn's disease;* sprue;* other chronic inflammatory disorders; jejunal diverticula; intestinal malignancies; fish tapeworm infestation; previous intestinal resection or blind intestinal loop; enteric fistulas. hepatosplenomegaly. alcoholic liver disease. * giant epithelial cells. hyperthyroid goiter; thyroiditis. demyelination of cerebral white matter (in advanced cases). demyelination in posterior and lateral columns of spinal cord, most frequently in thoracic and cervical segments. demyelination of peripheral nerves. retinal hemorrhages; demyelination of optic nerves. hypercellular; megaloblastic. myeloproliferative disorder. brain other organs if mycotic aneurysms are expected and microbiologic studies are intended, follow procedures described below under "aneurysm, mycotic aortic." request verhoeff-van gieson, gram, and grocott's methenamine silver stains. for cerebral arteriography, see chapter . if arteriography cannot be carried out, rinse fresh blood gently from base of brain until aneurysm can be identified. record site of rupture and estimated amount of extravascular blood. for paraffin embedding of aneurysms, careful positioning is required. expected findings depend on type of aneurysm. mycotic aneurysms are often multiple and deep in brain substance. berry aneurysms are the most frequent types and often are multiple. most frequent sites are the bifurcations and trifurcations of the circle of willis. saccular atherosclerotic aneurysms are more common than dissecting aneurysms, which are very rare. with congenital cerebral artery aneurysm: coarctation of aorta;* manifestations of hypertension;* and polycystic renal disease. with mycotic aneurysm: infective endocarditis;* pulmonary suppurative processes; and pyemia. aneurysm, dissecting aortic (see "dissection, aortic.") aneurysm, membranous septum of heart note: for general dissection techniques, see chapter . most aneurysms ofthe membranous septum probably repre-sent spontaneous closure of a membranous ventricular septal defect by the septalleafiet of the tricuspid valve. aneurysm, mycotic aortic note: (i) collect all tissues that appear to be infected. ( ) request aerobic, anaerobic, and fungal cultures. ( ) request gram and grocott methenamine silver stains. ( ) no special precautions are indicated. ( ) no serologic studies are available. ( ) this is not a reportable disease. chest and abdominal organs aorta other organs submit blood samples for bacterial culture. en masse removal of adjacent organs is recommended. photograph all grossly identifiable lesions. aspirate material from aneurysm or para-aortic abscess and submit for culture. prepare sections and smears of wall of aneurysm and of aorta distant from aneurysm. request verhoeffvan gieson and gram stains. septicemia and infective endocarditis. * streptococcus, staphylococcus, spirochetes, and salmonella can be found in mycotic aneurysm. para-aortic abscess. septic emboli with infarction or abscess formation. aneurysm, syphilitic aortic part ii / diseases and conditions heart and aorta other organs en masse removal of organs is recommended. for coronary arteriography, see chapter . request verhoeff-van gieson stain from sections at different levels of aorta, adjacent great vessels, and coronary arteries. see also under "syphilis." aneurysm usually in ascending aorta. may erode adjacent bone (sternum). syphilitic aortitis may cause intimal wrinkling, narrowing of coronary ostia, and shortening of aortic cusps. disruption of medial elastic fibrils. aortic valvulitis and insufficiency;* syphilitic coronary arteritis; syphilitic myocarditis. external examination aorta prepare chest and abdominal roentgenograms. open aorta along line of blood flow, or bisect into anterior and posterior halves. photograph tear(s). measure bloody effusions in body cavities. measure or estimate amount of blood in mediastinum. request verhoeff-van gieson stain. cutaneous impact trauma. mediastinum widened by hemorrhage in case of tarnponaded dissection. a bleed into a body cavity of less-thanexsanguinating volume should point to an alternate mechanism of death such as neurogenic shock or lethal concussion; a posterior neck dissection may be required in such instances. microscopy may show transmural rupture, false aneurysm, or localized dissection. angiitis (see "arteritis, all types or type unspecified.") angina pectoris note: see under "disease, ischemic heart" and chapter . angiokeratoma corporis dittusum (see "disease, fabry's.") angiomatosis, encephalotrigeminal (see "disease, sturge-weber-dimitri.") angiopathy, congophilic cerebral synonyms and related terms: beta amyloid angiopathy due to~-amyloid peptide deposition (~a ) (associated with alzheimer's disease; hereditary cerebral hemorrhage with amyloid angiopathy of dutch type; or sporadic beta amyloid angiopathy); hereditary cerebral amyloid angiopathy, due to deposition of other amyloidogenic proteins such as cystatin c (icelandic type) and others (e.g., transthyretin, gelsolin) ( ). procedures possible or expected findings request stains for amyloid, particularly congo red, and thioflavine s (examine with polarized and ultraviolet light, respectively). request immunostain for~a . some tissue should be kept frozen for biochemical studies. multiple recent cerebral cortical infarctions or small cortical hemorrhages, or both, or massive hemispheric hemorrhages, both recent and old. amyloid deposition in leptomeninges and cortical blood vessels. senile plaques are usually present. in some cases, angiopathy is part of alzheimer's disease. * other organs a prepare material for electron microscopy. electron microscopic study permits definite confirmation of diagnosis. organs and tissues may be minimally affected by amyloidosis. anomaly, coronary artery possible associated conditions: with double outlet right ventricle; persistent truncal artery; tetralogy of fallot;* and transposition of the great arteries.* note: coronary artery between aorta and pulmonary artery, often with flap-valve angulated coronary ostium. coronary artery may communicate with cardiac chamber, coronary sinus, or other cardiac veins, or with mediastinal vessel through pericardial vessel. saccular aneurysm of coronary artery with abnor-mal flow, infective endarteritis of arteriovenous fistula, and myocardial infarction may be present. ifone or both coronary arteries originate from pulmonary trunk, myocardial infarction may be present. heart perform coronary angiography. if infective endarteritis is suspected, submit blood sample for microbiologic study. ectopic origin of coronary arteries or single coronary artery. sudden death. for a detailed description of possible additional findings, see above under "note." anomaly, ebstein's (see "malformation, ebstein's") anorexia nervosa note: sudden death from tachyarrhythmias may occur in advanced cases and thus, autopsy findings may not reveal the immediate cause of death. external examination all organs record height and weight, and prepare photographs to show cachectic features. record abnormalities as listed in righthand column. follow procedures described under "starvation." record weight of endocrine organs and submit samples for histologic study. cachexia, often with preserved breast tissue; hirsutism; dry, scaly, and yellow skin (carotenemia). mild edema may be present. parotid glands may be enlarged. manifestations of starvation.* ovaries tend to be atrophic; other endocrine organs should not show abnormalities. synonyms: cutaneous anthrax; gastrointestinal anthrax; pulmonary (inhalational) anthrax. note: ( ) collect all tissues that appear to be infected. this is a reportable disease. bioterrorism must be considered in current cases. external examination and skin blood photograph cutaneous papules, vesicles, and pustules. prepare smears and histologic sections. submit samples for bacteriologic study. submit sample for serologic study. disseminated anthrax infection may occur without skin lesions. edema of neck and anterior chest in nasopharyngeal anthrax. anthrax septicemia. see above under "note." part ii i diseases and conditions lungs gastrointestinal tracts and mesentery neck organs record character and volume of effusions. after sampling for bacteriologic study (see above under "note") perfuse one or both lungs with formalin. extensive sampling for histologic study is indicated. extensive sampling for histologic study is indicated. photograph meningeal hemorrhage in situ. pleural effusions;* hemorrhagic mediastinitis; anthrax pneumonia (inhalational anthrax; woolsorter's disease). histologic sections reveal hemorrhagic necrosis, often with minimal inflammation and gram-positive, spore-forming, encapsulated bacilli. gastrointestinal anthrax with mucosal edema and ulcerations. hemorrhagic mesenteric lymphadenitis. tongue, nasopharynx, and tonsils may be involved. hemorrhagic meningitis (hemorrhage tends to predominate). external examination distal colon and rectum photograph perineum. measure depth of anal pit, if any. dissect distal colon, rectum, and perirectal pelvic organs in situ (as much as possible). search for opening of fistulous tracts from lumen. use roentgenologic study or dissection, or both, to determine course of tract. absence of normally located anus; anal dimple. abnormal termination of the bowel into the trigone of the urinary bladder, the urethra distal to the verumontanum, the posterior wall of the vagina, the vulva, or the perineum. aortitis note: see also under "arteritis" and "aneurysm, ascending aortic." heart and aorta other organs and tissues remove heart with whole length of aorta and adjacent major arteries. record width and circumference of aorta at different levels. describe and photograph appearance of intima and of orifices of coronary arteries and other aortic branches. submit multiple samples for histologic study and request verhoeff-van gieson stain. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. secondary aortic atherosclerosis or intimal fibroplasia. widening of aorta; syphilitic aneurysm. * giant cell aortitis; rheumatoid aortitis; syphilitic aortitis; takayasu's arteritis.* manifestations of rheumatoid arthritis, * syphilis,* systemic sclerosis,* hodgkin's lymphoma, and many other diseases associated with vasculitis. external examination brain spine and spinal cord other organs prepare roentgenogram of spine. for removal and specimen preparation, see chapter . for removal of spinal cord and specimen preparation, see chapter . expose nerve roots. record appearance and photograph spinal cord in situ. submit samples of spinal cord and inflamed tissue for histologic study. request gram, gomori's iron, and grocott's methenamine silver stains. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. signs of previous spinal surgery or lumbar puncture (myelography). evidence of previous trauma or previous myelography. cerebral arachnoiditis. fibrous arachnoidal adhesions and loculated cysts. tuberculosis;* syphilis;* fungal or parasitic infection. systemic infection (see above). ascending urinary infection or other manifestations of paraplegia. arch, aortic, interrupted synonym: severe coarctation. note: the basic anomaly is a discrete imperforate region in the aortic arch, with a patent ductal artery joining the descending thoracic aorta. type a interruption is between the left subclavian and ductal arteries; type b between the left subclavian and left common carotid arteries; and type c (rare) between the left common carotid and brachiocephalic (innominate) arteries. for general dissection techniques, see part i, chapter . possible associated conditions: bicuspid aortic valve (with type a); di george syndrome* with thymic and parathyroid aplasia (with type b); hypoplasia of ascending aorta (with all types); persistent truncal artery (truncus arteriosus); ventricular septal defect. arrhythmia, cardiac note: see also under "death, sudden cardiac." toxicologic studies may be indicated, for instance, if digitalis toxicity (see "poisoning, digitalis") is suspected. if a cardiac pacemaker had been implanted, the instrument should be tested for malfunction. arteriosclerosis (see "atherosclerosis.") arteritis, all types or type unspecified synonyms and related terms: allergic angiitis and granulomatosis (churg-strauss);* allergic vasculitis; anaphylactoid purpura* and its synonyms; angiitis; buerger's disease;* cranial arteritis; giant cell arteritis;* granulomatous arteritis (angiitis); hypersensitivity angiitis; infectious angiitis; necrotizing arteritis; polyarteritis nodosa;* rheumatic arteritis; rheumatoid arteritis, syphilitic arteritis; takayasu's arteritis;* temporal arteritis; thromboangiitis obliterans; and others (see also below under "note"). note: autopsy procedures depend on ( ) the expected type of arteritis, such as giant cell arteritis,* polyarteritis nodosa,* or thromboangiitis obliterans (buerger's disease*); and ( ) the nature of suspected associated or underlying disease, such as aortic arch syndrome,* beh~et's syndrome,* cogan's syndrome, degos' disease,* dermatomyositis,* erythema nodosum and multiforme,* goodpasture's syndrome,* polymyositis, rheumatic fever, * rheumatoid arthritis,* syphilis,* and other nonspecific infectious diseases, systemic lupus erythematosus,* systemic sclerosis (scleroderma),* or takayasu's disease. for histologic study of blood vessels, verhoeff-van gieson stain or a similar stain is recommended. temporal and ophthalmic arteritis. arteritis of ciliary and retinal vessels. clinically, polymyalgia. anemia. arteritis, takayasu's synonyms: aortic arch syndrome; pulseless disease. external examination heart, aorta, and adjacent great vessels kidney eyes and optic nerve brain for in situ aortography, clamp distal descending thoracic aorta and neck vessels as distal as possible from takeoff at aortic arch. remove heart together with aorta and long sleeves of neck vessels. for coronary arteriography, see chapter (method designed to show coronary ostia). test competence of aortic valve. open aortic arch anteriorly and measure (with calipers) lumen at origin of great neck vessels. photograph aorta and neck vessels and submit samples for histologic study. request verhoeffvan gieson stain. submit tissue for histologic examination. for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . facial muscular atrophy and pigmentation. narrowing at origin of brachiocephalic arteries. dilated ascending aorta. narrowing of coronary arteries at origins. myocardial infarction. aortic insufficiency. * aortic atherosclerosis. thromboses of brachiocephalic arteries. giant cell arteritis. * diffuse mesangial proliferative glomeulonephritis ( ) . atrophy of optic nerve, retina, and iris; cataracts; retinal pigmentation. ischemic lesions. artery, patent ductal synonym: patent ductus arteriosus. note: the basic anomaly is persistent postnatal patency of the ductal artery, usually as an isolated finding (in % of cases in infants, and in % in adults). it is more common in premature than full-term infants and at high altitudes than at sea level. possible complications in unoperated cases include congestive heart failure, * plexogenic pulmonary hypertension,* ductal artery aneurysm or rupture, fatal pulmonary embolism,* or sudden death. in some conditions, such as aortic atresia* or transposition with an intact ventricular septum,* ductal patency may be necessary for survival. possible associated conditions: atrial or ventricular septal defect;* coarctation ofthe aorta;* conotruncal anomalies; necrotizing enterocolitis in premature infants; postrubella syndrome; and valvular or vascular obstructions. artery, persistent truncal synonym and related terms: type i, pulmonary arteries arise from single pulmonary trunk (in %); type , pulmonary arteries arise separately but close-by (in %); type , pulmonary arteries arise separately but distal from one another (in %). note: the basic anomaly is a common truncal artery, with truncal valve, giving rise to aorta, pulmonary arteries, and coronary arteries, usually with a ventricular septal defect. interventions include complete rastelli-type repair, with closure of ventricular septal defect, and insertion of valved extracardiac conduit between right ventricle and detached pulmonary arteries. possible associated conditions: absent pulmonary artery (in %); atrial septal defect (in %); absent ductal artery (in %); coronary ostial anomalies (in %); di george syndrome;* double aortic arch; extracardiac anomalies (in %); interrupted aortic arch* (in %); right aortic arch (in %); truncal valve insufficiency (uncommon) or stenosis (rare); trun-cal valve with three (in %), four (in %), or two (in %) cusps. heart and great vessels if infective endocarditis is suspected, follow culture procedures for endocardial vegetation described in chapter . request verhoeff-van gieson stain. infective endocarditis,* usually of truncal valve. late postoperative conduit obstruction. postoperative late progressive truncal artery dilation with truncal valve insufficiency. hypertensive pulmonary vascular disease. cerebral abscess,* if right-to-ieft-shunt was present. arthritis, all types or type unspecified note: for extra-articular changes, see under the name of the suspected underlying conditions. infectious diseases that may be associated with arthritis include bacillary dysentery, * brucellosis, * gonorrhea, rubella,* syphilis, * tuberculosis, * typhoid fever, * and varicella. * noninfectious diseases in this category include acromegaly,* beh<;et's syndrome,* felty's syndrome,* gout,* rheumatoid arthritis,* and many others, too numerous to mention. remove synovial fluid and prepare smears. submit synovial fluid for microbiologic and chemical study. for removal of joints, prosthetic repair, and specimen preparation, see chapter . for removal and specimen preparation, see chapter . in the polyarticular variant, facial asymmetry may be noted. rheumatoid factor positive in some cases. pericarditis.* interstitial pneumonitis; pleuritis. (see also under "arthritis, rheumatoid.") lymphadenopathy. splenomegaly. monarthritis or severe, erosive polyarthritis; see also under "arthritis, rheumatoid" and above under "externalexamination and skin." ankylosing spondylitis* may be present. chronic iridocyclitis. see "arthritis, rheumatoid." arthritis, rheumatoid synonyms and related terms: ankylosing spondylitis;* felty's syndrome;* juvenile rheumatoid arthritis* (still's disease); rheumatoid disease; and others. possible associated conditions: amyloidosis;* polymyositis (dermatomyositis*); psoriasis;* sjogren's syndrome;* systemic lupus erythematosus;* systemic vasculitis, and others. subcutaneous rheumatoid nodules on elbows, back, areas overlying ischial and femoral tuberosities, heads of phalangeal and metacarpal bones, and occiput. deformities and subluxation of peripheral joints (see also below under "joints"). subaxial dislocation of cervical spine may be cause of sudden death. pneumothorax;* pleural empyema.* t-cell abnormalities ( ) . bacteremia. positive rheumatoid factor. rheumatoid granulomas in myocardium (septum), pericardium, and at base of aortic and mitral valves; constrictive pericarditis;* aortic stenosis;* coronary arteritis. systemic vasculitis (arteritis*). rheumatoid granulomas in pleura and lung (with pneumoconiosis*); bronchopleural fistula; rheumatoid pneumonia with interstitial pulmonary fibrosis and honeycombing; bronchiectasis;* bronchiolitis with cystic changes; pulmonary arteritis. pneumoconiosis* in caplan arthrogryposis ( ) may be a primary muscle disease, or it may involve abnormalities of the brain, spinal cord, and/or peripheral nerves. etiologies are numerous, as are the modes of inheritance. critical to making the appropriate diagnosis is the collection of muscles from various sites for routine histology, muscle histochemistry, and electron microscopy. portions of peripheral motor nerves must also be prepared for histology and electron microscopy. abdominal cavity intra-abdominal lymphatic system puncture abdominal cavity and submit fluid for microbiologic study. record volume of exudate or transudate and submit sample for determination of fat and cholesterol content. prior to routine dissection, lymphangiography (see below) may be indicated. possible associated conditions: with pulmonary aspergillosis-bronchiectasis; * bronchocentric granulomatosis;* sarcoidosis;* tuberculosis. * with systemic aspergillosisleukemia;* lymphoma;* and other conditions complicated by immunosuppression (l, ) . other organs a carefully make multiple parasagittal sections through the unperfused lungs. culture areas of consolidation. if diagnosis was confirmed, perfuse lungs with formalin. prepare histologic sections from walls of cavities, cavity contents, and pneumonic infiltrates. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. assault note: all procedures described under "homicide" must be followed. asthma note: spray death* may occur in asthma sufferers from pressurized aerosol bronchodilators. record thickness and position. perfuse one lung with formalin. because mucous plugs may block bronchial tree, attach perfusion apparatus to pulmonary artery or to bronchus and pulmonary artery. monitor perfusion to ensure proper inflation. prepare photograph of fixed cut section. submit samples of pulmonary parenchyma and bronchi for histologic study. request azure-eosin and verhoeff-van gieson stains. record weight and thickness of walls. leave attached to stomach. photograph and submit samples for histologic study. eczema. conjunctival hemorrhages and subcutaneous emphysema may be present after fatal attack. pneumothorax;* mediastinal emphysema. low diaphragm (see below). increased igeconcentrations in fatal asthma; postmortem tryptase determination is of doubtful value in this regard ( ) . hypertrophy. low position of diaphragm. hyperinflated lungs. thick-walled bronchi with prominent viscid mucous plugs. typical microscopic inflammatory changes ( ) . asthmatic bronchitis with eosinophilic infiltrates. bronchocentric granulomatosis.* pulmonary atherosclerosis with breakup of elastic fibers. paucity of ecosinophils in mucous ( ) . cor pulmonale. refl ux esophagitis ( ) . peptic ulcer. * pneumatosis of small intestine; emphysema of colon. centrilobular congestion and necrosis. petechial hemorrhages in hypothalamus; necrosis of cerebellar folia; anoxic changes in cortex, globus pallidus, thalamus, sommer's sector of hippocampus, and purkinje cells of cerebellum. suspected changes in anterior hom cells of spinal cord in patients with asthma-associated poliomyelitis-like illness (hopkins syndrome) ( ). allergic polyps and other allergic inflammatory changes ( ) . increased erythropoiesis. atresia, aortic valvular synonym: aortic atresia; aortic atresia with intact ventricular septum; hypoplastic left heart syndrome. note: the basic anomaly is an imperforate aortic valve, with secondary hypoplasia ofleft-sided chambers and ascending aorta. for possible surgical interventions, see two-stage norwood and modified fontan procedures in chapter . possible associated conditions: atrial septal defect* (or patent foramen ovale, usually restrictive); dilatation of myocardial sinusoids thatcommunicate with coronary vessels; dilatation of right atrium, right ventricle, and pulmonary trunk; fibroelastosis ofleft atrial and left ventricular endocardium; hypertrophy of ventricular and atrial walls; hypoplastic left atrium, mitral valve, left ventricle, and ascending aorta; mitral atresia* with minute left ventricle; patent ductal artery (ductus arteriosus); small left ventricle with hypertrophic wall; tubular hypoplasia of aortic arch, with or without discrete coarctation. synonyms and related terms: congenital biliary atresia; extrahepatic biliary atresia; infantile obstructive cholangio-pathy; syndromic (alagille's syndrome) or nonsyndromic paucity of intrahepatic bile ducts ("intrahepatic" biliary atresia). possible associated conditions: alpha]-antitrypsin deficiency;* choledochal cyst;* congenital rubella syndrome;* polysplenia syndrome* ( ); small bowel atresia; trisomy - ; trisomy ; turner's syndrome;* viral infections (cytomegalovirus infection;* rubella*). dissect extrahepatic bile ducts in situ or leave hepatoduodenalligament intact for later fixation and sectioning (see below). record appearance and contents of gallbladder and course of cystic duct. in postoperative cases, submit sample of anastomosed hepatic hilar tissue for demonstration of microscopic bile ducts. remove liver with hepatoduodenalligament. prepare horizontal sections through ligament and submit for histologic identification of ducts or duct remnants. prepare frontal slices of liver and sample for histologic study. request pas stain with diastase digestion. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. jaundice. congenital rubella and other viral infections. alpha]-antitrypsin deficiency;* defects in bile acid synthesis. chromosomal abnormalities. in atresia of the hepatic duct, the gallbladder will be empty. in isolated atresia of the common bile duct, the gallbladder contains bile but it cannot be squeezed into the duodenum. atresia or hypoplasia of bile duct(s); choledochal cyst(s). biliary drainage created by kasai operation. obliterative cholangiopathy ( ) . intrahepatic cholelithiasis; postoperative ascending cholangitis; secondary biliary cirrhosis; giant cell transformation; paucity of intrahepatic bile ducts. pas-positive inclusions in alphal-antitrypsin deficiency.* polysplenia syndrome* ( ) with malrotation, situs inversus, preduodenal portal vein, absent inferior vena cava, anomalous hepatic artery supply, and cardiac defects. for other abnormalities outside the biliary tree, see under "possible associated conditions"). nephromegaly ( ) . atresia, cardiac valves (see "atresia, aortic valvular," "atresia, mitral valvular," "atresia pulmonary valvular, with intact ventricular septum," "atresia, pulmonary valvular, with ventricular septal defect," and "atresia, tricuspid valvular.") atresia, duodenal possible associated conditions: with membranous obstruction of the duodenum-annular pancreas; atresia of esophagus* with tracheoesophageal fistula; congenital heart disease; cystic fibrosis;* down's syndrome;* hirschsprung's disease; imperforate anus* or other congenital obstructions of the intestinal tract ( ); intestinal malrotation; lumbosacral, rib-, and digitllimb anomalies; single umbilical artery; spinal defects; undescended testis ( ). see also under "atresia, small intestinal." the basic anomaly is an imperforate pulmonary valve, with a hypoplastic right ventricle. in unoperated cases, ductal closure is the most common cause of death. for possible surgical interventions, see modified blalock-taussig shunt, mod-ified fontan procedure, and pulmonary valvulotomy in chapter . for general dissection techniques, see chapter . possible associated conditions: dilated myocardial sinusoids that may communicate with epicardial coronary arteries or veins; patent ductal artery (ductus arteriosus); patent oval foramen (foramen orale); tricuspid atresia with minute right ven-tricle; tricuspid stenosis with hypoplastic right ventricle (in %); tricuspid insufficiency with dilated right ventricle (in %). synonym: tetralogy of fallot with pulmonary atresia. note: the basic anomaly is atresia of the pulmonary valve and ofvariable length ofpulmonary artery, and ventricular septal defect (membranous or outlet type), with overriding aorta, and with pulmonary blood supply from ductal or systemic collateral arteries. for possible surgical interventions, see rastelli-type repair and unifocalization of multiple collateral arteries in chapter . possible associated conditions: right ventricular outflow tract a short blind-ended pouch ( %) or absent ( %); atresia of pulmonary artery bifurcation, with nonconfluent pulmonary arteries; right aortic arch ( %); atrial septal defect ( %); persistent left superior vena cava; anomalous pulmonary venous connection; tricuspid stenosis or atresia; complete atrioventricular septal defect; transposed great arteries; double inlet left ventricle; asplenia, polysplenia, or velocardiofacial syndromes; dilated ascending aorta, with aortic insufficiency. related term: jejuno-ileal atresia. possible associated findings: esophageal atresia* with tracheoesophageal fistula; lumbosacral, rib-, or digit/limb anom -alies; undescended testes (l) . note: see also under "atresia, duodena ." fascia lata, blood, or liver these specimens should be collected using aseptic technique for tissue culture for chromosome analysis (see chapter ) . intestinal tract for mesenteric angiography, see chapter . leave mesentery attached to small bowel, particularly to the atretic portion. trisomy . multiple atresias; proximal dilatation; volvulus; malrotation; meconium impaction; other evidence of cystic fibrosis. anorectal malformation (l) . annular pancreas ( ). atresia, tricuspid valvular note: the basic anomaly is an absent right atrioventricular connection ( %) or imperforate tricuspid valve ( %), with a hypoplastic right ventricle ( %), muscular ventricular septal defect ( %) that is restrictive ( %), and a patent oval atresia, urethral foramen ( %) or secundum atrial septal defect ( %). for possible surgical interventions, see modified fontan or glenn procedures in chapter . for general dissection techniques, see chapter . possible associated conditions: juxtaposed atrial appendages; large left ventricular valvular orifice; large left ventricular chamber; persistent left superior vena cava; pulmonary atresia; transposition of the great arteries ( %), with aortic co-arctation ( % of those); anomalies of musculoskeletal or digestive systems ( %); down's,* asplenia, or other syndromes. heart aorta and cervical arteries brain if infective endocarditis* is suspected, culture using the method described in chapter . for dissection of carotid and vertebral arteries, see chapter . for removal and specimen preparation, and cerebral anteriography, see chapter . if a foreign body is discovered during a medicolegal autopsy or if the discovery of a foreign body may have medicolegal impli-cations (e.g., presence of a surgical instrument in the abdominal cavity), the rules of the chain of custody apply. for the handling of bullets or bullet fragments, see "injury, firearm." if analysis offoreign material is required, commercial laboratories may be helpful. bolus (see "obstruction, acute airway!') burns note: fatal bums should be reported to the medical examiner's or coroner's office. the questions to be answered by the pathologist depend on whether the incident was accidental, sui-cidal, or homicidal, and whether the victim survivied to be treated in the hospital. a pending death certificate should be issued if the fire and police investigators are not sure of the circumstances at the time of the autopsy. for electrical bums, see under "injury, electrical." for victims who were treated at the hospital, autopsy procedures should be directed toward the discovery or confirmation of the mechanism of death, such as sepsis or pulmonary embolism.* death can be caused primarily by heart disease, with other-wise minor bums and smoke inhalation serving as the trigger that leads to lethal ventricular arrhythmia. because carbon monoxide concentrations are halved approx every min with % oxygen therapy, the pathologist must obtain the first clinical laboratory test results for co-hemoglobin. soot can be detected with the naked eye or d after inhalation of smoke. ambulance records should be examined to determine whether a persistent coma might have been caused by hypoxic encephalopathy following resuscitation from cardiac arrest at the scene. admission blood samples should be acquired to test for cohemoglobin and alcohol. this may not have been done in the emergency room. persons suffering from chronic alcoholism succumb to fire deaths more often than persons who do not drink. a very high initial serum alcohol concentration suggests a risk factor for the fire and presence of chronic alcoholism. patients with chronic alcoholism typically are deprived of alcohol when they are in the bum unit and this can cause sudden, presumably cardiac, death,just as it occurs under similarcircum-stances, not complicated by bums. under these circumstances, the heart fails to show major abnormalities. this mode of dying seems to have no relationship to the presence or absence of liver disease. if the body is found dead and charred at the scene, prepare whole body roentgenograms, before and after removal of remanants of clothing. see also under "identification of the body" and "external examination" in chapter ). one or two fingerpads may yield sufficient ridge detail for identification. if this is not possible, ante-and postmortem somatic and dental radiographs must be compared for identification, or dna comparison must be used. external examination, heart and lungs abdominal cavity and liver see below under "cardiomyopathy, dilated." record volume of ascites. record actual and expected weight of liver. request iron stain. see below under "cardiomyopathy, dilated." alcoholic cirrhosis and alcoholic cardiomyopathy rarely coexist. however, in genetic hemochromatosis,* cirrhosis and heart failure are common findings. cardiomyopathy, dilated (idiopathic, familial, and secondary types) note: for general dissection techniques, see chapter . external examination heart other organs and tissues record actual and expected weights. record ventricular thicknesses and valvular circumferences. evaluate relative atrial and ventricular chamber sizes. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. note: huntington's disease maps to the short arm of chromosome . the gene is widely expressed but of unknown function; it contains a cag repeat sequence, which is expanded (range, to ) in patients with huntington's disease. a sensitive diag-nostic test is based on the determination of this cag sequence, which can be done on fresh-frozen tissue or blood ( ) . in the absence of genetic confirmation, sampling of organs and tissues cannot be excessive because a complex differential diagnosis must be resolved. note: disseminated intravascular coagulation (dic) often is a complication of obstetrical mishaps such as abruptio placentae or amniotic fluid embolism,* or it complicates malignancies (such as adenocarcinomas or leukemia*) or bacterial, viral, and other infections. other conditions such as aortic aneurysm* or hemolytic uremic syndrome* are known causes also. ifthe nature of the underlying disease is known, follow the procedures under the appropriate heading also. note: this is a cause of diarrhea. microscopic colitis is associated with older age; collagenous colitis is associated with female sex ( ). the colon is grossly normal but microscopically, increased lymphocytes in the lamina propria and a subepithelial band of collagen is found. if only the lymphocytic infiltrate is found, the term "lymphocytic colitis" or "microscopic colitis" should be applied. a trichrome stain should be ordered in all instances, because the collagen band may be difficult to see without the special stain. i death, anaphylactic synonym: generalized anaphylaxis. note: autopsy should be done as soon as possible after death. neck organs should be removed before embalming. if death is believed to be caused by drug anaphylaxis, inquire about type of drug(s), drug dose, and route of administration (intravenous, intramuscular, and oral or other). this will determine proper sampling procedures-for instance, after penicillin anaphylaxis. allergy to bee stings, wasp stings, fire ants, and certain plants may also be responsible for anaphylaxis. however, envenomation also can be fatal in the absence of anaphylaxis. external examination search for injection sites or sting marks. if such lesions are present, photograph and excise with -cm margin. freeze excised tissue at - °c for possible analysis. prepare chest roentgenogram. foam in front of mouth and nostrils. swelling of involved tissue. antigen-antibody reaction in involved tissues. antibodies against suspected antigen. laryngeal edema may recede soon after death. foamy edema in trachea and bronchi; diffuse or focal pulmonary distention ("acute emphysema") alternating with collapse; pulmonary edema and congestion; accumulation of eosinophilic leukocytes. eosinophilic leukocytes in red pulp. death, anesthesia-associated. note: there are many possible causes of anesthesiaassociated death that are not drug-related, such as acute airway obstruction* by external compression, aspiration, arrhythmia of a heart not previously known to be diseased, tumor, or an inflammatory process. some ofthe complications are characteristically linked to a specific phase of the anesthesia, and many are not revealed by customary morphologic techniques. the task for the pathologist charged with investigating an anesthesia-associated death is to reconstruct the chain of physiologic events culminating in cessation of vital signs. autopsy morphology plays a supporting role; the main investigations center around the record left by the anesthesiologist, testing of anesthesia equipment, and toxicological testing. a consulting anesthesiologist can divine much more information from the anesthesia and recovery room records than can the pathologist, and can suggest avenues of further investigation. therefore, the most important step in these autopsies is to obtain the anesthesiaassociated records and to secure the consulting services of an independent anesthesiologist. the changes in the vital signs during and after anesthesia will help to focus the investigation toward a cardiac mechanism ofdeath or depression ofbrainstem function as a terminal mechanism. when information is gathered about drugs and chemical agents that have been administered or to which the victim may have had access, the pathologist must keep in mind that some non-medical chemicals and many drugs are known to affect anesthesia. drugs and their metabolic products, additives, stabilizers, impurities, and deterioration products (one of which can be carbon monoxide) may be present and can be identified in postmortem tissues. therefore, all appropriate body fluids and solid tissue should be submitted for toxicological examination. if the anesthetic agent was injected into or near the spinal canal, spinal fluid should be withdrawn from above the injected site into a standard toxicologist's collection tube with fluoride preservative. if the anesthetic agent was injected locally, tissue should be excised around the needle puncture marks at a radius of - em. serial postmortem analysis of specimens may permit extrapolation to tissue concentration at the time of death. the time interval between drug administration and death sometimes can be calculated from the distribution and ratio ofadministered drugs and their metabolic products. for a review of anesthetic death investigation, see ref. ( ) . halothane anesthesia and some other anesthetic agents may cause fulminant hepatitis and hepatic failure. the autopsy procedures suggested under "hepatitis, viral" should be followed. note: for special autopsy procedures in postoperative deaths, see chapter . in some instances, procedures described under "death, anesthesia-associated" may be indicated. for a review of investigational procedures and autopsy techniques in operating-room-associated deaths, see ref. ( ) . if the autopsy will involve anatomy or dissection techniques that are unfamiliar, the pathologist should not hesitate to invite the surgeon to the autopsy. in patients who develop a cerebral infarction after open heart surgery, arterial air embolism should be considered as a possible cause. the diagnosis often must be based on excluding other causes because the air has been absorbed prior to death. if a patient dies rapidly, the hospital records may be incomplete or scanty. for example, if a patient bleeds to death despite attempted repair of hepatic lacerations, hospital records may not suffice to reach the correct cause-of-death opinion; personal accounts from the surgeon and anesthesiologist may be needed. autopsy data on patients dying following thoracic surgery may be found in ref ( ) . d death, restaurant (see "obstruction, acute airway.") death, sniffing and spray related terms: glue sniffing; sudden sniffing death syndrome. note: no anatomic abnormalities will be noted at autopsy. sudden death may occur after cardiac dysrhythmia or respiratory arrest. procedures possible or expected findings lungs brain if poison had been inhaled at the time when death occurred, tie main bronchi. submit lungs in glass container for gas analysis. submit samples of small bronchi for histologic study. for removal and specimen preparation, see chapter . submit samples of fresh or frozen brain for toxicologic study. submit samples in glass containers (not plastic) for toxicologic study. trichloroethane, fluorinated refrigerants, and other volatile hydrocarbons are most often involved in the "sudden sniffing death syndrome." spray death may occur in asthma sufferers using pressurized aerosol bronchodilators. freons and related propellants may also be responsible for sudden death. toxic components of glue-such as toluene-accumulate in the brain of glue sniffers. also present in various glues are acetone, aliphatic acetates, cyclohexane, hexane, isopropanol, methylethyl ketone, and methylisobutyl ketone. aerosols may occlude the airway by freezing the larynx. carbon tetrachloride sniffing may cause hepatorenal syndrome (see also under "poisoning, carbon tetrachloride"). death, sudden unexpected, of adult note: medicolegal autopsies are usually indicated, and appropriate procedures should be followed. ifanaphylactic death is suspected, see also under that heading. for all unexpected deaths, the pathologist should learn the circumstances of the death, in order to determine whether the mechanism of death was rapid or slow, and to guide the selection of ancillary tests. whenever paramedics attended a person, the run sheet should be obtained to look for a history of recent drinking or ofchronic alcoholism may be an important clue. the combination of a history ofalcoholism, a negative test for ethanol, and absence ofcardiovascular disease, should suggest alcohol withdrawal as the cause ofa sudden death. the list of"possible or expected findings" below is not complete. for general toxicologic sampling, see chapter . possible associated conditions: atrial septal defect;*bicuspid aortic valve;* coarctation,* hypoplasia, or interruption (type a) of aortic arch; coronary artery from main pulmonary artery; right atrial arch; patent ductal artery;* right pulmonary artery from ascending aorta; subaortic stenosis;* tetralogy of fallot;* ventricular septal defect. * (in approx % of the cases, one or more of these associated conditions are found.) defect, atrial septal note: the basic anomaly is a defect of the atrial septum, usually at the oval fossa (in %). possible complications in unoperated cases include atrial arrhythmias, congestive heart failure; paradoxic embolism; plexogenic pulmonary hypertension « %), and pulmonary artery aneurysm. possible surgical interventions include surgical and transcatheter closure of defect. for deficiency, vitamin c synonyms: hypovitaminosis c; scurvy. external examination and skin other organs bones, joints, and soft tissues record extent and character of skin lesions; prepare sections of skin. describe appearance of gums, and prepare sections. record evidence of bleeding. for removal, prosthetic repair, and specimen preparation of bones and joints, see chapter . hyperkeratotic hair follicles with perifollicular hemorrhages (posterior thighs, anterior forearms, abdomen); petechiae and ecchymoses (inner and posterior thighs); subcutaneous hemorrhages. gingivitis. in rare instances, gastrointestinal or genitourinary hemorrhages. hemorrhages into muscles and joints. subperiosteal hemorrhages occur primarily in distal femora, proximal humeri, tibiae, and costochondral junctions (scorbutic rosary). deficiency, vitamin d synonyms: hypovitaminosis d; rickets. note: features or rickets may be found in familial hypophosphatemia (vitamin d-resistent rickets; fanconi syndrome). vitreous or blood (serum) other organs prepare skeletal roentgenograms. in infants with suspected rickets, record size of anterior fontanelle and shape of head; state of dentition; and shape of costochondral junctions, wrists, long bones, and spine. submit samples for calcium, magnesium, and phosphate determination. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. weigh parathyroid glands and submit samples for histologic study. submit samples of intestine for histologic study. for removal, prosthetic repair, and specimen preparation, see chapter . in infantile rickets, diagnostic sites for histologic sampling are costochondral junctions, distal ends of radius and ulna, and proximal ends of tibia and humerus. for adults, see under "osteomalacia." in infants, rachitic changes at costochondral junctions; in adults, osteoporosis* and osteomalacia*-with or without pseudofractures (milkman's syndrome ( ) . note: the term spinocerebellar degeneration encompasses a variety of lesions whose classification is controversial. a new approach has come from linkage analysis and molecular biology. for instance, friedreich's ataxia, the classic form of hereditary ataxia, is due to an intronic expansion of a gaa tri-nucleotide repeat. other forms are also identified by their specific gene loci. neuropathologic examination still is important and ample sampling is suggested, which should include cerebral cortex, basal ganglia (caudate nucleus, putamen, and globus pallidus), thalamus, subthalamic nucleus, midbrain (red nucleus and substantia nigra), pons (pontine nuclei), spinal cord (at cer-vical, thoracic, and lumbar levels), optic tract, optic nerves with lateral geniculate nucleus, and sensory and motor peripheral nerves. for removal and specimen preparation, see chapter . enlargement of head. poor demarcation between cortex and gelatinous white matter. extensive demyelination and vacuolation of white matter, particularly subcortically. optic atrophy. degeneration, striatonigral (see "atrophy, multiple system.") related term: thirst. note: possible underlying conditions not related to inaccessibility of water include bums, exposure to heat, gastrointestinal diseases, recent paracentesis, renal diseases, and use of diuretic drugs. see also under "disorder, electrolyte(s)." external examination vitreous urine prepare histologic sections of blisters, ulcers, or skin abrasions. submit sample for sodium, chloride, and urea nitrogen determination. skin turgor may be decreased and eyes may be sunken. microscopic changes help to decide whether skin lesions are antemortem or postmortem. sodium concentrations more than meqll, chloride concentrations more than meq/ and urea nitrogen concentrations between and meq/dl indicate dehydration. absence or minimal amount of urine. dementia (see "disease, alzheimer's.") drug abuse, amphetamine(s) note: methamphetamine abuse may be suggested by poor condition of the dentition. methylenedioxymethamphetamine ("ecstasy") abuse is often suggested by friends with whom the decedent was abusing drugs. follow procedures described under "dependence, drug(s)." drug abuse, cocaine note: cocaine is spontaneously hydrolyzed by blood esterases, even after death. however, one of its major metabolite, benzoylecgonine, is routinely identifiable by immunoassay screening tests. when cocaine is abused concurrently with heroin or other depressant drugs, it may be difficult to ascribe deth to a single agent, unless circumstances clearly point to a rapid cardiac mechanism or a slow brainstem depression mechanism. note: if narcotic paraphernalia and samples of the drug itself are found at the scene of the death, they should be submitted for analysis. helpful information about the nature of a drug may be obtained from witnesses. state crime laboratories may provide much assistance. if name of drug is known, see also under "poisoning,..." the slang name of a drug may be insufficient for identification because these names often are used for different compounds at different times of places. opoid narcotics can be injected intravenously, or subcutaneously, or snorted. death may occur with such speed that the bodies may be found with needles and syringes in the veins or clenched in the hands. drug abuse may be associated with a multitude of local (see below) or systemic complications, including malaria* and tetanus. * as stated in chapter , for a growing number of analytes, most notably tricyclic antidepressants, peripheral blood is preferred over central blood. peripheral blood is aspirated by percutaneous puncture before autopsy, from the femoral vein or the subclavian vein. the authors prefer the femoral approach in order to avoid any question of artifact in the diagnosis of venous air embolism. it may be pru-dent to add naf to some of the samples. related term: childhood dermatomyositis (or polymyositis) associated with vasculitis; dermatomyositis (or polymyositis) associated with neoplasia or collagen vascular disease; primary idiopathic dermatomyositis; primary idiopathic polymyositis. possible associated conditions: carcinoma (lung, stomach, intestine, and prostate in males; breast, ovary, and uterus in females; miscellaneous sites in both sexes); lymphoma* (rare) and other malignancies ( ); lupus erythematosus;* mixed connective tissue disease; progressive systemic sclerosis;* rheumatoid arthritis;* sjogren's syndrome;* and others. vasculitis of childhood polymyositis (dermatomyositis). external examination and skin heart lungs esophagus and gastrointestinal tract photograph grossly involved skin. prepare sections of involved (anterior chest, knuckles, knees) and grossly uninvolved skin and subcutaneous tissue. prepare roentgenograms. submit samples from myocardium for histologic study. perfuse one lung with formalin. submit samples from all segments for histologic study. arteritis* and phlebitis* with thrombosis, fibrosis, and infarctions. steatohepatitis and manifestations of diabetes mellitus* may be found ( ) . myositis with muscular atrophy and fibrosis; vasculitis in childhood cases. polyneuropathy (rare) ( ). arthritis. diabetes mellitus synonyms: type i (insulin-dependent or juvenile-onset) diabetes mellitus; type ii (insulin-independent or adult onset) diabetes mellitus; secondary diabetes mellitus (e.g., due to drugs or pancreatic disease). note: in infants of diabetic mothers, macrosomia and congenital malformations must be expected. record size and weight of placenta and total weight and length, crown to rump length, and crown to heel length of infant. compare with expected measurements (see part iii). expected histologic finding in-clude hyperpla-sia with relative increase ofb cells of the islands of langerhans with interstitial and peri-insular eosinophilic infiltrates, decid-ual changes of the endometrium, enhanced follicle growth in the ovaries, and leydig cell hyperplasia. possible associated conditions: acanthosis nigricans; acro-megaly;* amyotrophic lateral sclerosis; * ataxia telangiectasia;* fanconi's anemia;* friedreich's ataxia;* gout;* hemochro-matosis; *hyperlipoproteinemia; * hyperthroidism;* obesity;* turner's syndrome;* and many others, too numerous to mention. note: the term "caroli's syndrome" often is used for cases that also show histologic features of congenital he-patic fibrosis or other manifestations of fibropolycystic liver disease,* whereas the name "caroli's disease" refers to idiopathic dilatation of intrahepatic bile ducts, without associated abnormalities. possible associated conditions: choledochal cyst* and related extrahepatic biliary abnormalities ( ); congenital hepatic fibrosis; * cysts of kidneys (renal tubular ectasia or medullary sponge kidney; autosomal-recessive polycystic kidney disease, and rarely, autosomal-dominant polycystic kidney disease [ ] )* and of pancreas. record volume of effusions. prepare smears of fresh blood or of buffy coat, or make thick-drop preparation. submit sample for xenodiagnosis or animal inoculation and for serologic study. record weight. in chronic chagas' disease, perfuse intact heart with formalin (chapter ) and slice fixed heart in a frontal plane so as to create anterior and posterior halves. prepare photographs. histologic samples should include conduction system. include several sections of atrial (auricular) walls for histologic study of autonomous ganglia. perfuse at least one lung with formalin. leave affected hollow viscera intact and fill with formalin. cut fixed organs in half, photograph, and cut histologic sections on edge. record liver weight and submit samples for histologic study. record weight. prepare photographs of abnormalities. weigh and examine. prepare histologic sections. for removal and specimen preparation, see chapter . autopsy is desirable in suspected cases because the diagnosis can only be firmly established after neuropathologic examination. serologic studies are not available. unfortunately, all tissues (not just the brain and spinal cord) may remain infectious even after prolonged fixation and histologic processing. thus, the autopsy recommendations for most other infectious diseases do not apply here. this is a reportable disease in some states. special precautions are indicated and therefore, the procedures described here should be followed strictly ( ) ( ) ( ) ( ) : all persons in the autopsy room must wear disposable long-sleeved gowns, gloves, and masks. contamination of the autopsy table should be prevented by covering it with a disposable, non-permeable plastic sheet. autopsy generally should be restricted to the brain. if organs in the chest or abdomen need to be examined, this is best done in situ. to prevent aerosolization of potentially infectious bone dust, a hood or other protective device should be used while opening the skull with a stryker saw. after completing the autopsy, instruments and other potentially contaminated objects should be autoclaved in a steam autoclave ( h at °c). porous load is considered more effective than gravity displacement autoclaves. immerse autopsy instruments in distilled water before and during autoclaving, in order to protect them from corrosion. ifno autoclave is available, chemical disinfection (see below) is a satisfactory alternative. disposable items should be put in a container for infectious hospital waste and ultimately incinerated. contaminated objects not suitable for autoclaving (such as the stryker saw) should be soaked with a nnaoh solution for h (alternatively, nnaoh may be used for h). contaminated surfaces should be thoroughly washed with the same solution. aluminum should be treated for h with a fresh % naoci (sodium hypochlorite) solution with at least , ppm free chloride. wash waters should be collected; if no autoclave is available, n naoh or > volumes of % sodium hypochlorite bleach should be added to the water and left for a minimum of h before being discarded. before removing the body from the autopsy room, it should be sponged with % sodium hypochlorite. to deactivate cjd infectivity, tissue blocks, mm or less in thickness, should be fixed in formalin in a formalin-totissue ratio of at least : for at least h and then soaked in concentrated formic acid ( - %) for i h, followed by another h of formalin fixation. the fixation fluid should be collected and decontaminated, as described earlier for wash water. glassware and tissue carriers should also be decontaminated as previously described. after this deactivation, the tissue blocks can be processed in a routine fashion. at any stage of these procedures, special care must be taken to avoid cuts with potentially contaminated glassware, blades, or other objects. parenteral exposure to potentially contaminated material also should be avoided. remains of patients who have died of the disease should not be accepted for anatomy teaching for students. if specimens are prepared for pathology collections, they should be handled with great caution. morticians and mortuary workers should be warned of possible hazards posed by tissues of patients with transmissible spongiforme encephalopathies; they should be advised about proper use of disinfectants. clinical laboratories that receive autopsy tissues or fluids must be warned about the infectious nature of the material. if possible, decontamination should be done at the site where the autopsy was done. for the shipping of potentially infected material, see chapter . increased concentrations of nse ( ). spongiforme changes, astrocytosis, neuronal loss, amyloid plaque formation, prp deposition, and proliferation of activated microglia ( ). cerebrospinal fluid brain submit sample for neuron-specific enolase (nse). for removal and specimen preparation, see chapter and above under "note." submit fresh-frozen material for confirmation of diagnosis by histoblot technique on protease k-digested frozen tissue or western blot preparations on brain homogenates. immunohistochemical localization ofprp and hla-dr protein on paraffin-embedded tissue is possible. disease, demyelinating (see "degeneration, spongy, of white matter," "encephalomyelitis, all types or type unspecified," "leukodystrophy, globoid cell," "leukodystrophy, sudanophilic," "sclerosis, multiple;' and "sclerosis, schilder's cerebral.") disease, diffuse alveolar synonym: diffuse pulmonary disease. note: autopsy procedures are listed under the more specific diagnoses, such as "hemosiderosis, idiopathic pulmonary," "lipoproteinosis, pulmonary alveolar," "microlithiasis, pulmonary alveolar," "pneumonia, lipoid," and "syndrome, goodpasture's." glycosphingolipid storage in cornea; lens opacities; dilated vessels in conjunctiva and lens; thrombi in blood vessels ( ). disease, fibropolycystic, of the liver and biliary tract note: "fibropolycystic disease of the liver and biliary tract" comprises a group of well defined conditions, which may occur together and hence need a collective designation. the conditions include autosomal-recessive (infantile) and auto-somal dominant (adult) polycystic disease of the liver; caroli's disease or syndrome;* choledochal cyst,* congenital hepatic fibro-sis,* multiple biliary microhamartomas, and related disorders. for autopsy procedures, see also under more specific designations. disease, glycogen storage synonyms: andersen's disease or brancher deficiency (glycogenosis, type iv); cori's or forbes' disease (glycogenosis, type ill); cyclic amp dependent kinase (type x); glycogen synthetase deficiency (type ); hers' disease (glycogenosis, type vi); mcardle's disease (glycogenosis type v); phosphorylase b kinase deficiency (types ixa, b, and c); pompe's disease (glycogenosis, type it); tarui disease (glycogenosis type vii); von gierke's disease (glycogenosis, type ia); x-linked glycogenosis (type vill). note: if the diagnosis had not been confirmed prior to death, samples of liver, skeletal muscle, blood, and fascia (for fibroblast culture, see below) should be snap-frozen for enzyme assay, which will determine the specific deficiency. types ia and b, iii, vi, and hepatic phosphorylase b kinase deficiency (types ixa, b and c) are hepatic-hypoglycemic disorders, whereas types v and vii affect muscle energy processes. type ii also affects the musculature, whereas type iv may cause cirrhosis and death in infancy from extreme hypotonia. determination of type of glycogenosis usually can be based on (i) pattern of glycogen storage in liver, ( ) presence or absence of nuclear hyperglycogenation in liver, ( ) cytoplasmic lipid in liver, ( ) presence or absence of liver cirrhosis, and ( ) presence or absence of glycogen and basophilic deposits in skeletal muscles. possible associated conditions: fanconi syndrome* or gout* with type ia glycogenosis; neutropenia, recurrent infections, and crohn's disease with types ib or ie. glycogen primarily in retinal ganglion cells and ciliary muscle. glycogen in sympathetic nerve ganglia and neurons of cranial nerves in type vii. gouty arthritis. disease, graft-versus-host note: this disease occurs most commonly after bone marrow transplantation. the disease has also occurred after transfusion of viable lymphocytes, for example, to patients with cancer or leukemia. * in patients with graft-versus-host disease (gvhd), autopsy also may reveal recurrence of the underlying disease such as leukemia. possible associated conditions: alphal-antitrypsin deficiency;* amyloidosis;* ankylosing spondylitis;* primary sclerosing cholangitis;* sjogren's syndrome. * see also below under "possible or expected findings." note: in many instances, either chronic ulcerative colitis or crohn's disease* had been diagnosed clinically, but sometimes, the distinction is difficult to make, even at autopsy. many features described below occur in chronic ulcerative colitis but some manifestations of crohn's disease or conditions that may occur in all types of inflammatory bowel disease also are listed so that both positive and negative findings can be recorded properly. osteoporosis;* ankylosing spondylitis;* arthritis of peripheral joints; periarthritis; hypertrophic osteoarthropathy;* tendinitis (particularly of ankle and achilles tendons). disease, iron storage (see "hemochromatosis.") related terms: atherosclerotic heart disease. note: the most common anatomic finding at autopsy in subjects older than yr is coronary atherosclerosis. unusual under-lying or associated conditions include chronic aortic stenosis or regurgitation; coronary artery anomalies; coronary artery dissection; coronary embolism; coronary ostial stenosis (due to calcification of aortic sinotubular junction or, rarely, to syphilitic aortitis); coronary vasculitis (for instance, in polyarteritis nodosa* or acute hypersensitivity arteritis); hyperthyroidism,* gastrointestinal hemorrhage; * hypothyroidism, * idiopathic arterial calcification of infancy; intramural coronary amyloidosis; pheochromocytoma, polycythemia vera; * pseudoxanthoma elasticum,* radiationinduced coronary stenosis; severe pulmonary hypertension (with right ventricular ischemia); sickle cell disease;* and others. if bypass surgery had been performed, see "surgery, coronary bypass." macular rash ( ). multifocal fibrinopurulent pneumonia with sparing of the bronchi and bronchioles. exudate is rich in phagocytes, fibrin, and karyorrhectic debris. synonym: lyme arthritis note: this infection is caused by the spirochete, borrelia burgdoiferi, which is transmitted from rodents to human by the hard deer ticks, ixodes dammini, . ricinus, and others. brain and spinal cord for removal and specimen preparation, see chapter . request luxol fast blue stain for myelin. symmetric and zonal demyelination in corpus callosum, anterior commissure, optic chiasm, optic tracts, and white matter of frontal lobes. external examination and skin; oral cavity lungs aorta record distribution of skin lesions and submit tissue samples for histologic study. for preparation of angiograms of the pulmonary arterial and venous vasculature, see chapter . if aneurysm or dissection is present, follow procedures described under those headings. telangiectatic (often papular) lesions most commonly found in cheeks, scalp, nasal orifices, oral cavity, ears, neck, shoulders, fingers, toes, and nail beds. cyanosis and clubbing may be prominent. arteriovenous malformations/fistulas. aneurysm; * aortic dissection. * if cirrhosis is present, prepare angiograms of hepatic arteries and veins (chapter ). photograph and prepare sections of angiomatous lesions. note: parkinson's syndrome is caused by conditions that may simulate parkinson's disease; these include carbon monoxide* and manganese poisoning, corticobasal degeneration, druginduced parkinsonism, huntington's disease, multiple system atrophy,* progressive supranuclear palsy* (steele-richardson-olszewski syndrome), space-occupying lesions (rare), trauma (dementia pugilistica), and causes related to tumors and vascular diseases. brain for removal and specimen preparation, see chapter . histologic sections should include midbrain (substantia nigra), upper pons (locus ceruleus), medulla, nucleus basalis (substantia innominata), and basal ganglia. if parkinsonian syndrome was diagnosed, follow procedures described under the name of the suspected underlying condition (see above under "note"). depigmentation of substantia nigra and locus coeruleus; neuronal loss and reactive gliosis; eosinophilic intracytoplasmic inclusion bodies (lewy bodies) in some of the surviving neurons; no significant changes in basal ganglia. disease, pelizaeus-merzbacher synonyms: sudanophilic (orthochromatic) leukodystrophy. brain and spinal cord for removal and specimen preparation, see chapter . request luxol fast blueipas stain for myelin and bielschowsky's stain for axons. prepare frozen sections for sudan stain. brain generally atrophic. myelin loss in centrum ovale, cerebellum, and part of brain stem, with a tigroid pattern of residual myelin near vessels. axons are preserved. diffuse gliosis with relatively few lipoid-containing macrophages, compared to the myelin loss. lipoid material stains with sudan. brain and spinal cord for removal and specimen preparation, see chapter . request silver stains (bielchowsky or bodian stain). histochemical stains in pick's cells and bodies reveal phosphorylated neurofilaments, ubiquitin, and tubulin. some tissue should be kept frozen for biochemical studies. severe cerebral atrophy, involving primarily frontal and anterior temporal lobes (knifeblade atrophy; walnut brain). microscopically, severe neuronal loss accompanied by astrocytosis. characteristic argyrophilic, intracytoplasmic inclusions (pick's bodies), particularly in hippocampus and swollen, distended "ballooned" neurons (pick's cells). these changes are not always present. external examination, skin, and adipose tissue blood cerebrospinal fluid heart liver and kidneys brain, spinal cord, and peripheral nerves eyes submit sample for determinaion of phytanic acid concentration and for molecular studies. for obtaining a sample, see chapter . sample for histologic study. for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . ichthyosis. phytanic acid accumulation in adipose tissues. phytanic acidemia, mutation of phyh or pex ( ). increased protein concentrations. cardiomyopathy.* phytanic acid accumulation. axonal neuropathy. retinitis pigmentosa. hypoalphalipoproteinemia. lymphadenopathy with diffuse deposition of cholesterol esters. premature atherosclerotic cardiovascular disease ( ). hepatosplenomegaly with foam cells. enlarged tonsils with characteristic orange discoloration. polyneuropathy ( ) . in adults, corneal infiltrates. foam cells. request pas stain. in granulomas, bacilli are not always pas positive ( ) . section all grossly involved tissues for histologic examination. submit section for electron microscopy. emaciation. hyperpigmentation, particularly of exposed skin and in scars. hyperkeratosis. arthritis involving ankles, knees, shoulders, and wrists. ascites; fibrinous peritonitis. * nodules in peritoneum containing sickle-form particlecontaining cells (spc cells submit sample for determination of sodium, potassium, chloride, glucose, urea nitrogen, and creatinine concentrations. calcium and phosphate concentrations can also be tested. if sample is small, indicate priority for testing. if indicated, submit sample for chemical study. submit tissue samples for histologic study. considerably increased or decreased values for sodium (more than meqll or less than meqll) and chloride (more than meqll or less than meqll) indicate that changes were present before death. for further interpretation, see chapter . postmortem electrolyte concentrations are quite unreliable. may be useful for calcium determination. vacuolar nephropathy (vacuolar changes in proximal convoluted tubules) in potassium deficiency (may also occur after infusion of hypertonic solutions). disorder, hemorrhagic (see "coagulation, disseminated intravascular," ''disease, christmas:' ''disease, von willebrand's," "hemophilia," and "purpura,.••") disorder, inherited, of phagocyte function note: several conditions represent phagocyte function disorders. autopsy procedures for one of these disorders can be found under "disease, chronic granulomatous." consult this entry for other phagocyte function disorders. synonyms and related terms: fabry's disease* (angiokeratoma corporis diffusum); gangliosidosis;* gaucher's disease;* glycogenosis,* type ii; leukodystrophies (krabbe's or globoidcell,* metachromatic leukoencephalopathy*); mucopolysaccharidoses* (hunter, hurler, morquio, and sanfilippo disease); mucolipidosis; niemann pick disease* (type a, b, c, or sphingomyelinase deficiency); neuraminidase deficiency; neuronal ceroid lipofuscinosis (batten's disease or kufs' disease). hypopharyngeal pulsion diverticulum (zenker's diverticulum) at lower margin of inferior constrictor muscle of pharynx. traction diverticulum at midesophagus after an inflammatory process-for instance, tuberculous lymphadenitis. epiphrenic diverticulum may also occur. luxtacardiac or juxtapyloric diverticulum. heterotopic tissue in meckel's diverticulum, with or without peptic ulceration. colonic muscular hypertrophy and stenosis, usually in sigmoid colon. diverticulitis with perforation, fistulas, or peritonitis. * diving (see "accident, diving (skin or scuba).") related terms: dry drowning; fresh-water drowning; near-drowning; salt (sea)-water drowning (see the following table). primary drowning ("immediate drowning") deaths occurring within minutes after immersion, before or without resuscitative measures deaths from hypoxia and acidosis caused by glottal spasm on breath holding. there may be no evidence of water entering stomach or lungs and no appreciable morphologic changes at autopsy. note: the diagnosis is one of exclusion. the pathologist should help the police to determine: i) how did the person (or dead body) get in the water, and ) why could that person not get out of the water? it is not enough to ask if a person could swim but investigators should find out how well (what strokes did the victim know?) and how far he or she could swim. the inquiry must include the depth of the water and must address hazards such as undertow or underwater debris, and the behavior deaths occurring from within min to several weeks after resuscitation, because of metabolic acidosis, pulmonary edema, or infective or chemical pneumonitis deaths from hypoxia and acidosis caused by obstruction of airway by water related to: hypervolemia hemolysis hyponatremia hypochloremia hyperkalemia of the victim immediately before submerging. deaths of adults in bathtubs and swimming pools are usually from natural, cardiac causes, or they are suicides, unless the victim was drunk. diatom tests ( ) have not proven useful in the united states but there is enthusiasm for such tests among european pathologists. the distinction between hyponatremic deaths in fresh water and hypernatremic deaths in salt water derives from experimental studies; in practice, one cannot reliably predict the salinity of the immersion medium from autopsy studies. because many bodies of drowning victims are recovered only after the body floats to the surface, decomposition will often obscure even the nondiagnostic findings such as pleural effusions, which are often associated with drowning. external examination and skin (wounds) organ samples for diatom search serosal surfaces and cavities if identity of drowning victim is not known, record identifying features as described in chapter . prepare dental and whole-body roentgenograms. submit tissue samples for histologic study of wounds. inspect inside of hands. collect fingernail scrapings. record appearance and contents of body orifices. record features indicative of drowning. photograph face from front and in profile. take pictures of all injuries, with and without scale and autopsy number. remove vitreous for analysis. if diatom search is intended, clean body thoroughly before dissection to avoid contamination of organs and body fluids with algae and diatoms (see below). submit sample for toxicologic study. sample early during autopsy, before carrying out other dissections. use fresh instruments for removal of specimens to avoid contamination. submit subpleural portion of lung: subcapsular portions of liver, spleen, and kidneys; bone marrow; and brain. store samples in clean glass jars. for technique of diatom detection, see below. record volume of fluid in pleural spaces. photograph petechial hemorrhages. photograph layerwise neck dissection if strangulation* is suspected. open airways posteriorly, and photograph, remove and save mud, algae, and any other material in tracheobronchial tree. record size and weight of lungs. there may be wounds that were inflicted before drowning occurred-for instance, in shipwrecks or vehicular and diving accidents. other wounds may be inflicted after deathfor instance, from ship propellers or marine animals. sometimes, premortem and postmortem wounds can be distinguished histologically. object (hair?) held by hands in cadaveric spasm. cutis anserina and "washerwoman" changes of hands and feet are of no diagnostic help. foreign bodies; semen (see also under "rape"). foam cap over mouth and nose. in the autopsy room, water running from nose and mouth is usually pulmonary edema or water from the stomach. high concentrations of alcohol indicate intoxication (see under "alcoholism and alcohol intoxication"). evidence of alcohol intoxication may be found. diatoms may occur in the liver and in other organs of persons who have died from causes other than drowning. comparison with diatoms in water sample from area of drowning may be helpful. penny-sized or smaller hemorrhages may indicate violent respiratory efforts or merely intense lividity. presence of pleural fluid suggests drowning. for diatom detection (l) , boil - g oftissue for -- min in rnl of concentrated nitric acid and . rnl of concentrated sulfuric acid. then, add sodium nitrate in small quantities until the black color of the charred organic matter has been dispelled. it may be necessary to warm the acid-digested material with weak sodium hydroxide, but the material must soon be washed free from alkali to avoid dissolving the diatoms. the diatoms should be washed, concentrated, and stored in distilled water. for examination, allow a drop of the concentrate to evaporate on a slide, and then mount it in a resin of high refractive index. all equipment must be well-cleaned, and distilled water must be used for all solutions. there are several variations and adaptations of this method. drug abuse, amphetamine(s) note: methamphetamine abuse may be suggested by poor condition of the dentition. methylenedioxymethamphetamine ("ecstasy") abuse is often suggested by friends with whom the decedent was abusing drugs. follow procedures described under "dependence, drug(s)." ductus arteriosus, patent (see "artery, patent ductal.") synonyms and related terms. achondroplastic dwarf; asexual dwarf; ateliotic dwarf; micromelic dwarf; normal dwarf; pituitary dwarf; true dwarf; and many other terms, too numerous to mention. external examination bones and joints record height and weight. prepare skeletal roentgenograms. for removal, prosthetic repair, and specimen preparation, see chapter . growth retardation. abnormal growth of epiphyseal cartilage with enlargement of metaphysis. long bones and pelvis most commonly affected. cavernous hemangiomas (maffucci's syndrome). see above under "external examination." chondrosarcoma. dyscrasia, plasma cell note: these conditions are characterized by abnormally proliferated b-immunocytes that produce a monoclonal immunoglobulin. multiple myeloma, * plasma cell leukemia, plasma-cytoma, and waldenstrom's macroglobulinemia* as well as heavy-chain diseases and monoclonal gammopathies of unknown type belong to this disease family. amyloidosis* is closely related to these conditions. for autopsy procedures, see under "amyloidosis," "macroglobulinemia," or "multiple myeloma" and under name of condition that may have caused the plasma cell dyscrasia. such conditions include carcinoma (colon, breast, or biliary tract), gaucher's disease,* hyperlipoproteinemia, * infectious or noninfectious chronic inflammatory diseases, and previous cardiac surgery. synonym: shigella dysentery. note: (i) collect all tissues that appear to be infected. blood bowel eyes joints submit sample for culture and for serologic study. submit sample of feces or preferably bloodtinged mucus for culture. if bacteriologic diagnosis has already been confirmed, pin colon on corkboard, photograph, and fix in formalin for histologic study. submit sample of vitreous for study of sodium, potassium, chloride, and urea nitrogen concentrations. for removal and specimen preparation of eyes, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . escherichia coli septicemia. colitis with microabscesses; transverse shallow ulcers and hemorrhages, most often in terminal ileum and colon. dehydration* pattern of electrolytes and urea nitrogen. serous arthritis* of knee joints is a late complication. external examination record extent of pigmentation, facial features, and primary and secondary sex characteristics. prepare skeletal roentgenograms. for removal, prosthetic repair, and specimen preparation, see chapter . record size of apertures of cranial nerves in base of skull. unilateral skin pigmentation and precocious puberty in females (albright's syndrome), less commonly in males. synonyms and related terms: becker's muscular dystrophy; congenital muscular dystrophy; duchenne's progressive muscular dystrophy; dystrophinopathy; em-ery-dreifuss mucular dystrophy; facioscapulohumeral dystrophy; limb girdle dystrophy; myotonic muscular dystrophy. external examination record pattern of scalp hair. record status of skeletal musculature. obtain sections for histologic examination. dystrophin staining of the sarcolemma is absent in duchenne's muscular dystrophy and patchy in becker's dystrophy. frontal baldness (in myotonic muscular dystrophy). atrophy and wasting of muscles (generalized or local: predominantly distal in myotonic muscular dystrophy). pseudohypertrophy of calf muscles in duchenne's muscular dystrophy. dystrophic changes include variations in fiber size, fiber degeneration and regeneration, peri-and endomysial fibrosis, and fatty replacement of muscle. the liver, especially the right lobe, is the most common site of involvement. secondary infection or calcification may be present. the lung is the second most common site of involvement. fluid and air may be visible on the roentgenogram. cysts may be present in the abdominal cavity, muscles, kidneys, spleen, bones, heart, and brain. eosinophilia. edema, angioneurotic synonym: angioedema. note: possible causes and suggested autopsy procedures are described under "death, anaphylactic." related term: silo-filler's disease. n<yfe: this condition is causedby inhalationoftoxic gases, such as oxides of nitrogen (silo-filler's disease) and phosgene (coci ). see also "bronchitis, acute chemical" and "poisoning, gas." ( ) gunshot and shotgun wounds of the head involving dural sinuses; ( ) injury to large veins, particularly cranial sinuses (during neurosurgical procedures) and veins ofthe neck (knife wounds, surgery) or uterus (criminal abortion); ( ) insufflation offallopian tubes (particularly in pregnancy or during menstrual period); ( ) infusion of blood components or crystalloid; ( ) malfunctioning of dialysis machines; ( ) subclavian vein catheterization in the semi-fowler position; and ( ) fracture in the hub of a central venous catheter used for parenteral nutrition. possible causes of arterial air embolism include: ( ) open heart surgery involving the aorta, left atrium, or left ventricle; ( ) positive-pressure ventilation in newborn infants; and ( ) underwater ascent with closed glottis (see accident, diving) ifair embolism is suspected, the autopsy should be performed as soon after death as possible. decomposition gases may be produced within a few hours. roentgenography of the whole body may detect large quantities of air, and the roentgenograms may serve as a guide to the most advantageous way of dissection. the postmortem diagnosis of arterial air embolism is made largely on the basis of medical history and circumstances. the autopsy serves to rule out competing conditions. the diagnosis of venous air embolism is made by chest roentgenography before the autopsy ( ). the air in the right chambers of the heart can be confirmed at autopsy by aspiration into a syringe. the formerly recommended procedure of clamping the internal mammary vessels below the sternoclavicular joints, and then cutting across the sternum distal to these clamped vessels so that the sternoclavicular joint area remains intact, is designed to prevent the production of a vacuum that pulls air into the veins. the procedure is not necessary if the air is welldocumented by roentgenography before autopsy. at autopsy, a large fatal pulmonary air embolism is readily apparent. the right atrium and ventricle are distended with fine, frothy, brightred blood, which also may distend the pulmonary arteries and superior vena cava. microbiologic examination ofblood and pericardial sac contents may help to rule out the presence of gas-forming bacteria that may simulate air embolism (fig. ii-i). however, the presence of putrefactive emphysema in any part of the body points toward a bacterial origin of the gas. differentiation of air and decomposition gases at the autopsy table with the pyrogallol test is described below. a % pyrogallol solution is prepared (it should be waterclear). two lo-ml syringes (syringe a and syringe b) are loaded with ml of the pyrogallol solution in each, without permitting any air to enter the system. immediately before the solution is used, drops of . n naoh is aspirated through the needle of syringe a to adjust the ph to about ( drop per ml of solution); the mixture will turn faint yellow. six ml of gas is then aspirated from the heart or blood vessels. the needle is immediately sealed with a cork or replaced by a cap, and the syringe is vigorously shaken for about min. in the presence of air, the pyrogallol solution will turn brown. if the solution remains clear, decomposition gases were present. in the latter instance, drops of . n naoh and ml of room air should be aspirated into syringe b, which is then also sealed and shaken for min. the mixture should turn brown, thus serving as a fig. · . gas-forming bacteria simulating air embolism. the pericardial sac is opened and filled with water. the heart is kept submerged with a pair of scissors. the coronary arteries have been incised with a scalpel. note gas bubbles and foam on the water surface. no discoloration of % pyrogallol was noted. blood cultures were positive for enterococcus organisms. microscopically, gram-negative rods were found in most tissues. control that the pyrogallol solution had been properly prepared. syringe b may also serve as a reserve. if only one syringe is used, the decomposition gas can be expel ed and room air can be aspirated for the control test. if only small amounts of gas can be aspirated, the volume of the pyrogallol solution should be decreased so that the gas-fluid volume ratio is at least : . if no bacterial gas formation is present, the edges of the pericardial incision are elevated and the pericardial sac is fil ed with water. clamping of the ascending aorta and venae cavae prevents the escape of gas into these vessels. the heart is held under water while the coronary arteries are incised, and the escape of bubbles is recorded. when the right coronary artery is opened, care must be taken that the right atrium is not incised. air in the coronary arteries indicates systemic embolism. the heart chambers are then incised. when there is gas in any of the arteries or heart chambers, gas bubbles rise to the surface of the water in the pericardial sac ("bubble test"). sometimes the vessels have to be somewhat compressed in order to cause the gas to escape. because large amounts of air or other gases cause the heart to float, it must be kept submerged before the vessels and chambers are incised. basically the same procedure is used for demonstrating the presence of gas in the superior or inferior vena cava and the pelvic veins (for example, in cases of criminal abortion). in this situation, the abdominal cavity is filled with water and the inferior vena cava and its tributaries are incised. in support of the diagnosis of systemic arterial air embolism, the skull vault may be removed without puncturing the meninges, so that the cerebral arteries can be inspected for gas bubbles. the demonstration of gas bubbles in the meningeal vessels and in the circle of willis is meaningful only when the neck vessels are still intact and the internal carotid artery and basilar artery have been clamped before the brain is removed. in acute cases, gas bubbles will be visible within the cerebral vessels. they are released under water when the clamps are removed and the vessels are slightly compressed. for the collection of gas from blood vessels or cavities, a system oflittle quantitative reliability is an air-tight, water-filled glass syringe with a needle. the needle is inserted into the vessel or cavity in question and gas is carefully aspirated. a combined qualitative and quantitative method has been described by kulka ( , ) (see fig. - ). he devised an apparatus for gas collection and described it as shown in fig. - and caption. the entire system is filled with mineral oil so that, when the funnel is level with the upright bottle, the oil fills only about half of the funnel. in operation, the funnel is first raised to a position - cm above the level of the upright bottle. all the cocks are opened and the position is held until every trace of gas has been driven from the system through the needle, which is thereby coated on the inside by a film of oil. after all air has been expelled, the cocks are closed and the funnel is lowered to its original position. as a precautionary measure and control, the air-tightness of the whole system should be tested before operation. this is done by inserting the needle into musculature or skin and attempting aspiration in the manner described in the next paragraph. to make the test, the bottle is inverted and the needle is inserted into the cavity in question. when the needle is in position, all cocks are opened. the funnel is lowered about - cm, or until adequate suction is created. this aspirates the contents of the cavity, which may consist of air or other gases, either pure or mixed with blood or other liquid. any gas or liquid entering this system may be observed through the wall of the short bent glass tubing. in a positive test, gas bubbles will collect in the bottle above the level of the oil. if desired, this gas can be saved for further examination by closing all the cocks and returning the bottle to its upright position ( ). the volume ofintravenous air needed to cause death in adults depends of the cross sectional area of the cardiac cavity or great vessel that is the site of the gas lock, which in tum depends on the position of the decedent at the time of the embolism ( ). ml of gas can pass through an intravenous hub in just a few seconds. small amounts of air entering the systemic circulation may cause death within minutes. delayed air embolism with fatal outcome may also occur. other organs if purpura is present, prepare photographs and record extent. submit sample (from right atrium) for microbiologic study. collect blood from right atrium and right ventricle. after the heart has been removed, allow blood in pulmonary vessels to pool in the pericardial sac. centrifuge this blood and submit sample of flocculent layer above buffy coat for microscopic study ( ) . submit a section of lung for bacteriologic study. dissect pulmonary arteries; prepare histologic sections of all lobes; request mucicarmine stain and the aldan blue and phloxinetartrazine stain of lendrum. also request sudan stain on frozen sections. skin purpura. vernix, lanugo hairs, and meconium can be found in pericardial blood pool. meconium-type material in blood vessels. in histologic sections, squamous epithelium, meconium, and fat from vernix caseosa. complete or incomplete lower uterine tear; chorioamnionitis. manifestations ofdisseminated intravascular coagulation* and fibrinolysis. intrauterine pneumonia. large amounts of debris in the blood vessels of all sections of the lungs may be considered to be lethal if there is no other cause of death. small amounts in one or more blocks of pulmonary tissue are more likely incidental ( ). a small uterine tear is more likely followed by a fatal amniotic fluid embolization than is a large tear, which may result in fatal hemorrhage or fibrinogen depletion. chorioamnionitis, intrauterine pneumonia, and positive lung cultures of the mother indicate infection of the amniotic fluid. record weight and sample for histologic study. for removal and specimen preparation, see chapter . photograph horizontal sections through brain, brain stem, and spinal cord. prepare frozen sections and request sudan stain. prepare frozen sections of one-half of gland and paraffin sections of the other half. petechial hemorrhages of skin (chest, neck, and face). wounds; other traumatic lesions. bone fractures. petechiae of conjunctivas and retinas. fat may accumulate on surface ofblood pool. no useful technique is available for estimating the amount of fat globules in the blood. fat emboli in lumen of small vessels and in pulmonary air spaces. severe fatty changes may be the cause offat embolism. fractures are the most common cause of fat embolism. petechial hemorrhages, fat emboli ( ). abdominal cavity submit sample of subphrenic exudate for gram stain and cultures. record location and volume of subphrenic exudate. possible causes of subphrenic empyema include appendicitis, cholecystitis, * diverticulitis, intrahepatic abscess, pancreatitis,* ruptured viscus; penetrating abdominal wound(s), perforated ulcer of stomach or duodenum,* and other conditions. pleural cavities and lungs e procedures record volume of effusion or exudate in pleural space. basal pleuritis and pneumonia, adjacent to empyema. encephalitis, au types or type unspecified synonyms and related terms: acute disseminated encephalomyelitis;* acute hemorrhagic encephalitis; acute infective encephalitis or encephalomyelitis; acute poliovirus encephalitis or encephalomyelitis; amoebic encephalitis; arbovirus encephalitis (japanese encephalitis; eastern encephalitis, western encephalitis, venezuelan equine encephalitis, st. louis encep-halitis); bulbar encephalitis;* brain stem encephalitis;* herpes encephalitis (cytomegalovirus encephalits, epstein-barr virus encephalitis, varicella-zoster encephalitis); herpes simplex ence-phalitis; hiv encephalitis; measles encephalitis; measles inclusionbody encephalitis; postinfectiousencephalitis; postvac-cinal encephalitis; progressive multifocal leukoencephalitis or leukoencephalopathy; rabies* encephalitis; subacute encephalitis; subacute sclerosing panencephalitis; viral encephalitis, west nile encephalitis and other terms ( ), too numerous to mention. see also under "note" and under "possible or expected findings." note: if the condition that caused the encephalitis is known, see also under that heading. if the cause of the encephalitis is unknown, submit samples of tissue for microbiologic and toxicologic study, particularly if there is a suspicion of lead poisoning.* see also under "encephalitis, brain stem," "encephalomyelitis,...," "encephalopathy" and "myelopathy, myelitis." encephalitis, brain stem synonyms and related terms: brain stem abscess; infectious brain stem encephalitis; listeria monocytogenes brain stem encephalitis; viral brain stem encephalitis. note: see also under "encephalitis, limbic." brain for removal and specimen preparation, see chapter . necrotizing encephalitis, with or without abscess formation ( enterocolitis, other types or type undetermined note: a multitude of infectious and noninfectious agents may cause inflammation of the small bowel, large bowel, or both. if the condition is not listed under "colitis," "enteritis," or "enterocolitis" or under another specific heading such as "dysentery, bacillary," obtain sufficient material for microbio-logic and histologic study to identify organisms such as clos-tridium, chlamydia, shigella, salmonella, yersinia, helicobacter, verotoxic e. coli, and others. if lymphogranuloma venereum,* or tuberculosis* are suspected, see also under these headings. see also under "disease, inflammatory bowel" and "disease, crohn's." synonyms and related terms: c. difficile colitis; darmbrand; hemorrhagic necrosis (gangrene; infarction) of intestine; ischemic enteritis or enterocolitis;* neutropenic enterocolitis;* pseudomembranous colitis. note: the name "pseudomembranous enterocolitis" is descriptive; the condition may be infectious, ischemic, or both. if the intestinal changes are clearly ischemic, see above under "enterocolitis, ischemic." if the cause is in doubt and if pseudomembranes can be identified, follow the procedures described here. (l) collect all tissues that appear to be infected. for other infectious intestinal diseases, see under specific names, such as "enterocolitis, neutropenic" or "enterocolitis, staphylococcal." intestinal tract and mesentery other organs collect material from pseudomembranes for culture and for c. difficile toxin assay. sample intestinal wall with pseudomembranes for histologic study. if the condition is suspected to be caused by ischemia, follow procedures described above under "enterocolitis, ischemic." note: myoclonic seizures also have been described in a number of progressive encephalopathies with complex neurological symptoms, such as gmi and gm gangliosidosis,* and niemann-pick* and krabbe's disease but also acquired disorders, including alzheimer's disease,* creutzfeldt-jakob epilepsy, myoclonus (continued) disease,* posthypoxic encephalopathy, and subacute sclerosing panencephalitis. mitochondrial encephalomyopathy also can present with myoclonus epilepsy and a mitochondrial myopathy with ragged red fibers (merrf syndrome) in skeletal muscles. lafora-body-type material in the heart, liver, retinas, peripheral nerves, skeletal muscles, and sweat gland ducts (especially axillary). ragged red fibers in mitochondrial myopathies. epilepsy, symptomatic note: possible causes or underlying conditions include cerebrovascular diseases, congenital malformations ofthe brain, degenerative and demyelinating diseases of the brain, head injury,* intracranial and cerebral infections, toxic or metabolic disorders (alcoholism,* barbiturate,* carbon monoxide,* and lead poisoning,* hemodilution, hypocalcemia, or hypoglycemia),* and tumors of the brain. * f failure, congestive heart note: coronary atherosclerosis and manifestations of ischemic heart disease, * valvular heart disease, congenital cardio-vascular diseases, and manifestations of systemic or pulmonary hypertension are the most frequent findings in patients dying of or with congestive cardiac failure. other causes include cardiomyopathies* and secondary myocardial disease (such as amyloid or pericardial constriction). if the cause of the congestive cardiac failure is unknown or not immediately evident after dissection of the heart and of the great vessels, myocardium and other appropriate tissues may be submitted for microbiologic study-including viral cultures-and for electron microscopy. specimens can also be snap-frozen for possible immunofluorescent, biochemical, or histochemical studies, particularly of the myocardium. possible causes of congestive cardiac failure are too numerous to mention. dilatation of heart, with or without mural thrombosis. myocardium may be soft, normal, or firm. pulmonary congestion, with or without hemosiderosis; congestion of viscera with organomegaly. other organ manifestations include bowel edema or hemorrhagic enteropathy (without mechanical vascular occlusion) and zonal hepatic steatosis, fibrosis, or necrosis, with or withoutevidence of liver failure. acute renal tubular necrosis may be present also. synonyms and related terms: acute kidney failure; chronic kidney failure; renal failure; uremia. note: if acute kidney failure had been diagnosed, the autopsy procedures will depend on the expected causes, such as poisoning with ethylene glycol,* lead,* mercury,* or methyl alcohol;* disseminated intravascular coagulation* and its various underlying conditions; glomerulonephritis* and its various underlying conditions; diabetes mellitus;* or multiple myeloma. * the procedures described below deal primarily with chronic renal failure. if the patient had had dialysis, see also under "dialysis (for chronic renal failure )." if transplantation had been carried out, see also under "transplantation, kidney." lassa fever is a highly communicable disease and autopsy studies are not recommended in the usually available surround-ings. if lassa fever is suspected, contact the state health department and the centers for disease control and prevention, atlanta, ga, for disposition and further studies ( ).ifan autopsy is done, disinfection can be accomplished by washing instruments with . % phenol in detergent (i.e., lysol), . % hypochlorite solution, formalin, or paracetic acid. for shipping procedures, see chapter . this is not a reportable disease. synonyms: borreliosis; louseborne (epidemic) relapsing fever; tickborne (endemic) relapsing fever. note: (i) collect all tissues that appear to be infected. ( ) rat/mouse inoculation with infected blood is the most sensitive method for the detection of the organism. consult the state health department. ( ) before the autopsy, consultation with the microbiology laboratory is advised. ( ) request direct dark-field examination and giemsa or wright stain. ( ) no special precautions are indicated. ( ) serologic studies are of questionable value due to the antigenic variability of the organism. ( ) fever, scarlet note: usually, this disease is a nonfatal group a streptococcal tonsillitis and pharyngitis with skin rash. potentially fatal complications include suppurative otitis media,* mastoiditis, and pharyngeal abscess ( ), with or without septicemia. ( ) collect all tissues that appear to be infected. ( ) atresia, but may also be seen with viral myocarditis, type ii glycogen storage disease (pompe disease) and carnitine deficiency. thus, a metabolic disorder must be considered. it is ideal to perform the autopsy as soon after death as possible ( ) . urine plasma for removal, prosthetic repair, and specimen preparation, see chapter . malnutrition ( ) muscle necrosis (clostridial myonecrosis) and accumulation of gas; little leukocytic infiltration. other organs g procedures depend on expected findings or grossly identified abnonnalities as listed in right-hand column. see also above under "note" and under "skeletal muscles." synonyms and related terms: acute postinfectious glomerulonephritis (nonstreptococcal postinfectious glomerulonephritis;*minimalchangedisease;mesangialproliferativeglomerulonephritis;* focal and segmental glomerulosclerosis with hyalinosis (focal sclerosis); poststreptococcal glomerulonephritis; idiopathic nephrotic syndrome; iga nephropathy (berger's disease); membranous glomerulonephritis; membranoproliferative glomerulonephritis; mesangial proliferative glomerulonephritis; rapidly progressive glomerulonephritis (associated with systemic infectious or immunologic multisystem diseases; drug idiosyncrasy; or as primary crescentic glomerulonephritis or superimposed on another primary glomerular disease). possible associated conditions: acquired immunodeficiency syndrome (aids);* alport's syndrome;* amyloidosis; anaphylactoid purpura; bee stings; chronic allograft rejection; dennatomyositis;* dennatitis herpetiformis; diabetes mellitus;* drug dependence;*fabry's disease;* goodpasture's syndrome;* guillain-barre syndrome;* henoch-schonlein purpura;* hemolytic uremic syndrome;* infective endocarditis;* leprosy;* malig-nancies;mixedconnectivetissuedisease;myxedema;polyarteritis nodosa;* rheumatoid arthritis;* preeclamptic toxemia; renovascular hypertension; sarcoidosis;* serum sickness;* sjogren's syndrome;*syphilis;*systemiclupuserythematosus;*systemic sclerosis;* thrombotic thrombocytopenic purpura;* thyroiditis;* vasculitis; viral hepatitis;* wegener's granulomatosis;* and many other conditions. urate deposits in scleras and corneas. granulocytopenia note: midline granulomas may belong to the angiocentric immunoproliferative lesions, which are related to lymphomatoid granulomatosis* and malignant lymphoma. the name "idiopathic midline granuloma" should be reserved for the few cases without evidence of malignant lymphoma or wegener's granulomatosis* ( ). the diagnosis of idiopathic midline granuloma also can be ruled out if studies reveal fungal organisms or features of leishmaniasis;* leprosy,* rhinoscleroma, pseudotumor of the orbit or tuberculosis. * complications of nasal cocaine abuse also may mimic midline granuloma ( ). eosinophilic pneumonitis (degenerating eosinophils with charcot-leyden crystals) and granulomas. angiitis (mostly arteritis), typically with giant cells in tunica media ( ) . findings resemble those in polyarteritis nodosa. * heart ( ), grastrointestinal tract ( ), skin, muscles, and joints are commonly involved. however, renal disease is often (but not always) mild or absent. necrotizing vasculitis of small arteries and veins is present, with extravascular granulomas and eosinophilic infiltration of vessels and perivascular tissues. optic neuritis may be found ( ). may be affected by the vasculitis ( ). pcr studies on paraffin sections via rna in situ hybridization may confirm presence of epstein-barr virus-positive b-cell proliferations combined with dense t-cell accumulations ( ) ( ) ( ) . the condition closely resembles angiocentric t-/nk cell lymphoma ( ). infiltration of lymphocytoid cells, plasma cells, and macrophages with necroses and granulomatous features, which are found primarily in the vicinity of blood vessels. special stains may reveal evidence of infection. lymphoreticular and granulomatous infiltrates (see "lung"). lymphoreticular and granulomatous infiltrates (see "lung"). characteristic infiltrates may be present in all organs and tissues. involvement of spleen, lymph nodes, and bone marrow is uncommon. in rare instances, the disease is confined to the abdomen. in most instances, characteristic infiltrates are present ( ). septicemia; circulating immunoglobulin complexes, and antiendothelial antibodies ( ). angiocentric granulomatosis ( ) hemorrhage, intracranial (see under "hematoma, subdural" and under name of suspected underlying condition, such as "aneurysm, cerebral artery," "infarction, cerebral," "injury, head," and "tumor of the brain." hemorrhage, subarachnoid (see under name of suspected underlying condition, such as "aneurysm, cere-bral artery," "infarction, cerebral," "injury, head," and "tumor of the brain." hemosiderosis, idiopathic pulmonary note: this diagnosis is made by exclusion; involvement of organs other than the lungs (see below under "kidneys") suggests another disease. hepatitis, chronic synonyms and related terms: autoimmune hepatitis; chronic viral hepatitis b (with or without d) and c. note: the term "chronic hepatitis" is not a complete etiologic diagnosis and related names such as chronic active (aggressive) hepatitis, chronic active liver disease, and chronic per-sistent hepatitis are obsolete. most cases in these categories represent autoimmune hepatitis or chronic viral hepatitis b or c. many other liver diseases, including drug-induced hepatitis, inborn errors ofmetabolism (e.g., alphal-antitrypsin deficiency* or wilson's disease*), developmental disorders, and chronic biliary diseases such as primary biliary cirrhosis or primary sclerosing cholangitis also may present as chronic hepatitis. ifchronic hepatitis was the cause ofdeath, submassive hepatic necrosis or cirrhosis* is usually present, often with manifestations ofportal hypertension,*hepatic encephalopathy, hepatorenal syndrome,* and with ascites or spontaneous bacterial peritonitis. possible associated conditions: see also below under "possible or expected findings." conditions that may be associated with hepatitis c include ( ): autoimmune hepatitis; behcet's disease; diabetes mellitus (type );* glomerulonephritis;* guillain-barre syndrome;* idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; iga deficiency; lichen planus; mixed essential cryoglobulinemia; mooren's corneal ulcers; polyarthritis; porphyria cutanea tarda;* thyroiditis. * note: coinfection with other hepatitis viruses (e.g., c and g) and/or systemic viruses such as the immunodeficiency virus are common, particularly in drug addicts ( , ) . in many cases of fulminant hepatitis, tests for known hepatitis viruses are negative ( , ) . homicide note: not all of the following procedures can be carried out or will be required in all cases, nor will this checklist be sufficient in all instances. consult also the entries indicating the cause of death, such as "injury, firearm" or "injury, stabbing." if the victim is an infant, see all under "infanticide." before the body arrives or before autopsy is begun: . investigate the scene where the body was found and where the crime may have been committed (these may be two separate locations). if this is not possible, study the report and photographs submitted by the investigator or the police. study all available information. request previous medical records and roentgenograms of the victim. . emphasize to first responders and autopsy personnel that the body of the victim should not be undressed, washed, or otherwise disturbed until it has been inspected by the pathologist. embalming is not permitted before completion of the autopsy. advise first responders or transporters to put paper bags over the hands of the victim. this will protect possible evidence, such as hair from the assailant. . prepare record sheets to document the time of arrival and release of the body; chain of custody for the body and specimens; the name, age, sex, and other information about the victim; the names ofthe technician, pathologist and guests; and the specimens taken. . prepare roentgenographic and photographic equipment. after body arrives but before autopsy is begun: . if the body is left unguarded-for instance, overnight-a lock should be placed on the refrigerator or cool room where the deceased is kept, and the key should be retained by the technician. . if the pathologist is not accustomed to a busy autopsy room, he or she should feel free to ask all persons other than the pathologist(s), technicians, and law enforcement personnel who are not immediately involved in the actual performance of the autopsy to leave the morgue. . the body temperature of the victim can be recorded at the autopsy facility, but this is rarely useful, particularly if the victim seems to have been deadfor longer than a day ortwo or ifthe body had previously been stored in arefrigeratoror cool room. insert thermometer deep into the anus (about - cm). record temperature and manner and time of procedure. . aspirate vitreous from one or both eyes and store the specimen in a refrigerator. . prepare roentgenograms. in each case, a decision must be made whether roentgenograms should be made of the entire body or only of parts of it-or not at all-and whether they should be made before the victim is undressed, after the victim is undressed, or at both times. . take overall survey photographs that depict the anterior surfaces of the body as it is on arrival to the facility, before any undressing, manipulation for roentgenographs, or cleaning. . take close-up photographs of any trace evidence such as fibers or flakes of gunpowder before undressing or cleaning. . photograph the face of the victim for identification purposes after it has been cleaned of any blood and foreign matter. to avoid perspective distortion from wide angle lenses, the lens should be about ft from the face. . photograph all injuries and other forensically significant findings after blood and foreign matter have been cleaned off the body. a moist towel is useful; brushes are too abrasive. two photographs should be taken of each finding. one should include the autopsy number and a scale. a second photograph should be taken without any extraneous objects. collection and documentation of evidence: . fingerprinting can be done before or after the autopsy but should be done in all homicide cases. in cases involving close contact between assailant and victim, fingernail scrapings or clippings (use a new clipper) and hair with roots should be collected, and its source should be identified (hair pulled from scalp, axillae, and pubis is identified as that of the victim; hair in hands or under fingernails or on clothing of victim may be from the assailant). hair exemplars can be collected in cases of homicide by firearm but are rarely of use. if the body is decomposed or mutilated or for any other reason has not been identified, prepare roentgenograms ofthe head, neck, and torso before the autopsy (the radiographic appearance is altered by the autopsy). these can be used for comparison purposes if antemortem films are located. if films of the extremities are needed they can be prepared after the autopsy. dental roentgeno-.grams are taken, usually after the autopsy, when investigators have located antemortem dental records. detailed descriptions and sizes of clothing, with photographs of clothing, can be useful then there is no putative identity. . in cases in which sexual assault may have been involved, collect pieces of clothing that may contain seminal fluid stains. follow procedures described under "rape." . preserve clothing or part of clothing as evidence. wet clothing should be dried before it is stored in labeled and sealed bags. the autopsy: . the measured length and weight, extent of rigor, and color and distribution of livor should be recorded, along with the state of preservation, nutrition, and hydration. do not omit examination of the hands, particularly of the volar surfaces. . if air embolism is suspected, see procedure described under part ii "embolism, air". if pneumothorax is suspected, see procedure described under part ii "pneumothorax". if there is evidence of strangulation or other neck injury, perform a layerwise dissection of the neck that includes the hyoid bone and tongue. . prepare diagrams of wounds and identify their location by anatomic region. for wounds of the torso, state the distance from the soles of a foot and the distance laterally from to the right or left of the midline. . submit samples of wounds for histologic study when there is any question of the age of the wounds. . the records should show when body fluids and tissues were collected for laboratory analysis, the volume and appearance of such specimens, and what was done with them. if most of the toxicology specimens are collected immediately after the internal examination has commenced, the time of the internal examination serves as the collection time. in all instances, the following items should be collected: blood ofvictim for dna comparison and toxicologic study (determination of alcohol, carbon monoxide, and drug concentrations will be requested most frequently); vitreous; urine; gastric contents; at least one solid organ specimen for toxicologic study (liver and brain have the most comparison data if an extracerebral congenital malformation is suspected, follow procedures described under "malformation, arnold-chiari." if cerebrospinal fluid is aspirated with a syringe, record volume. record weight of brain; record size of brain in relation to inner dimensions of skull. describe size of ventricles. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. if a surgical shunt is present, its location should be recorded and both ends of the implanted specimen that was used for shunting may be submitted for microbiologic study. if the shunt is not patent, record site and nature of obstruction. related terms: antibody-mediated hydrops fetalis; erythroblastosis fetalis;* nonimmune hydrops fetalis. note: the classic example of antibody mediated (rh incompatibility) hydrops fetalis is hemolytic disease of the newborn (erythroblastosis fetalis*). however, nonimmune hydrops fetalis also may be caused by hematologic disorders, e.g., alpha-thalassemia* ( ) or it may have no known cause. infec-tions, e.g., with human parvovirus bl ( ), cytomegalovirus, or syphilis;* heart and vascular diseases ( ) (cardiac tumors, cardi-omyopathy,* myocarditis,* arterial calcification, and others); storage disease ( ); tumors (including neonatal leukemia*); and many other fetal (e.g., congenital chylothorax* or lymphatic dysplasia; pulmonary sequestration and cystic adenomatoid malformation) or maternal conditions, e.g., maternal thyrotoxicosis, also may cause nonimmune hydrops fetalis. if coronary insufficiency or myocardial infarction is suspected, follow procedures described under "disease, ischemic heart." for coronary arteriography, see chapter to. record distribution of atherosclerotic lesions in aorta. samples for histologic study should include aorta, coronary arteries, and peripheral arteries. see also above under "heart." submit samples of head, corpus, and tail for histologic study. if applicable, see also under "diabetes mellitus." for special procedures and stains, see above under "heart." other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for removal and specimen preparation, see chapter . obesity* is a common finding. eruptive xanthomas (palms, elbows, knees) in some but not all types of hyperlipoproteinemia. most prominent in apoprotein cii deficiency. xanthomas of tendons (knees, elbows, dorsum of hands), xanthelasmas, and arcus comeae in familial hypercholesterolemia. gangrene of lower extremities (see below under "arteries"). severe coronary atherosclerosis and myocardial infarcts in type hyperlipoproteinemia and multiple lipoprotein-type hyperlipidemia. atherosclerosis of abdominal aorta and its branches and of carotid arteries. coronary atherosclerosis (see above). pancreatitis* in familial apoprotein cii deficiency. foam cells with triglycerides in liver, spleen, and bone marrow in familial lipoprotein lipase deficiency. manifestations of diabetes mellitus* and hypothyroidism* in some cases of type hyperlipoproteinemia. cerebral infarct (stroke*) in type hyperlipoproteinemia. hypernatremia (see "disorder, electrolyte(s).") hyperoxaluria synonyms and related terms: oxalosis; primary hyperoxaluria type i (a anineglyoxylate aminotransferase deficiency); primary hyperoxaluria type ii (d-glyceric acid dehydrogenase deficiency); secondary hyperoxaluria (see under "note"). note: in ethylene glycol poisoning,*oxalatecrystals in media ofsmall arteries, with associated ischemic lesions. similardeposits may occur after long-term hemodialysis ( ). these conditions must be distinguished from the genetic disease. also, oxa-iate nephropathy may be a complication of short bowel syndrome. if patient with congenital hyperoxaluria underwent liver or combined liverlkidney transplantation ( ) , see also under these headings. remove vitreous for biochemical evalvation. submit tissue (i.e., fascia lata) for karyotype analysis. polycystic ovaries, testicular adrenal rests ( note: there are no diagnostic autopsy findings for hypoxia. possible causes of acute hypoxia include anesthesia-associated death,' compression of the torso by a vehicle, diving accident,' exposure to toxic gases-forinstance, carbon monoxide poisoning;' mechanical failure ofan oxygen supply system, as in an airplane; and sudden mechanical airway obstruction,' as in aspiration ofa foreign body orstrangulation. causes ofchronic asphyxia include prolonged exposure to high altitude and chronic pulmonary disease. profound medial hypertrophy of small pulmonary arteries and of pulmonary veins from chronic exposure to hypoxia. acute pulmonary edema may also occur in chronic hypoxia. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. malnutrition. empty and collapsed colon; small amounts of gray and dry meconium in terminal ileum; meconium masses in dilated and hypertrophied mid-ileum; liquid contents in proximal intestine ( ); appendicitis; bowel perforation. glandular inspissation and atrophy of intestinal mucosa. volvulus, infarction, necrosis, perforation, peritonitis, and acquired intestinal atresia may be present. absence of neural plexuses in congential megacolon* (hirschsprung's disease). manifestations of cystic fibrosis, with or without cirrhosis;* biliary atresia* ( ). immunodeficiency (see "syndrome, acquired immunodeficiency" and "syndrome, primary immunodeficiency.") impression, basilar note: basilar impression constitutes an upward bulging of the margins of the foramen magnum. when occipital condyles are displaced above the plane of the foramen magnum, basilar invagination is present. possible associated conditions: klippel-feil syndrome;* osteogenesis imperfecta;* osteomalacia;* paget's disease of bone;* rheumatoid arthritis; rickets; syringobulbia; syringomylia. * compression and secondary ischemic injury to lower brain stem and spinal cord. see also above under "skull and spine" and under "possible associated conditions." incompetence,••• (see "insufficiency,..•") related terms: battered-child syndrome; child-abuse or child-neglect death. note: vitreous should not be aspirated until the skull has been opened and trauma ruled out, because there is a risk of artifactual damage to the retina. in the presence of craniocerebral trauma the pathologist can opt to examine the eyes by removal, fixation, and histologic study; or retinal photography. follow general procedures described under "homicide" and, if necessary,. the procedures described under "rape." external examination see above under "note." prepare roentgenograms of entire body. see above under "note." in other situations, or after study of the fundus, submit sample of vitreous for chemical and possible toxicologic study. umbilical cord attachment prepare histologic sections of umbilicus. and end of umbilical cord blood submit sample for toxicologic study. consider retaining dried blood on filter paper for possible dna testing for paternity investigation. if there is a possibility that the cadaver represents a stillbirth, see part ii, "stillbirth". if infant is thought to have died shortly after birth, determine the location of air in the intestinal tract; roentgenograms may be helpful. save stomach contents and record amount. other organs see also under "homicide." in the abused child, bruises, hematomas, burn marks, or other patterned injuries. in any child, diaper rash, mongolian spots, self-inflicted fingernail scratches, skin infections, and emaciation. in the previously battered child, fractures in various states of healing. in hypertonic dehydration,' sodium concentrations more than meq/l. this may be caused by organic disease, improper medical treatment, or physical neglect. if infant was born alive, inflammatory changes may be found, depending on survival interval. for the hydrostatic lung test, see "stillbirth." the test is unreliable. extraneous material in air passages indicates that child was alive. air reaches the stomach after min, the small intestine after - h, the colon after - h, and the rectum after l h. there is no difference in the speed of gas propulsion between full-term and premature infants. bacterial gas production and previous resuscitation attempts are potential sources of errors. in questionable stillbirth, presence of milk proves that infant was alive and had been nursed. traumatic lesions and signs of neglect may be present. unilateral ulcers in visceral zoster. in rare instances, diffuse meningoencephalitis may occur. limited necrotic and inflammatory lesions in the cord or brain stem at the level of the affected ganglion are common. posterior hom myelitis ( ). ganglion cell necrosis; lymphocytic infiltration, hemorrhage, and, later, fibrosis. as a rule, only one ganglion is severely involved, but less severe lesions may occur in the ganglia that are immediately adjacent. diffuse lymphocytic infiltration; demyelination; axonal destruction; fibrosis. conjunctivitis; keratitis; iridocyclitis; retrobulbar neuritis; neuroretinitis; occlusion of retinal vessels. evidence of hematologic malignancies ( ) or other conditions, as listed above under "note." infection, middle ear (see "otitis media.") infection, pneumocystis carinii synonym: pneumocystosis. note: ( ) collect all tissues that appear to be infected. ( ) this organism cannot be cultured at present but is frequently associated with viral, bacterial, or fungal infections that can be diagnosed by culture. ( ) for rapid staining of aspirates, use gram-weigert stain, which will stain cysts of pneumocystis carinii and also fungi and bacteria. pneumocystis carinii is best demonstrated with grocott's methenamine silver stain. ( ) no special precautions are indicated. ( ) usually, no serologic studies are available. ( ) this is not a reportable disease. injury, fire (see "burns.") injury, firearm note: protect all drains of autopsy table, which will prevent accidental loss of bullets or bullet fragments. recovery of bullet fragments and pellets can also be improved by passing tissue fragments, blood, and other appropriate materials through a fine nonmetallic sieve. caution must be exercised because sharp edges andjagged projections ofbullets and bullet fragments may cause injury ( ). this applies particularly to the black talon bullet. bullets and bullet fragments should not be touched with forceps or other metal instruments that may produce artifactual markings; they must be placed in properly labeled evidence containers, and the chain of custody must be preserved. from a birdshot wound, at least pellets should be recovered. the firearms examiner will divide the total pellet weight by and derive median pellet weight. from a buckshot wound, all pellets should be recovered. in many of these cases, procedures described under "homicide" must also be followed. do not excise wounds before completion of autopsy (see below). as an academic exercise, excised firearm wounds may be used later for analysis of metal traces by neutron activation or for tests for carboxyhemoglobin. in practice, however, a high quality photograph is adequate to establish the presence or absence of gunpowder stippling or soot deposition toward the end of establishing the range of fire. the dimensions of the stippled areas and soot deposits should be recorded. after completion of external examination, dry the wet clothing and keep as evidence. clothing may also be used for possible test firing or for stain, powder, or particle analysis. external examination if identity of victim is unknown, follow procedures described in chapter . prepare initial roentgenograms of the body regions that have been shot, before disrobing of body, and then lateral films of body regions with bullets. follow up with films of other body regions as needed in the course of autopsy. if the body is decomposed to the extent that the external examination cannot be relied upon to determine cutaneous gunshot perforations, prepare roentgenograms of the entire body before autopsy. record location and number of bullet holes in all layers of garments, indicating whether the involved area is bloodstained or shows gunpowder or soot. if there are several cutaneous perforations, number or letter each consecutively and refer to these numbers in all records. location of bullet holes should be described by recording distance from soles of feet or top of head, and from midline of body. prepare diagrams and photograph holes, with and without labels. photographs should show surrounding garments and extent of blood stains. in hairy areas, shave around bullet wounds for better photographic documentation. for evaluation of distance from where a shot had been fired, see fig. additional roentgenograms during the autopsy may be needed to find bullets embolized to the femoral veins or down the spinal canal. systemic roentgenograms may reveal bullets from obscure entrance wounds, particularly in decomposed bodies, old bullets, bullets in the skin flaps reflected at autopsy, or bullets external to the body in clothing. bullet(s) may have been arrested in hollow viscus or blood vessel and may have been transported to distant sites by peristalsis or bloodstream ("bullet embolus"). bullets may be deflected in unexpected directions from bony surfaces. soot ("smudging") and gunpowder stippling may occur around entrance wound, depending on the muzzle-to-skin distance. there may also be an impression from a recoiling handgun or from a power piston. wounds may be stellate, round, jagged, or slit-like, with or without wide margins of abrasion. primer residues on hand of suicide victim after use of a handgun. fatal secondary injuries, particularly hemorrhages. alcohol intoxication is a frequent finding. fig. · . bullet wounds. differences in the appearance of cutaneous wounds of entrance and of exit and differences in wounds of entrance according to the distance between muzzle and skin at the moment of fire. entrance wounds often differ from exit wounds in that the former are usually surrounded by a narrow zone of abrasion. if the muzzle of a gun is in close contact with the skin at the moment of fire, the combustion products will be blown into the wound and will not be visible on the surface. for close-range wounds, the stippling of the skin around the wound, produced by particles of burned and unburned powder, becomes progressively more dispersed as the range of fire increases and is ordinarily not perceptible if the range has been greater than inches ( synonyms and related terms: acute radiation syndrome; chronic (delayed) radiation injury; radiation enterocolitis; radiation nephritis; radiation pneumonitis. note: procedures and expected findings depend on type of radiation damage, whether acute or chronic, localized or whole-body irradiation. if suspected radiation injury was associated with the administration of radionuclides such as p, , or au, follow procedures suggested in chapter . in fatal whole-body irradiation, findings are most likely related to bone marrow injury, and the suggested procedures and expected findings are those described under "pancytopenia." record extent of oropharyngeal and intestinal ulcerations and hemorrhages. late complications include malignant tumors (carcinoma, leukemia,* lymphoma*), manifestations of hypothyroidism,* and cataracts. organ changes in localized radiation injury depend on site of irradiation (lung, brain, kidney, intestine). the skin is involved in both acute (erythema) and chronic (atrophy, epilation) radiation injury. related terms: cutting injury; knife injury. note: in many of these cases, procedures described under "homicide" must also be followed. insuffiency, adrenal synonyms and related terms: adrenocortical insufficiency; polyglandular autoimmune syndrome (type i, usually in childhood, with parathyroid insufficiency and chronic mucocutaneous moniliasis; type ii, usually in adults, with two or more autoimmune endocrine disorders such as thyroiditis and diabetes mellitus*); primary adrenal insufficiency (addison's disease); secondary adrenal insufficiency (in hypothalamic-pituitary disease or steroid induced); x-linked adrenal hypoplasia. is caused by anatomic changes (see below under "adrenal glands"), drugs (enzyme inhibitors or cytotoxic drugs), or acth-blocking antibodies. possible associated conditions: aids with systemic infections ( ); antiphospholipidantibody syndrome ( ); autoimmune hepatitis; chronic lymphocytic thyroiditis; type i diabetes mellitus;* hypoparathyroidism;* hypothyroidism;* megaloblastic anemia;* surgical procedures, such as heart surgery or orthopedic procedures. large cell lymphoma ( ). should be removed as soon as possible (before embalming), either from cervical midline incision or from chest (neck of cadaver must be well-extended). photograph obstruction before larynx is opened, and inside of larynx and epiglottis after larynx is is opened in posterior midline. make gram-stained touch preparations. make histologic sections of larynx and epiglottis. hemophilus injluenzae (cannot always be isolated from larynx synonyms and related terms: acute or chronic lymphocytic leukemia, acute or chronic myelogenous leukemia, and hairy cell leukemia. multiple subtypes have been identified; they are characterized by cell surface markers, chromosomal abnormalities, staining reactions, and morphologic features. note: at the time of autopsy, most leukemias have been properly classified and often treated. in these cases, the goal of the autopsy is to document the extent of the disease and the presence of complications. if the leukemia had not been classified or if the features might have changed from the time of the last work-up (e.g., in suspected cases of superimposed diffuse large cell lymphoma [richter's syndrome]), material should be snap-frozen and studied in more detail. if the patient was treated by bone marrow transplantation,* see also under that heading. possible associated conditions: agnogenic myeloid metaplasia with myelofibrosis; bloom's syndrome;* cutaneous mastocytosis; down's syndrome;* immunodeficiency syndromes* (bruton's disease; louis-bar syndrome; wiskott-aldrich syndrome); infantile genetic agranulocytosis; klinefelter's syndrome;* lymphoma;* multiple myeloma;* polycythemia;* and many others. for sampling and specimen preparation, see chapter . increased protein concentration. material in sediment stains red with toluidine blue. metachromatic material. arylsulfatase-a deficiency. excessive loss of myelin with large amounts of metachromatic material (see above under "urine") in white matter and also in some neurons. demyelination with metachromatic material (see above under "urine"). leukoencephalopathy, progressive multifocal possible associated conditions: aids* and other immunosuppressed states; carcinoma; malignant myeloproliferative or lymphoproliferative disorder; sarcoidosis;* tuberculosis. * procedures submit portion of fresh brain for viral culture. fix remainder of brain and spinal cord in formalin and submit samples for histologic study. in situ hybridization for ic virus is available on paraffin-embedded tissue. small patches of demyelination with tendency to form confluent areas in the cerebral white matter. white matter necrosis may be present. eosinophilic intranuclear inclusions occur in affected oligodendroglia cells. subsequently, large, bizarre astrocytes develop. no inflammatory (lymphocyte) cell reaction is present. lightning (see "injury, lightning.") lipoproteinemia (see "hyperlipoproteinemia.") lipoproteinosis, pulmonary alveolar synonym: idiopathic alveolar lipoproteinosis. note: the condition has been described in allografts ( ); in such cases, see also under "transplantation, lung." elephantiasis of penis, scrotum, or vulva (in chronic cases); skin rash (l) and conjunctivitis (in acute cases); genital ulcers. suppurative or fibrosing inguinal, iliac, or pelvic lymphadenitis, with or without sinus tracts. rectal strictures and fistulas in chronic cases ( ) . systemic involvement in the acute stage with pericarditis,* and arthritis,* and meningitis,* proctitis ( ) lymphoma synonyms and related terms: aids-related lymphoma; adult t-cellieukemiallymphoma; angioimmunoblastic lymphadenopathy; b-celllymphoma; burkitt's lymphoma; cutaneous t-cell lymphoma (includes mycosis fungoides and sezary syndrome); hodgkin's disease; non-hodgkin's lymphoma (low grade, intermediate grade, high grade, all with multiple subtypes too numerous to list, which vary in natural history); natural killer cell neoplasms; post-transplant lymphoproliferative disorders (ptld); t-cell lymphoma. note: at the time of autopsy, most lymphomas have been properly classified and often treated. in these cases, the goal of the autopsy is to document the extent ofthe disease and the presence of complications. if the lymphoma had not been classified or if the features might have changed from the time of the last work-up, material should be snap-frozen and studied in more detail. if the patient was treated by bone marrow transplantation, * see also under that heading. for current terminologies of hodgkin's disease and non-hodgkin lymphomas as well as for staging criteria, appropriate hematologic textbooks should be consulted. possible associated conditions: acquired immunodeficiency diseases (e.g., after organ transplantation; human immunodeficiency virus-l infection); autoimmune disease (e.g., celiac sprue,*rheumatoid arthritis,* systemic lupus erythematosus,* or sjogren's syndrome*); chemotherapy with or without radiation treatment; epstein-barr virus infection; human t-cell leukemia virus infection; inherited diseases with immunodeficiency (e.g., klinefelter syndrome; * common variable immunodeficiency disease, wiskott-aldrich syndrome); radiation. the lesions are found most commonly in the urinary bladder and other parts of the urinary tract, but may also occur at many other sites, including skin ( ) and upper respiratory tract ( ). note: (i) collect all tissues that appear to be infected. ( ) usually, cultures are not indicated. ( ) request giernsa or wright stain. tissue blocks should be rinsed of blood and be as thin as possible before fixation in refrigerated buffered and neutral % formalin solution. this is to avoid precipitationofformalin pigment that may be confused with malaria pigment. the formalin solution should be used in a ratio of parts formalin to one part tissue and should be agitated every few hours. if one is dealing with tissues that contain formalin pigment, this pigment may be removed with a bleaching solution. ( ) usually, no special precautions are indicated. ( ) possible associated conditions: histoplasmosis* and other chronic fungal infections; immune connective tissue diseases such as rheumatoid arthritis* (l) ; malignancies (l); sarcoidosis;* silicosis;* tuberculosis* (l) . note record location and extent of skin changes or skin defects on back. prepare skeletal roentgenograms. if meningitis is suspected, submit sample of cerebrospinal fluid for culture. dse the posterior approach to remove the spinal cord. atrophic skin over meningocele, lacking rete pegs and skin appendages; skin defect in complete rachischisis. bony defects of spine. in meningocele and spina bifida occulta, arachnoid and dura herniate through the vertebral defect. spinal cord and roots are generally not involved. lumbosacral mass in meningomyelocele, with a highly vascular mass (area medullovasculosa) in spina bifida aperta. neural defects in complete rachischisis. diastematomyelia, hydrocephalus ( ) . pyelonephritis;* enlarged urinary bladder ("neurogenic bladder"). external examination heart lungs procedures prepare chest roentgenogram. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. record weights. prepare photographs and roentgenograms of fresh and fixed lung specimens. perfuse one lung with formalin. for preparation of paper-mounted sections, see chapter . submit one lobe for microbiologic and chemical study. decalcify tissue for histologic study. request van gieson's, hale's colloidal iron, pas, and sudan stains. miliary mottling in lower lung fields. mitral stenosis* may be a cause of microlithiasis (mostly intra-alveolar ossification). * cor pulmonale and heart failure ( ) (l) , see also under that heading. ( ) collect all tissues that appear to be infected. ( ) viral isolation, especially with ebv, is not diagnostically useful, due to long incubation periods. ( ) note: these diseases are characterized by a deficiency of a variety of hydrolases, resulting in accumulation of gly-cosaminoglycans (mucopolysaccharides) and glycolipids within lysosomes of fibroblasts, macrophages, white cells, and parenchymal cells of many organs ( , ) . mucopolysaccharides are also excreted in the urine. the general approach is similar in all types. formalin may dissolve all of the stored material and leave empty vacuoles in the involved cells. therefore, frozen sections should be utilized or tissues should be fixed in absolute alcohol. the accumulated material will show intense metachromasia if stained with toluidine blue. it will also stain with pas, alcian blue, and colloidal iron. oil red a will also stain the material from frozen sections. for specimen preparation for elec-tron microscopy, see chapter is. characteristic external features include dwarfism; thickened long bones; coarse facial features; coarse hair; macrocephaly; prognathism; hypertelorism; malformed teeth, and scaphocephalic skull with hyperostosis of sagittal suture; short neck; chest deformity; umbilical and inguinal hernias; lower thoracic and lumbar gibbus; genu valgum and coxa valga; pes planus and other joint deformities; wide hands (clawhands) and feet. coarse thickened skin, covered with lanugo-like hair. hyperlordosis; ovoid deformities of vertebrae; odontoid hypoplasia; large, shoe-shaped sella turcica; kyphosis; hypoplasia of femoral heads; osteoporosis.* if patient underwent bone marrow transplantation ( ), see also under that heading. chronic upper respiratory infections. large cytoplasmic granules in neutrophils. storage of mucopolysaccharides in osteocytes, chondrocytes, and fibroblasts of periosteum, tendons, fasciae, and other connective tissues; dysostosis multiplex. other tissues histologic sampling cannot be excessive. ( ) collect all tissues that appear to be infected. ( ), see also under that heading. blood; other organs and tissues record extent of skin lesions and prepare photographs; prepare sections of affected and unaffected skin. request gram stain of sections and smears. submit samples of blood and grossly affected organs or tissues for microbiologic study. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. extensive epidermal necrosis. shedding of granular and horny layers of epidermis. septicemia; staphylococcal infection of nose, throat, ears, eyes, heart valves, urogenital tract, and other sites. bronchial epithelial detachment and bacterial pneumonia ( ). synonyms and related terms: acute kidney failure; *acute tubular necrosis; lower nephron nephrosis. note: the morphologic diagnosis of this condition may be difficult to discern from autolysis. the features that suggest tubular necrosis are: tubular dilation with epithelial flattening, intertubular edema and necrotic epithelial cells in the collecting ducts. the autopsy should be performed as soon as possible. needle specimens of the kidneys obtained in the immediate postmortem period may yield acceptable material. ifnephrotoxic drugs or chemicals are thought to be responsible for tubular necrosis, submit samples for toxicologic study (see also under synonyms and related terms: multiple endocrine neoplasia (men), type (parathyroid hyperplasia or adenoma; pancreatic islet cell hyperplasia, adenoma, or carcinoma; pituitary hyperplasia or adenoma); or type a (medullary thyroid carcinoma, parathyroid hyperplasia or adenoma; and pheochromocytoma); or type b (medullary thyroid carcinoma, pheochromocytoma, mucosal and gastrointestinal neuromas, and marfanoid features). note: in men, type , foregut carcinoids and subcutaneous and visceral lipomas also may be found. in type a, cutaneous lichen amyloidosis may be observed. mixed syndromes include (i) familial pheochromocytoma and islet cell tumor, ( ) von hippel-lindau syndrome, pheochromocytoma and islet cell tumor, ( ) neurofibromatosis* with features of men or , and myxomas, spotty skin pigmentation, and generalized endocrine overactivity (carney complex). in all instances, the autopsy should be done as soon as possible so that tissues for biochemical study can be frozen without delay. nephritis note: see under specific designation, such as "glomerulonephritis" and "pyelonephritis," or under name of suspected underlying condition, such as "gout" or "lupus erythematosus, systemic." nephroblastoma (see "tumor of the kidney(s).") synonyms and related terms: renal stones; urolithiasis. possible associated conditions: carcinomatosis; cushing's syndrome;* cystinuria;* fanconi syndrome;* hyperoxaluria;* hypervitaminosis d;* gout;* multiple myeloma;* osteoporosis;* polycystic renal disease;* primary hyperparathyroidism;* rheumatoid arthritis* ( ); sarcoidosis* ( ). kidneys ureters, urinary bladder, and urethra other organs remove kidneys, ureters, and urinary bladder en bloc. excise and bivalve kidneys to reveal renal pelves. open ureters. record size, number, and appearance of stones, and save for chemical analysis ( ). record heart weight. dissect and record weights of all parathyroid glands. other procedures depend on suspected underlying conditions, as listed above under "possible associated conditions." nephropathy note: see under name of suspected underlying condition, such as "diabetes mellitus," "disorder, electrolyte(s)" (hypercalcemia, potassium depletion), "gout," "hypertension (arterial), all types or type unspecified," or "poisoning,.. ." (heavy metal). if kidney failure was present, procedures under that heading should also be followed. renal tissue may need decalcification or fixation in water-free solution. ( ) note: in this condition, lesions in the brain and cranial nerves, spinal cord, and spinal roots may be schwannomas (including bilateral vestibular schwannomas); multiple meningiomas; gliomas (generally of spinal cord), mostly ependymomas ( %) and pilocytic astrocytomas; or schwannosis of spinal dorsal root entry zones. intracortical meningioangiomatosis; glial hamartia (intracortical, basal ganglia, thalamus, cerebellum, and dorsal horns of spinal cord) and cerebral calcifications also may be found. cutaneous abscess (j). acute necrotizing nocardial pneumonia with abscesses or sinus formation into surrounding tissues; empyema. pulmonary and mediastinallymph nodes other organs submit samples for culture and histologic study. submit samples from all organs and tissues with suspicious gross lesions for culture and histologic study. poorly encapsulated abscesses of any organ; endocarditis ( ) . related term: total parenteral nutrition. note: air embolism* or blood loss may have occurred if line became detached from the catheter hub. metabolic complications such as fluid overload or disturbances of acid-base and electrolyte balance often cannot be diagnosed reliably at autopsy. the disease(s) that may have necessitated parenteral nutrition therapy are not considered here; they include the acquired immunodeficiency syndrome (aids);* cancer cachexia; inflammatory bowel disease; liver or kidney failure;* severe pancreatitis;* short bowel syndrome, and others. obstruction, acute airway synonyms and related terms: aspiration; bolus death; "cafe coronary"; croup; restaurant death. note: ifpermission has been obtained, remove neck organs through straight incision from chest to chin to avoid dislodging a foreign body. ifdissection has to be accomplished from chest, neck of unembalmed cadaver should remain well extended during procedure. inspect larynx and trachea from above and below, respectively, before opening them carefully along the posterior midline. for removal, prosthetic repair, and specimen preparation, see chapter . submit samples of osteocartilaginous and synovial tissues for histologic study; sagittal or frontal saw section through spine provides for best routine evaluation. heberden's nodes at interphalangeal joints of fingers. degenerative changes, primarily of spine, hip joints, and knee joints. histologic and macroscopic degeneration of cartilage; exposure of subchrondral bone; formation of marginal osteophytes; bone cysts; synovial fibrosis; hypertrophic synovitis. o procedures if artificial joints (e.g., hip or knee) had been implanted, record state of implant site. loose joint prostheses. synonyms: hypertrophic pulmonary osteoarthropathy; pac-hydermoperiostosis (idiopathic hypertrophic osteoarthropathy [ j). note: in all instances, an underlying disease must be identified; they include cardiac disease (cyanotic congenital heart dis-ease with right-to-left shunt; infective endocarditis*); gastroeso-phageal reflux ( ); neoplasms of lungs, esophagus, intestine, and liver; chronic liver disease; inflammatory bowel disease;* pulmonary disease (e.g., abscess;* bronchiectasis;* cystic fibrosis;* emp-yema;* emphysema;* lipoid pneumonia* ( ); pneumocystis pneumonia; sarcoidosis;* tuberculosis*); hyperthyroidism. * external examination elastic arteries other organs prepare roentgenograms of extremities. for removal, prosthetic repair, and specimen preparation, see chapter . record presence of aneurysms (thoracic aorta, subclavian) or arteriovenous fistula of brachial vessels. if abdominal aortic aneurysm had been surgically repaired, search for evidence of graft infection ( ) . procedures depend on expected findings or grossly identified abnormalities as listed above under "note." clubbing of fingers or toes (see below under "elastic arteries"); swelling of extremities. periosteal new bone formation in distal shafts of bones of forearms and legs. all bones of extremities may be involved. see above under "external examination." unilateral clubbing. clubbing of toes but not of fingers. swelling; fistulas. bone defect(s) and focal osteosclerosis. bacterial or fungal infections, most common in metaphyseal region of bones; paravertebral or psoas abscess in osteomyelitis of spine. bacterial or fungal osteomyelitis, with or without cavitation and fistulas. trauma, surgery, insertion of prosthesis, generalized ( ) or contiguous infection, inflammatory bowel disease ( ), diabetes mellitus,* and peripheral vascular diseases, deep vein thrombosis ( ). synonyms and related terms: aseptic necrosis of bone; avascular necrosis of bone; idiopathic osteonecrosis; perthes' dis-ease; postfracture osteonecrosis; renal transplant associated osteonecrosis. note: possible underlying conditions include chronic alcoholism,* decompression sickness,* diseases that have been treated with high doses of corticosteroids ( ), gaucher's disease,* human immunodeficiency virus infection* ( ), tuberculosis* ( ), sickle cell disease, * systemic lupus erythematosus,* tuberculosis* ( ), and bisphosphonate therapy ( ). other organs submit sample for biochemical study. for removal, prosthetic repair, and specimen preparation, see chapter . if osteonecrosis is suspected because one of the possible underlying conditions (see above) is present, prepare saw sections through femoral heads, medial femoral condyles, and heads of humeri. procedures depend on suspected underlying conditions, as listed above under "note." osteopetrosis synonymsand related terms: albers-schonberg disease; autosomal-dominantosteopetrosis; carbonic anhydrase-it deficiency; malignant infantile osteopetrosis ( ); marble bone disease. note: manifestations of renal tubular acidosis may have been a clinical complication. possible associated conditions: bone marrow transplantation* (for infantile osteopetrosis). anemia, recurrent infections, bleeding, and bruises may have resulted from myelophthisis associated with osteopetrosis. upper airway obstruction in malignant infantile osteopetrosis may have necessitated tracheostomy ( ). in heritable osteoporotic disorders of connective tissue (osteogenesis imperfecta,* marfan' s syndrome,* and others) are pre-sented separately. for"osteomalacia," see above. for "osteodystrophy," see under "failure, kidney." possible associated conditions: acromegaly;* chronic alco-holism;* chronic obstructive pulmonary disease; chronic kidney failure* ( ); cushing's syndrome;* debilitating disease (various kinds, often with immobilization); diabetes mellitus* ( ); epilepsy;* hyperthyroidism ( );* hypogonadism; malabsorption syndrome;* malnutrition;* primary biliary cirrhosis;*rheu-matoid arthritis;* scurvy;* steroid therapy or anticonvulsant medication. normal parathyroid glands in uncomplicated cases. hyperparathyroidism* ( ) (without osteitis fibrosa) may be present, however. features of osteitis fibrosa (osteoclastic osteoporosis; see "hyperparathyroidism") or osteomalacia* exclude the diagnosis of uncomplicated osteoporosis. osteoporosis, which may be localized, occurs in various neoplastic (e.g., mastocytosis) and inflammatory diseases. external examination brain and base of skull with middle ears examine external ear canal. for removal and specimen preparation, see chapter . culture any lesion appearing to be infectious. draining, foul-smelling greasy material associated with acquired cholesteatoma. bacterial or viral infection, with or without mastoid osteitis. neck abscess, sinus thrombosis ( ) and brain abscess* and meningitis* may complicate otitis media. otosclerosis ( , ) note: otosclerosis may be a measles-virus-associated disease ( ) and therefore, studies to rule out a past infection may be indicated. for removal and specimen preparation, see chapter . for current methods of temporal bone studies, see ref. ( ) . spongy bone in the capsule of the labyrinth. trabeculae of woven bone show pagetoid changes. if stapedectomy had been done, a prosthesis may be in place. brain is externally normal or mildly atrophic. characteristic is midbrain atrophy with aqueduct dilatation and depigmentation of the substantia nigra. neuronal loss with reactive gliosis, associated with neurofibrillary tangles (globose tangles). primarily affected are globus pallidus, subthalamic nucleus, red nucleus, substantia nigra, tectum, periaqueductal gray matter, and dentate nucleus (grumose degeneration). palsy, pseudobulbar (see "disease, motor neuron.") related terms: acute pancreatitis; alcoholic pancreatitis; chronic (or chronic fibrosing) pancreatitis; interstitial pancreatitis. note: some causes of pancreatitis such as adverse drug reactions (e.g., due to azathioprine, furosemide, or estrogens) cannot be diagnosed at autopsy. possible associated conditions: acute fatty liver of pregnancy; apolipoprotein cli deficiency; cystic fibrosis; *hyperparathyroidism;* kidney transplantation. * status post endoscopic retrograde cholangiopancreatography. synonyms and related terms: calcifying panniculitis; histiocytic cytophagic panniculitis; mesenteric panniculitis (mes-enteric lipodystrophy); "sclerema neonatorum." note: the term weber-christian disease described systemic panniculitis with fever, bleeding, pulmonary and pancreatic lesions, and other abnormalities also involving lungs and pancreas, among others. however, this condition is not a specific entity and thus, the name has become obsolete. the term histiocytic cytophagic panniculitis is more descriptive and preferred. leukemia* and subcutaneous t-celllymphoma* may closely simulate panniculitis. possible associated conditions: alphaj-antitrypsin deficiency;* dermatomyositis;* rheumatoid arthritis;* scleroderma and morphea; sjogren's syndrome;* systemic lupus erythematosus.* external examination, skin, subcutaneous tissue, and breasts chest heart lungs liver and spleen record extent and character of skin lesions. record size, location, and gross appearance of subcutaneous nodules. submit tissue samples for histologic study of grossly unaffected skin, skin lesions, and subcutaneous nodules. request verhoeff-van gieson, gram, and grocott's methenamine silver stains. request s-l protein stain. ascertain that cell infiltrates are not leukemic or lymphomatous ( ) . dimpling of skin; necroses; fistulas. panniculitis with subcutaneous nodules in trunk, breasts, and thighs ( ) . calcification may occur in breast tissue but also at other sites (e.g., in kidney failure*). pancreatic enzymeinduced fat necroses associated with severe pancreatitis. widespread hardening of fat tissue with rupture of fat cells and crystal formation in "sclerema neonatorum." focal traumatic panniculitis also may occur in newborns. s-ioo stain negative in panniculitis but positive in rosai-dorfman disease (sinus histiocytosis with massive lymphadenopathy). mediastinal panniculitis. pericarditis;* interstitial myocarditis. * pneumonia;* pleuritis. fat embolism. * features of alphal-antitrypsin deficiency* ( ) . fatty changes of liver; splenitis. intestinal mucosal erosions and ulcers, with or without perforation. massive gastrointestinal hemorrhage in histiocytic cytophagic panniculitis. blind intestinal loop ( ). for sampling and specimen preparation, see chapter . prepare samples for electron microscopy. vacuolar myopathy. ( ) . external examination, skin, and mouth record extent of skin lesions; photograph; submit multiple samples for histologic study, preferably of areas that are free of secondary infection. prepare sections for immunofluorescent staining. bullous and other lesions of scalp, eyelids, nose, axillae, umbilicus, inframammary areas, back, hands, groins, genitalia, anus, knees, and feet. similar lesions may occur in the mouth. acantholysis is suprabasal or near granular layer. igg deposits on the surfaces of keratinocytes. note: (i) collect all tissues that appear to be infected. collect inguinal, popliteal, axillary, and supraclavicular lymph nodes for aerobic culture. photograph enlarged lymph nodes, and prepare smears of fresh cut surfaces. submit consolidated areas for microbiologic study (see above under "note"). perfuse both lungs with formalin. submit samples of pulmonary tissue and bronchial lymph nodes for histologic study. submit samples of grossly abnormal organs, exudates, or drainage fluids for culture and gram stain. hemorrhagic necrosis; variable suppuration. severe hemorrhagic edema; pneumonia with lobular to lobar features. large areas of necrosis teeming with organisms and minimal to suppurative inflammation. plasmacytoma (see "myeloma, multiple.") platybasia note: possible causes or associated conditions include arnold-chiari malformation;* basilar impression* orinvagination; fusion ofatlas to the foramen magnum; klippel-feil syndrome;* malpositioning of odontoid process; osteitis deformans (paget's disease of bone*); osteogenesis imperfecta;* osteomalacia;* rickets; syringobulbia, syringomyelia. * skull and spine prepare roentgenograms of skull and cervical spine. flattening of the base of the skull (angle formed bythe planeoftheclivus andtheplane of the anterior fossa exceeds °). pleuritis (see "effusion(s) and exudate(s), pleural.") pleurodynia, epidemic synonyms: bornholm disease; devil's grip; epidemic myalgia; epidemic myositis. blood heart and pericardium submit samples for viral culture. sample for histologic study and for viral cultures (coxsackievirus a and b; echoviruses). if pericardia! fluid can be obtained, submit for viral culture also. cultures may be negative and search for viral rna by in situ hybridization may be indicated. chest organs other organs dissect thoracic duct and its tributaries (see chapter ). perfuse one or both lungs with formalin. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. submit samples of cystic lesions for histologic study. submit samples of cystic lesions for histologic study. gas in thoracic duct. emphysema* of lungs. necrotizing enterocolitis in premature infants. pyloric stenosis, colitis ( ), redundant sigmoid colon, ischemic bowel disease. mucosal pseudolipomatosis ( ) . usually, cysts are subserosal in adults and located between muscularis mucosae and muscularis propria in infants and children. mucosa may be inflamed. extraintestinal cysts, as listed above under "abdomen." cysts may also occur in vaginal mucosa. include bright-field and polarized light microscopy, transmission electron microscopy, scanning or transmission electron microscopy with energy dispersive x-ray analysis ( ), ion beam instrumentation, and secondary ion mass spectrometry. the last three methods are time-consuming, require much skill and expensive equipment, and do not lend themselves well to quantitation. ideally, bulk analysis and in situ microanalysis should be used in combination. analyses can be conducted in specialized laboratories at the following centers (for charges and other information, consult the appropriate laboratories): prepare chest roentgenogram. submit sample for microbiologic study. refrigerate sample for possible immunologic study. submit one lobe or samples of all lobes for bulk analysis and for in situ microanalysis (see above under "note"). microincineration may permit preliminary dust analysis. for demonstration of asbestos fibers, see chapter and ref. ( ) . submit one lobe or segment for microbiologic study. for pulmonary arteriography and bronchography, see chapter . prepare roentgenograms of entire lungs and slices. perfuse one lung (or both, if only routine studies are intended) with formalin. submit samples for histologic study of nodular dust lesions, diffuse fibrotic lesions, grossly uninvolved areas, bronchi, and bronchopulmonary lymph nodes. for preparation of paper-mounted sections, see chapter . prepare samples for transmission and scanning electron microscopic study. for removal, prosthetic repair, and specimen preparation, see chapter . alveolar rupture with dissection of air into the mediastinum in neonates with respiratory distress (see "syndrome, respiratory distress, of infant") and in adult patients ventilated on volume respirators. external examination prepare chest roentgenogram. photograph mediastinum. explore major veins and record compression in cases of tension pneumomediatinum. roentgenograms provide the best permanent record of a pneumomediastinum. air bubbles in mediastinal soft tissues. part ii / diseases and conditions abdomen and neck organs perfuse one lung with formalin. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. search for evidence of trauma of other lesions that may have allowed air to enter soft tissues. intubation injury (j); perforation or rupture of major bronchus, trachea, or esophagus. alveolar rupture, e.g., in asthma* ( ), may not be discernible. bronchiolitis obliterans ( ), interstitial pneumonia* ( ) and other lung conditions also may lead to pneumomediastinum. dissection of air from lesions in abdomen (e.g., retroperitoneal colonic perforation [ ] ) or in neck area. pneumonia, all types or type unspecified note: if the type of underlying infection is known, follow procedures suggested under the name of the infectious disease. if the etiologic agent of the pneumonia is unknown, proceed as follows: (l) collect all tissues that appear to be infected. and grocott's methenamine silver stains. ( ) special precautions may be required (see chapter ). ( ) serologic studies may be helpful once a specific etiologic agent is suspected. thus, collect serum at the time of autopsy or procure serum that was collected prior to death. ( ) this may be a reportable disease. related terms: acute interstitial pneumonia (hamman-rich syndrome); desquamative interstitial pneumonia (dip); idiopathic organizing pneumonia (or "bronchiolitis obliterans with patchy organizing pneumonia [boop]" or "cryptogenic organizing pneumonitis"); idiopathic pulmonary fibrosis; lymphoid interstitial pneumonitis (lip); nonspecific interstitial pneumonia (nsip) (or "cellular interstitial pneumonia" [eip]); usual interstitial pneumonia (uip); fibrosing alveolitis; pulmonary alveolitis; and many others. note: the conditions listed under "related terms" are histologic variants of idiopathic interstitial pneumonia. vip is synonymous with idiopathic pulmonary fibrosis (ipf) ( ). diffuse alveolar damage is the histologic finding in patients with the adult respiratory distress syndrome* (ards) causing interstitial and intra-alveolar fibrosis. this is an acute condition, referred to as acute interstitial pneumonia when it occurs as an idiopathic form of rapidly progressive interstitial pneumonia. possible associated conditions: acquired immunodeficiency syndrome* (aids) in patients with with lip or nonspecific interstitial pneumonia ( , ); trauma and shock in ards. secondary pulmonary fibrosis from inhalants (extrinsic allergic alveolitis or pneumonia; pneumoconiosis*), in drug-induced pneumonia, hypersensitivity pneumonitis (microgranulomatous hypersensitivity reaction of lung), rheumatoid arthritis,* sjogren's syndrome,* and other collagen-vascular diseases; primary biliary cirrhosis in patients with nonspecific interstitial pneumonia ( ). external examination postmortem chest roentgenograms provide the only reliable and permanent record of a pneumothorax and its main complication, mediastinal shift due to a tension pneumothorax (fig. - ) . if roentgenograms cannot be prepared, a reasonably reliable diagnosis still can be made if the prosector inserts a needle through the lateral chest wall. the needle should be connected to a water-filled flask. ifa pneumothorax is present, gas bubbles appear in the flask as shown in fig. - . one can also expose the intact parietal pleura and observe if the lung tissue is separated from the parietal pleura by gas. incising the thorax at the base of a water-filled skin pocket is the least reliable method. infants can be totally submerged under water before the chest cavity is incised. however, care must be taken not to make an accidental incision into the underlying lung tissue. poisoning, all types or type unspecified note: if a specific substance is suspected-for instance, arsenic or ethylene glycol-follow procedures described under the appropriate entry. similar entries can be found for poisons whose general character or source is known-for instance, gas or mushroom poisoning. for some substances, the appropriate entry can be found under "abuse,...," "death,...," or "dependence, ..." in all instances, routine sampling of toxicologic material should be done as described in chapter . if no specific substances can be incriminated, the toxicologist must be provided with all available clinical information, as shown in chapter . in most cases of fatal poisoning, the coroner or medical examiner must be notified. poisoning, alkaloid note: see under specific name of alkaloid-for instance, "dependence, cocaine," "poisoning, atropine," "poisoning, digitalis," or "poisoning, strychnine." only a fraction of this large group of plant poisons has been listed. whether the specific name of the alkaloid is known or unknown, complete toxicologic sampling is recommended. poisoning, antimony ote: toxicologic material should be submitted for anal ysis, as suggested under "poisoning, arsenic." iatrogenic antimony toxicity may occur after treatment with antimony compounds for conditions such as filariasis, fungal infections, and schistosomiasis.* external examination and eyes pharynx and gastrointestinal tract heart, liver, and kidneys record skin changes and eye abnormalities. for toxicologic sampling of contents, see chapter . submit tissue samples for histologic study. request frozen sections for sudan stain. if exposure was from du t in smelting work, dermatitis and conjunctivitis may be present. severe gastroenteritis in acute poisoning. if victim drank antimony trichloride, ulcerative pharyngitis and gastritis may be present. fatty changes of myocardium and hepatic and renal parenchyma. poisoning, arsenic note: toxicologic material will be contaminated by bringing it in contact with fluids. keratinized tissues take up arsenic from solutions. put plastic bags over hands of victim. if exhumed bodies are investigated for arsenic poisoning, include material from surrounding soil and coffin along with tissues submitted for chemical analysis. interpretation of toxicologic findings: after fatal poisoning, arsenic concentrations in the liver tend to exceed . - . mg/ioo g wet tissue. in acute poisoning, arsenic concentrations in hair may reach ! g/g ( ) and in nails ! g/g. organs collect all contents, particularly in accidental poisoning in children. body dry and warm after death. mydriasis. iatrogenic atrioventricular block ( ) . fruits of atropa belladonna or seeds of datura stramonium may be found. no characteristic findings. poisoning, barbiturate(s) note: this type of poisoning has become uncommon. barbiturates may cause sudden death. in all instances, concomitant alcohol intoxication* must be ruled out. standard toxicologic sampling is sufficient. blood bile urine esophagus and stomach liver and brain procedures submit samples of blood from portal vein and peripheral veins or heart for toxicologic study. refrigerate for possible toxicologic study. record total volume and ph value. request tests for protein, glucose, and ketones; request drug screen. submit all contents and record their character. analyze for barbiturates and alcohol. submit samples for toxicologic study. evidence of alcohol intoxication.* poisoning by other addictive drugs. gritty residues of unabsorbed tablets, powder, or capsules. mucosal corrosion, ulceration, and discoloration from capsules may occur. concentration of barbiturate in parenchyma important for interpretation. poisoning, bismuth note: accidental poisoning is common (industrial exposure or drugs with soluble bismuth compounds). search also for other heavy metals. acute kidney failure* may be the cause of death. external examination and oral cavity stomatitis with bluish black discoloration of gums; loose teeth; sticky white membranous patches in mouth and throat. jaundice. protein casts and tubular epithelial cells in sediment. gray or black mucosal membranes; swelling of mucosa; intestinal ulcers that may be perforated. hemosiderosis. fatty changes; hemosiderosis. fatty changes; renal tubular degeneration with amorphic basophilic deposits in epithelium of convoluted tubules. hemosiderosis. see above under "external examination." for removal and specimen preparation, see chapter . peripheral neuritis. synonyms: bromine poisoning; bromism. note: the lethal dose is about . g in children and i g in adults (ingested). after fatal methyl bromide poisoning, headspace gas chromatography revealed a subclavian blood concentration of . microgram/ml whereas inorganic bromide concentrations were micrograms/ml in the blood ( ). tissue concentrations were lower than those in the blood. toxicologic samples should include liver and kidneys. chemical bums on face and conjunctivitis indicate direct exposure; skin pustules over body and nodose bromoderma of the legs indicate bromism. blood is best suited for bromide determination. after ingestion of bromide, necrosis with brown discoloration of mucosa of upper gastrointestinal tract may be present. after inhalation of bromide, swelling and inflammation ofmucous membranes in upper and lower respiratory tracts may be present. there may be pulmonary edema. pneumonia occurs in bromism. organs to be analyzed for cd should have no contact with water or be contaminated with blood; they should be sealed in polyethylene bags. cd leaks into fixation fluid. postmortem blood concentrations are very high and no indicator of the antemortem values ( ). external examination and oral cavity blood urine gastrointestinal tract other organs procedures submit sample for toxicologic study. submit sample for determination of cadmium concentration. submit sample for toxicologic study and a portion of one lobe for microbiologic study. perfuse one lung with formalin. fix bowel as soon as possible. collect renal tissue for light microscopic and electron microscopic study. sample for toxicologic study. submit samples for histologic study also. poisoning, carbon monoxide note: if the victim had been in a fire, see also under "bums." carbon monoxide poisoning may rarely be responsible for automobile accidents. relatively low carboxyhemoglobin concentrations may contribute to death if there is concomitant poisoning-forinstance, with alcohol or drugs, particularly sedatives. anemia, atherosclerotic heart disease, and chronic pulmonary disease also increase sensitivity to carbon monoxide. ifblood had been withdrawn at time of hospital admissionfor instance, for crossmatching-submit this for carboxyhemoglobin determination. if no blood can be obtained, see under "heart, kidneys, and other organs." for quick-orienting qualitative tests, for quantitative methods of carbon monoxide determi-nation, and for interpretation of toxicologic findings, see below. request also determination of hemoglobin concentrations and of blood alcohol. request drug screen. for shipping of blood and tissues for carbon monoxide determination, see chapter . it should be noted that losses of up to % of the original saturation occurred when blood was kept in uncapped container at room temperature for yz wk or at °c for wk. external examination blood heart, kidneys, and other organs brain record color of fingernails, particularly in heavily pigmented persons in whom lividity is difficult to discern. record appearance of blood and submit sample of postmortem blood for toxicologic study. see also above under "note." if no blood can be obtained, prepare water extract of spleen, kidneys, or other organs. request determination of carbon monoxide content and of carbon monoxide-binding capacity of this mixture. submit tissue samples for histologic study. for removal and specimen preparation, see chapter . pink skin and fingernails; bullous edema of skin; decubital ulcers. blood tends to be cherry red. for interpretation of toxicologic findings, see below. necrosis of papillary muscles in the heart or myocardial infarction may occur. renal tubular degeneration may also be found. acute kidney failure* has been observed after rhabdomyolysis complicated by compartment syndrome ( ) . hemorrhagic necrosis of basal ganglia (lenticular nucleus in globus pallidus); diffuse petechial hemorrhages in white matter; cerebral edema. acute hydrocephalus in infants ( ) . many methods of carbon monoxide determination have been described. currently, carboxyhemoglobin is detected in most medical examiner toxicology laboratories by visible spectrophotometry or gas chromatography. in hospitals, carboxyhemoglobin is frequently detected and reported in the course of routine arterial blood gas analysis. pink discoloration of skin and organs usually indicates the presence of more than % carboxyhemoglobin (but rule out cyanide poisoning* and exposure to cold*). in a healthy, middle-aged person, a carboxyhemoglobin concentration greater than - % is usually fatal. if the victim was anemic or suffered from chronic lung disease, particularly emphysema* or atherosclerotic heart disease, the concentration may be lower. in association with alcohol, sedatives, and other drugs, carboxyhemoglobin levels may also be much lower and yet fatal. a heavy cigarette smoker may have a carboxyhemoglobin concentration of - %, and higher levels may occur in police officers and other persons exposed to automobile exhaust in dense traffic. if the victim survived the carbon monoxide poisoning for several hours, postmortem blood samples usually will fail to show the presence of carboxyhemoglobin. in these instances, blood taken at the time of admission to the hospital may still be available and of particular value. if the victim had spent h in fresh air before death, - % of the carbon monoxide will have been removed, and - % will have been removed during each subsequent hour. even though clearance may be complete, death may still occur-primarily from brain damage and infectious complications in prolonged coma. or delayed by only a few hours, particularly after inhalation of carbon tetrachloride. sudden death probably is caused by cardiac dysrrhythmia. alcohol concentrations should be determined in all cases or, if death was delayed, evidence of drinking at the time of exposure should be sought. alcohol considerably increases the hazards of carbon tetrachloride. note: see also under "bronchitis, acute chemical" and under "poisoning, gas." hydrochloric acid is sold by plumbing supply houses and pool supply companies as muriatic acid. it is a liquid. chlorine is a water-soluble gas. as supplied for pool sanitation, liquid chlorine is usually acidic. for convenience, chlorine and hydrochloric acid are discussed here together. prepare photographs of face. conjunctivitis and cyanosis in chlorine gas poisoning; burns of lips from hydrochloric acid. see also above under "larynx and trachea." photograph opened esophagus and stomach. sample for histologic study, particularly if there is doubt whether a perforation was antemortem or postmortem. for removal and specimen preparation, see chapter . severe pulmonary edema, bronchopneumonia, and swelling of mucous membranes in chlorine poisoning. arterial thrombosis may occur. pulmonary fibrosis may develop after prolonged survival. swelling and ulceration of mucous membranes in chlorine poisoning; acute laryngotracheitis. tracheoesophageal perforation. corrosion of mucosa with thickening, hemorrhage, and blackish discoloration after ingestion of hydrochloric acid. antemortem and postmortem perforation may occur. glomerular capillary thromboses. hemorrhages in white matter ( ). poisoning, cyanide synonym: hydrocyanic acid (hydrogen cyanide) poisoning. note: hydrocyanic acid (hydrogen cyanide, hcn) is a water-soluble gas. its salts, sodium cyanide and potassium cyanide are sold as "eggs" to the jewelry industry. hydrocyanic acid is formed when cyanide salts are dissolved in acidic solutions. containers from which the poison might have been ingested or inhaled should also be submitted for toxicologic examination. for cyanide screening tests in the autopsy room and for interpretation offindings, see below. caution: stomach may still contain cyanide gas, formed by acidic reaction of cyanide salt. it may be best to open the stomach under a hood ( ). the odor is quite characteristic for cyanide poisoning but most persons are unable to smell this odor. it is helpful to know in advance if any person in an office or laboratory can smell cyanide. forensic pathologists who can smell the compound state that it has its own specific odor, which differs from the often quoted smell of bitter almonds. autopsies also can be done in a negatively pressured isolation room ( ). for odor, see above under "note." bright red skin color is not always present. corrosion around mouth and in oral cavity may be found after ingestion of potassium or sodium cyanide. blood is fluid and sometimes bright red. if potassium or sodium cyanide was ingested, brown-red mucosal corrosion may be present in stomach or in upper digestive tract. pulmonary edema. for odor, see above under "note." if death was not instantaneous, there may be hyaline thrombi in small blood vessels, minute hemorrhages, and necroses of lenticular nuclei. this test can be used for blood and gastric contents ( ) . dip squares of filter paper in a small amount ofsaturated picric acid. let these squares dry until barely moist. place a drop ofthe material to be tested-e.g., blood or gastric contents--on a piece of paper. let material dry for a moment, and then place one drop of % sodium carbonate in the center of the material to be tested. ifcyanide is present, a reddish purple color will chromatograph out from the material. the higher the concentration of cyanide the more blue the color will be. it is possible to recognize whole blood because the blood turns a rather dark brown and the reddish to purple color is clearly visible. high concentrations of sulfide interfere by giving a false-positive test. another screening test is done as follows ( ) . dip filter paper into normal blood. then treat the paper with potassium chlorate, whereupon brown methemoglobin forms. place this preparation into the fluid suspected of containing cyanide (e.g., blood, gastric contents, pulmonary edema fluid). if bright red cyanmethemoglobin forms, the reaction is positive. if the concentration of cyanide in the stomach is high and the concentration in the lungs is low, cyanide was ingested. alternatively, if the pulmonary cyanide concentration is high and the concentrtaion in the gastric contents is low, hydrogen cyanide most likely was inhaled. occasionally, minimal cyanide levels will be present in decomposed bodies. related term: digoxin toxicity. note: certain drugs may interfere with correct digitalis determination. blood heart vitreous procedures submit sample of peripheral blood for digoxin radioimmunoassay. freeze fresh myocardium for digitalis extraction. submit sample for digoxin radioimmunoassay. poisoning, drug(s) (see "dependence, drug(s), all types or type unspecified" or under "poisoning,•••" followed by specific name of drug.) poisoning, ethanol (ethyl alcohol) (see "alcoholism and alcohol intoxication," "cardiomyopathy, alcoholic," "disease, alcoholic liver," "syndrome, fetal alcoholic," and syndrome, wernicke-korsakorr.") poisoning, ethylene glycol related term: antifreeze poisoning. note: pulmonary and cerebral manifestations are the main findings in acute poisoning, and renal tubular necrosis is the primary finding in chronic poisoning. for general toxicologic sampling, see chapter . calcium oxalate crystals can be demonstrated in routine histologic sections but also in scanning electron micrographs of thick deparaffinized sections. eyes blood urine for removal and specimen preparation, see chapter . in acute cases, submit sample for ethylene glycol determination; in chronic cases, request determination of calcium concentrations. prepare sediment. papilledema; optic nerve atrophy. ethylene glycol in serum (i) . protein casts; calcium oxalate crystals ( ) . crystals are light yellow and birefringent, arranged as sheaves, rhomboids, or prisms. poisoning, food related terms: bacillary dysentery* (shigella food poisoning); botulism;* clostridium perfringens food poisoning; favism; mushroom poisoning;* salmonella food poisoning; staphylococcal food poisoning. note: if cause of food poisoning is unknown, submit suspected food for aerobic and anaerobic cultures, gram stain of smears, and routine toxicologic study. this should include tests for heavy metals (antimony, cadmium, and lead) that may have leaked from old cooking utensils. test for the presence of staphylococcal enterotoxin are done only in specialized laboratories. if botulism is suspected, follow procedures described under that heading. mushroom poisoning also is listed as a separate entity. if salmonella food poisoning is suspected, see under "fever, typhoid." see also under "enteritis" or "enterocolitis" or under another specific heading such as "dysentery, bacillary." obtain sufficient material for microbiologic and histologic study to identify organisms such as chlamydia, clostridium (type f strains), salmonella, shigella, verotoxic e. coli, yersinia, and others. external examination gastrointestinal tract submit contents for aerobic and anaerobic cultures (see above under "note"); prepare smears of contents for gram stain. submit samples for histologic study. debilitated states; patients in extremes of life. enteritis or enterocolitis. poisoning, gas note: anesthesia-associated death, * carbon monoxide poisoning,* and sniffing and spray death* are presented under the appropriate headings. procedures discussed here deal with other volatile substances, including chemical irritants such as ammonia (nh ), chlorine or hydrochloric acid poisoning (see also under that heading); methylene chloride, phosgene (coci ), sulfurous acid (h s ), or sulfur dioxide (s ) ' gases from body cavities, heart chambers, or blood vessels can be removed as described under "embolism, air." gases can also be trapped with a rubber dam after cutting organs under water. samples from various organs should be shipped in hermetically sealed nonplastic containers or in analyzing solutions. external examination, and oral cavity blood larynx and trachea record extent of chemical bums. submit sample for gas analysis. in many instances, inhaled gases can be demonstrated chromatographically in gas from head space above sealed blood specimen. chemical bums in and around mouth or conjunctivas. chemical bums. other organs if gas was inhaled and is to be analyzed, submit intact lungs with bronchi ligated in airtight, nonplastic container to laboratory that can conduct gas analysis. if survival was short, formalin perfusion of lungs is not recommended; it may cause artifactual ballooning and internal ruptures of organ. submit samples of tissue for routine histologic study. see above under "note." chemical pneumonia; pulmonary edema. after longer survival, obliterating fibrous bronchiolitis, chronic bronchitis, and saccular bronchiectasis* may occur. poisoning, glycol (see "poisoning, ethylene glycol.") poisoning, halogen (see "fluorosis," "poisoning, bromide," "poisoning, chlorine or hydrochloric acid," "poisoning, gas?, and "poisoning, iodine!') poisoning, heavy metal (see "poisoning, antimony," "poisoning, arsenic," "poisoning, cadmium," "poisoning, lead," poisoning, mercury," "poisoning, thallium!') poisoning, insecticide (see "poisoning, organophosphate(s)*) poisoning, iodine related terms: lugol's solution; tincture of iodine. for toxicologic sampling, see chapter . external examination and eyes urine, blood, and parenchymal organs lungs and upper respiratory tract stomach record color of skin and extent of corrosive lesions. submit samples for toxicologic study. submit samples for histologic study. submit contents for toxicologic study; photograph mucosa; prepare histologic sections. see above under "stomach." perioral corrosive lesions; yellow discoloration of skin; conjunctivitis after exposure to vapors. acute inflammation of respiratory tract after inhalation of vapors. corrosive gastritis; if starch was used as antidote, gastric lining will be bluish. histologically, well-preserved mucosa is present because of in vivo fixation. mucosa may show same changes as stomach. swelling of tubular epithelium. synonyms: propanol; rubbing alcohol. procedures see under "alcoholism and alcohol intoxication." nonspecific autopsy findings: visceral congestion; pulmonary and cerebral edema. poisoning, lead note: lead-free syringes and lead-free polyethylene containers should be used. blood lead concentrations can be determined by inductively coupled plasma mass spectrometry ( ). for screening methods, see ref. ( ) . this is a reportable disease in some states. external examination, oral cavity, and hair bluish lead line at gingival margin in victims with poor oral hygiene. external examination, oral cavity, and hair for diagnosis of chronic plumbism, analysis of scalp hair may be useful. analysis is done by neutron activation (see also under "poisoning, arsenic"). remove samples with lead-free syringe (see above under "note") or -ml vacutainer tubes (becton, dickinson and company). do not add anti-coagulant or preservative. for coliection procedures, see above under "blood" and under "note." request also determination of coproporphyrin concentrations. submit sample for histologic study; submit remaining tissue for toxicologic analysis. submit with contents for toxicologic study, particularly in acute poisoning. submit sample from each kidney for histologic study; submit remaining tissue of both kidneys separately for toxicologic study. submit at least g of fresh bone for toxicologic study. for removal and specimen preparation, see chapter . poisoning, lsd (d-lysergic acid diethylamide) (see "abuse, hallucinogen(s).") poisoning, lye related terms: ammonium hydroxide poisoning; calcium oxide or quicklime poisoning; poisoning by alkaline corrosives; potassium hydroxide poisoning; sodium hydroxide poisoning. external examination and oral cavity blood neck organs, esophagus, trachea, and lungs record extent of oral, perioral, and other facial corrosive injuries. photograph lesions. prepare histologic sections of tissue from inside of lips or mouth. submit sample for toxicologic study. after removal of heart, remove neck organs with hypopharynx, esophagus, larynx, and trachea. leave stomach attached to esophagus. open pharynx and esophagus along posterior midline. in acute cases, formalin perfusion of lungs is not recommended; it may cause artifactual baliooning and internal ruptures of organ. lye bums on face and chest in acute cases; scars and manifestations of malnutrition* in chronic cases. sweliing, edema, and necrosis of mucous membranes in acute poisoning. fibrosis and strictures in chronic cases. bronchitis* and bronchopneumonia. submit specimen from pharynx for histologic study. for removal and specimen preparation, see chapter . submit sample of brain for toxicologic study. exfoliative dermatitis. blue line at gingival margin; hypertrophy of gum; acute and chronic gingivitis; exfoliation and loss of teeth ( ) . degeneration of myocardium. increased concentrations of mercury ( ) . congestion. erosive gastritis and colitis. increased concentrations of mercury ( ) . degeneration of proximal tubules; calcifications. chronic kidney failure* may be the cause of death. induration of mucosa. increased concentrations of mercury ( ) . cortical hemorrhages. cholinesterase activity will be low. pulmonary edema if poison was inhaled. airways may contain aspirated material. cholinesterase activity can be determined reliably even after decomposition and embalming. clinically, guillain-barre syndrome has been observed after poisoning with organophosphate. in acute poisoning, the cholinesterase levels may be % of the normal values (see below). the cholinesterase levels in the blood are not affected by the duration of the postmortem interval; measurement may be attempted even on decomposed or exhumed bodies. severe fatty changes; periportal necroses. fatty changes in myocardium, skeletal muscles, and other organs. for toxicologic sampling (gastric contents, urine, blood, brain, and other organs), see chapter . rigor mortis after fatal strychnine poisoning may occur very soon after death and may be very severe (opisthotonos); it may persist until decomposition sets in. congestion of viscera; no characteristic morphologic autopsy findings. acute pancreatitis has been observed ( ). high strychnine concentrations (also demonstrable in exhumed bodies [ ] ). poisoning, thallium note: for toxicologic sampling, see below and chapter . thallium is used as a rodenticide and pesticide, and has some industrial applications. retrobulbar neuritis. chapter and . submit brain for toxicologic study. submit sections of brain and optic nerves for histologic study. submit specimens for toxicologic study (take from lower extremity). for removal, prosthetic repair, and specimen osteomalacia;* osteomyelofibrosis. preparation of bones, see chapter . for preparation of sections and smears of bone marrow, see chapter . submit samples for toxicologic study. synonym: acute anterior poliomyelitis. note: the disease has been nearly eliminated in the usa but not in many other countries. ( ) collect all tissues that appear to be infected. ( for removal and specimen preparation, see chapter . in acute cases, submit portions of brain and spinal cord for viral culture. neurogenic atrophy of skeletal muscles in areas of paralysis. electrolyte disorder. * hypertensive heart disease; myocarditis.* aspiration or bronchopneumonia (or both); edema; atelectasis; embolism;* alveolar wall necrosis (acute or organizing diffuse alveolar damage) after oxygen toxicity. acute ulcers. acute gastric dilatation; acute gastroduodenal ulcers; gastrointestinal erosions and hemorrhages. dilatation of colon; perforation of cecum. urolithiasis and nephrolithiasis,* pyonephrosis and pyelonephritis. * phlebothrombosis of legs, most commonly on left side. necrosis of anterior hom cells of spinal cord, with neuronophagia and perivascular inflammatory reaction. old lesions show neuronal loss and gliosis. medulla ("bulbar polio") and other areas of brain stem, cerebellum, and cerebrum, particularly the motor cortex, may be affected in various degrees. part ii / diseases and conditions pregnancy note: in some instances, procedures described under "death, abortion-associated," "embolism, amniotic fluid," or "toxemia of pregnancy" may be indicated. synonym: werner syndrome. external examination and skin abdomen procedures record volume of intraperitoneal fluid; prepare smears; submit samples of peritoneum for histologic study. colloid carcinoma of stomach or colon. well-differentated adenocarcinoma of ovary or, rarely, of appendix; ruptured appendiceal mucinous adenoma is the most common cause of peritoneal adenomucinosis. pseudotumor cerebri synonym: benign intracranial hypertension; meningeal hydrops. note: this condition, which generally affects young, obese females, is characterized by symptoms and signs of increased intracranial pressure without a demonstrable cause. hence, intra-cranial mass lesions, infections, and related conditions should be excluded. such conditions include adrenal insufficiency;* guillain-barre syndrome* (increased colloid-osmotic pressure); hyperadrenalism; hypervitaminosis a* (e.g., after treatment of acne); hypoparathyroidism;* hypothroidism;* infectious mono-nucleosis;* lyme disease; pregnancy; sydenham's chorea; throm-bus ofthe lateral or superior sagittal sinus (otitic hydrocephalus); and wiskott-aldrich syndrome. submit samples of all accessible organs and tissues, with or without gross lesions. submit material for electron microscopy. for removal and specimen preparation, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . heart small bowel liver procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. fix the bowel as soon as possible. record weight. submit samples for histologic study. for removal, prosthetic repair, and specimen preparation, see chapter . aortitis involving ascending aorta and aortic valve with regurgitation; mitral valve and adjacent myocardium and conduction system also may be involved. sprue-like changes with loss of villi. fibrosis or cirrhosis and other abnormalities, particularly in patients who had been taking methotrexate. psoriatic arthritis and spondylitis. synonyms and related terms: allergic purpura; anaphylactoid purpura; hypersensitivity vasculitis. external examination and skin rabies note: (i) in most instances, an autopsy limited to the brain is sufficient to confirm the diagnosis. ( ) rabies virus is especially infectious and thus, universal precautions should be strictly followed (see chapter ) . avoid the use of scalpels whenever possible. the generation ofaerosols should be assidu- see above under "note." if a complete autopsy is done, sample heart, lungs, kidneys, pancreas, submaxillary salivary glands, and adrenal glands; freeze or refrigerate sampled tissues and submit for viral study (see below under "brain and spinal cord"). obtain serum for serologic studies. freeze or refrigerate cerebral tissue immediately after removal and submit frozen to special laboratory for fluorescent antibody staining. take these sections from hippocampus or brain stem. place the refrigerated tissues in % neutral glycerol saline solution for preservation. fix remaining brain and spinal cord tissue in % formalin and submit for histologic study. as an alternative to freezing of tissue, immunoperoxidase methods for detection of rabies viral antigens can now be applied to formalin-fixed tissue ( in almost all instances, the procedures described under "assault" and under "homicide" must also be followed. see also refs. ( ) and ( ) . for the evaluation of bite marks, photographs with and without scales and black and white film should be used. a forensic dentist is required to compare the victim's bite marks to the teeth of suspects. swabs of possible sperm or other fluids must be sent to the crime lab for proper evaluation. external examination other organs and tissues genital organs comb pubic hair over a towel and then pull sample; also, pull samples of hair from head. collect fingernail clippings and place in containers marked "right" and "left." collect blood, hair, fibers, and residues of urine or saliva and/or semen that may have stained the victim's clothing or that may be found on the skin of the victim. for study of stains and scrapings, see below. introduce sterile dry cotton swab into the posterior vault of the vagina or-preferablyinto the cervical canal. prepare smear on glass slide and send to crime laboratory for identification of sperm (see also above under "note" using a sterile cotton swab moistened with sterile saline, lift suspected dried spermatic fluid from hair or skin of external genitalia, perineum, buttocks, or other sites. stains on clothing will be extracted by forensic laboratory personnel. let specimens air dry in absence of sunlight and then place in paper bags or envelopes and seal. smears are made for the demonstration of spermatozoa, cytologic changes, bacteria, and other possible findings (some crime labs prefer to make their own smears from the swabs). other samples are used for the determination of acid phosphatase, as described below. usually, the survival time of morphologically recognizable spermatozoa in the vagina is less than h, but on occasion this may be much longer. thus, within the first h after coitus, % of cervical smears have been found to be positive for spermatozoa. at day , spermatozoa have been found in % of the smears. obviously, if the assailant had had a vasectomy, spermatozoa will not be found at any time. spermatozoa have been found in the vagina of some women several days or weeks after death. dried stains (see above) may give positive results after longer intervals. acid phosphatase activities greater than bodansky units (for method, see above) indicate that probably less than h have elapsed since the time of intercourse (i) . in another study, vaginal swab specimens showed acid phosphatase activities of more than , king if there is evidence of parotid involvement, other salivary glands should also be studied. parotid gland can be biopsied from scalp incision. submaxillary gland can be removed with floor of mouth. for sampling and specimen preparation, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . chronic meningitis; space-occupying lesions (submeningeal nodular granulomas). granulomatosis. iridocyclitis; chorioretinitis; papilledema; posterior uveitis; keratoconjunctivitis sicca; conjunctival follicles; cataracts. involvement of lacrimal glands and other orbital tissues ( ) . sarcoidosis of parotid gland is common. sarcoid neuropathy and sarcoid myopathy. cystic changes, primarily of small bones of hands and feet. sarcoidosis of joints ( ). synonyms and related terms: bilharziasis; schistosoma haematobium infection; schistosoma japonicum infection; schis-tosoma mansoni infection. note: unless specifically stated, the changes listed below refer to chronic schistosomiasis mansoni and japonica. ( ) collect all tissues that appear to be infected. ( ) request direct examination for schistosoma. the following procedures have been described and recommended ( ). for demonstration of schistosoma eggs, compress -mm tissue fragments-for instance, mucosa of the urinary bladder-between glass slides. if this gives negative results, digest a -g portion of tissue in potassium hydroxide. for the recovery of adult worms of schistosoma mansoni and schistosoma haematobium, remove the viscera en bloc and rinse with water. separate the intestines from the mesentery. subsequently, perfuse the portal vein system, the liver, and one lung with saline ( ) . then pass the perfusion fluid through a monofilament nylon cloth with an aperture size of m. submerge the cloth in water and examine with a dissecting microscope. fix worms in formalin solution. examine the intestinal mucosa directly. from the urinary bladder, ureters, and surrounding connective tissue, worms can be recovered as follows. inject water into the tissue until the tissue increases or times in thickness. then compress the tissue gently with a glass plate. cut slices . - . cm in thickness. compress these slices between the glass plate and the stage of a dissecting microscope and examine for the presence ofadult worms. many worms also will be present in the fluid expressed from the tissue as it is cut. for the counting of eggs in tissues, urine, and feces, see ref. ( ) . immunodiagnostic methods (elisa and imrnunoblot) also have been developed prepare skeletal roentgenograms. there are no diagnostic laboratory tests but it still is advisable to save a blood sample. record heart weight. test competence of valves (chapter ). open heart in line of blood flow. photograph and measure valvular lesions. prepare sections of valves, myocardium, conduction system (if there was a history of heart block), and ascending aorta. perfuse at least one lung with formalin. submit any consolidated area for microbiologic study. fix intestines as soon as possible. abnormalities as listed in right-hand column. sample for histologic study and request amyloid stains or renal parenchyma. prepare roentgenograms of spine, sacroiliac joints, symphysis ossium pubis, and manubriosternal, sternoclavicular, and humeroscapular joints. if spine cannot be removed in its entirety, it can be split in midline and one half can be removed, with costovertebral and costotransversal joints. hip joints should be exposed. histologic sections should include synovia and periarticular tissue. secondary and peripheral osteoarthritis* may be present. leukemia* developed in some patients who had had radiation treatment ( or earlier). acute anterior uveitis. ( ) request fungal culture. ( ) request grocott's methenamine silver stain. ( ) record weight of all organs (for expected weights, see part iii). submit samples of all major organs, including endocrine glands, lymphatic and fat tissue, bone, and bone marrow for histologic study. hunger edema; skin changes secondary to vitamin deficiencies. hypoproteinemia. atrophy; hemosiderosis of spleen. degree of atrophy varies from organ to organ; atrophy of fat tissue, lymphoid tissue, and gonads usually is most pronounced. severe infections, such as tuberculosis,* may be present without having been apparent clinically. steatohepatitis, nonalcoholic (nash) note: the morphologic findings in the liver are indistinguishable from those in alcoholic liver disease* ( ). follow autopsy procedures described under "disease, alcoholic liver." if the patient had received a liver transplant, procedures described under "transplantation, liver" should be followed also. possible associated conditions: celiac sprue (rare); diabetes mellitus* (type ); hyperlipidemia; malnutrition* from bulemia (rare); morbid obesity with liver failure particularly after episodes of rapid weight loss (e.g., after recent gastroplasty); lipodystrophy; mild obesity;* short bowel syndrome (rare); total parenteral nutrition. * stenosis, congenital valvular pulmonary related terms: isolated (pure, simple, or dome-shaped) pulmonary stenosis. note: the pulmonary valve is usually acommissural in isolated congenital pulmonary stenosis. with other coexistant congenital heart disease (such as tetralogy), the pulmonary valve is usually bicuspid and hypoplastic, but may be unicommissural or dys-plastic and tricuspid. heart and great vessels; peripheral pulmonary arteries brain procedures culture any grossly infected valve. for general dissection techniques, see chapter . record weight of heart, thickness of ventricles, and annular circumferences. for removal and specimen preparation, see chapter . infective endocarditis* of pulmonary valve and tricuspid valve; infective endarteritis at bifurcation of pulmonary trunk. it is preferable to have autopsies of fetuses and stillborns performed by pathologists experienced in perinatal pathology. if such personnel are not immediately available, the attending pathologist may nevertheless collect important information. if attempts to induce abortion appear to have caused the death of the mother, see "death, abortion-associated." the placenta should be immediately procured from the delivery room should it not arrive in the laboratory with the fetus. this will avoid the possibility of the placenta being discarded by the delivery room staff. no fetal autopsy is complete without a careful examination of the placenta (see part i, chapter ). pathologic changes of placenta that are causative of stillbirth are summarized in ref. . fascia lata or other aseptically obtained tissue should be collected for tissue culture for karyotype analysis. if the fetus is at all autolyzed, then the fascia lata cells may not grow in tissue culture. therefore, if the fetus shows any evidence of autolysis, tissue should be taken aseptically, from placenta immediately beneath the chorionic plate. a portion ofplacenta and liver should also be snap-frozen for possible molecular analysis. the initial stage of the autopsy should include photography and radiography, taking anterior-posterior and lateral views. the photographs will record the degree of maceration, which can be roughly correlated with the duration of fetal demise before delivery [ ] external measurements should include body weight, circumference ofhead, chest and abdomen, crown-rump length, crown-heel length, and foot length. these measurements are compared with tables of standards for normal fetuses (see part iii of this book). assessment of growth retardation may be based on these data. a careful external examination should search for abnormalities such as jaundice, bulging fontanel, cranial bone softening, hyper-or hypotelorism, choanal atresia, external ear anomalies, cleft lip, cleft palate, macroglossia, micrognathia, colobomata, cystic hygroma, shortened neck, contractures, omphalocele, gastroschisis, abnormal external genitalia, anal atresia, absent vagina, sacral pits, open neural tube defects, hemihypertrophy, syndactyly, clinodactyly, transverse palmar creases, or incomplete descent of testes. the organ bloc may be removed in the manner similar to the adult, using the technique of letulle (see chapter ) . if the thyroid gland is noted to be in its usual location and if it appears normal, then the tongue may be left in the body. in macerated fetuses, it is suggested that the organ bloc be fixed overnight in formalin solution prior to dissection. to aid adequate fixation, the following simple steps may be done: i) wash the organ bloc thoroughly prior to fixation; ) place multiple transverse cuts through the liver and lungs; ) dissect the posterior leaves of the diaphragm away from the adrenal glands and kidneys; ) bivalve the adrenal glands and kidneys in the coronal plane; ) instill formalin in the lumen of the intestine, using a syringe; and ) gently instill formalin into both ventricles of the heart, being careful to avoid the ventricular septum. the procedure for dissection of the organs is similar to that of the adult except: ) the venous and arterial connections of the heart, including the patency of the ductus arteriosus must be determined before the heart is removed; ) the esophagus must be opened posteriorly prior to its complete removal so that esophageal atresia or tracheo-esophageal fistula may be recognized and photographed prior to further dissection; ) the location of the appendix and of the testes should be recorded. until the intestine has been examined for stenosis or atresia, the mesentery should be left attached. the degree of autolysis as seen grossly and with histologic examination of both the fetus and the placenta can be used to estimate the duration of time between fetal death and delivery ( , , ) . trichrome stain is useful for better visualizing histologic features in severely autolyzed tissue. to remove the brain, benecke's technique of one of its modifications may be used. stillbirth vs livebirth. a decision has to be made whether the infant was born alive or was stillborn. the hydrostatic lung test, described in the previous edition, appears unreliable. the presence of gas in the lungs does not rule out stillbirth. after death, air can be introduced into the lungs, or putrefaction gases might be present. however, air artificially introduced after death will not distend the alveoli and can be squeezed out, whereas this does not seem to be the case after active ventilation. the distribution of fat in the fetal zone of the adrenal cortex may indicate whether intrauterine death was acute, more prolonged, or chronic ( ). this is particularly helpful if the stillborn baby is macerated. if the mother died also, see under "death, abortion-associated" strangulation note: in many instances, procedures described under "hom-icide" must also be followed. if a rope or some other material had been used (see also under "hanging"), leave ligature in place until autopsy can be done. see also under "hypoxia." toxicologic sampling, particularly for alcohol, should be done in all instances (chapter ). results than body fluids. ( ) universal precautions should be strictly followed. the generation of aerosols should be minimized. to sterilize tissue surfaces in preparation for culture, swab the surface with povidone iodine. avoid searing the tissue surface since this will produce an aerosol. keep no more than one scalpel in the dissecting area at anyone time. have an assistant available with clean, gloved hands to receive specimens in containers, so as to minimize the degree of contamination on the outside of the containers. for cleaning procedures and related information, see chapter . ( ) hiv-l in tissue may be demonstrated using polymerase chain reaction (pcr), immunohistochemistry, in situ hybridization, or immunofluorescence. ( ) for immunocytochemical and molecular studies, fix tissue in ethanol or carnoy's solution. the virus can be identified using pcr in most tissues, whether fresh, frozen, or fixed in ethanol. ( ) serologic tests as well as direct fluorescent antibody tests are avail-able for many of the expected infections. ( ) this is not a reportable disease. external examination and skin record body weight and evidence of lipodystrophy following aids medications. record and photograph any skin lesions. examine oral cavity. if the diagnosis is in doubt, samples can be submitted for enzyme immunoassay. cachexia. severe loss of subcutaneous fat in face and extremities, associated with large fat deposits on upper back and upper abdomen ("protease paunch"). cutaneous kaposi's sarcoma (l) . test may be positive for many weeks after death ( ) . syndrome, myelodysplastic synonyms and related terms: chronic myelomonocytic leukemia;* refractory anemia; refractory anemia with excess of blasts; refractory anemia with excess of blasts in transformation; refractory anemia with ringed sideroblasts; refractory dysmyelopoietic anemias. note: the myelodysplastic syndromes are represented by a heterogeneous group of normocytic anemias, often with neutropenia, thrombocytopenia, and monocytosis. for expected bone marrow changes, see above under "synonyms and related terms." autopsy procedures are similar to those recommended for most cases of leukemia, with particular attention paid to intercurrent infections and thrombocytopenic hemorrhages. in all instances, material should be collected using aseptic technique for tissue culture for chromosome analysis. common findings in these conditions are deletion of the long arm ofchromosome , deletion of chromosome or , or trisomy . syndrome, nephrotic note: see under name of suspected underlying condition, such as amyloidosis,* anaphylactoid purpura,*diabetes mellitus,* glomerulonephritis,* goodpasture's syndrome,* heavy metal poisoning, hemolytic uremic syndrome,* infective endo-carditis,* polyarteritis nodosa,* syphilis, * or systemic lupus erythematosus. * if accelerated hypertension or constrictive pericarditis is the suspected underlying condition, see under "hypertension (arterial), all types or type unspecified" or "pericarditis," respectively. in all instances, the renal veins and the inferior vena cava should be opened in situ. "en masse" removal of organs is recommended for this purpose. if thrombosis is found, record exact location and size of clot and submit sample of clot with wall of veins for histologic study. see also under "thrombosis, venous." coronary atherosclerosis and its complications seem to be increased in patients with the nephrotic syndrome. submit sample for bacteriologic, viral, and serologic study. record weight and submit samples for histologic study. if heart block was present, submit samples of conduction system for histologic study (chapter ). submit consolidated areas for microbiologic study. perfuse at least one lung with formalin. for removal of urethra, see chapter . procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for removal and specimen preparation, see chapter . consult roentgenograms (see above under "external examination, skin, and oral cavity"). keratoderma (keratosis blennorrhagica) with vasculitis ( ) of sole of feet, of palms, and of circumcised glans penis. arthritis* of knees, ankles, and metatarsal and midtarsal joints, with or without ankylosis. osteoporosis.* usually, sterile culture. pericarditis; * myocarditis.* aortic valve lesions. pleuritis and pneumonia.* pulmonary fibrosis involving upper lobes. erosions, papules, and plaques in urethral or bladder mucosa. enteritis. thrombophlebitis. conjunctivitis; multifocal choroiditis; acute anterior uveitis; iritis; keratitis. arthritis* (see above under "external examination, skin, and oral cavity") resembling rheumatoid arthritis. * nonspecific synovitis. for removal and specimen preparation, see chapter . syndrome, reye's note: hypoglycemia* may have been present, but that condition is difficult or impossible to confirm after death. an immediate autopsy is indicated (see below under "liver" and "pancreas"). vitreous blood urine heart lungs submit sample for sodium, chloride, and urea nitrogen determination. submit sample for microbiologic (viral) and serologic study, for ammonia and bilirubin determination, and for determination of salicylate levels if there is a history of treatment with this drug. obtain sample for biochemical and toxicologic analysis. record weight. request frozen sections for sudan stain. submit fresh tissue for bacterial and viral culture. request paraffin sections and frozen sections for fat stain (see above under "heart"). influenza;* varicella.* manifestations of liver failure. evidence of salicylate administration. assay for organic acids should rule out acylcoenzyme a dehydrogenase deficiency, and toxicity, e.g., of acetaminophen and valproic acid (l) . cardiomegaly; fatty changes of myocardium and patchy myocytolysis. viral pneumonia rarely present. acute interstitial pneumonia;* bronchitis;* hemorrhages. lipid-laden histiocytes in alveoli. record body weight and length, stature, and distribution of head, axillary, and pubic hair. record and prepare photographs of features of face and neck. prepare skeletal roentgenograms. submit samples of breast tissues for histologic study. these specimens should be collected using aseptic technique for tissue culture for chromosome analysis (see chapter ) . procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. submit for histologic study. submit samples of all portions for histologic study. if biliary atresia is suspected, follow procedures described under that heading. dissect kidneys and ureters in situ and record findings. submit samples of gonads or-if gonads cannot be identified-equivalent ridges on mesosalpinx for histologic study. also submit samples of endometrium, cervix, and vagina. record weight and submit sample for histologic study. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for removal and specimen preparation, see chapter . procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for sampling and specimen preparation, see chapter . peroxidase-labeled gastrin antibodies seem to react with cells in all gastrinomas. aberrant gastrinoma may occur at hilus of spleen. metastases are found in regional lymph nodes and liver. there may be manifestations of multiple endocrine neoplasia. * secondary syphilis. levaditi's stain or warthin-starry stain is recommended for paraffin sections, and labeled fluorescent antibody techniques are recommended for frozen sections. india ink preparations or the fontana-masson silver stain has been used for the study of fresh lesions, and electron microscopy has also been employed. ( ) in adult autopsies, no special precautions are indicated (see below under "liver"). ( ) serologic studies are available from local and state health department laboratories. ( ) this is a reportable disease. external examination record and prepare photographs of all abnormalities listed in right-hand column. prepare smears and sections of acute lesions; prepare sections of older skin lesions or anogenital mucosal lesions. hunterian chancre in primary syphilis; condylomata lata. noduloulcerative gummas and scarring in later stages. cerebrospinal fluid lymph nodes heart and aorta other organs and tissues prior to wk gestation, the destructive effects of syphilis may not be seen. gummata are rare in neonates. tabes dorsalis is also uncommon. serologic diagnosis is difficult in the neonate because of transplacental transfer of maternal igg antibodies. acquired syphilis (syphilis in adulthood) is presented above under a separate heading. ( ) collect all tissues that appear to be infected. ( ) culture methods are not available, but animal inoculation can be performed. consultation with a microbiology laboratory is recommended. ( ) special stains for treponema pallidum rarely are positive except with material from fresh lesions of primary or secondary syphilis and of syphilitic hepatitis of the newborn. levaditi's stain or warthin-starry stain is recommended for paraffin sections, and labeled fluorescent antibody tech-niques are recommended for frozen sections. india ink preparations or the fontana-masson silver stain has been used for the study of fresh lesions, and electron microscopy has also been employed. ( ) in neonates, special precautions are indicated (see below under "liver") ( ) serologic studies are available from local and state health department laboratories. ( ) this is a report· able disease. (i) collect all tissues that appear infected. ( ) request aerobic and anaerobic cultures. however, the presence of tetanus bacilli established in culture is not diagnostic, since spores of c. tetani frequently contaminate wounds. record body weight and length and appearance of wound(s); photograph and excise wound(s) for histologic study. record evidence of parenteral drug abuse, especially subcutaneous injection (i.e., "skin popping"). prepare chest roentgenogram. evidence of weight loss; subcutaneous abscesses. tetanus may occur in drug addicts. tension pneumothorax* after mechanical ventilation. submit sample for microbiologic study. submit any consolidated area for microbiologic study. bacterial meningitis must be ruled out. aspiration and bronchopneumonia; embolism;* atelectasis. tetany note: see under name ofsuspected underlying conditions, such as hyperparathyroidism,* malabsorption syndrome,* or vitamin deficiency. * respiratory or metabolic alkalosis* cannot be confirmed after death; determination of blood ph is not helpful because acidity increases rapidly after death. the concentration of serum phosphates also increases after death. synonym: large ventricular septal defect with pulmonary stenosis* or atresia.* note: the basic anomaly consists of subpulmonary stenosis, ventricular septal defect, overriding aorta, and secondary right ventricular hypertrophy. for general dissection techniques, see chapter . surgical interventions include modified blalock-taus-sig subclavian-to-pulmonary arterial shunt; complete repair with patch closure of ventricular septal defect, and reconstruction of right ventricular outflow tract (with a patch or with an extracardial conduit). possible associated conditions: origin of left pulmonary artery from aorta; minor abnormalities of the tricuspid valve; absent ductal artery ( %); atrial septal defect* (in %; pentalogy of fallot); bicuspid pulmonary valve;* dextroposition of aorta; double aortic arch; hypoplastic pulmonary arteries; patent ductal artery;* patent oval foramen; complete atrioven-tricular septal defect* (usually with down's syndrome*); persis-tent left superior vena cava; pulmonary valve atresia (see "atresia, pulmonary valve, with ventricular septal defect"); right aortic arch ( %); second ventricular septal defect; origin ofleft anterior descending (lad) or right coronary artery (rca) from contralateral aortic sinus or coronary artery ( %); syndrome with absent pulmonary valve and massively dilated pulmonary arteries (rare). chest cavity heart lungs other organs record course of superior vena cava and of its tributaries. record course of thoracic aorta and of its main branches. record origin of pulmonary arteries. if infective endocarditis is suspected, follow procedures described under that heading (chapter ). for coronary arteriography, see chapter . perfuse both lungs with formalin. request verhoeff-van gieson stain. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. persistent left superior vena cava. right aortic arch with or without right-sided ductal artery; double aortic arch; absent ductal artery. origin of the left pulmonary artery from descending aorta. for possible additional findings, see above under "note" and under "possible associated conditions." infective endocarditis* (usually of pulmonary or aortic valve). see also above under "possible associated conditions." marked right ventricular hypertrophy. right ventricular dilatation and fibrosis with late postoperative right-sided heart failure or sudden death due to arrhythmia. old in situ thrombosis of small pulmonary artery branches. paradoxic embolism; cerebral abscess. * thalassemia synonyms and related terms: congenital hemolytic anemia; alpha-thalassemia; beta-thalassemia major (cooley's anemia); beta thalassemia minor (beta-thalassemia trait). note: the changes described below are observed primarily in beta-thalassemia major. unless the cause of the renal vein thrombosis and the nature of the complicating or underlying renal disease are known, follow procedures described under "glomerulonephritis." procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. in infants, manifestations of dehydration. * pulmonary embolism. * tumor of the kidney* (renal cell carcinoma); aortic aneurysm; lymphadenopathy; other mass lesions. inferior vena cava thrombosis involving orifice or whole length of renal veins. tumor thrombus (e.g., from renal cell carcinoma). femoral vein thrombosis. rare venous malformations also may cause renal vein thrombosis (l) . hemorrhagic infartion. parenchymal renal disease with nephrotic syndrome,* including amyloidosis* and vasculitis* (these last conditions may be associated with renal vein thrombosis). acute gastroenteritis in infancy. hyperparathyroidism,* pregnancy,* trauma, and other conditions. thrombosis, venous note: for peripheral venous thrombosis, the autopsy procedures are essentially similar to those described under "phlebitis." see also under "hypertension, portal," "syndrome, budd-chiari," "thrombosis, cerebral venous sinus," "thrombosis, lateral sinus," and "thrombosis, renal vein." thymoma (see "'fumor of the thymus.") thyroiditis synonymsand related terms: chronic fibrosing thyroiditis (riedel's struma); chronic thyroiditis with transient thyrotoxicosis; hashimoto's thyroiditis; pyogenic thyroiditis; subacute (granulomatous, giant cell, de quervain's) thyroiditis. possibleassociatedconditions: withhashimoto's thyroiditisautoimmune (chronic) hepatitis,*megaloblastic anemia,*rheumatoid arthritis,*sjogren's syndrome,*and systemic lupus erythematosus.* with riedel's struma-retroperitoneal fibrosis,* sclerosing cholangitis,* sclerosing mediastinitis,*and other conditions with idiopathic fibrosis. with subacute thyroiditis-viral infection. submit sample for determination of protein concentration; record appearance of sediment. for removal and specimen preparation, see chapter . thromboses of small vessels. glomerulonephritis.* hemorrhagic necroses. proteinuria; abnormal sediment. abruptio placentae, small placenta with accelerated maturation of villi; infarcts; fibrinoid necrosis of decidual arterioles. thrombotic occlusion of small vessels with hemorrhagic necroses; anterior lobe of pituitary gland may contain necroses (see also "syndrome, sheehan's"). submit samples for histologic study. if infection is expected, submit material for microbiologic study. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. transposition, complete, of the great arteries note: the basic anomaly is the origin of the aorta from the right ventricle, and of the pulmonary artery from the left ventricle, with a shunt, and usually with a right anterior aorta. there are four major types: ( ) with an intact ventricular septum ( %), ( ) with a ventricular septal defect* ( %), ( ) with a ventricular septal defect and subvalvular pulmonary stenosis* ( %), and ( ) with an intact ventricular septum and subvalvular pulmonary stenosis* ( %). for general dissection techniques, see chapter . interventions include atrial septostomy or septectomy; mustard or senning atrial switch procedure; rastelli-type repair with a valved extracardiac conduit; and jatene arterial switch procedure with lecompte maneuver. possible associated conditions: abnormal origin ofcoronary arteries ( %); atrial septal defect* ( %); coarctation of the aorta;* interrution of the aortic arch;* juxtaposition of atrial appendages ( %); overriding aorta ( %); overriding pulmonary artery ( %); patent ductal artery;* patent oval foramen; subvalvular pulmonary stenosis* ( %); tubular hypoplasia ofthe aortic arch;* ventricular septal defect* ( %), often mal-alignment type ( %). synonyms: atrioventricular and ventriculoarterial discordance; l-transposition. note: the basic anomaly is a mirror-image ventricular inversion, with a left anterior aorta, and with blood flow from right atrium to left ventricle to pulmonary artery, and from left atrium to right ventricle to aorta. for general dissection techniques, see chapter . interventions include patch closure of the ventricular septal defect; relief of pulmonary stenosis; relief of tricuspid insufficiency; and insertion of pacemakers. possible associated conditions: anterior and posterior av nodes ( %), prone to develop complete heart block; dysplasia or epstein's malformation* ofleft-sided tricuspid valve ( %); mirror-image epicardial coronary artery distribution ( %); right-sided mitral valve anomalies; subvalvular pulmonary stenosis* ( %); ventricular septal defect* ( %). kinyoun's, or other acid-fast stains. polymerase chain reaction for mycobacterial dna may be helpful in the differential diagnosis ofgranulomas ( ). ( ) universal precautions should be strictly followed and aerolization should be avoided. ( ) reliable serologic studies are not available. a definite diagnosis requires isolation of the organism. ( ) this is a reportable disease. cavitary, fibrocalcific, miliary, bronchial, and other types of pulmonary tuberculosis; granulomas in hilar lymph nodes. most organs and tissues may be involved, including liver, pancreas, spleen, kidneys, adrenal glands and other endocrine glands, gonads, and lymph nodes. tuberculous meningitis; tuberculoma. iridocyclitis or panophthalmitis. tuberculous arthritis and synovitis (hips, spine, knee); tuberculous osteomyelitis (anterior aspect of vertebrae; metaphysis of long bones). part ii / diseases and conditions procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. chronic ulcerative colitis may be associated with carcinoma of bile ducts, typically arising in psc.* metastases common in regional lymph nodes and lungs. i for removal, prosthetic repair, and specimen preparation and decalcification procedures, see chapter . if osteoblastic metastases appear to be present, search for primary tumor in prostate and breast, carcinoid tumors and hodgkin's lymphoma. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. cachexia. evidence of hypercalcemia (particularly in presence of osteolytic metastases). metastases to bone (e.g., from carcinoma of prostate, breast, bronchi, thyroid gland, kidney, or urinary bladder) usually involve red bone marrow. therefore, distal extremities are rarely involved by metastatic tumors in adults. metastases, commonly in lungs. metastatic calcification in patients with hypercalcemia. eosinophilia. myopathy.* metastases in liver and regional lymph nodes. see also above under "possible associated conditions." malakoplakia (rare) ( ) . part ii / diseases and conditions other organs and peripheral arteries tumor(s). if tumor is within a heart chamber (usually a myxoma), record extent of mobility and capability of tumor to obstruct a valvular orifice. submit samples of tumor(s) for histologic study and, particularly if the tumor is of unknown type, for immunohistochemical study and electron microscopy (chapter ). procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. metastatic carcinoma or melanoma. secondary cardiac effects by tumors include carcinoid heart disease, amyloid heart disease in multiple myeloma, and lymphocytic myocarditis in pheochromocytoma. treatment effects such as adriamycin cardiotoxicity may be noted also. tumor (myxoma) emboli in pulmonary or peripheral vessels ( ) . multiple aneurysms* of cerebral and other arteries may rarely be associated with atrial myxomas. procedures depend on expected findings or grossly identified abnormalities as listed above and in right-hand column. part ii / diseases and conditions if there was evidence of endocrine activity (see above), snap-freeze portion of fresh tumor for hormone assay. perfuse lungs with formalin. sample neoplastic and non-neoplastic tissue for histologic study. procedures depend on expected findings or grossly identified abnormalities as listed above and in right-hand column. for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . see above under "possible associated conditions." note that hypoglycemia* generally cannot be confirmed at autopsy. nonbacterial thrombotic endocarditis.* carcinoma may be associated with asbestosis or other types of pneumoconiosis,* chronic bronchitis,* emphysema,* interstitial pneumonia,* and many other bronchopulmonary diseases. see above under "possible associated conditions." metastases (regional lymph nodes, liver, bones, brain, and many other sites) and metastatic calcification. migratory thrombophlebitis.* encephalomyelitis;* cerebellar corticoid degeneration;* subacute spinocerebellar degeneration. * crooke cell hyperplasia. myasthenic syndrome (eaton-lambert syndrome); myopathy;* dermatomyositis.* peripheral neuropathy. see above under "external examination and skin." bones (with red marrow) are common sites of metastases. record presence or absence of testes. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. thmor of the soft tissues the possible sites and characteristics of soft tissue tumors vary so much that no universally applicable autopsy techniques can be presented. in all instances, the size, weight, and location of the tumor(s) must be recorded and tissue must be sampled for histologic study. if the tumor had not been classified prior to death, samples should be snap-frozen for immunohistochemical study. other samples should be prepared for electron microscopic study. evidence of paraneoplastic syndromes (see below) may require additional procedures. possible associated conditions: only a few paraneoplastic syndromes or systemic complications can be presented here. for the type of soft tissue tumor that was associated with each condition, see title of reference. kasabach-merritt syndrome ( ) (thrombocytopenia, microangiopathic hemolytic anemia, and acute or chronic coagulopathy associated with a rapidly enlarging hemangioma); liver function abnormalities ( ); neurofibromatosis ( ); osteomalacia ( ). heart esophagus, stomach, and duodenum other organs and tissues t in most instances, detennination of vitreous sugar concentration and of blood group is not indicated. inspect valves and prepare photographs and sections of vegetations. leave esophagus and part of duodenum attached to stomach. submit samples of tumor and of grossly uninvolved stomach for histologic study. request pas stain and warthin-starry stain for identification of h. pylori. portions of endocrine gastric tumor should be snap-frozen for immunohistochemical study and possible hormone assay. record location of tumor metastases. other organs procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for dissection of the thoracic duct (for search of tumor cell clusters), see chapter . tumor of the uterus (with cervix) possible associated conditions: acquired immunodeficiency syndrome* (aids) ( ) if peritonitis is present, submit exudate for bacteriologic study. record volume of exudate and location of perforation. see "disease, ischemic heart." other procedures depend on grossly identified abnormalities as listed in right-hand column. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. perfuse at least one lung with formalin. for celiac arteriography, see chapter . open stomach and duodenum in situ and record site of perforation or penetration. record measured or estimated volume of blood in gastrointestinal tract. rinse ulcer with saline to locate eroded vessel(s). pin stomach and duodenum on corckboard (serosa toward board) and fix specimen in formalin before sectioning. prepare histologic sections of ulcer(s) and of remainder of stomach. request warthin-starry stain for h. pylori. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. free air in abdomen suggests perforation of ulcer. peritonitis. * perforation of ulcer. coronary atherosclerosis and manifestations of coronary insufficiency are commonly associated with peptic ulcer disease. in rare instances, pericardial fistula may be present from ulcer in hiatus hernia. peptic ulcers may be associated with emphysema,* tuberculosis,* and other chronic pulmonary diseases. vasculitis (see "aortitis," "arteritis, .•.," "phlebitis," and "purpura,•••") ventricle, double inlet left ( ) synonyms: single functional ventricle; univentricular heart; univentricular atrioventricular connection; holmes heart. note: the basic anomaly is the connection of both atrioventricular valves to the left ventricle, often with transposed great arteries and a restrictive ventricular septal defect. there are four major types, based on the ventriculoarterial connection: ( ) with congenitally corrected transposition ( %); ( ) with complete transposition ( %); ( ) with normally related great arteries (holmes heart; %); and ( ) double outlet, persistent truncal artery, or pulmonary atresia ( %). for general dissection techniques, see chapter . possible associated conditions: bicuspid pulmonary valve; bilateral mirror-image mitral valves (without tricuspid morphology); subvalvular aortic stenosis,* often with hypoplasia, coarctation, or interruption of the aortic arch; subvalvular pulmonary stenosis;* dual av nodes and progressive heart block in patients with congenitally corrected transposition. ventricle, double outlet right synonym: origin of both great arteries from right ventricle; taussig-bing anomaly. note: the basic anomaly is the origin of the aorta and pulmonary artery primarily from the right ventricle, usually with a ventricular septal defect, and often with subpulmonary stenosis. for general dissection techniques, see chapter . possible associated conditions: complete atrioventricular septal defect (often with asplenia syndrome); muscular discontinuity between aortic and mitral valves; right ventricular infundibular stenosis; ventricular septal defect* that may be subaortic, subpulmonary, doubly committed, or remote. examine histologically with h&e and oil red a stains. hepatomegaly and splenomegaly, jaundice. deficiency of acid lipase ( ). foam cells in the lamina propria. hepatomegaly, severe steatosis with cholesterol clefts in hepatocytes and kupffer cells. fibrosis. splenomegaly with lipid-laden foam cells. symmetric enlargement with dystrophic calcifications, giving the adrenals a gritty texture. vacuolated cells of the inner zona fasciculata and entire zona reticularis with cholesterol clefts. foam cells may be found in the lungs, bone marrow, lymph nodes, vessel walls, as well as schwann and ganglion cells. new insights into lipoprotein assembly and vitamin e metabolism from a rare genetic disease angioid streaks associated with abetalipoproteinemia familial hypobetalipoproteinemia: genetics and metabolism aviation pathology scuba diving accidents: decompression sickness, air embolism aetiology and occurrence of diving injuries. a review of diving safety scuba decompression illness and diving fatalities in an overseas military community diving-related emergencies bodies found in water achalasia and squamous cell carcinoma of the esophagus: analysis of patients esophageal achalasia and adenocarcinoma in barrett's esophagus: a report of two cases and a review of the literature a technique for necropsy evaluation of stenosis of the foramen magnum and rostral spinal canal in osteochondrodysplasia mutation analysis of the men i gene in multiple endocrine neoplasia type i, familial acromegaly and familial isolated hyperparathyroidism. i increased incidence of neoplasia in females with acromegaly benign and malignant tumors in patients with acromegaly pathology of acromegaly ethanol in sequestered hematomas stages of acute alcoholic influence/intoxication electrolyte imbalance in alcoholic liver disease collection and storage of specimens for alcohol analysis analysis for alcohol in postmortem specimens disposition of alcohol in man medicolegal aspects of alcohol. garriott jc blood, urine and other tissue specimens for alcohol analysis relationship between postmortem blood and vitreous humor ethanol levels larson cpo alcohol: fact and fallacy gradwohl's legal medicine left ventricular hypertrophy is more prominent in patients with primary aldosteronism than in patients with other types of secondary hypertension intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism association of adrenal medullae and cortical nodular hyperplasia: a report of two cases with clinical and morpho-functional consideration amyloidosis: recognition, confirmation, prognosis, and therapy electron microscopy of primary and secondary cutaneous amyloidosis and systemic amyloidosis ocular amyloidosis current status review: cerebral amyloid spinal cord compression by amyloid deposits the burden of "sticky" amyloid: typing challenges quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with congo red histochemical stain kidney involvement in takayasu arteritis pathogenesis of rheumatoid arthritis splenic involvement in rheumatic diseases aspergillus sinusitis in patients with aids: report of three cases and review invasive aspergillosis in systemic lupus erythematosus aspiration (see "obstruction, acute airway aspergillus endocarditis, myocarditis and pericarditis complicating necrotizing fasciitis. case report and subject review aspergillus-related lung disease biliary atresia and the polysplenia syndrome: its impact on final outcome biliary atresia nephromegaly and elevated hepatocyte growth factor in children with biliary atresia coccidiomycosis pneumonia in a nonendemic area associated with inftiximab codeine (see "dependence, drug[s], all types or type unspecified all types or type unspecified (see "enterocolitis, other types or type undetermined chronic ulcerative (see "disease, inflammatory bowei cytologic diagnosis of cryp -tococcus neofonnans in hiv-positive patients cryptococcosis as an opportunistic infection in immunodeficiency secondary to paracoccidioidomycosis hypereosinophilia in disseminated cryptococcal disease cryptococcosis-a review of autopsy cases from a -year period in a large hospital cryptosporidiosis in persons with hiv infection broncho-pulmonary cryptosporidiosis in four hiv-infected patients cryptosporidiosis and inflammatory bowel disease sclerosing cholangitis associated with chronic cryptosporidiosis in a child with a congenital immunodeficiency disorder cyanide (see "poisoning, cyanide cyst(s), choledochal choledochal cyst-dinical features and classification cyst(s), liver (see "disease, fibropolycystic, of the liver and biliary tract pulmonary related terms: congenital cystic adenomatoid malformation; congenital pulmonary lymphangiectasis; intralobular bronchopulmonary sequestration. references infection or calcification of cysts; pyelonephritis;* perinephric abscess. obstructive uropathy in recessive polycycstic renal disease, congenital hepatic fibrosis is present and cystic bile ducts may be present in dominant cases ( ). see above under "possible associated conditions the pathology ofhuman renal cystic disease cystic kidney: genetics, pathologic anatomy, clinical picture, and prenatal diagnosis hepatic fibrosis associated with hereditary cystinosis: a novel form of noncirrhotic portal hypertension ophthalmic manifestations and histopathology of 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additional risk factor for cirrhosis and hepatocellular carcinoma? alpha i-antitrypsin deficiency and inflammatory bowel disease severe alphal-antitrypsin deficiency (piz homozygosity) with membranoproliferative glomerulonephritis and nephrotic syndrome, reversi-bleafterorthotopic livertransplantation klippel-feil syndrome associated with malfonned larynx. case report klippel-feil syndrome in association with a craniocervical dennoid cyst presenting as aseptic meningitis in an adult: case report klippel-feil syndrome accompanied by an aneurysm of the non-coronary sinus of valsalva the hereditary ataxias clinical and genetic characterizations of q-linked autosomal dominant spinocerebellar ataxia (ad-sca) and frequency analysis of ad-sca in the japanese population cocain-related medical problems. consecutive series of cases direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy the pathology and etiology of cocaineinduced heart disease ischemic colitis related to cocaine abuse hepatic dysfunction accompanying acute cocaine intoxication high incidence of malignancies in patients with dennatomyositis and polymyositis: an li-year analysis partial lipodystrophy associated with juvenile dennatomyositis: report of two cases chronic pneumomediastinum and subcutaneous emphysema: association with dennatomyositis spontaneous esophageal rupture in adult dennatomyositis polyneuropathy in juvenile dermatomyositis combined glucose and lactate values in vitreous humor for postmortem diagnosis of diabetes mellitus diabetes is related to cerebral infarction but not to ad pathology in older persons hepatic lesions resembling alcoholic liver disease relationship between cardiomyopathy and liver disease in chronic alcoholism cyanamide-associated alcoholic liver disease: a sequential histologic evaluation caroli's disease: - experiences caroli 's disease and autosomal dominant polycystic kidney disease: a rare asso-ciation? spontaneous rupture of a bile duct and its endoscopic management in a patient with caroli's syndrome bartonella henselae endocarditis in an immunocompetent adult cat-scratch disease and bacillary angiomatosis attack, transient cerebral ischemic" and "infarction, cerebral!') cholesteryl ester storage disease: hepatopathology and effects of therapy with lovestatin clinical, biochemical and histological analysis of seven patients with cholesterol ester storage disease cutaneous manifestations of chronic granulomatous disease. a report of four cases and review of the literature aspergillus endocarditis in chronic granulomatous disease colitis complicating chronic granulomatous disease. a clinicopathological case report hypertrophic cranial pachymeningitis with spinal epidural granulomatous lesion ocular pathologic findings of chronic granulomatous disease of childhood review: creutzfeldt-jakob disease survival of creutzfeldt-jakob disease virus in formol-fixed brain tissue guidelines for high risk autopsy cases: special precautions for creutzfeldt-jakob disease tissue handling in suspected creutzfeldt-jakob disease and other human spongiforme encephalopathies (prion diseases) cerebrospinal fluid concentration of neuron-specific enolase in diagnosis of creutzfeldt-jakob disease autopsy case of sporadic creutzfeldt-jakob disease presenting with signs suggestive of brainstem and spinal cord involvement metastatic crohn's disease: a rare cutaneous manifestation crohn's disease with pulmonary involvement in a year old boy mesenteric fibromatosis asso-ciated with crohn's disease cholangiocarcinoma and crohn's disease the pancreas as a site of granulomatous inflammation in crohn's disease dermatomyositis associated with crohn's disease cardiocyte storage and hypertrophy as a sole manifestation of fabry's disease. report on a case simulating hypertrophic non-obstructive cardiomyopathy an atypical variant of fabry's disease with manifestations confined to the myocardium pulmonary involvement in fabry disease cerebrovascular complications offabry's disease high incidence of thrombosis in fabry's disease oral involvement in chronic graft versus host disease after allogenic bone marrow transplantation massive pericardial effusion complicating the course of chronic graft-versus-host disease (cgvhd) in a child with acute lymphoblastic leukemia following allogeneic bone marrow transplantation the histological spectrum of pulmonary graft-versushost disease in bone marrow transplant recipients bronchiectasis in bone marow transplantation oncocytic metaplasia of bile duct epithelium in hepatic gvhd immune-mediated myelopathy after allogeneic marrow transplantation gunther's (see ''porphyria, congenital erythropoietic heavy-chain synonyms and related terms: gamma heavy-chain inflammatory bowel disease (first of two parts) takayasu's arteritis associated with idiopathic ulcerative colitis cerebrovascular complications ofinflammatory bowel disease pathology of inflammatory bowel disease legionnaires' disease source of infection for sporadic legionnaires' disease: a review legionnaire's disease associated with macular rash; two cases severe skin loss after meningococcal septicemia: complications in treatment osteonecrosis following meningococcemia and disseminated intravascular coagulation in an adult: case report and review rhabdomyolysis during the subacute stage of meningococcal sepsis primary meningococcal arthritis in a child: case report and literature review chondrosarcoma as a complicating factor in paget's disease of bone lymphoma arising in paget's disease osteoarthritis and paget's disease sickle cell disease sickle cell disease and sudden death: a retrospective/prospective study of autopsy cases and literature review vascular lesions of the liver in sickle cell disease. a clinicopathologic study in living patients whipple's disease and "tropheryma whippelii periodic acid-schiff-negative granulomatous lymphadenopathy in patient with whipple's disease. localization of the whipple bacillus to noncaseating granulomas by electron microscopy serial imaging studies of cerebral whipple's disease: from onset to end the wilson's disease gene is a putative copper transporting p-type atpase similar to menke's gene the liver biopsy diagnosis of wilson's disease. methods in pathology hepatolenticular degeneration (wilson's disease) venous air embolism in homicidal blunt impact head trauma: case reports a practical device for demonstrating air embolism amniotic fluid . kulka w. laboratory methods and technical notes: a practical device for demonstrating air embolism proof of fatal air embolism venous air embolism from head and neck wounds hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease liver involvement in hemorrhagic fever with renal syndrome hantavirus infection induces a typical myocarditis that may be responsible for myocardial depression and shock in hanta virus pulmonary syndrome lassa fever in the united states. investigation ofa case and new guidelines for management lassa fever: review of virology, immunopathogenesis, and algorithms for control and therapy early diagnosis of lassa fever by reverse transcription-pcr rheumatic pneumonia: reappearance of a previously recognized complication of rheumatic fever acute rheumatic fever and poststreptococcal acute glomerulonephritis caused by t serotype streptococcus scleritis, uveitis, and glaucoma in a patient with rheumatic fever comparison of clinical features and pathologic findings in fatal cases of typhoid fever during the initial and later stages of the disease typhoid fever complicated by acute renal failure and hepatitis: case reports and review hemophagocytosis and granulomas in the bone marrow of a child with down syndrome diseases involving intrahepatic bile ducts idiopathic eosinophilic esophagitis with stricture formation in a patient with longstanding eosinophilic gastroenteritis eosinophilic gastroenteritis presenting with colitis and cholangitis eosinophilic gastroenteritis presenting with acute pancreatitis idiopathic midline destructive disease: does it . mendenhallwmetai.lethalmidlinegranoloma-nasalnaturalkillerff-celi exist? nasal cocain abuse mimicking midline granuloma pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with epstein-barr virus infection recurrent bilateral spontaneous pneumothoraces associated with pulmonary angiocentric immunoproliferative lesion lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications wegener's granulomatosis: histological documentation of common and uncommon manifestations in patients necrotizing granulomatosis of the breast wegener's granulomatosis with gangrene of toes pathology of pulmonary granulomatous vasculitis. sarcoidosis gunshot (see "injury, firearm splenic involvement in rheumatic diseases wegener's granulomatosis, acute laryngotracheal airway obstruction and death in a -year-old female: case report and review of the literature antiendothelial antibodies in patients with wegener's granulomatosis: prevalence and correlation with disease activity and manifestations. i rheumatoi transfusion-transmitted disease references flattening, broadening, and possible fusion of villi. phlegmonous inflammation and edema, mainly in ileocecal region encephalitis.* leukopenia; thrombocytopenia; aplastic anemia ( ) (pancytopenia*) synovitis (arthritis*) hepatitis g virus infection in hepatitis c virus-positive patients co-infected or not with hepatitis b virus and/or human immunodeficiency virus hepatitis g and c coinfection in children tumor of the liver diaphragmatic related terms: congenital diaphragmatic hernia fulminant hepatitis in patients undergoing liver transplantation: evidence for anon-a, non-b, non-c marrow transplantation for hepatitis-associated aplastic anemia: a follow up oflong-term survivors langerhans cell histiocytosis research. past, present, and future an update on c onality, cytokines, and viral etiology in langerhans cell histiocytosis langerhans cell histiocytosis in adults pulmonary langerhans cell granulomatosis central nervous system disease in langerhans cell histiocytosis immunohistochemical analysis oflangerin in langerhans cell histocytosis and pulmonary inflammatory and infectious diseases pathological approach to the diagnosis of hydrocephalus thoracic lipomeningocele associated with diastematomyelia, tethered spinal cord, and hydrocephalus. case report infectious causes ofhydrops fetalis human parvovirus b infection associated with hydrops fetalis cardiac abnormalities associated with hydrops fetal is gmi-gangliosidosis presenting as nonimmune hydrops fetalis: a case report a case of recurrent infantile polycystic kidney associated with hydrops fetalis the pathologist and the hydropic placenta, fetus, or infant chronic diarrhea associated with thymoma and hypogammaglobulinemia (good's syndrome) systemic amyloidosis in a patient with hypogammaglobulinemia. i hcv infection in patients with primary defects of immunoglobulin production encepahomyelitis in primary hypogammaglobulinemia retinitis pigmentosaand hypogammaglobulinemia intestinal obstruction in the newborn with congenital syphilis meconium ileus and its equivalent as a risk factor for the development of cirrhosis: an autopsy study in cystic fibrosis biliary atresia and meconium ileus associated with nieman-pick disease postmortem cranial mri and autopsy correlation in suspected child abuse cytomegalovirus-associated pseudotumor simulating gastric malignancy in acquired immuno-deficiency syndrome: a case report with review of literature bone marrow fibrin ring granulomas and cytomegalovirus infection cutaneous reactions following herpes zoster infections: report of three cases and a review of the literature herpes zoster and internal malignancy posteriorhorn varicella-zoster virus myelitis death or injury caused by electrocution myocardial hemorrhagic necrosis in delayed death from electrocution safety in bullet recovery procedures: a study of the black talon bullet lightning injuries: prognostic signs of death lightning injuries adrenal insufficiency, recurrent bacteremia, and disseminated abscesses caused by nocardia asteroides in a patient with acquired immunodficiency syndrome ards and adrenal insufficiencyassociated with the antiphospholipid antibody syndrome adrenal insufficiency from bilateral adrenal hemorrhage after total knee replacement surgery non-hodgkin's lymphoma presenting with adrenal insufficiency and hypothyroidism: an autopsy case report a case ofprimary unilateral adrenal burkitt-like large cell lymphoma presenting as adrenal insufficiency effect of growth hormone on fatty liver in panhypopituitarism increased fracture frequency in adult patients with hypopituitarism and gh deficiency pituitary abscess the liver: an atlas and text of ultrastructural pathology intubation (see "injury, intubation iodine (see "poisoning, iodine attack, transient cerebral ischemic" and "infarction, cerebral heart (see "disease, ischemic heart isomorism (see "syndrome, polysplenia and asplenia a study on performance of two serological assays for diagnosis of leprosy detection of mycobacterium leprae infection by pcr pathology of eye in leprosy references intervillous abscesses containing grampositive, non-acid-fast bacilli bacteria are predominantly intracellular. enterocolitis. listeria monocytogenes can be cultured from meconium. generalized lymphadenitis. disseminated abscesses and/or granulomas, particularly after transplacental infection listeria monocytogenes empyema in an hiv infected patient fatal listeria meningitis, endocarditis and pericarditis in a patient with haemochromatosis liver abscesses due to listeria monocytogenes yust . brainstem abscess and meningitis due to listeria monocytogenes in an adult with juvenile chronic arthritis pulmonary hypertension associated with systemic lupus erythematosus: predominantly thrombotic arteriopathy accompanied by plexiform lesions the liver in systemic lupus erythematosus: pathologic analysis of cases and review of japanese autopsy registry data chronic pancreatitis: a complication of systemic lupus erythematosus disseminated perivenous necrotizing encephalomyelitis in systemic lupus erythematosus: report of an autopsy case skeletal muscle lymphocytic vasculitis in systemic lupus erythematosus: relation to disease activity clinically occult avascular necrosis of the hip in systemic lupus erythematosus storage histiocytes and hemophagocytosis: a common finding in the bone marrow of patients with active systemic lupus erythematosus extensive medium vessel vasculitis with sle: an unsual association cutaneous manifestations of sexually transmitted ing cause of proctitis in men who have sex with men lymphogranuloma venereum as a cause cutaneous malakoplakia in a patient with acquired immunodeficiency syndrome (aids) extensive malakoplakia ofthe nasopharynx: management of a rare disease malakoplakia and colorectal adenocarcinoma coinfection is common in measles associated pneumonia giant cell pneumonia: light microscopy, immunohistochemical, and ultrastructural study of an autopsy case subacute sclerosing panencephalitis manifesting as viral retinitis: clinical and histopathologic findings intestinal neuronal dysplasia thoracic lipomeningocele associated with diastematomyelia, tethered spinal cord, and hydrocephalus. case report disease, meningococcal encephalitis, all types or type unspecified" and "meningitis mercury (see "poisoning, mercury with myelofibrosis synonym: idiopathic myelofibrosis acute cardiac tamponade associated with pericardial extramedullary hematopoiesis in agnogenic myeloid metaplasia methyl alcohol) (see "poisoning, methanol (methyl alcohol) thrombotic thrombocytopenic (see "purpura, thrombotic thrombocytopenic epstein-barr virus in inflammatory diseases of the liver and liver allografts: an in situ hybridization study fulminant hepatitis due to epstein-barr virus infection the mucopolysaccharidoses: a clinical review and guide to management biochemical diagnosis of mucopolysaccharidoses: experience of diagnoses in a -year period ( - ) mucormycosis synonym: phycomycosis; zygomycosis. note: diseases that may be complicated by mucormycosis include bums,* diabetes mellitus,* leukemia,* lymphoma,* and tuberculosis cardiac involvement in mucopolysaccharidosis: effects of allogeneic bone marrow transplantation mitral and aortic regurgitation in patients with mucopolysaccharidosis toxic epidermal necrolysis possibly linked to hyperacute graft-versus-host disease after allogeneic bone marrow transplantation pulmonary complications in toxic epidermal necro-iysis: a prospective clinical study references possible or expected findings pyelonephritis;* nephrocalcinosis; granulomas; tumor infiltrates; manifestations of the conditions listed below under "other organs renal stones in patients with rheumatoid arthritis nephrolithiasis as a presenting feature ofchronic sarcoidosis: a prospective study nephrolithiasis and risk of hypertension posterior lens opacities; retinal hamartomas. peripheral neuropathy with focal schwannomatous changes or onion-bulb-like schwann cell or perineural cell proliferation neurofibromatosis type i. in: pathology and genetics of tumours of the nervous system neurofibromatosis type . in: pathology and genetics oftumours ofthe nervous system neurological complications involving the central nervous system in neurofibromatosis type i primary cutaneous nocardia asteroides infection after heart transplantation native valve endocarditis due to nocardia-like organisms hepatobiliary complications of total parenteral nutrition total parenteral nutrition: a histopathologic analysis of the liver changes in children obesity and breast cancer risk nonalcoholic steatohepatitis obesity cardiomyopathy: pathogenesis and pathophysiology bennett cpo pachydennoperiostitis in childhood unilateral hypertrophic osteoarthropathy associated with aortofemoral graft infection gastroesophageal reflux and esophagitis-associated hypertrophic osteoarthropathy hypertrophicosteoarthropathy caused by lipoid pneumonia achondroplasia" and dyschondroplasia, oilier's osteogenesis imperfecta synonyms and related terms: lobstein's syndrome osteogenesis imperfecta congenita; type i, ii, and iii; osteogenesis imperfecta cystica hypercalcemia in osteogenesis imperfecta treated with pamidronate gastrointestinal problems in patients who have type-iii osteogenesis imperfecta osteomalacia related terms: osteoporosis;* renal osteodystrophy; rickets. note: many possible causes of osteomalacia may not be apparent at autopsy, e.g., sodium fluoride or diphosphonate toxicity or use of anticonvulsant drugs osteomalacia associated with adult fanconi syndrome: clinical and diagnostic features epstein-barr virus in b-celllymphomas associated with chronic suppurative inflammation osteomyelitis and osteonecrosis in inflammatory bowel disease references hyperlipidemia; hyperuricemia. fracture or traumatic dislocation of hip see above under "note osteomyelitis and osteonecrosis in inflammatory bowel disease osteonecrosis and human immunodeficiency virus infection report of fifteen cases. therapeutic recommendations malignant infantile osteopetrosis: otolaryngological complications and management renal tubular acidosis and osteopetrosis with carbonic anhydrase ii deficiency: pathogenesis of impaired acidification spondylolysis in children who have osteopetrosis osteopetrosis with arnold chiari malformation type and brain stem compression osteoporosis and atherosclerosis in chronic renal failure endocrine disorders and osteoporosis otosclerosis: a measles virus associated inflammatory disease correlations between pathologic changes in the stapes and conductive hearing loss in otosclerosis the aetiology of otosclerosis: a review of the literature etiologic links between chronic pancreatitis and pancreatic cancer hyperparathyroidism and pancreatitis during pregnancy pancytopenia related terms: agranulocytosis;* aplastic anemia; fanconi's anemia.* note: some causes of pancytopenia such as adverse drug reactions (e.g., due to antimetabolites, sulfa drugs thrombotic thrombocytopenic purpura/hemolytic uremic syndrome secondary to pancreatitis retinopathy as asys-temic complication of acute pancreatitis references mesenteric panniculitis necrotizing pancreatitis. * vasculitis with thrombi; adrenocortical infarctions. vasculitis with thrombi and infarctions. relapsing polychondritis ( ). see also above under "possible associated conditions subcutaneous panniculitic t-cell lymphoma is a tumor of cytotoxic t lymphocytes abecassism. alpha i-antitrypsindefi-ciencyassociated panniculitis: resolution with intravenous alpha l-anti-trypsin administration and liver transplantation blind loop syndrome: an unusual cause of panniculitis. j am acad paracoccidioidomycosis synonyms: paracoccidioides brasiliensis infection cutaneous panniculitis and relapsing polychondritis: two cases normal subcutaneous fat, necrosis of adipocytes and classification of the panniculitides paraneoplastic pemphigus a case of pemphigus vulgaris with esophageal involvement rheumatoid constrictive pericarditis (clinical conference) benign paroxysmal (see "fever, familial mediterranean pneumatosis intestinalis in pediatric acquired immunodeficiency syndrome pneumatosis cystoides intestinalis: an unusual complication of systemic amyloidosis pneumatosis intestinalis in children with primary combined immunodeficiency pneumatosis cystoides intestinalis with abdominal free air in a -year-old girl after allogeneic bone marrow transplantation pneumatosis intestinalis: a review pneumatosis coli: a proposed pathogenesis based on study of cases and review of the literature collagenous inorganic dust pneumoconiosis, diffuse type: aluminosis; asbestosis; chronic pulmonary berylliosis; talcosis; collagenous inorganic dust pneumoconiosis, nodular type: silicosis; noncollagenous inorganic dust pneumoconiosis (includes mixed-dust fibrosis): baritosis; china clay pneumoconiosis; chromite pneumoconiosis; coal worker's pneumoconiosis; fuller's earth pneumoconiosis; hematite or magnetite miner's lung; siderosis or welder's lung; stannosis; organic dust pneumoconiosis: byssinosis. note: in addition to the aforementioned classic forms of pneumoconiosis, many other airborne substances have been impli-cated in recent years, for example, cerium uncommon causes ofoccupational interstitial lung diseases rare earth (cerium oxide) pneumoconiosis: analytical scanning electron microscopy and literature review diagnostic criteria for chronic beryl ium disease (cbd) based on the uk registry - pneumocystis carinii (see "infection, pneumocystis carinii this condition is diagnosed by inspection, palpation, and roentgenography. tension pneumomediastinum may autopsy evaluation of asbestos exposure: retrospective study of cases with quantitation of ferruginous bodies in digested lung tissue atypical mycobacteriosis as a complication of talc pneumoconiosis silicosis, mixed dust pneumoconiosis, and lung cancer complications associated with the use ofthe esophageal-tracheal combitube pneumomediastinum: an unusual complication of asthma in a young man spontaneous pneumomediastinum in a patient with bronchiolitis obliterans after bone marrow references i. katzenstein a-l, myers j. idiopathic pulmonary fibrosis: clinical relevance of pathologic classification update on lymphoid interstitial pneumonitis lymphocytic interstitial pneumonitis and nonspecific interstitial pneumonitis histologic diagnosis of extrinsic allergic alveolitis role of electron microscopy in interstitial lung disease detennination of arsenic in hair using neutron activation arsenic intoxication associated with tubulointerstitial nephritis atrioventricular block after administration of atropine in patients follow-ing cardiac transplantation death following intentional methyl bromide poisoning: toxicological data and literature review pulmonary edema, alveolar wall damage, and interstitial pneumonia after acute inhalation. severe pulmonary fibrosis may develop in chronic cases. gastroenteritis after nonlethal food poisoning. degeneration of proximal tubules and proteinuria in acute poisoning degenerative changes of liver and myocardium problems in the analysis of cadmium in autopsied tissues elevated urinary cadmium concentrations in a patient with acute cadmium pneumonitis cadmium-associated renal disease the effects of storage conditions on the stability of carbon monoxide in postmortem blood acute renal failure, poisoning, carbon tetrachloride synonym: tetrachloromethane poisoning. note: toxicologic sampling of body fluids and organs should be done routinely in all cases. in many instances, however, death occurs i wk to d after exposure, and by this time no carbon tetrachloride is demonstrable. death may be sudden compartment syndrome, and systemic capillary leak syndrome complicating carbon monoxide poisoning southern je acute hydrocephalus following carbon monoxide poisoning prevention of occupational cyanide exposure in autopsy prosectors gradwohl's legal medicine references possible or expected findings digoxin values in digitalis toxicity are greater than ng/ml ( ) digoxin concentration may be higher or lower than concentration in serum, depending on how long before death drug was taken (i) digoxin concentrations in postmortem specimens after overdose and therapeutic use a fluorimetric determination ofmyocardial digoxin at autopsy, with identification of digitalis leaf, digitoxin and gitonin ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis ethylene glycol poisoning: case report of a record-high level and a review lead concentrations in human plasma, urine and whole blood trace metals (lead and cadmium screening) an emg case report oflead neuropathy years after a gunshot injury aminoaciduria and glycosuria following severe childhood lead poisoning risk of nervous system cancer among workers exposed to lead demonstration of mercury in the human brain and other organs years after metallic mercury exposure spontaneous exfoliation of teeth following severe elemental mercury poisoning: case report and histological investigation for mechanism. oral surg oral med oral pathoi acute chemical pancreatitis associated with nonfatal strychnine poisoning homicide by strychnine poisoning coronary arteritis, with or without aneurysms and infarctions, primarily in childhood. myocardial hypertrophy secondary to hypertension. * minimal or no involvement by polyarteritis nodosa; considerable involvement in other types ofnecrotizing vasculitis (see "arteritis, all types or type unspecified") with or without formation of aneurysms and infarctions, may occur in all organs. the liver may show bile duct injury and rarely, nodular regenerative hyperplasia ( ) more frequently involved in giant cell elastic arteritis.* polyarteritis of small muscular arteries, including vasa nervorum. arthritis* may rarely be present with swollen joints. infarctions;* subarachnoid hemorrhage; arteritis of cerebral arteries. papillitis; retinal hemorrhages polyarteritis nodosa-like vasculitis in human immunodeficiency virus infection the coexistence of familial mediterranian fever and polyarteritis nodosa: report of a case microscopic polyarteritis during polymyalgia rheumatica remission development of polyarteritis nodosa in the course of inactive systemic lupus erythematosus bone marrow pathology in relapsing polychonditis: high frequency of myelodysplastic syndrome relapsing polychondritis associated with subclinical sjo-gren's syndrome and phlegmon of the neck giant cell arteritis and polymyalgia rheumatica posterior scleritis and polymyalgia rheumatica polymyalgia rheumatica in patients with ankylosing spondylitis: a report of cases inflammatory changes of hip synovial structures in polymyalgia rheumatica polymyositis (see "dermatomyositis polyneuritis (see "syndrome, guillain-barre familial, and related syndromes related terms: cowden's disease (multiple hamartoma syndrome); familial colonic polyposis gardner's syndrome; non-polyposis syndrome (hereditary nonpolyposis colorectal cancer syndrome) sampling for histologic study depends on expected findings or grossly identified abnormalities as listed in right-hand column. (see also below under "soft tissues syndrome; mucocutaneous pigmentations (buccal, perioral, priorbital, distal extremities) in peutz-jeghers syndrome;* papules in face and oral mucosa in cowden's disease; tumors of skin and subcutis (see below under "soft tissues gardner's syndrome. osteomas or exostoses (mandible, calvara desmoid in familial adenomatous polyposis malignant potential in intestinal juvenile polyposis syndromes ampullary carcinoma in familial adenomatous polyposis adenoma of the common bile duct in gardner's syndrome may cause relapsing acute pancreatitis orbital osteoma in gardner's syndrome myelopathylmyelitis," and "syndrome, guillain-barre.") references possible or expected findings hypertrichosis; erythrodontia; scarring and mutilation of hands and face. hemolytic anemia. erythrocytes contain large amounts of uroporphyrin i; nonnoblasts and reticulocytes exhibit intense red fluorescence uroporphyrin i and coproporphyrin i in high concentrations. splenomegaly (may have been treated by splenectomy) correction of congenital erythropoietic porphyria by bone marrow transplantation successful cord blood stem cell transplantation for congenital erythropoietic porphyria (gunther's disease) congenital erythropoietic porphyria associated with nephrotic syndrome atypical red cell inclusions in congenital erythropoietic porphyria possible associated conditions: adverse drug reaction; chronic alcoholism;* chronic hepatitis c ( ); human immunodeficiency virus infection porphyria cutanea tarda and human immunodeficiency virus: two cases associated with hepatitis c porphyria cutanea tarda and antibodies to hepatitis c virus an unhappy triad: hemochromatosis, porphyria cutanea tarda and hepatocel ularcarcinoma-a case report variegate porphyria possible associated conditions: ebstein's malformation of tricuspid valve. references possible or expected findings chronic eczematous skin lesions or superficial scarring; nail changes. perivascular pas-positive hyaline ( ) brown protoporphyrin deposits with red to yellow birefringence with a maltese cross configuration in hepatocytes, kupffer cells, and bile canaliculi erythropoietic protoporphyria cytofluorometry as a diagnosis of protoporphyria recessive inheritance of erythropoietic protoporphyria with liver failure pseudogout synonym: calcium pyrophosphate dihydrate (cppd) deposition disease puncture grossly affected joints and submit sample of synovial fluid for crystal analysis under compensated polarized light ( ) references possible or expected findings punctate calcium deposits in kneejoints and, less commonly, in joints of hips, ankles, shoulders, or wrists or in symphysis ossium pubis and intervertebral disks. arthritis* with synovitis. crystals of calcium pyrophosphate dihydrate in periarticular tissue ( ) and synovial fluid. cartilage contains calcium salts of pyrophosphate, hydroxyapatite, and orthophosphate. alkaptonuria;* gout calcium pyrophosphatedihydratedeposition disease presenting as tumoral calcinosis (periarticularpseudogout) calcifications in dermis; calcifications of blood vessels. diaphragmatic hernia.* hypertensive cardiomegaly. characteristic plaques in pericardium and endocardium, with or without mitral valve involvement. coronary atherosclerosis may have been a causeofangina( ).coronarythrombosisand myocardial infarction may be present also. accelerated atherosclerosis; calcification of peripheral vessels. gastrointestinal hemorrhage;* peptic ulcer degeneration of bruch's membrane with retinal hemorrhages; sclerosis of choroid vessels calcification of elastic fibers in pseudoxanthoma elasticum new report of severe coronary artery disease in an eighteen-year-old girl with pseudoxanthoma e asticum. case report and review of the literature hivrelated thrombotic thrombocytopenic purpura: report of cases and a review of the literature beham-pyelonephritis synonyms and related terms: acute ascending pyelone angiotropic large cell lymphoma presenting as thrombotic micro-angiopathy (thrombotic thrombocytopenic purpura) splenic pathology in thrombotic thrombocytopenic purpura emphysematous pyelonephritis in diabetic patients nephrobronchialfistulaandlungabscessresulting from nephrolithiasis and pyelonephritis a case ofan enterorenal pyothorax (see "empyema, pleurai.") fistula and pyelonephritis with airin renal pelvis systemic amyloidosis secondary to pyonephrosis. resolution after nephrectomy medicolegal investigation of death the laboratory's role in detecting sexual assault toluidine blue in the detection at autopsy of perineal and anal lacerations in victimes of sexual abuse sarcoidosis presenting as heart disease sarcoidosis and its ocular manifestations rheumatic features of sarcoidosis cutaneous sarcoidosis: differential diagnosis schistosoma mansoni and s. haematobium infections in egypt. i. evaluation of techniques for recovery of worms and eggs at necropsy. am i a quantitative post-mortem study of schistosomiasis mansoni in man immunodiagnosis of schistosomiasis. screen with fast-elisa and confinn with imrnunoblot hepatic connective tissue changes in hepatosplenic schistosomiasis schistosomiasis in women: manifestations in the upper reproductive tract sclerosis, systemic amyotrophic lateral (see "disease, motor neuron diffuse (see "sclerosis, schilder's cerebrai multiple synonyms and related terms: acute and subacute variants: acute multiple sclerosis (marburg type), acute necrotizing myelopathy; concentric sclerosis (ba type); concentric lacunar leukoencephalopathy; encephalitis periaxialis diffusa (schilder's type; see also next entry silicone ganuloma in acral skin in a patient with silicone-gel implants and systemic sclerosis organizing diffuse alveolar damage associated with progressive systemic sclerosis bayle , fiessinger in. brain involvement in scleroderma: two autopsy cases skeletal muscle pathology in systemic sclerosis mechanisms of scleroderma-induced lung disease thberous sclerosis complex and subependymal giant cell astrocytoma bilateral temporal arachnoid cysts associated with tuberous sclerosis poisoning, alkaloid accident, diving [skin or scuba scurvy (see "deficiency, vitamin c shigellosis (see "dysentery, bacillary shock related terms: anaphylactic shock; bacteremic shock; many others. note: see also under name of suspected underlying condition, such as "bums intestinal histological and ultrastructura inflammatorychanges in spondyloarthropathy and rheumatoid arthritis the sacroiliac joint in the spondyloarthropathies granulomatous ileitis in a patient with ankylosing spondylitis sporotrichosis synonym: sporothrix (sporotrichum) schenckii infection. note: ( ) mckiernan . partial lipodystrophy in coeliac disease coeliac disease and lymphoma: current status review: nonalcoholic steatohepatitis alcoholic and non-alcoholic wernicke's encephalopathy. be alert to the preventable and treatable disease non-alcoholic fatty liver disease in the metabolic syndrome the placenta in stillbirth estimating the time of death in stillborn fetuses: i. histologic examination of fetal organs: an autopsy study of stillborns estimating the time of death in stillborn fetuses: ii. histologic evaluation ofthe placenta; a study of stillborns estimating the time ofdeath in stillborn fetuses: iii. external fetal examination; a study of stillborns fat distribution in the adrenal cortex as an indication of the mode of intrauterine death stimulant(s) (see "dependence, drug(s), all types or type undetermined cutaneous manifestations of the acquired immunodeficiency syndrome aids: cardiac findings from autopsies the liver in hiv infection neuropathology of the spinal cord in the acquired immunodeficiency syndrome postmortem enzyme immunoassay for human immunodeficiency virus bk virus-associated renal failure among hiv patients - or write to american registry ofpathology sales office pathology of acquired immunodeficiency syndrome (aids) in children thymus involution in the acquired immunodeficiency syndrome micrencephaly in children congenitally infected with human immunodeficiency virus-a gross-anatomical morphometric study a rapid method for detecting the predominant ashkenazi jewish mutation in the bloom's syndrome gene bloom syndrome: multiple retinopathies in a chromosome breakage disorder severe eczema in a patient with di-george's syndrome digeorge's syndrome orthe iii -iv pharyngeal pouch syndrome: pathology and a theory of pathogenesis basal ganglia calcification and psychosis in q . deletion syndrome down's synonyms and related terms: mongolism possible associated conditions: acute lymphocytic, my references epicanthal folds; cleft lip/palate; high arched palate; furrowed tongue; rhagades. depressed nasal bridge small, broad or fiat nose; slanted palpebral fissures; fiat occiput; brachycephaly; palmar "simian crease"; short fifth middle finger ventricular septal defect;* complete atrioventricular septal defect* ( ). duodenal stenosis and atresia; imperforate anus. microcephaly; poorly developed secondary gyri hypoplastic brain stem, medulla and cerebellum; polymicrogyria; neurofibrillary tangles; meningomyelocoele. acute lymphocytic leukemia; acute myelocytic leukemia; acute megakaryocytic leukemia cardiovascular disease in down syndrome possible or expected findings hyperelasticity of skin, bruises or scars, hemorrhages, and hyperpigmentation. lipomatous pseudotumors that may be calcified or ossified. normal or abnormal amounts and fragmentation of elastic tissue. abnormalities of collagen. dislocation of hip, shoulder, patella, radius, or clavicle. loose-end clavicles; spondylolisthesis mitral valve prolapse; aortic insufficiency.* aortic dissection, aneurysm, ectasia, occlusion ( ). various congenital anomalies. congenital anomalies of gastrointestinal and genitourinary tracts. bleeding from various organ sites vascular ehlers-danlos syndrome: imaging findings note: this syndrome belongs to a large family (with more photograph abnormal features as listed in right-hand column. record appearance of external genitalia. prepare skeletal roentgenograms. procure long bones and vertebral bodies short-limb dwarfism* with narrowing of the rib cage; polydactyly; dysplasia of fingernails; thin and sparse hair; premature eruption of teeth; defective dentition; eye abnormalities; upper lip bound down by multiple frenula. cryptorchidism; epispadias; hypospadias. chondrodysplasia with acromelic micromelia (shortening of the distal segment of the limb); fusion of capitate and hamate bones of wrist; defects of lateral aspect of proximal tibia see lesions listed above under "external examination empty sella synonyms and related terms: primary empty sella syndrome; secondary empty sella syndrome (e.g., after surgical removal or spontaneous infarction of pituitary adenoma) chorea, philic pneumonia: histopathologic features in nine cases. am rev resp hereditary ascariasis and hookworm chronic eosinophilic pneupophosphatemic vitamin d-resistant rickets; galactosemia;transport defect; tyrosinemia. * excludes fan- weight and external measurements; record and photograph abnormalities as listed in right-hand column. prepare skeletal roentgenograms. radiographs of long bones. submit for tissue culture for possible enzyme analysis. possible or expected findings redlblond hair, fair skin (diminished pigmentation); dehydration;* stigmata of hypothyroidism;* delay of sexual maturation. rickets; osteomalacia.* positive rheumatoid factor. various types of pneumonia after splenectomy, presence of accessory spleen may account for treatment failure. manifestations of portal hypertension.* lymphadenopathy of mediastinal and paraaortic lymph nodes. anemia;* neutropenia sinusoidal lymphocytosis of the liver in felty's syndrome with a review of the liver involvement in felty's syndrome splenic involvement in rheumatic diseases felty's and pseudo-felty's syndrome nodular regenerative hyperplasia of the liver in rheu-matic diseases: report of seven cases and review of the literature fetal alcohol syndrome: craniofacial and central nervous system manifestations goodpasture's syndrome anti-glomerular basement membrane glomerulonephritis: a morphologic study of cases gronblad-strandberg (see "pseudoxanthoma elasticum acute inflammatory polyradiculoneuropathy; guillain-barre-strohl syndrome hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: pathophysiology and treatment cyclosporin-induced hemolytic uremic syndrome: factors that obscure its diagnosis enterohemorrhagic escherichia coli :h : an emerging pathogen hemolytic uremic syndrome as a presenting form of hiv infection hemolytic uremic syndrome in prostatic carcinoma diabetes secondary to genetic disorders. baillieres suprasellar tumors of maldevelopmental origin in klinefelter's syndrome. a report of two cases klippel-feu synonym: congenital fusion of cervical vertebrae primary yolk sac tumor of the prostate in a patient with klinefelter's syndrome extragonodal germ cell tumors are often associated with klinefelter syndrome organs and tissues procedures possible or expected findings external examination prepare roentgenograms of chest, neck, and head skull, spine, brain, and spinal cord myasthenia gravis disorders with dysraphia (see below), fusion of cervical vertebrae. congenital elevation of the scapula (sprengel's deformity) chiari malformation;* basilar impression;* meningomyelocele; platybasia;* spinal cord compression; weight and length; record and photograph abnormalities as listed in right-hand column. record weight and sample for histologic study. if renal transplantation ( ) had been carried out, see also under that heading. follow procedures described under "glomerulonephritis retinal dystrophy ( ) and other retinal changes the cardinal manifestations of bardet-biedl syndrome, a form of laurence-moon-biedl syndrome laurence-moon-biedl syndrome accompanied by congenital hepatic fibrosis pediatric renal transplantation in laurence-moon-biedl syn-drome possible or expected findings typical skeletal proportions. arachnodactyly; pectus excavatum genu recurvatum; dislocation of joints diaphragmatic hernia. * infective endocarditis. * atrial septal defect. * myxomatous transformation of mitral ring. mitral valve prolapse. aortic and pulmonary dilatation and valvular insufficiency.* aortic dissection* with dissection of adjacent vessels. ascending aortic aneurysm multiple cysts (see "cyst(s), pulmonary") aortopulmonary fistula: an uncommon complication in dystrophic aortic aneurysm peripartum acute myocardial infarction in marfan's syndrome aneurysm of the cervical internal carotid artery associated with marfan's syndrome--ease report noonan's syndrome in association with acute leukemia lymphatic dysplasia in a neonate with noonan's syndrome noonan syndrome: a clinical description emphasizing the cardiac findings cerebral arteriovenous malformation in noonan's syndrome clinical variability in a noonan syndrome family with a new ptpnii gene mutation peutz-jeghers syndrome bilateral large-cell calcifying sertoli cell tumor of the testes in peutz-jeghers syndrome: a case report ovarian tumors associated with the peutz-jeghers syndrome robin sequence and a deficiency of the left forearm in a girl with a deletion of chromosome g -gter congenital heart disease in the pierre robin syndrome glossoptosis-apnea syndrome chiari i malformation, caudal regression syndrome, and pierre robin syndrome: previously unreported combination risk factors for squamous cell carcinoma of the esophagus heterotaxy syndrome; ivemark's syndrome possible associated conditions: with asplenia: right isomerism (bilateral mirror-image right-sided symmetry) of heart, lungs, and abdominal viscera; common atrium; total anomalous pulmonary venous connection; absent coronary sinus; complete atrioventricular septal defect;* subpulmonary stenosis;* pulmonary valve atresia;* midline symmetric liver; malrotation of bowel; absent spleen. with polysplenia: left isomerism (bilateral mirror-image left-sided symmetry) ofheart and lungs, with variable sidedness ofabdominal viscera primary immunodeficiencies reiter's syndrome-like patternin aids-associated psoriasiformdermatitis reference pneumothorax;* pneumomediastinum;* pneumoperitoneum. septicemia. right ventricular hypertrophy and/or dilatation. intubation trauma and mural edema and hemorrhage in trachea; hyaline membrane disease intubation trauma. hemorrhages or other evidence of birth trauma; germinal matrix hemorrhages in premature infants; infarctions of subcortical white matter in term infants coalson . pathology of bronchopulmonary dysplasia pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia inborn errors of metabolism and reye's syndrome: differential diagnosis prevalence and non-specificity of microvesicular fatty changes liver histopathology in clinical reye syndrome ultrastructural study of intranuclear inclusions in the exo-crine pancreas in reye's syndrome neuropathologic findings in reye syndrome sanfilippo's (see "mucopolysaccharidosis scheie's (see "mucopolysaccharidosis segawa's (see "syndrome, dystonia severe acute respiratory (sars) note: this highly contagious illness, caused by a coronavirus (sars-cov)details, see biosafety level laboratory for autopsies of patients with severe acute respiratory syndrome: principles, practices, and prospects pathology and pathogenesis of severe acute respiratory syndrome pulmonary involvement in primary sjogren's syndrome polymyositis and sjogren's syndrome associated with bronchiolitis obliterans organizing pneumonia the gastrointestinal manifestations of sjogren's syndrome clinicopathological factors relating malignant lymphoma with sjogren's syndrome acute transverse myelopathy and cutaneous vasculopathy in primary sjogren's syndrome primary localized cutaneous amyloidosis with unusual clinical features in a patient with sjogren's syndrome disease, parkinson's erythema multiforme man related terms: armadillo disease; continuous muscle fiber activity; neuromyotonia autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options sudden infant death (sids) (see "death, sudden unexpected, of infant.") syndrome, superior vena cava related term: superior vena cava obstruction continue dissection of veins into neck and axillas. record and photograph site of thrombosis or of compression by surrounding pathologic conditions. submit samples for histologic study. benign or malignant tumors; fibrosing mediastinitis;* postradiation fibrosis; infectious disease (tuberculosis,* histoplasmosis*); thoracic aortic aneurysm;* chronic constrictive pericarditis;* chest trauma; arteriovenous fistula between ascending aorta and superior vena cava toxic shock synonyms and related terms: staphylococcal scarlet fever. note: ( ) collect all tissues this is a reportable disease. premature aging; increased number of pigmented nevi; infantile sex organs; webbed neck; broad chest with wide spacing of nipples. short fourth metacarpal; abnormal epiphyseal fusions; osteochondrosis-like changes of spine bicuspid aortic valve;* coarctation of aorta. * rarely other anomalies ( ) decreased/absent follicles. intestinal telangiectases. biliary atresia. * horseshoe kidney; double ureters. streak gonads without germ cells or follicles hashimoto's thyroiditis. * manifestations of diabetes mellitus,* hypertension,* or thyrotoxicosis. neuroblastoma and related tumors ( ). keratoconus acute aortic dissection, aortic insufficiency, and a single coronary artery in a patient with turner's syndrome neuroblastoma and related tumors in turner's syndrome turner's syndrome associated with bilateral retinal detachments weil's (see "leptospirosis related terms: alcoholic wernicke's encephalopathy; korsakoff's psychosis; nonalcoholic wernicke's encephalopathy ( , ); and specimen preparation, see chapter . for selection of histologic samples, see right-hand column melissas . wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity syndrome, respiratory distress, of infant.") syndrome, wiskott-aldrich (see "syndrome, primary immunodeficiency malformation, ebstein's" and "preexcitation, ventricular alcoholic and non-alcoholic wernicke's encephalopathy. be alert to the preventable and treatable disease cerebro-hepato-renal syndrome; infantile refsum's disease. * note: this congenital familial cholestatic syndrome results from impaired assembly of peroxisomes and has its main manifestations in the brain, liver, and kidneys postmortem findings and prenatal diagnosis ofzellwegersyndrome. case report alcoholism and alcohol intoxication" and "disease, alcoholic liver possible associated condition: multiple endocrine neoplasia primary cardiac gastrinoma causing zollinger-ellison syndrome localization, syphilis, acquired synonym: treponema pallidum infection. note: congenital syphilis is presented below under a separate heading and surgical management of gastrinoma fundic argyrophil carcinoid tumor in a patient with sporadic-type zollinger-ellison syndrome nonimmune hydrops fetalis due to congenital syphilis associated with negative intrapartum mater-nal serology screening syringomyelia synonyms and related term: hydromyelia; idiopathic syringomyelia; secondary syringomyelia; syringobulbia. possible associated conditions: with idiopathic syringomyelia-arnold chiari malformation, type i;* basilar impression;* . oppenheimer eh, dahms bb. congenital syphilis in the fetus and neonate congenital syphilis: detection of treponema pallidum in stillborns with secondary syringomyelia-intramedullary gliomas (ependymoma, pilocytic astrocytoma) and vascular tumors; spinal arachnoiditis and pachymeningitislisted in right-hand column. prepare roentgenograms of spine and joints. for removal and specimen preparation, see chapter . for histologic sampling, see right-hand column. hypertrophy of body parts. muscle atrophy of upper extremities and hands cervical spinal cord is swollen and tense, with cavitation (syrinx) containing clear fluid. wall of cavity consists of degenerated glial and neural elements, with marked gliosis. spinal cord parenchyma is markedly compressed. see also above under hydrops fetalis caused by alpha-thalassemia: an emerging health care problem limb defects in homozygous alpha-thalassemia: report of three cases poisoning, thallium thirst (see "dehydration thromboangiitis obliterans (see "disease, buerger's purpura, thrombotic thrombocytopenic" and "syndrome, hemolytic uremic the pathological manifestations of pulmonary toxoplasmosis in the acquired immunodeficiency syndrome a spectrum in the pathology of toxoplasmosis in patients with acquired immu transfusion (see "reaction to transfusion bone marrow note: if the patient had symptoms of acute or chronic graft-versus-host disease (gvhd), see "disease, graftversus-host morphology and diagnostics of human toxoplasmosis fatal myocardial coinfection by toxoplasma gondii and parvovirus b in an hiv patient if there is evidence of infection, submit material for microbiologic studies. if there is evidence of recurrent leukemia or lymphoma, sample as described under those headings. if the patient had symptoms of thrombotic thrombocytopenic purpura (tip) or hemolytic uremic syndrome (hus), see these headings. record average size. fix specimens in b-plus®. make touch preparations. request giemsa or wright stain. for preparation of sections and smears (imprints), see chapter . manifestations of graft-versus-host disease (e.g., scleroderma-like changes).* septicemia. interstitial pneumonia* and cytomegalovirus infection* or human herpesvirus infection ( ). bacterial, fungal bacterial or fungal infections in gvhd.* other manifestations of gvhd. * recurrent leukemia,* lymphoma* (including posttransplant, epstein-barr virus associated lymphoproliferative disorder). recurrent solid tumor, e.g., carcinoma of breast, lung (small cell carcinoma), ovary lymphomatous or leukemic infiltrates myeloid cells may be absent in marrow graft rejection or nonimmunologic marrow graft failure. references hematomas; hemorrhagic necroses; infarcts; bacterial or fungal infections leukoencephal-opathy; vascular siderocalcinosis; neuro-axonal spheroids ( ) human herpesvirus infection and associated pathogenesis following bone marrow transplantation pulmonary veno-occlusive disease in an adult following bone marrow transplantation. case report and review of the literature acute renal failure following bone mar-row transplantation transplantation-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome thrombotic microangiopathies associated with drugs and bone marrow transplantation record status of all vascular anstomoses. if there are hemorrhages, record volume and site. record weight, ventricular thickness, and valve circumferences. take multiple sections from all areas of myocardium. cut coronary arteries in cross sections; request verhoeff-van gieson stain. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. references cushingoid features (see "syndrome, cushing's") after steroid therapy. suture dehiscence. hemothorax or hemomediastinum in recent cases. left ventricular hypertrophy, from cyclosporine-related hypertension. acute transplant rejection (for grading, see ref. ). chronic transplant vasculopathy with coronary artery stenosis ( ) opportunistic infection ( ). pneumonia a working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart and lung rejection study group autopsy findings in cardiac transplant patients: a lo-year experience fulminant toxoplasmosis following heart transplantation banff schema for grading liver allograft rejection: an international consensus document record status of all vascular anstomoses. if there are hemorrhages, record volume and site. record lung weights separately. if lung infection is suspected, submit material for microbiologic possible or expected findings cushingoid features (see "syndrome, cushing's") after steroid therapy. suture dehiscence. hemothorax or hemomediastinum in recent cases. opportunistic infection (in patients with a single lung transplant, infections may involve references the nontransplant lung, as well). chronic bronchitis* and bronchiectasis.* acute rejection (rare); chronic airway rejection (obliterative bronchiolitis); chronic vascular rejection. (for grading of rejection, see ref .) post-transplant lymphoprolijerative disorder a working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart and lung rejection study group recurrent salmonella enteritidis and hepatic tuberculosis tularemia synonyms and related terms: francisella tularensis infection; pasteurella tularensis infection cerebral abscesses complicating tularemia meningitis endocrine (see "neoplasia, multiple endocrine any type note: ifthe tumor had been treated by surgery, irradiation, chemotherapy, or other means (the most common situation possible associated conditions: with adrenocortical adenoma-conn's syndrome with adrenocortical carci-noma-cushing's syndrome;* hypoglycemia;* virilization. with pheochromocytoma-cerebellarhemangioblastoma ery-throcytosis; hypercalcemia; hypertension,* multiple enarteries record body weight and abnormal features. photograph skin changes. record heart weight and thickness of ventricles. procure multiple sections of myocardium possible associated conditions.") focal myocarditis. * hypertensive cardiovascular disease (see "hypertension myocardial infarction without severe coronary artery disease (with pheochromocytoma) asystematicreviewoftheassociationbetween barrett's esophagus and colon neoplasm malakoplakia and colorectal adenocarcinoma an unusual case of colonic mixed adenoendocrine carcinoma: collision vs composite tumor. a case report and review of the literature submit lymph nodes for histologic study. remove neck organs with tongue together with esophagus. open pharynx and esophagus in posterior midline. if fistulas and abscesses are suspected, dissect esophagus but leave attached to mediastinum, stomach and diaphragm. record width of lumen of esophagus at various levels. photograph and record size and location of tumor; sample tumor and uninvolved esophagus for histologic study. request pas stain of uninvolved esophagus (sample from all levels). procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. references cachexia. eczematoid dermatitis with adult renal cell carcinoma. cushing's syndrome,* galactorrhea or feminization or masculinization in some cases of renal cell carcinoma. evidence of hyperalcemia. pulmonary tumor embolism after invasion of renal vein and inferior vena cava. acquired renal cystic disease prolactin, renin, and prostaglandins in some renal cell carcinomas. see above under "possible associated conditions wilms tumor associated with polycythemia: case report and review of the literature renal medullary carcinoma: a potential sickle cell nephropathy of children and adolescents acquired cystic kidney disease byler's disease, carcinoid syndrome,*cirrhosis* of any type (mostly nonbiliary), congenital hepatic fibrosis, * cushing's syndrome,* erythrocytosis, genetic hemochromatosis, * glycogen storage disease (type ),* hepatitis b or c virus infection, hereditary tyrosinemia (type i),* hypercalcemia, hypercholesterolemia, hypoglycemia,* neurofibromatosis,* osler-rendu-weber disease* (hereditary hemorrhagic telangiectasia), polycythemia,* porphyria (acute intermittent and porphyria cutanea tarda), * pseudohyperparathyroidism,* and thorium (thorotrast) deposition. with bile duct carcinoma (cholangiocarcinoma}-clonorchis sinensis or opisthorchis viverrini infection, fibropolycystic liver and biliary tract disease,* hepatolithiasis, hypercalcemia, pri-mary sclerosing cholangitis,* and thorium (thorotrast) deposition. with hepatoblastoma-alpha-fetoproteinemia, cardiac and renal malformations, cleft palate, diaphragmatic hernia,* down's syndrome,* familial colonic polyposis,* hemihypertrophy, nephroblastoma. with angiosarcoma-thorium (thorotrast) deposition. see also below under "possible or expected findings describe and photograph cut surfaces. sample tumor and nonneoplastic liver for histologic study. if thorium deposition is suspected, prepare roentgenograms of liver slices and submit samples for energy-dispersive x-ray microanalysis of paraffin sections. procedures depend on expected findings or grossly identified abnormalities as listed above and in right-hand column. cachexia. precocious puberty. feminization and gynecomastia in rare cases of hcc. spider angiomas; clubbing of fingers. see above under "possible associated conditions thorotrast storage may cause cirrhosis, hcc, bile duct carcinoma, or angiosarcoma. see above under "possible associated conditions tumor of the lung or bronchus possible associated conditions: abnormal concentrations of hormons or other metabolites in blood and tumor tissue (adrenocorticotropic, antidiuretic, growth hormone, parathyroid-like substances, or -hydroxyindolacetic acid); acanthosis nigricans s syndrome;*dermal hyperpigmentation; feminization; hyperglycemia; hypercalcemia; hypoglycemia;* hypokalemia; hyponatremia; precocious puberty. for syndromes affecting the brain, peripheral nerves or muscles, see below under "possible or expected findings organs and tissues procedures possible or expected findings external examination and skin record body weight. record abnormal features as listed in right-hand column; prepare photographs. prepare histologic sections of normal and grossly abnormal skin clubbing of fingers; spider angiomas. for other rare tumor-related changes, see above under "possible associated conditions thmor of the pancreas possible associated conditions: with carcinoma of the exocrine pancreas--cushing's syndrome;* diabetes mellitus* (rare); hypercalcemia; hyperglycemia with islet cell tumor-abnormal concentrations of hormons in blood and tumor tissue (see below under "pancreas"); features. dermal hyperpigmentation. for other rare tumor-related changes, see above under "possible associated conditions biliary obstruction caused by tumor in head of pancreas. islet cell tumor with adrenocorticotropic hormone, gastrin, glucagon, insulin, or other peptide hormones. see above under "possible associated conditions paraneoplastic pemphigus associated with pancreatic carcinoma pancreatic cystadenocarcinoma in peutz-jeghers syndrome testes may have been surgically removed to achieve androgen deprivation. urinary obstruction and hydronephrosis. * osteoblastic metastases hemolytic uremic syndrome in prostatic carcinoma thmor of the small intestine possible associated conditions: acquired immunode oncogenic osteomalacia associated with prostatic cancer gardner's syndrome) submit sample of non-neoplastic small bowel for histologic study. procedures depend on expected findings or grossly identified abnormalities as listed above. cachexia. mucocutaneous pigmentations associated with peutz-jeghers syndrome. * carcinoid tumor. lymphoma (see also above under "possible associated conditions"). familial polyposis or related syndrome. * celiac sprue. * crohn's disease. * see above under "possible associated conditions kasabach merritt syndrome in infants paraneoplastic hepatopathy associated with soft tissue sarcoma neurofibro-thmor of the spinal cord possible associated conditions: with angioma-cerebellar hemangioblastoma; segmental cutaneous vascular nevi; with matosis in children with soft tissue sarcoma tissues record abnormal features; photograph and submit nevi for histologic study. for removal and specimen preparation, see chapter . see also below under "vertebral column bone erosion and calcification of spinal canal. vertebral hemangiomas may be associated with arteriovenous malformation of spinal cord. manifestations of von hippel-lindau disease. * thmor of the stomach possible associated conditions: hypoglycemia;* megaloblastic anemia;* skin changes (as listed under "possible or expected findings)weight. record abnormal features; photograph and submit samples of normal and abnormal skin for histologic study. possible or expected findings cachexia; lower leg lymphoedema ( ) metastases common in liver, retroperitoneal and supraclavicular lymph nodes (virchow's node), ovaries (krukenberg tumor), and peritoneal cui de sac (blumer's shelf') carcinoma of the stomach with hyperkeratosis palmaris and plantaris and acanthosis of the esophagus gastric lymphoma ofmucosa-associated lymphoid tissue and helicobacter pylori gastric signet-ring cell carcinoma: unilateral lower extremity lymphoedema as the presenting feature thmor of the testis possible associated conditions: demyelinating neuropathy record location, size, and weight of both testes and of testicular tumor. submit samples of tumor and of ininvolved testis and epididymis for histologic study. snap-freeze tumor tissue for hormone assay. possible or expected findings cachexia. cryptorchism; hypospadia. gynecomastia. increased concentrations of alphafetoprotein and human chorionic gonadotropin testicular microlithiasis. secondary testicular tumors (metastases to the testes) are rare, except in association with leukemia* in children. references pulmonari embolism.* paraneoplastic diseases as listed above under "possible associated conditions chronic inflammatory demyelinating polyneuropathy (clop) associated with seminoma dermatomyositis associated with intratubular germ cell tumor and metastatic germ cell cancer testicular cancer in association with developmental renal anomalies and hypospadias submit samples of lymph nodes, spleen, peyer's plaques, and bone marrow for histologic study. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. references cachexia. dermal hyperpigmentation. pemphigus foliaceus (rare). hypogammaglobulinemia and other immunoglobulin abnormalities. usually, thymoma presents as an infiltrating, anterior mediastinal mass that rarely metastasizes. carcinoid tumor, malignant lymphoma* (hodgkin's disease), and metastases from carcinomaofthe breast* and other tumors also may occur in this location herpes simplex*) and fungal infections (e.g., candidiasis*) due to thymoma-related immunodeficiency ( ). manifestations of paraneoplastic diseases and conditions as listed above under "possible associated conditions thrombotic thrombocytopenic purpura accompanied by transient pure red cell aplasia and thymoma glomerulonephritis associated with myasthenia gravis thymoma and cellular immune deficiency in an adolescent possible associated conditions: with papillary carcinoma-familial adenomatous polyposis thyroid carcinoma associated with familial adenomatous polyposis an association between acromegaly and thyroid carcinoma thyroid carcinoma causing fatal laryngeal obstruction prostate cancer metastasis to thyroid gland schistosomiasis and the risk of bladder cancer in human papilloma virus infection ( ) or herpesvirus infection ( ) with invasive cervical carcinoma. erythropoietin may be found in some tumors. thrombosis. * myopathy* may be associated with carcinoma of the cervix. cerebellar cortical degeneration* may be associated with carcinoma of the uterus. manifestations of uremia (see "failure, kidney") invasive cervical cancer in human immunodeficiency virus-infected and uninfected hospital patients association of risk factors for cervical cancer and human papilloma viruses in invasive cervical cancer association of herpesvirus infection with the development of genital cancer tyrosinemia type ii: a challenge for ophthalmologists and dermatologists hereditary tyrosinemia type i (chronic form): pathologic findings in the liver richner-hanhart syndrome (tyrosinemia ii): early diagnosis of an incomplete presentation with unusual findings acute pancreatitis-associated acute gastrointestinal mucosal lesions: incidence, characteristics, and clinical significance uncinariasis (see "ancylostomiasis uremia (see "failure, kidney from: handbook of autopsy practice urticaria pigmentosa of childhood (see ''mastocytosis, systemic acute aortic dissection;* aneurysma(s) of cerebral arteries; aortic insufficiency;* calcific aortic stenosis,* coarctation of the aorta;* infective endocarditis;* shone's syndrome; turner's syndrome. * organs and tissues procedures possible or expected findings heart if infective endocarditis is suspected, see chapter . open heart in cross-sections (see chapter ). photograph aortic valve and test valvular competence note: reye's syndrome* is a possible postviral complication of varicella that must be distinguished from varicella encephalitis. varicella may also cause exacerbation of tuberculosis.* (i) collect all tissues that appear infected bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions varicella-zoster virus infection in children with underlying immunodeficiency virus infection group a beta-hemolytic streptococcal epiglottitis as a complication of varicella infection optic neuritis: a rare complication of primary varicella infection hsv-l-induced acute retinal necrosis syndrome presenting with severe inflammatory orbitopathy, proptosis, and optic nerve involvement varicella with acute motor axonal neuropathy descending necrotizing mediastinitis in a child with chicken pox double outlet right ventricle with intact ventricular septum respiratory syncytial (see "pneumonia, all types or type unspecified vitamin a (see ''deficiency, vitamin a" and "hypervitaminosis a vitamin bt (thiamine) (see "syndrome, wernicke-korsakott vitamin bt (see "anemia, megaloblastic deficiency deficiency, vitamin d" and "hypervitaminosis d waldenstrom's macroglobulinemia (see ''macroglobulinemia, waldenstrom's.) waterhouse-friderichsen syndrome (see "disease, meningococcal wegener's granulomatosis (see "granulomatosis, wegener's werdnig-hottman disease (see "disease, motor neuron acid esterase activity in cultured skin fibroblasts and amniotic fluid cells using -methylumbelliferyl palmitate which may be secondarily infected by bacteria. dark field microscopy will identify the organism expected findings mucosal ulcers, resembling those of typhoid fever, primarily of distal ileum and colon. villous shortening, crypt hyperplasia with mucosal microabscesses. microabscesses in regional mesenteric lymph nodes zellweger's syndrome (see "syndrome mucormycosis" and procedures under "diabetes mellitus abscesses and granulomas may occur in all organs and tissues. granulomatous lesions in central nervous system ( ) and eyes ( ). fungal osteomyelitis* that may be multifocal, including sites such as metacarpals and metatarsals. external examination other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. osteosclerosis of vertebrae, ribs, clavicles, pelvic bones, scapulae, skull, and metaphyseal ends of femur and humerus. osteomyelofibrosis or osteoreticulosis; rarely, panhyperplasia of bone marrow; increase of megakaryocytes.changes associated with chronic granulocytic leukemia* or with polycythemia vera* may imitate idiopathic myelofibrosis. widespread extramedullary hematopoiesis ( ) with splenomegaly. infectious diseases, including tuberculosis;* gouty arthritis; ascites and other manifestations of portal hypertension;* or hepatic vein thrombosis (budd-chiari syndrome*). cardiac tamponade ( ) . synonyms and related terms: hepatic porphyria; protoporphyrinogen oxidase deficiency ( ) .note: the manifestations of the disease closely resemble those in porphyria cutanea tarda and hereditary coproporphyria. measurements of porphyrins and porphyrin precursors are the only clearly distinguishing features. for autopsy procedures, see under "porphyria cutanea tarda." fibrin and platelet thrombi, with or without microaneurysms and purpura in kidneys, adrenal glands, pancreas, heart, and brain; lesions may also be present in liver; spleen ( ), lymph nodes, muscle, bone marrow, and synovium. fibrin thrombi can be demonstrated with labeled antihuman fibrin antibodies. lesions in precapillary arterioles. hypertrophic osteoarthropathy* (with pleural mesothelioma).pleural effusions. * asbestosis may be complicated by pleural mesothelioma. other organs and tissue sample bladder tumor and uninvolved urinary bladder for histologic study.cachexia. hydronephrosis* (obstructive uropathy) and hydroureter, usually caused by distal ureteral obstruction. recurrent nephrolithiasis* or pyelitis may have been present and is a risk factor for urinary bladder carcinoma.chronic urocystitis; infestation with schistosoma haematobium ( ) (uncommon in north america). manifestations of uremia (see "failure, kidney"). key: cord- -ycj sf z authors: perotin, jeanne‐marie; dury, sandra; renois, fanny; deslee, gaëtan; wolak, aurore; duval, véronique; de champs, christophe; lebargy, françois; andreoletti, laurent title: detection of multiple viral and bacterial infections in acute exacerbation of chronic obstructive pulmonary disease: a pilot prospective study date: - - journal: j med virol doi: . /jmv. sha: doc_id: cord_uid: ycj sf z few studies have evaluated the contribution of multiple virus and bacterial infections in acute exacerbation of chronic obstructive pulmonary disease. this study estimated the burden of multiple viral and bacterial respiratory infections in moderate to very severe chronic obstructive pulmonary disease patients that were prospectively followed‐up during a ‐month pilot study. clinical data were collected monthly and sputum was collected at the time of each acute exacerbation event. classical culture techniques for bacteria and multiplex polymerase chain reaction (pcr) and microarray detection assays were performed to identify viral and atypical bacterial pathogens in the sputum. overall, patients were included and acute exacerbation events were investigated clinically and microbiologically. among the acute exacerbation events, % had evidence of viral infection involving human rhinovirus (hrv) and metapneumovirus (hmpv) in % and %, respectively. intracellular bacteria were not found in sputum by pcr. common bacterial pathogens were identified in % of acute exacerbation patients, most frequently branhamella catarrhalis, streptococcus pneumoniae and haemophilus influenzae. viral or virus and bacteria co‐infections were detected in % of acute exacerbation events (n = ) with hrv and hmpv involved in % of cases. patients with co‐infections did not present greater clinical severity scores at exacerbation and more recurrence of acute exacerbation events at and months than those with single infections (p > . ). these results suggest that hrv and hmpv may be contributors or cofactors of aecopd. these findings indicate that viral or virus and bacterial co‐infections do not impact significantly on the clinical severity of acute exacerbation of chronic obstructive pulmonary disease and recurrence at and months. j. med. virol. : – , . © wiley periodicals, inc. acute exacerbation of chronic obstructive pulmonary disease is an important cause of morbidity and mortality. this disease is associated with worsening quality of life and decline in lung function [seemungal et al., ; donaldson et al., ] . acute exacerbation of chronic obstructive pulmonary disease is triggered by bacterial or viral infection of the airways but the pathophysiological importance of these infectious agents is not fully understood [melbye et al., ; falsey et al., ; dowell et al., ; soler et al., ]. classical bacteria are usually isolated in - % of sputum sampled at the time of acute exacerbation of chronic obstructive pulmonary disease but - % of patients with stable chronic obstructive pulmonary disease have also positive sputum cultures suggesting that bacteria may sometimes be innocent bystanders [sethi et al., ] . the role of viruses has been largely investigated with recent reports describing viral infection in - % of acute exacerbation of chronic obstructive pulmonary disease events. using pcr techniques, the most common detected viruses in upper respiratory airway samples of acute exacerbation of chronic obstructive pulmonary disease patients were rhinoviruses, respiratory syncytial viruses, influenza a and b viruses, parainfluenza viruses, coronaviruses, and adenoviruses [mohan et al., ] . viral infections can also be detected in stable chronic obstructive pulmonary disease patients suggesting that some respiratory viruses may cause persistent lowgrade infection contributing to the pathogenesis of the disease [seemungal et al., ; papi et al., ; mohan et al., ] . only few recent studied investigated the presence of mixed viral and classical and intracellular bacterial infections in sputum samples taken at the time of acute exacerbation event [soler et al., ; bandi et al., ; papi et al., ; wilkinson et al., a; de serres et al., ]. in the present time, the burden of multiple viral and bacterial respiratory infections as contributors of acute exacerbation of chronic obstructive pulmonary disease remains to be investigated. in this prospective -year follow-up study, the burden of multiple viral and bacterial respiratory pathogens was assessed in moderate-to-severe chronic obstructive pulmonary disease patients and its relationship with the clinical severity criteria of acute exacerbation of chronic obstructive pulmonary disease and the frequency of recurrence at and months was assessed. patients with chronic obstructive pulmonary disease were consecutively recruited from the department of respiratory medicine of reims (france) from january to december . chronic obstructive pulmonary disease was clinically defined in accordance with the global initiative for chronic obstructive lung disease criteria (gold) [rabe et al., ] with post-bronchodilator fev < % and fev /fvc < %. at inclusion, all patients were stable with no acute exacerbation of chronic obstructive pulmonary disease for weeks. patients with asthma, bronchiectasis, cancer, or other respiratory diseases were excluded. the hospital ethics committee approved the study (uch reims, champagne ardenne; number - , france) and a written informed consent was obtained from the patients. clinical characteristics of the patients were assessed at the time of inclusion, monthly and at the time of each acute exacerbation of chronic obstructive pulmonary disease event during year. a diary card was given to each patient to determine a daily clinical score based upon self-reported symptoms: dyspnoea, sputum production, and purulence. symptoms were noted as (as usual), (worse than usual), or (much worse than usual). acute exacerbation was defined as a minor worsening (þ ) of at least two symptoms or a major worsening (þ ) of at least one symptom for at least days [seemungal et al., ; sethi et al., ] . patients remained on their regular treatment for the duration of the study. patients were consulting monthly to record changes in symptoms; medication and lung function and they were asked to contact the study team at each acute exacerbation of chronic obstructive pulmonary disease. for each patient a physical exam was performed to assess acute exacerbation of chronic obstructive pulmonary disease severity. arterial blood gases, chest x-ray, and pulmonary functional tests were performed. induced sputum was obtained prior to initiation of aecopd treatment. one week after acute exacerbation of chronic obstructive pulmonary disease event, recovery was clinically assessed and monthly follow-up was resumed. pulmonary functional tests were performed using a body box plethysmograph (medisoft, sorinnes, belgium). sputum samples collected at the time of acute exacerbation were induced with hypertonic saline at %, % then % concentration delivered by ultrasonic nebuliser as previously described . bacteriological assays. samples were homogenized as described previously [sethi et al., ] . serial dilutions were placed on blood, chocolate, and mac conkey agar plates. bacterial identification was performed by standard techniques. sputum isolates were classified as potential pathogens microorganisms or normal flora. potential pathogens microorganisms were: haemophilus influenzae, moraxella catarrhalis, streptocuccus pneumoniae, pseudomonas aeruginosa, staphylococcus aureus, and other gram-negative rods [sethi et al., ] . colony forming units (cfu)/ml were then calculated. classical virological assays. immunofluores-immunofluorescence assays for detection of respiratory syncytial viruses a and b, influenza viruses, parainfluenza viruses, and adenoviruses antigens were performed as described previously [bouscambert-duchamp et al., ] . virus isolates were typed by the standard method of virus neutralization onto cell culture for enteroviruses and by classical immunofluorescence antigen detection assays onto infected cell monolayers [bouscambert-duchamp et al., ; jacques et al., ] . multiplex pcr assays detection of viruses and atypical bacteria. total nucleic acid extraction (dna/rna) was performed using the nuclisens easy-mag instrument (biomérieux, lyon, france). nucleic acids were eluted in a final volume of ml and then stored at À c [boom et al., ; loens et al., ] . clart pneumovir and clart fluavir kits (genomica, madrid, spain) were performed according to the manufacturer's instructions allowing a simultaneous detection and identification of different types and subtypes of human respiratory viruses (influenza a (seasonal a/h n and a/h n and new influenza a/h n v/ strains), influenza b and c, parainfluenza (piv , , , a, b), respiratory syncytial virus (rsv a and rsv b), human rhinovirus (hrv), adenovirus, human enteroviruses, human bocaviruses, human coronavirus e- , human metapneumovirus (hmpv-a and hmpv-b) [renois et al., ] . rt-pcr inhibitors were not detected in the analyzed samples as demonstrated by the positive detection of the internal control [renois et al., ] . each sputum sample was also tested for the presence of intracellular bacteria using a multiplex pcr and microplate assay (chlamylege assay, argene, varhiles, france) allowing the detection of legionella pneumophila, chlamydia pneumoniae, and mycoplasma pneumonia [ginevra et al., ] . hrv genotyping. in cases of positive hrv genomic rna detection, the vp region and part of the vp genome region (vp -vp ) were amplified with specific primers as described previously [savolainen-kopra et al., ; wisdom et al., ] . to determine the rhinovirus type, the obtained consensus sequences of vp -vp were compared to all corresponding hrv sequences available in genbank for each region by using blast software. sequence alignments were performed using the clustal w program (version . ). phylogenetic and molecular evolutionary analyses were conducted using mega (version . ) software and allowed us to perform reliable hrv genotyping identification [savolainen-kopra et al., ; wisdom et al., ] . the sequences generated in the present study have been assigned to the following genbank accession numbers: jq -jq . statistical analyses. clinical or biological data were expressed as mean values ae standard deviation. chi-squared test, mc nemar chi-squared test, fisher's exact test or wilcoxon rank-sums test was carried out when necessary using the sas software, version . . (sas institute, cary, nc). a p-value < . was considered significant. fifty-one chronic obstructive pulmonary disease patients were included consecutively from january to december . according to gold classification, patients ( %) were classified as gold ii (moderate), ( %) gold iii (severe), and ( %) were gold iv (very severe). twenty-five patients ( %) reported at least one acute exacerbation of chronic obstructive pulmonary disease during the -month follow-up (mean: . ae . acute exacerbation event per year; table i ). eleven patients ( %) reported one acute exacerbation of chronic obstructive pulmonary disease, nine patients ( %) reported two acute exacerbations, four patients ( %) reported three acute exacerbations, and only one patient ( %) reported four acute exacerbations. a total of acute exacerbations of chronic obstructive pulmonary disease were reported and analyzed in the study. nine acute exacerbations events ( %) required hospitalization. one patient died from acute respiratory failure. the retrospective analysis of diary cards showed that acute exacerbation events were not reported. comparison between patients with no reported acute exacerbation of chronic obstructive pulmonary disease, one acute exacerbation of chronic obstructive pulmonary disease, and > acute exacerbations of chronic obstructive pulmonary disease did not show any differences, except a slight difference for age ( ae years for no acute exacerbation vs. ae years for > acute exacerbation events, p < . ; table i ). sputum samples were analyzed in acute exacerbations of chronic obstructive pulmonary disease (table iia) . no pathogen was found in acute exacerbations of chronic obstructive pulmonary disease ( %). viruses were detected by pcr in ( %) acute exacerbations of chronic obstructive pulmonary disease cases: one virus in eight cases ( %), two viruses in two cases ( %), and co-infection virus and potential pathogen microorganisms in cases ( % ; table iib ). hrv or hmpv represented % of detected viruses. as expected, viral detection rates by pcr were significantly greater than those observed by classical viral culture assays ( % vs. %, respectively, p < . ). hmpv was mainly detected in spring whereas hrv was predominant in autumn and spring (fig. ) . in case of positive hrv detection at time exacerbation (n ¼ ), hrv genotyping assay on vp /vp capsid viral genes was performed as previously described [wisdom et al., ]. these genotyping results identified several hrv phylogenetic groups corresponding to the common geno-groups a (serotypes and ) and b (serotype ) and interestingly to the newly described geno-group c (not shown). potential pathogen microorganisms were detected in acute exacerbations of chronic obstructive pulmonary disease ( %): one in cases, two in one case, and three in one case (table iia) . m. catarrhalis, h. influenzae, or streptococcus pneumoniae were found in % of potential pathogen microorganism detection. the bacterial load in positive samples was cfu/ml or greater. intracellular bacteria (legionella pneumophila, mycoplasma pneumoniae, and chlamydia pneumoniae) were not found in sputum samples at time of acute exacerbation of chronic obstructive pulmonary disease by pcr. viral or virus and bacteria co-infections were detected in % of acute exacerbations of chronic obstructive pulmonary disease (n ¼ ). hrv and hmpv were involved in / co-infections ( % ; table iib) . hrv was associated with h. influenzae in four co-infection cases ( %). the influence of the viral infection and the impact of multiple infections on severity of acute exacerbation of chronic obstructive pulmonary disease were analyzed. interestingly, viral detection by pcr at time of acute exacerbation of chronic obstructive pulmonary disease was not associated statistically with the severity of exacerbation in term of hospitalization rate and clinical score, fev and pao variations from baseline (p > . ; table iii ). in addition, coinfections cases (virus/bacteria or virus/virus) did not present greater clinical severity scores at exacerbation than those with single infections (p ¼ . ; table iii ). next, we analyzed the potential statistical relationships between the frequency of acute exacerbation recurrence and multiple infections. we observed no significant statistical differences in the frequency of recurrence after acute exacerbation of chronic obstructive pulmonary disease between patients with À . ae À . ae . ae . À . ae À . ae . data are presented as mean ae sd. d, difference from baseline. a no significant differences between all groups. and without multiple viral or bacterial infections at months ( % vs. %, respectively, p ¼ . ) and at months ( % vs. %, respectively, p ¼ . ; data not shown). multiple infection rates were not significantly different in cases of frequent (> per year) or infrequent acute exacerbation of chronic obstructive pulmonary disease (< per year) ( % vs. % of exacerbations, respectively, p ¼ . ). finally, co-infected patients did not present greater clinical severity scores at exacerbation and more recurrences of exacerbation at and months than those with single infections (p > . ; table iii) . several studies have measured the burden of viral or bacterial infections, but only few have assessed the importance of both pathogens and the presence of mixed viral or virus and bacteria multiple infections [soler et al., ; de serres et al., ] . in this prospective -year follow-up study, patients were included and acute exacerbation events were clinically and microbiologically investigated. of the acute exacerbation events studied, % had evidence of viral infections, % demonstrated classical bacterial pathogens, and % had evidence of multiple viral or virus and bacteria co-infections (table ii ). the detection rates of classical bacterial pathogens and of respiratory viruses by rt-pcr techniques were in agreement with those previously published in recent reports [melbye et al., ; falsey et al., ; dowell et al., ; soler et al., ; de serres et al., ] . however the distribution of type of respiratory viruses appeared to be different from previously published studies with identification of hrv and hmpv as the primary contributors to acute exacerbation while rsv and influenza were infrequently detected during this -year pilot study. potential pathogen microorganisms were detected in % of acute exacerbation events demonstrating as previously described the predominance of m. catarrhalis, haemophilus influenza, and streptococcus pneumoniae that represented % of classical bacteria. no intracellular bacteria were detected at time of acute exacerbation events in patient with chronic obstructive disease (table ii) . in the present study, hmpv was identified as one of potential primary contributors of acute exacerbation events whereas this respiratory virus has been rarely detected at time of exacerbation in previous studies ranging from % to . % with a weighted mean prevalence of . % in a recent review (table ii) [beckham et al., ; rohde et al., ; mohan et al., ] . these discrepant results could be explained by the sensitivity of the used techniques and by the design of the study or the temporal epidemiological characteristics. hrv was previously identified as a one of the major contributor of acute exacerbation of chronic obstructive pulmonary disease and interestingly our genotyping analyses showed that the geno-group c could trigger acute exacerbation events. because hrv group c strains are not easily detectable by classical culture techniques; these results indicate the need to use pcr techniques to explore the relationship between virus infections and acute exacerbation of chronic obstructive pulmonary disease. in the present study, viral respiratory pathogens were detected by use of a multiplex pcr-dna and microarray detection assay allowing a rapid and accurate detection of conventional and newly discovered viral respiratory pathogens. respiratory viruses were detected in % of acute exacerbations of chronic obstructive pulmonary disease by multiplex pcr-dna microarray system, a rate . higher than those obtained by classical viral detection techniques. however, this qualitative molecular approach was not able to distinguish an ongoing infection from a chronic or persistent viral shedding [seemungal et al., ; kuypers et al., ; de serres et al., ] . further prospective clinical studies testing the viral load levels at time of acute exacerbation versus stable state are now necessary to differentiate ongoing infection from past or beginning viral infections in acute exacerbation of chronic obstructive pulmonary disease cases. one of the main objectives of this study was to evaluate the potential relationships between multiple bacterial and viral infections and the severity and risk of recurrence of acute exacerbation of chronic obstructive pulmonary disease. in the present study, multiple infections were not related to demographic characteristics, smoking history, lung function or inhaled treatment, in accordance with previous studies [seemungal et al., ; wilkinson et al., b ]. finally, clinical outcomes of acute exacerbation of chronic obstructive pulmonary disease that were depending on multiple infections were analyzed. mixed infections (virus-virus or virus-bacteria) were not found to be associated with the severity of acute exacerbation of chronic obstructive pulmonary disease or with an increased risk of recurrence at and months (p > . ). a recent study using pcr detection methods for nasal aspirate samples described that acute exacerbation of chronic obstructive pulmonary disease cases of mixed virus-bacterial infections do not appear to be more severe among virus-infected patients [de serres et al., ] . the present study provides additional data on the impact of mixed virus or bacterial infections onto the clinical severity and the risk of recurrence of acute exacerbation that are critical elements in chronic obstructive pulmonary disease management. however, it must be pointed out that the present monocentric study was conducted in a relatively low number of chronic obstructive pulmonary disease patients and acute exacerbation of chronic obstructive pulmonary disease events. further multicentric studies involving larger population are needed to come to definitive conclusions regarding the clinical impact of multiple infections in acute exacerbation of chronic obstructive pulmonary disease. the present results demonstrated chronic obstructive pulmonary disease patients infected by two respiratory viruses therefore suggesting a potential intrinsic susceptibility to particular triggers of acute exacerbation of chronic obstructive pulmonary disease [seemungal et al., ] . this susceptibility could be related to polymorphism of genes encoding ccl , a chemotactic factor for leukocytes [takabatake et al., ] , mannose binding lectin (mbl ) [yang et al., ] or surfactant protein b [foreman et al., ] , altering host defense factors against pathogens. recently, an experimental human model of hrv infection clearly showed the role of hrv as triggering factor in acute exacerbation of chronic obstructive pulmonary disease [mallia et al., ] . a deficient induction of type iii interferon-l by hrv in asthmatic primary bronchial cells and alveolar macrophages was correlated with the severity of hrv related asthma exacerbation [contoli et al., ] . the hypothesis of a lower immunological response against viral infections in acute exacerbation of chronic obstructive pulmonary disease remains to be investigated in further clinical prospective studies. in conclusion, these results suggest that hrv and hmpv may be contributors or cofactors of acute exacerbation of chronic obstructive pulmonary disease. these findings indicate that viral or virus and bacterial co-infections do not impact significantly on the clinical severity of acute exacerbation of chronic obstructive pulmonary disease and recurrence at and months. infectious exacerbations of chronic obstructive pulmonary disease associated with respiratory viruses and non-typeable haemophilus influenzae respiratory viral infections in patients with chronic, obstructive pulmonary disease rapid and simple method for purification of nucleic acids detection of human metapneumovirus rna sequences in nasopharyngeal aspirates of young french children with acute bronchiolitis by real-time reverse transcriptase pcr and phylogenetic analysis role of deficient type iii interferon-lambda production in asthma exacerbations importance of viral and bacterial infections in chronic obstructive pulmonary disease exacerbations relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults respiratory syncytial virus and influenza a infections in the hospitalized elderly polymorphic variation in surfactant protein b is associated with copd exacerbations development and evaluation of chlamylege, a new commercial test allowing simultaneous detection and identification of legionella, chlamydophila pneumoniae, and mycoplasma pneumoniae in clinical respiratory specimens by multiplex pcr association of respiratory picornaviruses with acute bronchiolitis in french infants comparison of real-time pcr assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children evaluation of nuclisens easymag for automated nucleic acid extraction from various clinical specimens experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation pneumonia-a clinical or radiographic diagnosis? etiology and clinical features of lower respiratory tract infection in adults in general practice prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: gold executive summary rapid detection of respiratory tract viral infections and coinfections in patients with influenzalike illnesses by use of reverse transcription-pcr dna microarray systems relevance of human metapneumovirus in exacerbations of copd ' noncoding region alone does not unequivocally determine genetic type of human rhinovirus strains effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease new strains of bacteria and exacerbations of chronic obstructive pulmonary disease airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (copd) requiring mechanical ventilation a single nucleotide polymorphism in the ccl gene predicts acute exacerbations in chronic obstructive pulmonary disease effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd respiratory syncytial virus, airway inflammation, and fev decline in patients with chronic obstructive pulmonary disease screening respiratory samples for detection of human rhinoviruses (hrvs) and enteroviruses: comprehensive vp -vp typing reveals high incidence and genetic diversity of hrv species c mannose-binding lectin gene polymorphism predicts hospital admissions for copd infections key: cord- -xhx pzhj authors: nan title: nd world congress on pediatric intensive care rotterdam, the netherlands, – june abstracts of oral presentations, posters and nursing programme date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: xhx pzhj nan we present the results of a prospective population-based audit of paediatric intensive care activity in two comparable communities with markedly different delivery systems. in the trent region of the uk ( . million people), children receive intensive care largely without the supervision of a paediatric intensivist in a variety of hospitals, few of which have designated paediatric intensive care units (picus). critically ill children otherwise receive intensive care in children's wards, special care baby units (scbus) or adult intensive care units. in the australian state of victoria ( . million people), children receive intensive care almost exclusively in one centre -a picu staffed by full time paediatric intensivists. the two regions are otherwise demographically comparable. in both groups, data were collected on all children admitted to an intensive care unit between / / and / / and children who received intensive care (defined by levels of intervention and nurse dependency) in other sites during the same period. values of each variable at first contact with the icu, and the highest and lowest values over the first hours were recorded. the principal outcome was survival to discharge from the intensive care unit. severity of illness was assessed using pim (paediatric index of mortality) and prism. risk-adjusted mortality was compared using flora's z test and logistic regression. the rate of utilisation of intensive care (> admissions in each region) were similar. there was some variation in case mix between the two groups, but crude mortality rates were similar ( . % in trent and . % in victoria). however severity corrected data and other measures of picu performance were dramatically better in' the centralised delivery system. the substantial excess mortality in the trent region provides strong evidence for the benefits of centralisation of paediatric intensive care services. there are considerable difficulties in evaluating the efficiency and effectiveness oflcare in children presenting with respiratory failure during acute medical illness. optimal outcomes for such episodes include survival and the shortest length of stay (los) in intensive care with negligible risk of readmission. we have tried to determine whether or not the time course of acute severe medical illness with respiratory failure is predictable. study i (n= ): a retrospective study of intubated and mechanically ventilated children (> days, < years) with acute severe medical illness. measures: diagnosis, intensive care los in calender days, and survival. results: the underlying diagnosis fell within one of three broad categories: respiratory disease (n= , mortality . %), central nervous system (cns) disease (n= , mortality . %), and systemic inflammation or multisystem (sims) disease (n= , mortality . %. the los in survivors was: respiratory -median (interquartile range) ( - ) days, cns ( - ) days, £p, £ ( -g) days. :i'~'-+cen diag~,~is-rc!ated-grnnp~ (drgs) were identified ( respiratory, cns, sims disease) and each have been characterised by mortality and los. study ii (n= ): a prospective study of patients supported by the hypothesis that los for the above drgs was predictable (compared with study i data). in certain instances attributable causes for variances in los were identified: e.g. disease severity, timing ofdrug therapy, and associated disease. with daily paediatric risk of morality scoring within each drg, four profiles of instability were identified. discussion: the time course of acute severe medical illness with respiratory failure is predictable and variance may be attributable to specific care or diagnostic factors. we are now developing a means of linking drg-specific clinical care pathways with an integrated computerised decision support and education facility at the bedside. the objective of this open, prospective study was to assess the relation between basic patient characteristics as well as effectiveness of treatment on the one hand and resource utilization in pediatric intensive care on the other. as universal, non-monetary indicators of resource utilization we used the therapeutic intervention score system (tiss) and length-ofstay (los), from which indicators for total resource utilization per admission (tisstot) and average daily resource utilization (tiss-mean = tisstot/los) were obtained. overall admissions, totalling days, were included. mortality was . %; non-survivors accounted for . % of overall resource utilization. in non-survivors, both total resource utilization per admission and average daily resource utilization were higher, whereas los was not different from survivors'. severity of illness, surgical status, the presence of substantial chronic comorbidity, emergency admission and transfer from another hospital constituted the major predictive determinants of tisstot (r:= . ) and tissmean (ra= . ) in multiple regression analysis (p< . ). hence these indicators are appropriate non-monetary measures of resource utilization, a considerable proportion of which are determined by a concise set of basic clinical characteristics. subsequently we analysed the relation between effectiveness of care and resource utilization by assessing severity of illness corrected mortality in low, medium and high resource users, respectively. these categories were delineated by percer/tiles of resource utilization (< p , p -ps , > ps ). despite on average long los and high resource utilization in the high risk group, a relatively low standardized mortality was found, probably warranting prolonged intensive treatment in this patient category. summary: objective:the primary purposes of intensive care are to provide treatments to patients with life-threatening physiological dysfunction or to monitor and observe patients perceived to be at significant risk of dying. this collaborative study was performed to describe our patients and their outcome. in order to improve our results we tried to identit~ high risk groups, patients and methods: picus entered the study, the data included all the admissions with > hs. during a days period between the l°june and the th september . the records included: age, sex, weight, mechanical ventilation (mv), post-operative condition (p.op), malnutrition, diagnosis, length of stay, prism score and outcome. student test, mann-whitney or wileoxon were performed for univariate analysis. fisher exact test or chi square for dicotomic variables. risk group analysis was performed by logistic regression, odds ratio and % confidence interval. results: patients entered the study. mean age was . months (ds hh¢# ) and median months. we found significant statistical differences in calculated ,is observed mortality rate comparing malnourished with euthrofic patients; mechanical ventilated (mv) with non mv patients. no differences in ter ~,h of stay or di~ noses were found. effect of the un sanctions on the morbidity rate araong the iraqi small children ( below years old of age ) in bagdad. abdulsamad a.abood / institute of medical technology, bagdad. meningitis is essentially a childhood disease (i). the risk of infection are increased by powerty and overcrowding ( ). the impah'ed immunity may be an important pathogenic factor underlying the susceptibility to infections in undernourished subjects ( ). in general, malnutrition is a man made disease and it begins quite in the womb and ends in the grave (i). small children, below years of age were admitted to the pediatric hospital in washash with meningitis over cold months in i , in contrast to only child admitted with meningitis over the same period in . all of the children who admitted in were frankly undernourished, % of them were infected with enterobacteriae, because they were exposed to faulty hygiene and lack of asepsis. these facts showed precisely that our small children had suffered at most from the un_ sanctions against iraq, because of food, milk and drug shortage, since years which had resulted a severe undernutrition among them, which impaired their immune status. m wells, of riera-fanego, j lipman. baragwanath intensive care unit, university of the witwatersrand, south africa. background the use of prism or other scoring systems in the icu is of great importance for evaluating the efficacy and efficiency of a particular icu, the prism score was developed and validated in the usa and europe but has recently been shown to be inaccurate in a south american population, a south african population as well as several european studies. part of the poor performance of the prism score is as a result of differences in the case mix between the reference population and other paediatric icus. since scoring systems should generally be used only in populations similar to the reference population from which the prediction model was developed, a modification of the prism score is necessary to improve its discriminatory ability in a wide range of patient groups, aim to improve the predictive power of the prism score in a south african paediatdc icu population. patients & methods we analysed prism, demographic and clinical data collected prospectively from consecutive paediatrie icu admissions. the prediction of actual mortality by prism was evaluated by standard statistical methodology (goodness-of-fit test and receiver operating characteristic (roc) analysis), the components of the prism logistic regression equation (prism score, operative status and age) and the physiological variables making up the prism score in addition new variables analysed (nutritional index, the need for inotropes and institution of mechanical ventilation) were subjected to discriminant analysis to determine their association with outcome. results the goodness-of-fit test showed a significant failure of prism to accurately predict mortality over a wide range of expected mortality (chi [ ] = , p = ). prism underpredicted mortality at lower prism scores, but overpredicted mortality in patients with high prisms. similarly roc annysis indicated apoor predic~jve power (az = . ± . ), with an area under the curve significantly less than that for the prism reference population (p = ), prism showed equally poor discriminatory function at all age groups and diagnosfic categories. '~mth the addition of an index of nutrifional status (proportional weight-far-age), and indicators of early respiratory and cardiovascular failure to the logistic regression formula, and a recalibration of the acute physiological score component, the roc can be improved to . ± . , with a good fit described by the goodness-of-fit test (cn ] = , p = . ). discussion the prism score is not accurate in our patient population has been recalibrated in view of the poor discriminatory function that we have shown. part of the inaccuracy derives from the different demographic characteristics of our icu population and a different pattern of diseases. in addition to assessments of acute physiological aberrations, an assessment of nutritional status and early respiratory and cardiovascular failure significantly improve the discriminatory ability of the prism score, these parameters have been devised with a view to improving the accuracy of prism in our population, while not decreasing its accuracy in icus similar to the reference population. in interviewing parents regarding how physicians have communicated bad news, the response i have received is that it has not infrequently been done without appropriate care, understanding and compassion. personal experience and the lessons learned from parents, chaplains and others who deal extensively with these situations have provided me with an approach that has been supportive, compassionate, and caring. an especially difficult communication situation for the intensivist occurs when the parents have to be informed of the death of their child. for the parent, death is the hardest loss of all -the ultimate unalterable loss. circumstances surrounding the death are an important consideration (e.g., a fatal crash caused by a drunken driver, a prolonged illness, a suicide, aids). each produces a different grief reaction. the physician needs to inform parents of their child's death sympathetically coming right out with the news and leaving details until later. allow pauses and time for the paren~ to express sorrow and grief, the best communication may be thoughtful silence and a tender touch. there is disbelief that this happened. it is necessary to repeat oneself. acknowledgment of the parent's "feeling terrible" and the physician's acknowledgment of how terrible he/she feels that the life of the child could not be saved is an important first step in the parent's dealing with this tragic loss. with prolonged resuscitation, it is helpful to have a member of the icu team talk to the parents while the resuscitative efforts are ongoing so that the parents are not left unsupported at this time. a progress report should be delivered in a caring, lucid, and sensitive.manner, indicating that every effort is being made to save the life of their desperately injured child. after a child has died, it is helpful to the family if the physician maintains some contact with them. this should take the form of follow-up telephone calls at approximately , , and months. this can help to screen for depression in the parents. in giving bad news to the family and making every effort to support them through this tragic time, it is necessary to remind oneself that the intensivist has personal needs for dealing with grief and will also require support to pass through this stage. direct evidence that child mortality is lower in specialist pediatric icus comes from studies. a study in oregon (ccm ; : - ) found that mortality adjusted for severity of illness was % of expected in pediatric units and % of expected in general units (p< . ). a study in holland (ccm ; : - ) found that mortality in high risk patients was % of expected in tertiary pediatric units, and % of expected in nontertiary units (p< . ). a third unpublished study, has found that children in victoria (who almost all receive intensive care in a pediatric icu) have a much lower standardised mortality rate than children in the trent region of the uk (where many children receive intensive care in adult icus). there is indirect evidence that icus looking after many children are likely, on average, to perform better than icus looking after few children: numerous studies in many specialities have found that units looking after many cases of a particular disease have better results than units with few cases. see luft hs, "hospital volume, physician volume, and patient outcomes", happ, ; and farley d, medical care ; : - . compared to general icus, medical and nursing staff in pediatric icus are likely to be better at looking ~fter children, and plcu rmos have greater skills in pediatric intubation, ventilation, iv drip insertion and drug doses. picus are more likely to have appropriate equipment to manage children -especially for uncommon but life-threatening situations. icus in pediatric hospitals are more likely to have physicians and surgeons with pediatric expertise available for consultation at all times. the american academy of pediatrics, the society of critical care medicine, the british paediatric association and the australian nh&mrc have all said that children should receive intensive care in'specialist pediatric units. the weight of authoritative opinion, and direct and indirect evidence is strongly in favour of looking after children in dedicated pediatric icus. neurological deficit showed higher cbf values ( . / . ml/ g/ rain.) than the patients with good outcome (mean cbf . sd + . ; cbf . sd _+ . ml/ g/rain}. discussion: in asphyxia decrease of ph is due to reduced tissue oxygenation and indicates the severity of metabolic derangements. co reactivity in newborns with perinatal asphyxia correlates with the lowest ph and therefore may reflect severity of asphyxia. continuous monitoring of cerebral activity is carried out in our unit on all admissions at risk of cerebral dysfunction, a number of monitors are commercially available and we report our experience with the cfam which provides in addition to amplitude integrated eeg analysis, continuous raw eeg display and frequency distribution. bilateral recordings are commenced as soon as possible and continued while clinically indicated. forty one children ranging in ages from weeks to years were monitored for periods from hours to i days, diagnoses included traumatic brain injury ( ), sepsis/meningitis/encephalitis ( t), status epilepticus ( ) and miscellanous others ( ). results are tabulated below. patients status epilepticus * beta activity * background voltage * < i o/zv or more of above * (*z p < , ) asymmetry developed in children, all of whom died. positive predictors of good outcome included a mean background activity of > zzv, the presence of faster frequencies (usually ) in response to sedative drugs and the absence of seizures. all monitoring is performed by the picu staff and increasing expertise in interpretation has resulted in earlier therapeutic and diagnostic interventions. regional it was previously found that histamine, a vasoactive mediator, accumulated in brain compartments (kov~ics et al neurosci lett : ) , and antihistamines prevented brain edema formation (dux et al. neuroscience : ) in asphyxiated newborn pigs. in the present study we investigated the effect of intracarotid histamine injection on the blood-brain barrier (bbb) permeability, left internal carotid artery of newborn pigs ( - h; , - , g; ketamine anesthesia, mg x kg ) was catheterized through the external branch and different doses of histamine ( , - , xi - , - , x , m, respectively, in groups of animals; n= in each) diluted in . ml isotonic saline was injected into the vessel through rain. bbb permeability was determined for a small (sodium fluorescein, sf, da) and a large (evans blue/albumin, eba, kda) tracer ( %, mlxkg , rain circulation time for both dyes) concomitantly in frontal, parietal and occipital cortex, hippocampus, and periventrieular white matter both on left and right sides h after the challenge. then, intravascular dyes were removed by perfusion and bbb permeability for both tracers was quantified by fluorescence spectrophotometry (wavelengths for excitation and emission were nm and nm for sf; and nm and nm for eba, respectively). histamine injection, in doses higher than . m, significantly (p< . ; kruskal-wallis one way anova on ranks followed by dunn's test) increased bbb permeability for both tracers in each brain region. changes in left hemisphere were more intense (p< . ) than those in right one after the doses of xi - and - m in each region, i m histamine administration induced similar edema in both sides. increased intracarotid histamine levels resulted in a dose-dependent vasogenic brain edema formation. histamine might have a pathogenetic role in neonatal hypoxicischemic cerebral injuries. supported by otka f- and h-u.s,-jfno. , $ in coma caused by traumatic brain jnjury, an indication of the likely outcome is provided by the best motor response to pain in the first .$ hours after the insult. in a study in our picu, the proportion of children who died or had a severe disability was % in who had no response to pain, % in with an extensor response, % in with a flexor response, and % in who localized in response to pain. the long term outcome of traumatic brain injury appears to be worse in children < years old. other risk factors in traumatic brain injury are absent basal cisterns, midline shift or subdural haemorrhage on ct scan (or loss of grey-white differentiation in nontraumatic injury); or an intracranial pressure > mmhg despite hyperventilation, mannitol and barbiturate infusion. apart from brain death, there are two findings implying such a poor prognosis that consideration should be given to stopping treatment: first, after traumatic injury, the absence of any motor response to painful stimulus in the cranial nerve distribution (providing drug effects and a post-ictal state have been excluded); and second, in acute brain injury from trauma, infection, hypoxia, or ischaemia, the b{lateral absence of short-latency somatosensory evoked potentials (providing brain stem haemorrhage, subdural and extradural effusions, and decompressive craniectomy have been excluded). in children over months of age, recovery from prolonged coma or a vegetative state is exceedingly rare when more than months have elapsed after traumatic brain injury, and when more than months have elapsed after nontraumatic injury. overproduction of nitric oxide (no) via an inducible isoform of" no synthasc (inos) produces profound vasodilatation in adult septic shock. high nitrate levels have been reported in hypotensive children with sepsis syndrome ]. cardiovascular collapse is a prominent feature of severe meningocoecai disease (mcd). however, systemic vascular resistance (svr) was slightly higher in a group of non-survivors ~ and the rote of no in ivicd remains unclear. children with a presumptive diagnosis of mcd were enrolled. parental consent was obtained. blood was drawn on admission and hrly thereafter. plasma was separated immediately and stored at - °c. the final concentrations reported represent the product of nitrite and nitrate (nox). nox was measured spectrophotometrically using the greiss reaction. children were studied (median age (range); m ( - )). the diagnosis of mcd was confirmed in children, of whom had a glasgow meningococcal score (gms) of" ~ . in this group with severe mcd there were deaths. peak nox was significantly higher (,. ( - ) vs ( - )nmol/ml, median) and systolic btood pressure was significantly lower in children with severe mcd than mild mcd (p< . . wilcoxon rank test). there was a significant correlation between peak nox and gms (spearman's rank correlation r= . (p= . )) and prism (r= . (p: . )). nox production from adm.ission onwards was also higher in the severe mcd group (p: . , kmskal ~wallis). we have demonstrated that plasma nox levels are elevated in children with mcd, correlate directly with the severit ' of disease and are inversly related to systolic blood presssure. similar to hypotensive septic syndrome, mcd appears to be associated with an up-regulation of the l-arginine-no pathway.. non-survivors with mcd have higher svrs and may be relatively hypovolaemic. in our group of severe mcd there was a significantly lower systolic pressure and increased no formation. excess inos expression at different stages in mcd may contribute to the pathology of the disease. the identification of agents which can boost and/or inhibit no reiease may therefore represent different treatment strategies for mcd. u. merz, th. peschgens, g. kusenbach, m. b hle, h. h rnchen in this controlled, prospective study ventilated premature infants with a birth weight < g were randomized to receive treatment with dexamethasone (dex) either on day of life or on day of life. dex was given over days tapering from . mg/kg/day to . mg/kg/day. the infants treated with dex on day of life could be weaned earlier from the ventilator -in median after days (range - ) versus days (range - ) in the [ate treatment group (p = . ). the need for supplemental oxygen was shorter in the early treatment group -in median days (range - ) versus days (range - ) (p = . , ns). the incidence of chronic lung disease was lower in the early treatment group - of infants ( . %) versus of patients ( . %) (ns). to evaluate the long-term efficacy of early dex treatment we performed a respiratory function test in the age of - months using an infant whole body-plethysmograph. the intrathoracic gas volume (itgv), the airway resistance (r.w) and the airway conductance (gaw) were measured and no significant differences could be detected between the groups. the frequency of adverse effects due to dex therapy was found to be without significant differences between the early and the late treatment group. we conclude that early dex treatment had short-term improvements in pulmonary outcome in our study population, long-term efficacy however, remained unproven. several factors contribute to the development of chronic lung disease (cld) in premature infants including structural immaturity of the lung, mechanical ventilation, and oxidative stress. reactive oxygen species are formed during normal cellular metabolism but they are generated in higher concentrations during inflammation or inhalation of high oxygen concentrations. to study the relationship between increased oxidative stress, antioxidants and the development of cld we examined ventilated premature infants with birth weights below t g. infants developed severe chronic lung disease of prematurity (cld), defined by radiological signs of cld and an increased oxygen requirement at a postconceptional age of weeks, and infants had moderate cld with an increased oxygen requirement on day but not at an age of weeks. ventilator settings (fio , peak inspiratory and mean airway pressure) and the incidence of early-onset-sepsis were significantly higher in the severe cld group than in infants with moderate cld or without cld (n= ) during the first week of life. plasma concentrations of the two antioxidative substances bilirubin and uric acid (ua) were comparable in all groups during the first days of life. however, on day seven bilirubin and ua were significantly decreased in the plasma of infants with severe and moderate cld compared to the non cld group (p<o. ). there was no difference between both cld groups. in serially obtained tracheal aspirate fluids (taf) malondialdehyde (mda) was measured by hplc as an indicator of lipid peroxidation reflecting oxygen injury of the lung. ua was found in higher concentrations in taf than bilirubin. ua has been proven to be a potent antioxidant, capable to react especially with hydroxyl radicals and hydrochlerous acid, which play an important role in the induction of lipid peroxidation. infants with severe cld had significantly higher mdnua ratios in taf from day to compared to the non-cld group (p<o. ). mdnua ratios in taf of infants with moderate cld were significantly higher from day on but still lower than in the severe cld group. in addition, the ratio oxidized / reduced glutathione was significantly increased in taf of infants with cld compared to infants without cld between day and . the data support the hypothesis that an imbalance of oxidative stress and antioxidant defense contributs to the onset of cld at the end of the first week of life. introduction. rocuronium bromide (roe), a neuromuscular blocking agent with an onset time dose to that of succinyleholine l'z, has been studied in american society of anesthesiologists' physical status (asa) i or ii pedlatrie patients under non-critical elective conditions. there is a paucity of studies looking at the pharmacodynamics of roc under emergent conditions, involving pediatric patients who are asa iii or iv, without the use of adjuvant inhaled anesthetics ~. methods. with approval of our committee on clinical investigations (irb), roe . mg/kg was administered to asa iii/iv pediatric intensive care patients (age days to months; m:f= : ) on intravenous sedation. the time to reach % a~d % of b~elinc tetanie stimulus response was recorded using a r.elaxogra'ph/qmt- nerve stimulator/recorder (datex, helsiaki). depth of clinical relaxation at the % level was recorded. results. the time from rapid bolus to % was . + . see with a range of - see; and to % was . + . see, with a range of - see. at the % level, excellent clinical relaxation was seen. conduslon. in critically ill children, use of roe at . mg/kg produces rapid onset of neuromuscular blockade and excellent clinical relaxation, such that roe should be considered for rapid sequence intubation. int anesth clin. ; ( ): - . anesthesiology. ; ( ) computed tomography of the chest (ct) in mechanically ventilated adults can detect intrathoracic pathology not appreciated on chest radiographs (cxr) and influence intensive care management. no such data exists for ventilated children. aims: ) to assess if ct provides additional information over cxr regarding extent and nature of intrathoracic disease in ventilated children. ) to determine whether such information alters clinical management, inclusion criteria : ventilated children with cxr changes inconsistent with their respiratory status underwent ct if either a) pao :fio ratio < and/or mean paw> cm h or b) there was an unexplained increase in ventilatory requirement. methods : high resolution ct was performed in patients and spiral ct in patierits, to ensure minimal transport related morbidity, patients were transferred to the ct scanner by a specialised mobile intensive care team. results: in / patients ct demonstrated greater extent of disease than appreciated on cxr but did not significantly alter clinical management. in / patients ct provided additional information regarding the nature of disease present, in / children this involved a further diagnosis and in / children the exclusion of a suspected pathology. new information led to a positive therapeutic intervention in children, prevented inappropriate manoeuvres in , and had no significant effect on acute management in children. conclusions: initial data suggests that in a selected group of mechanically ventilated children chest ct can add to the sensitivity and specificity of intrathoracic diagnosis provided by the chest radiograph and directly influence acute management. case selection criteria and choice of the most appropriate protocol requires further study. pressure control ventilation (pcv) utilizes a decelerating flow pattern which may improve gas distribution and lead to alveolar recruitment. in contrast, volume control ventilation (vcv) employs a constant flow. in children, the effects of pcv as compared to vcv are unclear. the purpose of this study was to determine how these two modes compare in terms of dynamic compliance (cdyn). peak iaspiratory pressure (pip), and mean airway pressure (paw) at equivalent minute ventilation. methods: sixteen infants and pediatric patients ranging in age from day to years were studied. diagnoses included ards ( ), postoperative cardiac surgery ( ), head trauma ( ), and resfrictive lung disease ( ). patients were randomized to pcv ( ) or vcv ( ). initial measurements of gas exchange (abg's) and respiratory mechanics (ventrak, novametrix medical systems) were obtained after a minute stabilizadon period. respiratory mechanics included pip, peep, paw, delivered tidal volume, and cdyn (avolume/apressure). the patients were then crossed over to the alternate mode of ventilation holding delivered tidal volume, peep, inspiratory time, minute ventilation, and fio constant. data were collected after minutes, in each mode the absence of intrinsic peep was confirmed. to assure that the measurements were not affected by changes in clinical status, the patients were returned to the initial mode of ventilation and measurements repeated (final) . patients were ventilated with a siemens c or sv . reselts: data were analyzed using -way analysis of variance with repeated measures. ~ < . vs. vcv) vcv pcv ~ initial ] final ! cdljn . _+ . . _+ . * . _+ . . _+ . i , pip + . l-_t. * _+ , +- , paw . _+ . . i-_ . * . + . . -!-_ . pao _+ +- _+ _+ discussion: at the same minute ventilation, the decelerating flow pattern of pcv resulted in a % increase in cdyn and an % increase in paw while decreasing pip by %. the lack of a significant change in oxygenation may be a result of the limited time in each ventilator mode as well as the inclusion of patients with both normal and abnormal lungs. there was no significant difference in initial and final measurements indicating patient stability. the beneficial effects of iecre~l~iug cdyn and paw while decreasing pip indicate that pcv may be a preferable mode of ventilation in patients with lung injury. further randomized studies examining the effect of pcv on respiratory outcome measures in pediatrics are indicated. prolonged positive pressure ventilation following repair of cdh is associated with a high prevalence of iatrogenic lung injury, in our unit dudng - late deaths after repair of cdh were due to chronic lung disease. since babies requiring assisted ventilation for more than days following surgery were transferred to a cnep chamber to limit lung injury. cnep of - cm of h was combined with positive pressure ventilation via an endotracheal tube dudng the transition phase. immediate reduction of peak inspiratory and positive end pressures were possible and following extubation respiratory support was maintained by cnep v~th appropriate inspired oxygen. overall outcome: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] n= deaths before surgery (%) ( ecmo during - / who were ventilated for more than days received cnep and there were no deaths and no chronic lung disease in that group. cnep assisted ventilation may be an important management option for babies who require prolonged respiratory support to avoid the adverse effects of chronic positive pressure ventilation, introduction so far modes of liquid ventilation (lv) have been used in experimental animals and, exceptionally, in humans: . total liquid ventilation (tlv)-functional residual capacity (frc) is filled by perfluorocarbons (pfc), and slow tidal volume (tv) breathing is performed by pfc. . partial liquid ve, ti,la~ion (page) -only frc is filled by pfc. gas tv is delivered by conventional mechanical ventilation (cmv), high frequency jet ventilation (hfjv) or high frequency oscillation (hfo). the aim of our study is to present our limited experience with page in newborns and infants. page was used in two groups of infants: , in infants with brain death before disconnection from cmv, because recipients for organ transplantation were not available. these infants have relatively normal lungs (fio~ less than . ). infants stayed on page for hour, during that period no ventdator manipulations were made. after page, infant were switched to cmv for next hours. . very critically diseased infants with ards (rds) - on ecmo more than days, before cannulation for ecmo, on hfo because of intractable respiratory failure, preoxygenated rm (miteni, italy) was used in the doses up to ml/kg intratrachealy. blood gases and parameters of pulmonary mechanics were followed (dynamic compliance -c dyn, airway resistance -raw, bicore monitor). page was combined with no inhalation ( - p.p.m, in infants). in both groups ad hoc an approvement from e local ethical commission and informed parental consent were obtained. in the first qroud with relatively normal lung parameters of oxygenation drops after pfc instilation intratracheally and stayed depressed for - hours. slight pco retention occured in both cases during page. c dyn increased almost double during page period, raw drops transitorily after pfc instilation but in minutes they were identical like in prepage period, parameters of oxygenation (peo /fio ) after - hours after page improved and were better than in prepage period. after that time infants were disconnected and died. in the second group no improvement of oxygenation was seen in one ecmo baby, in spite ()f transient improvement of c dyn. in the second ecmo baby, oxygenation improved and flow of pump could be decreased by more than %. none of these babies, however, survived, improvement was only transient in spite of repeated dosis of pfc. in these babies serious problems were to maintain the adequate frc by liquid, because of severe air leak, in babies on hfo/hfjv with severe ards/rds the improvement of oxygenation were seen in all the cases immediately after pfc instiletion for the period of - hours. after that period, pfc dose had to be repeated. two babies of this group survived. conclusion. page is going steadily from tabs to clinical practice. it is simple, could be performed anywhere, cheaper than tlv. however, because liquivent -perflubren (aliance pharmaceutical) is not available in europe, rm of (mitenti, italy) is the only solution, which could be currently used here. before the widespread use of page in clinics, liquid network among most nicus and picus must be built up, the criteria for page must be defined and ethinal-legal problems resolved as well. after resolution of these particular problems page can be life saving procedure for very special part of critically ill newborns end infants. catherine caronia, peter silver, laura nimkoff, cad quinn, jack gorvoy, and mayer san. division of pediartic critical care, medici,, schneider children's hospital, new hyde park, ny , imroduetiun: cystic fibrosis (cf) patients awaiting lung transplantation present a therapeutic dilenuna when severe respir, aory decompemalion occurs, endotracheal intubation and mechanical ventilation is known to have no long term benefits and is associated with high morbidity and mortality. noninvasive respiratory support appears to be a beneficial alternative. methods: we instituted bipap (respironics, inc,, murrayville, pa) in end-stage cf patients who were admitted to the pediatric icu with severe respiratory decompeusation. all patients were awaiting tung transplantation. after a control period, bipap was applied via a tight fitting nasal or facial mask, using the spo~aneous breathing mode, expiratory pressures were set at - cm hhzo. inspiratory pressures were started at cm ~i o and increased in cm i-i increments until the patient's respiratory comfort was achieved and substantiated by non-invasive monitoring. patients were instructed to use bipap during night sleep and whenever subjectively required, data are reported as mean _+ s.d. results: all patiems utilized nocturnal bipap for - hours/day during a follow-up period of - months. compared to their pre-bipap status, the patiems' oxygen requirement and respiratory rate both oz~ cundusion: bipap tl~rapy improves the respiratory status of decompeusatir!g end-stage cf paacnts. it is well tolerated for long term use at home, and provides an extended period of respiratory comfort and stability for cf patients awaiting lung transplantation. l. bindl*, g. kiihl**, p. lasch***, appel**, j.m er**** and the "arbeitsgemeinschaft ards im kindesalter" background acute respiratory distress syndrome (ards) is a therapeutic challenge in pediatric intensive care in view of the high mortality, in about german paediatlic hospitals founded a working group aiming on collaborative clinical research in this field. aims and methods the aim of both a prospective and retrospective survey conducted in german pediatric intensive care units in was to accumulate data on the epidemiology, risk factors, natural history and treatment strategies in a large group of pediatric ards patients who were treated in the tt~ee year period from to .all patients had acute bilateral alveolar infiltration of noncardiogenic origin and a po ~io ratio < mmhg. the influence of sex, underlying disease and single organ failure was analyzed using the fischer's exact test, the influence of additional organ failure on mortality was tested with the cochran-mantel-haenszet statistics. results patients were reported giving an incidence of cases per admissions to pediatric icus. median age was month. in % of the cases, ards was associated with a pulmonary, in % with a systemic underlying disease. in % immunocompetence was impaired. mortality was % and not dependent on age, sex and triggering event. the number of associated organ failures, however, strongly influenced mortalib,. mortafity in immuno-compromised patients was t %. the analysis of treatment modalifies employed in the patients revealed a lack of uniform therapeutic strategies. on the other hand, the patients were exposed to interventions not yet supported by controlled trials. conclusions the observation of the lack of uniform treatment strategies led to the elaboration of recommendations on ventilator therapy and patient monitoring within the working group. the data gathered in this survey provide the basis for the design of prospective multicenter studies urgently needed to evaluate innovative treatment modafities in pediatric ards. recurrent apnea and respiratory failnre due to severe lower respiratory tract disorders such as bronchiolitis or pneumonia are the most common reasons for mechanical ventilation during respiratory syncytial virus (rsv) infection. acute respiratory distress syndrome (ards) has been described as a complication of severe rsv infectionj in contrast to the low mortality rates associated with rsv infection (< %), mortality rates in the range of - % have been reported in pediatric patients with ards. however, studies on ards are usually lumped in respect to causation and the disease course of rsv induced ards has not been previously studied. we examined the lung function abnormalities of infants with rsv induced respiratory failure requiring assisted ventilation, measurements included respiratory mechanics, maximal expiratory flow-volume curves and lung volumes, ards was defined clinically using the criteria which were recently proposed by the american-european consensus conference on ards~: acute disease onset, pao /fio~ ratio _< mrn hg, bilateral infiltrates on chest radiograph and absence of clinical evidence of left atrial hypertension. we calculated the murray lung injury scores modified for use in pediatric patients from total respiratory system compliance, radiographic findings, ventilator settings and blood gas results. we identified infants with severe restrictive lung disease that fialfilled the clinical criteria fbr classification as ards. all had lung injury scores above . which is the recommended cut-off for a diagnosis of ards, twenty-seven infants had obstructive disease consistent with a clinical diagnosis of bronchiolitis. the ards patients were significantly younger, had a longer time of assisted ventilation (p < . ) and a greater proportion of infants with preexisting illnesses (p= . , odds ratio = . ) when compared to the patients with obstructive disease. with the exception of one immunodeficient patient, none of these infants died. given the low mortality despite a clinical picture of severe lung injury, there is evidence that rsv induced respiratory failure may represent a relatively benign cause of ards in pediatric patients, bachmann an audit of patients with severe acute bypoxic respiratory failure (ahrf) receiving highfrequency oscillatory ventilation (hfov) in our unit ( n= , mortality %) revealed that sub-groups with severe underlying disease (n= , mortality %)and those with mu~pie organ failure ( > systems failing, n= mortality %) accounted for all the deaths beyond the neonatal period. v~ therefore hypothesized that in a modem paedistric intensive care unit (picu): a) children greater than one month of age with ahrf do not die in the absence of severe, pre-existing disease or multi-organ dysfunction syndrome, b) respiratory parameters alone will predict outcome poorly in ahrf. method prospect~/e sty/of all adm~ns to our tertiary picu. data it, citing the respiratory parameters (oxygena~n index [ol] , aiveolar-artedal oxygen tension gradient , pao /fio ratio) were collected hourly from the bedside charts throughout admission. patients were included in the study if ahrf was present at admission either none or in combination with other organ dysfun~on. ahrf was defined as the acute (< hour) onset of respiratory dysfunctk:~l with a pao /fio ratio.< for six consecutive hours dunng the first hours of admission (with no evidence of left anal hypertension), x-ray review defined a sub-group of patients with acute respiratory distress syndrome (ards) by the presence of bilateral interstitial infiltrates. results to date children (ages - months, weight . - kg) have been admitted in ahrf. of these also had ards. the overall mortality was . % ( / ), and greater in the ards group than the non-ards group ( t , . % vs, , . %, p< o. ) . it was not possible to predict survivors from non-survivors on the basis of the seventy of the respiratory failure alone, the a-ado on the day of admission (best in hours) was not significantly different between survivors and non-survivors: (mean, + sd)( mmhg +_ , vs mmhg _+_ ). kdl non-survivors were immunodeficient (n= ), previously extmrnsly premature infants (< ),(n= ) or suffedng fcom chronic metabolic or gastrointestinal disease (n= ). no previously normal child died. conclusion the severity of respiratory failure does not allow predioljon of outcome in our patients. we believe that this reflects that modem picu is so effective at providing respiratory support that pre-existing pathology alone de~ prognosis. this suggests that an abnormally regulated host response or abnormal persistence of a pathogen may be required to induce lung injury of sufficient severity that the resulting respiratory failure cannot be supported in a modem picu. introduction: postural changes (supine to prone) is a therapeutic intervention that could be useful in children with adult respiratory distress syndrome. objective: to determine the effects of postural changes in the oxygenation of young children with ards. method,s: a prospective stud ," was performed in eleven subjects aged to months (mean= ) with the diagnosis of ardsreceiving vendlatory support. (mean peep and fio of and . respectively). postural changes was performed every - hours, during a period of time ranging from to days. arterial blood gases were determined before and - n~n after the postural change, no modification in the mechattical ventilation other that changes in the fio were performed. the oxygenation was determined by the index pao /fi (p/f). to study the differences between the oxygenation mean, before and after the postural changes the wilcoxon test for paired samples was used, results: changes were performed ( from supine to prone and from prone to supine). a % increased p/f ratio was obtained after the change from supine to prune. although, not all the patients receiving postural changes improved their p/f. six of them (group i) showed an improve in the p/f when changed from supine to prone, returning to their base line when positioned from prone to supine. no improvement on the p/f was observed in the remaining subjects (group ii)after postural changes (table ) . during the maneuver no complications were observed. two patients had a pneumothorax, not related with the postural change. conclusions: postural changes (supine to prone) is an easy way to improve oxygenation in some children with ards. change to prone change to supine introduction: the common noninvasive diagnostic efforts to identify possible obstruction of the intrathorucic airway, are of limited value. invasive procedures such as bronchoscopy and bronchography may also be noncontributory and entail risks. we evaluated the usefulness of d-ct in the diagnosis and management of pediatric patients with suspected intrathoracic airway obstruction (itao). methods: we used a diagnostic algorithm (see diagram) in patients with suspected itao resulting in respiratory distress. three-dimensioual imaging of the tracheobronchial tree was reconstructed, following high speed spiral ct scan, by specific computer software (advantage window computer work station, general electric, milwaukee, wisconsin). non-ionic contrast medium was injected, in some patients, to delineate the intrathoracie large vessels.. results: eight patients were studied. in patients the d-ct revealed intrathoracic airway abnormalities. these patients underwent further invesive studies which confirmed the following diagnoses: patients had bronchomalacia, had bronchial stennsis due to a dilated pulmonary artery mad patients had subglottie stenosis extending to the thoracic cavity. three patients had no significant disruption in the configuration of the tracheobronchial tree and thus did not require invasive diagnostic procedures. conclusion: computer reconstruction of three dimensional images of the tracheobronehial tree is a safe and reliable diagnostic tool for itao. ards and ecmo; preliminary data from a randomized clinical trial. j fackler, c steinhart, d nichols, d bohn, m heulitt, t green, l martin, k newth, m klein, j ware. many suggest ecmo be considered experimental for ards and undertaken only with careful data collection and reporting. a mtflticenter pediatric rct is in progress to determine whether ) ecmo and/or ) permissive hypercapnia, offer significant advantage for the treatment of ards. methods: all patients aged wk to yr (without congenital heart disease) are eligible for study. data collection begins when a patient receives at least % oxygen and a peep of cm h for hours (stage t). if the predicted mortality reaches % within days (stage ), eligible patients are asked for written consent for randomization. patients are excluded from randomization with significant chronic lung disease, immune compromise, cardiac disease; or profound acute central nervous system damage. the prime outcome variable is survival. at the studies onset, pts were estimated to be required so that pts were randomized per arm. results: patients are enrolled from centers. data are complete on . patients never reached stage (i.e. % mortality). patients improved and died. of the latter, had randomization exclusion criteria even if stage was reached. patients reached stage . had exclusions from randomization and all died. eight patients ( survivors were eligible for randomization; consent was obtained in no case. two patients received ecmo. overall survival is % ( / ). in patients without randomization exclusions, survival is % ( / ). morbidity m survivors (discharge -admission popc or pcpc score >_ ) was seen in none of the stage surviviors and % ( / ) of those who reached only stage !. conclusion: the rct requires completion. the records of hospital in-patients at king faisal specialist hospital and research center who received external cardiac massage as part of their cardiopulmonary resuscitation were reviewed. success of resuscitation was analyzed as ( ) short term (restoration of spontaneous circulation), and ( ) long term (discharge from hospital). of such patients, ( . %) survived the initial resuscitation, and ( . %) were discharged. success of outcome was not related to age, location of patient, time of day, or rhythm at arrest, including asystole. longer resuscitation time was associated with less chance of restoration of spontaneous circulation (p< . ), but not associated with hospital discharge rate. results for patients with congenital heart disease were similar to those with other medical or surgical conditions. in this series, . % of ward in-patients survived to discharge, compared to two "*;'~r ~r;~' ,.,.'her,, the r-e~ult~ were c/ "'~d ~, ~,°(. overall, % of patients who survived the initial resuscitation were discharged from hospital. where resuscitation continued for more than minutes, . % of patients had tong term survival. outcome from asystole was no worse than for other cardiac rhythms, we believe that previous reports of poor outcome from asystole in pediatric cardiac arrest should noi influence decisions to stop resuscitation for pediatric in-patients prematurely. successful restoration of spontaneous circulation with long term survival can be achieved after prolonged resuscitation. abdelmoniem~ lindsey jahusou~,mariano fiallos, university of florida, prudential drive, suite jacksonville, florida usa central acidosis is well recognized as a marker of inadequate tissue perfusiou, and ventilation. however, obtaining central venous blcod is difficult and fraught with complications in the child undergoing cardiopuimonary resuscitation. intraosseous blood may be used instead of central venous blood to judge ph and pcoz during short durations of cardiopulmonary resuscitation and during hemorrhagic shock. the purpose of this study is to compare the ph and pcoz status of intraosseous and central venous during prolonged cardiopulmonary resuscitation after fluid and drug infusion. we hypotbesized that there would be no difference in ph and pco values of simultanecusly obtained intraosseous and central venous blood samples. eighteen ( ) introduction: cardiopulmonary arrest (cpa) in children is usually preceded by a deterioration of cardiac or respiratory function due to sepsis, dehydration and hypovolemia. early recognition of clinical and laboratory signs followed by immediate intervention are essential for prevention of cpa. the purpose of the present study was to identify factors which contributed to high rates of mortality from cpa in patients admitted to a paediatric intensive care unit (p cu). methods: a prospective study was done of all non-surgical patients with cpa who were admitted to the picu, hospital baca ortiz, quito ecuador from january to october . clinical and laboratory variables before and after admission to the picu, time from hospital admission to picu admission and the pediatric risk of mortality score (prism) were recorded on a questionnaire designed specifically for this study. results: of the non-surgical patients admitted to the picu, ( %) were admitted after developing cpa on the general pediatric wards. mean age was + . months, with of patients under months of age. initial diagnoses upon picu admission included meningitis (n= ), respiratory failure (n= ), congenital heart disease (n= ), severe neurological impairment (n= ), end stage neoplastic disease (n= ), hypovolaemic shock (n=l), peritonitis (n=l) and sepsis (n=l). mean time from hospital admission to p cu admission was _+ . hours. the mean prism score upon hospital admission was + . (score > = > % mortality). % ( / ) of the patients died. one of the three survivors had severe neurologie injury. prior to picu admission, patients experienced tac~,cardia (n= ), hypotension (n= ), neurological deterioration (n= ), respiratory, distress (n= ), oliguria (n= ), bradycardia (n= ), metabolic acidosis (n= ), hyponatremia (n= ), hypokalemia (n= ), hypocalcemia (n= ) and severe hypoglycemia (n= ). there were serious delays from the time of development of clinical and laboratory abnormalities to the time of admission to picu. conclusion: in the critically ill pediatric patient, rapid recognition of clinical and laboratory signs of deterioration, followed by immediate intervention, are required to prevent end stage shock and cpa. we found serious delays in intervention following development of important premonitory clinical and laboratory abnormalities in patients less than months of age on the general pediatric wards, which iikely contributed to the dismal % mortality rate. hospitals throughout ecuador should institute immediate improvements in ctinical supervision, and provide training in paediatric advanced life support (pals) to decrease excessively high rates of and mortality from cpa. intraosscous access is recommended by the american heart association and american academy of pediatries as a means of rapid access to the vascular system for childhood emergencies. bone marrow and fat embolism is a concern and has been reported post intraosseous infusion in stable animals but has never been studied in animals subjected to cardiopuimonary resuscitation. we undertook this study to investigate the incidence and magnitude of lat and bone marrow embolism with the use of intraosseous infusion during prolonged cardiopuhaonary resuscitation and after fluid and drug infusion. we hypothesized that there will be no difference in the magnitude of fat embolism between cardiopulmonary resuscitation only and other cxperirnental conditions. thirty-one ( ) piglets were anesthetized, mechanically ventilated, and instrumented (carotid artery, pulmonary artery and intraosseous earmulas ). the animals then underwent bypoxic cardiac arrest followed by chest compressions with the mechanical thumper (michigan insmunents) and mechanical ventilation for a minimum of minutes. the animals were divided in groups: a (n= ) which had no intraosseous, ~'oup b (n= ) had intraosscous with no infi~ion, and groups c (n= ), d (n= ), e (n= ) had intraosseous with infusion of adrenaline, normal saline and sodium bicarbonate, at cessation ofcardiopulmonary resuscitation, representative lung samples were collected fi'om upper and lower lobes of each lung, embedded in ocp and firozen immediately. ltmg specimens were stained using oil red-o dye and observed for fat globules and bone marrow elements. the amount of emboli present was rated as a percentage in relationship to iung tissue, by a pathologist blinded to the experimental groups. buffy coat specimens were collected before and at cessation of cardiopuimonary resuscitation, stained with oil red-o dye and observed for fat globules. percentage of fat present were compared using analysis of variance. fat globules were seen in the prebronchial blood vessels and in intravascular areas throughout all lung fields. there was no difference in appearance or distribution of fat globules between groups. quantity varied in the different groups[(a) %, (b) %, (c) % (d) %, (e) %], but were not statistically significant (p = . ). fat globules in the buffy coat were few and inconsistent with lung findings. fat and bone marrow emboli were present in all experimental conditions, the use of the intraosseous cannula does not increase the magnitude of embolization during cardiopuimonary resuscitation. the decision to use the intraosscous route should not be influenced by the risk of embolization. tzareva iv/,, md*, nedialkova r, md**, *dept. of pathophysiol, *~dept. of child surg. and icu, emergency medical institute pirogov, sofia, among children with blunt abdominal trauma, treated in emi pirogov during the last five years, children had serious disturbances of the basic vital functions, connected with the trauma, and most often with massive haemorrhage, for this reason being an object of reanimation and intensive care. in the group of children who survived - , predominated the trauma of only one abdominal organ (mainly the spleen, rarely the kidneys, the intestine) and only children had injuries of more than one abdominal organ. in the same group, in children the abdominal trauma was combined with chest or head trauma or bone fractures. in the group of children who died - , a profound combined trauma was present. the haemodynamic parameters in all children showed a characteristically significant tachycardia along with normal or even high blood pressure, while hypotonia was present in only % of the children on the first trauma day. despite the fact that only . % of the children had direct chest injury as well, the gas exchange was considerably disturbed - ' of the children were hypoxemic during the first, and % during the third trauma day -in % significant -below . kpa ( mmhg). together with the markable decrease in haemoglobin levels, this determines the pronounced disturbance in oxygen transport. during the first trauma day all the children were acldo~c, and a metabolic alkalosis was present during the following days. twelve of the children with severe combined trauma died within several hours, with the symptoms of irreversible haemorrhagic shock, or in the next - days, developing multiple organ failure. in conclusion, the intensive therapy of children with severe abdominal and combined trauma, should take in consideration the special haemodynamical trauma answer in children, and requires dynamic monitoring of the most influenced homeostatic parameters -blood gases, acid-base metabolism, haemostasis. introduction: endocrine emergencies, other than diabetic ketoacidosis, are uncommon causes of pediatric intensive care unit (picu) admissions. we report our experience of children diagnosed of adrenal insuficiency (ai) admitted in the picu, during the last four years. subjects: five eases of ai requiring intensive care unit admissions are presented. four females anna male, with ages ranging from days to years, none of them had a previous systemic or endocrine diseases that could suggest al the initial clinical manifestations were: dehydration ( ), vomits ( ), abdominal pain ( ), seizures ( ), lethargy ( ) and hyperpigmentation in the muco-genitat area in a newborn male and ambigna genitalia in a newborn female. the reason for their admission in the p cu were: shock in two subjects; three because of hyperkalemia and hyponatremia (k/na: . / ; / ; , / meq/l); and two with severe hyponatremia (na: ; meq/l). laboratory findings: severe hyponatremia ( ), increased concentration of urinary sodium and chloride ( ); metabolic acidosis ( ); hyperkalemia ( ); increased levels of urea ( ) and hypoglycemia ( ). in all of them, the electrolytes abnormalities did not normalize with replacement and only normalized after the administration of hydrocortisone. tile ai was due to: autoimmtme disease in two subjects, congenital adrenal hypoplasia, congenital adrenal hyperplasia secondary to alia hydroxylase deficiency and in one no etiology was found, at the present time, comments: aiis an uncommon disease in the pediatric age. anearly diagnosis is crucial, as if the treatment is delayed could lead to patients death. in subjects with arterial hypotension and electrolytes abnormalities refractory to the usual treatment, they should be treated with corticosteroids, if no etiology is found. although, previously samples must be obtained to make the diagnosis, : denotes the number of cases. gerbaka b; hakme c; akatcherian c. toxics are frequently involved in domestic accidents during childhood; among non medical products ingestion, carbohydrate poisoning is a serious injury often made possible by inadequate stocking. over years, children aged years and less were examined in the emergency department of hotel-dieu de france hospital for carbohydrate ingestion. , % are boys; age goes from months to years (moan = , years). kerosene is found in , % of cases; all were admitted (mean = , days). , % were symptomatic on first examination but % of all children presented signs of gastric ( %) or respiratory ( , %) irritation sometime during their history; , % had neurological signs and , % presented some fever. leucocytosis is found in % of cases; , % of the children received antibiotics. chest x ray was abnormal in , % of cases: mainly parahilar infiltrates were found, all children survived; , % with a normal course ( , days of hospital stay) whereas those who presented complications (severe pneumonia, coma) stayed in the hospital for days (mean) with short course of assisted ventilation for two of them; long term follow up was not possible. we fonnd nick's criteria for hospital admission to be of value: -symptomatic children with normal x ray } to hours monitoring -asymptomatie children with x ray abnormality } -symptomatic children with x ray abnormality: hospital admission -asymptomatic children with normal x ray : no admission. these criteria would have helped to avoid admission in children and would have allowed a short t hours stay for more. we found chest x ray to be mandatory in carbohydrate ingestion; other tests were not helpful, aside arterial blood gases measurement in case of respiratory involvement; we now also advocate more restriction in antibiotic use. prevention remains efficient and should be stressed on. severe liver failure [slf] is a rare but severe condition in infants. we report our experience. patients: slf was defined as liver insufficiency with hepatic encephalopathy and a decrease in the level of factor v to below %. between and , infants (mean : mo) were admitted for slf (neonates excluded). main causes were metabolic disorders ( . %) (tyrosinemian= , hemochromatosis n= , reye's syndrome n= , other n= ), virus-induced flf ( . %) and hematologic diseases ( . %). in cases, the causes remained undetermined. results: olt was contraindicated in cases because of multiple organ failure (n= ), or underlying disease. all of them died within days after admission. patients had no indications for olt, all but one are alive. ( of them was transplanted later for tyrosinemia and died lately (virus induced-slf). among the t infants who underwent emergency olt, are alive and died because of primary non function of the graft. conclusion: slf in infants admitted before their first birthday is a severe condition with an overall mortality rate reaching %. inherited metabolic disorders are the first cause of slf at this age. contraindications for olt are frequent because of underlying disease or multiple organ failure. a number of children undergo primary graft failure after liver transplantation. it is unknown if there is any increased morbidity or mortality following retransplantation. this study seeks to explore these issues. methods: a pediatric intensive care/iiver transplant database is in formation. records of all liver transplant patients are reviewed and abstracted. this data is then computerized to allow analysis. this data provides the source for this study. statistical analysis was performed via student's t-test where appropriate. results: of the patients who have thus far received at our center orthotopic liver ransplants, the records of who underwent transplants form the basis for this review. twenty-three patients underwent multiple transplants, required one additional, three required organs, and one patient survived after a fourth organ transplant, there was no significant difference in age at first transplant between those who received multiple organs and those who did not ( vs, months, p=ns). the anesthesia time for the procedure did not significantly increase tbr subsequent transplants ( . vs, , hours), nor did time in the intensive care unit (t . vs. . days), nor did time on the ventilator ( . vs. . days) subsequent transplants did not predispose to having more bleeding in the intensive care unit for usage of packed red blood cells or platalets was not significantly altered ( vs ml and vs ml respectively). patients who required retransplantatior~ did receive mere fresh frozen plasma (ffp)daring their first transplant than in the subsequent ones ( vs ec, p < . ). however ffp use was not significantly different than patients who did not require retransplant. patients who underwent retransplant had a markedly increased mortality ( %) than the overall mortality for liver transplants at our center ( %), conclusion: children who require another liver transplant have a markedly increased mortality. bleeding and prolonged icu stay is not significantly different between the first and subsequent transplants, fulminant hepatic failure and ortothopic liver transplantation.dr.sasb n,j;centeno,m;entin,e;acarenza,m;ciocca, m:gofii,j;bianco,g;weller, g;imventarza,o. unidad de cuidados intensivos.hospital de pediatria "dr.j.p. garrahan" .buenos aires.argentina. introduction:fulminant hepatic failure (fhf) is a clinical syndrome, defined by the development of hepatic encefalopathy within weeks from onset of illness in a previously healthy person.by far,the most comun cause of pediatric fhf in all series, is acute viral hepatitis.we report our experiences with the pediatric fhf and ortothopic liver transplantation (olt) as attemative of treatment. patients: childrens with fhf diagnosis were admitted at the picu from / / to / / .symptomatic treatment was given to all children and all were put on list for olt,) following the king's college criterion (protrombina time,age,atiologies,bilirrubin,and encefalopathy state). results:etiologic causes corresponded to the childrens were: , hav ( %); , noa nob ( %); ,autoinmune ( %).the age was mean: years (range: month- years).seventeen patients were transplanted, chidmn were discarded because:no donors: ;withdrow of the list: ,because sepsis in and bleeding of cns ;and no admission at list: because genetic syndrome ,massive intestinal necrosis, ,mitral valvulopathy and sepsis, . patients ( %) had at least one complication dudng the post operative period.the most frequent was the acute renal insufficiency(ari) and patients requiered continuos hemofiltration.the gtobal mortality rate was %.the mortality of patients without olt was % and the mortality of patients with olt was %, patients dayed because sepsis, ( candidiasis) and the others because mof.the actuarial survival at year is % and the follow up of months. conclusions:the fhf is a very severe and frequent disease at picu. supportive treatment only is associated with a very poor prognosis and high mortality rate.the most frequent etiology in our country is the hav. the olt is applicable in this cases and is a valid alternative of treatment (mortality in our series %).the ari is the most frequent complication during the post opeative period.in argentina,due the high prevalence of hav,prevention must be considered the main and only way to avoid this catastrophic illness.- to assess the efficacy of gastric intramucosal ph (phi) for evaluation of tissular perfusion and prediction of hemodynamic complications m critically ill children. patients and methods: thirty critically ill children ( boys and girls) whose age ranged from month and years old were studied. a tonometry catheter was placed in the stomach of all patients at their °admission in pediatric icu. intramucosal ph measures were made at the admission and each - hours during the study: a total of determinations were made. the catheter was removed after extubation and/or checking of hemodyrmmic stability of the patient. the intramucosal ph was derived from application of the henderson-hasselbaeh formula using the pco value from the tonometer and the arterial bicarbonate. values of phi between . and . were considered normal. the relationship between phi and severity of patient measured through prism, presence of major (cardiorespiratory arrest, shock) and minor (hypotension, hypovolemia or arrhytlmtias) hemodynamic complications, mortality and stay in the picu, was analysed. results: the admission value of phi was . -t- . (range . - . ). five patients ( %) had an admission phi < . . no relationship was found between an admission phi < . and a higher incidence of hemodynamic complications. sixteen patients ( %) showed some values of phi < during their evolution. patients with phi < . had a higher number of hemodynanuc complications than the rest (p< . ). every cardiorespiratory arrest (cra) and shock cases were related to a phi < . . patients with major complications (cra and shock) had a phi lower (p= . ), as well as a higher number of measurements of low phi (p= . ) than patients with minor hemodynamie complications. the value of phi lower than presented a % of sensibility and % of specificity with regard to hemodymanic complications. there was no relationship between phi < . and prims score and stay in picu. patients with phi < . presented a prims higher than the rest of patients (p< . ). conclusions: the phi value may be an early sign of presence of hem dyaaimc complications in the critically ill child. we tested the hypothesis that gastric intramural ph (phi) can be used as an early sign of failure m weaning pediatric patients because the blood flow from nonvital areas is diverted to meet the increased demands of respiratory muscles. methods: children (mean age ( . _+ . ) years + sd) who were thought by their physicians to be weanable from mechanical ventilation (mv.). these patients were ventilated on serve c ventilators, receiving ranitidine, and had intestinal tonometer (tonometrics, inc.) minutes before obtaining a sample.. all children were placed on pressure support (ps) at levels judged to overcome the resistance of the endotracheal tube and ventilatory circuit ( em h.,o). a sample of arterial blood and a sample oftonometer were obtained during vm and weaning (ps). phi, hemodynamic and respiratory data were recorded during vm and weaning we did not interfere with the primary caretaker's decisions regarding extubation. patients were considered to be successfully weaned if they were able to sustain spontaneous ventilation for more than hours after extubation. paired t-test were used to compare the values obtained during mechanical ventilation with those obtained during weaning trials. unpaired ttest were used to compare values from the group that was successfully weaned (a=i ) with those from the group that were not (b= ). results: we did not find statistical differences in any of those variables mesured during mv for patients who were successfully weaned(group a) and those who were not (group b). gastric phi was in group a: . + . (vm) and + . (weaning); in group b: . _+ . (vm) and . t _+ . (weaning). discussion: although we did not find differences in gastric phi during vm, the group a had a lower value than group b because of the number of cardiac patients ( %) and transfusion therapy, in fins group. in group b % of patients showed a problem in upper airway (subglottic edema, and enlarged tonsils). we found it after extubation. conclusion: ) gastric phi is a good predictor of risk in critically ill patients but maybe because of the small size of the sample, in our study is not of practical value as a predictor of failure in weaning pediatric patients from vm. ) this test is not a predictor of problems in upper airway~ important etiology of failure weaning in children. objectives: i-to determine the prognostic value of the gastric intramueesal phi in mortality and multiple organ dysfunction (sdmo) in critically ill children. -to compare this value, with the pediatrics risk index mortality score (prims). methods: aprospective study was performed with critically illcbildren, aged from mouth to years. the athnittiug diagnosis was: post-surgery ( neurosurgery, spinal fusion and thoracic or abdominal surgery), sepsis, polytraumatism, adult respiratory distress syndrome and with miscellaneous. all the subjects were monitorized on picu admission and treated for their underlying condition. gastric intramucnsal pt{ was measured following the tonometric method, ou admission and every - hours depending on the patients state. the severity of the clinical condition was evaluated using the the prims, on admission (prims-i) and during the first hours, when the clinical condition deteriorate, the worse score was utilized for the statistical analysis (prims- ). to perform the statistical analysis the subjects were divided in two groups, one with the phi< . and the other with phi> . .aunivariate analysis (student's tand wilcoxon two tailed test, chi-square) and multivariate analysis were used. results: out of the subjects dyed. of children developing multiorgan failure (mof) expired. % of the patients admitted to the picu with sepsis, ards and miscellaneous had a phi < . . in contrast, with % of post-surgical and none of the postqraan~atism. the mortaliry rate, in children with a phi< . was % (ci %: . ; , ) and . % (ci %: , ; . ) in children with phi> . (p= . ). mofwas observed in , % of children withphi< . v.s, . % with phi > . .no relatiouship was observed between the phi and the score of prims-i and . perforating an unconditional logistic regression analysis, two independent variables have mortality predictive value: the phi and the prism- . (table i) following induction of anaesthesia, a laser doppler probe (moorsoft instruments ltd) was inserted cm into the patient's rectum, the probe's special design ensuring that the optical prism lay against the mucosa. continuous monitoring of rectal mucosal perfusion ("flux") was continued throughout the operation. after rain cpb at °c, "steady state" readings of nasopharyngeal temperature, mean femoral arterial pressure (map) and flux were recorded over a further min before cpbinduced core cooling to - °c. steady state was defined as a rain period with no change in core temperatures or map. other rain steady state recordings were taken immediately prior to low flow, immediately prior to rewarming and after rewarming to °c, before initiation of any vasoactive drugs. the cpb flow rate was kept at m l k g - min q, the pcv at _+ %, the p~co at . + . kpa and the pro at + kpa. results: initial warm and rewarm map (both mmhg) were significantly lower ( = . ) than during the cold cpb periods ( & mmhg). the mean cold flux before ( ) and after ( ) low flow were both significantly lower (p= . ) than the mean initial warm cpb flux ( ). the mean rewarm cpb flux ( ) was significantly lower than all other flux values (p= . ). there were no siglaificant correlations between map and flux except at the first warm cpb period (r= , , p= . ). conclusions: although hypothermia significantly reduces rectal mucosal perfusion, rewarming produces an even greater reduction in gut perfusion which, considering that mucosal oxygen constmaption is highest during this time, may prove crucial in the postoperative development of mof. therapy aimed at improving gut perfusion during cpb should be directed at the rewanning period in particular. abstract this work is aimed at establishing a clinical procedure for the diagnosis of enteritis necroticans (en), even at the communal level, and to define criteria for diagnosis able to distinguish between acute forms. subjects and method : cases admitted at the institute for protection of children's health dpch), having characteristic symptoms, were examined clinically, by roentgenography of the abdominal cavity, with the analysis of the blood (total protein, electrolytes, hematocrite) and cultures of intestinal fluid and faeces. through surgical operations, the pathological lesions were observed and recorded. results: common epidemiological features: the average age is - years old ( - ) ; male/female : . ; in % of the cases, the disease occurred after a meal rich in protides. the acute toxic form accounted for % : severe shock appearing early, with very severe dehydration associated with profoundly decreased blood protein concentration and lowered natriemia as well. the lesions of the small intestine were expanded, all of them were necrotic. in the surgical form ( %), the predominant feature was an obstruction -peritonitis syndrome, the peritoneal fluid showed a characteristic inflammatory reaction. for the rest of cases % were the internal form, the shock syndrome was less severe, the abdominal distention was light and disappears gradually, the inflammatory reaction of the peritoneal fluid was not so characteristic. conclusion (ino) is a selective pulmonary vesodilator that is rapidly inactivated compared to intravenous vasodilators. these qualities make ino an attractive agent for the treatment of pulmonary hypertension (pittn). the efficacy of ino has been studied in persistent fetal circulation, acute respiratory distress syndrome (ards), and congenital heart disease (chd). potential adverse effects oflno include: nitrogen dioxide (no toxicity, methemoglobinemia, and platelet dysfimction. our objective was to evaluate the safety of ino in pediatric patients (pts). methods: pediatric pts. with phtn from ards or chd were studied under an established, approved protocol conforming to fda guidelines tbr an investigational new drug. informed consent was obtained for each child prior to treatment. no was sequentially titratad from parts per million (ppm) to , , , and ppm at ten minute intervals. parameters monitored before and during therapy included nitric oxide (no) and no~ concentrations (cone.), mean arterial blood pressure (map), and percent methemoglobin (mhg). no and noz levels were continuously monitored using an inline dr~ger electrochemical detection device. ~,litp was continuously measured with an indwelling arterial catheter. mhg was measured by co-oximetry. a mhg level e % or no cone. ~ ppm were considered adverse effects by study criteria. pretreatment map was compared to map at and ppm ino using paired t-tests. ap value < . was considered statistically significant. results: thirty-two mechanically ventilated children with phtn ( with ards, with chd) were studied. five pts. were treated following cardiopulmonary bypass. methemoglobin (met-hb) levels were routinely measured in two prospective clinical studies on no inhalation in pediatric patients with pulmonary hypertension following heart surgery with extracorporeal circulation and in pediatric and neonatal ards patients, the observed differences between the groups prompted in an in vitro study, red blood cells (rbc) of patients sampled before and after surgery with and without extracorporeal circulation (ecc), respectively, were incubated with ppm no for rain, met-hb, atp, and nadht nadph concentrations were compared, during therapeutic exposure no increased met-hb from . - -_ . to . _+ . % in cardiac surgery patients and from . ± , to . ± . % in ards patients (p < . ). rbc's having undergone ecc were more susceptible to met-hb formation (p< , ) whereas intracellular coenzymes did not differ neither between the groups (table) nor before and after no exposure. ecc predisposes to increased methemoglobinemia upon exposure to no both in vivo and in vitro. our data suggest a reduced activity of met-hb reducing enzymes rather than diminished availability of energetic substrates, variation of the inhaled nitric oxide concentration with the use of a continuous flow ventilator. anne pmc de jaegere ~, frans im jacobs , nico gc laheij , john n van den anker t . dept. of paediatrics ~, central instrumentation , sophia children's hospital, erasmus university rotterdam, rotterdam, the netherlands. objective: to investigate the homogeneity of nitric oxide (no) concentration in a delivery system with a continuous flow ventilator. design: bench study, setting: biomedical laboratory. interventions: a nitrogen/nitric oxide (njno) gas mixture was injected at three different sites in the patient circuit: just before and just behind the humidifier, and centimetres before the y-connector. ventilator flow ( , , l/rain), ventilator rate ( to , increments of ) and compliance of the testlung ( . ; . ; . ml/cm h ) were changed. carbon dioxide (co ) instead of n /no was injected at the same points in the circuit. measurements and main results: a) though the flow ratio of the njno and the ventilator gas were kept constant, the no concentration ([no]) raised with increasing ventilator rates. the increase in [no] was up to % when the n /no injection site was close to the y-connector of the ventilator circuit. minimal changes in [no] were noticed when the n~/no was mixed to the ventilator gas before the humidifier. b) analysis of the ventilator flow pattern showed variations at different places in the ventilator circuit. the magnitude cf the p, ow change depended on the meas~:rement site. the closer to the expiratory valve the highest the flow change was. the duration of the flow change was inversely proportional to the adjusted ventilator flow. c) real time measurements of the co concentration ([coz]) showed variations during tile respiratory cycle. these [co ] variations were higher when the co gas was blended closer to the yconnector. conclusions: the ventilator flow variations in relation to the fixed side flow of the n /no gasmixture result in changes of the inhaled [no] during the respiratory cycle. the no concentration during inspiration is always higher then during expiration. this could not be detected with the available monitoring system. to ensure a constant [no] by blending a njno gas balance in a continuous flow ventilator, the site of injection should be as close as possible to the inspiratory outlet. nitric oxide, a potent and selective pulmonary vasodilator, has recently been successfully used to treat pulmonary hypertension of variable etiology in infants and children. side-effects and complications in infants are so far not well known. we describe here two cases in which prolonged ( and- days respectively) high-dose ( - ppm) nitric oxide was used to treat refractor~¢ pulmonary hypertension. one patient was a newborn infant with pulmonary hypertension secondary to a large leftsided diaphragmatic hernia. nitric oxide was begun under conventional ventilation (babylog ) at hours of life with a slight initial improvement in oxygenation. he was then placed on oscillation with the same nitric oxide concentration due to worsening respiratory failure. he died on th day of life. monitored nitric dioxide concentration never exceeded ppm. the other patient was a months old infant with severe pulmonary hypertension due to a complete atrioventricular septal defect. he required high-dose nitric oxide to come off cardiopulmonary bypass after surgical repair of his heart defect. he slowly improved over the week following surgery but developped suddenly respiratory failure due to massive pulmonary hemorrhage and died. surprisingly, a particular autopsy finding in both infants was a massive acute necrotizing tracheobronchitis. we conclude that nitric oxide is an excellent and sometimes lifesaving treatment of pulmonary hypertension in infants. tracheobronchitis has not yet been reported as a possible complication of nitric oxide administration. we suggest that caution needs to be taken with prolonged high-dose administration and this possible complication to be looked for at autopsy. introduction: permissive hypereapnia (ph) is a beneficial strategy for patients with acute respiratory distress syndrome (ards) to minimize barotrauma by decreasing the peak inspiratory pressure (pip). hypercapnia and hypoxia cause pulmonary vasoconstriction, pulmonary artery (pa) hypertension, and, thus, an increased afterload to the right ventricle. this increased afterload may result in increased right ventricular (rv) work load and subsequent rv dysfunction. one therapeutic approach is the use of inhaled nitric oxide (inn), a selective pa vasodilator. the objectives of this study were to test the hypothesis that in a swine model of ards with ph, inn would improve rv work load and not change intrinsic rv contractility. methods: in swine ( - kg), ards was induced by surfactant depletion. hypercapnia was achieved by decreasing the pip while increasing the peep to maintain a constant mean airway pressure, inn was administered in concentrations of , , and ppm in a random order. pulmonary blood flow (qpa) was determined by an ultrasonic flow probe. rv total power (tp) and stroke work (sw) were calculated by fourier transformation of the pa pressure (ppa) and qpa data. preload recruitable stroke work (prsw), a preload and afterload independent measure of ventriculur contractility, was determined by a shen-subtraction method and vena caval occlusion. respiratory failure with pulmonary hypertension in piglets gerfried zobel*, bernd urlesberger*, drago dacar**, siegfried rtdl*, fritz reiterer* and ingeborg friehs** depamnents of pediatrics* and cardiac surgery**, university of graz,austria objective: to evaluate gas exchange, pulmonary mechanics and bemodynamic data during partial liquid ventilation (plv) combined with inhaled nitric oxide (no) in acute respiratory failure with pulmonary hypertension. design: prospecfive~ randomized, controlled study. setting: university research laboratory. subjects: twelve piglets weighing to kg. interventions: acute respiratory failure with pulmonary hypertension was induced by repented lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. thereafter the animals were randomly assigned either for plv or conventional mechanical ventilation. initially perfhiorocarbon liquid ( ml/kg) was instilled into the endotracheal tube over min followed by - ml/kg~. all animals were treated with different concentrations of no ( - - ppm) inhaled in random order. measurements and results: continuous monitoring included ecg, cvp, mpap, map, san and svo measurements. during plv pao /fio increased significantly from _+ . mmhg to ± mmhg (p< . ) within rain, while pao ]fio remained constant at -+ . mmhg. qs/qt decreased significantly from -+ % to -+ % (p< . ) during plv and did not change during conventional mechanical ventilation. static pulmonary compliance (cstat) increased significantly ff~m . r± . to . _+ . ml/cmh /kg (p< . ) during plv and decreased slightly from . _+ . to . e . ml/cmh /kg during conventional mechanical ventilation. the infusion of the endoperoxane analogue resulted in a sudden decrease of pao /fio from _+ to _+ . mmhg in the plv group and from ± to +_ . mmhg in the control group. inhaled no significandy improved oxygenation in both groups (pao /fio : _+ mmhg during plv and +_. mmhg during conventional mechanical ventilation). during inhalation of no mpap decreased significantly from -+ m ± mmhg (p< . ) in both groups. there was no significant change in oxygenation and mpap during inhalation of and ppm no. conclusions : plv significantly improves oxygenation and pulmonary compliance in acute respiratory failure. the additional application of inhaled no further improves oxygenation and pulmonary hemodynamics when acute respiratory failure is associated with severe pulmonary hypertension. inhaled no is very effective in improving oxygenation and pulmonary blood flow even at low doses. the work was supported in part by grants of the austrian nationalbank nr . as in neonates, severe respiratory failure in infants and children can be aggravated by pulmonary hypertension, resulting in further deterioration of oxygenation due to increasing intrapulmonary shunting. we analysed the influence of inhalational nitric oxide (ino) in treatment, course and outcome of severe ards in a pediatric population. since infants and children (age: - months) with ards and oi > (mean value: . ± ) underwent a trial with ino (concentration: , , , and ppm) to prevent further respiratory failure. patients had a significant improvement of their oxygenation (rise of pa > mm hg) for at least hours (responders); mean best ~fficient no dose: . ppm. the non-responders had only a short-term improvement or ino had no effect. in responders and nonresponders there was no significant difference with regard to age, underlying disease, ards severity, time on mechanical ventilation, blood gases and ventilator settings before notrial, nor was there a different grade of pulmonary hypertension (estimated by echocardiography). the only difference was an higher ol in the group of the non-responders: . ± .i vs. . ~ . , p < . . in the group of the respenders there was a secondary deterioration of lung function after i - days on ino in children (transient responders): in these patients, as well as in the group of the non-responders, alternative modalities of treatment (hfov and/or ecmo) became necessary. children ( %) died: transient respenders and non-responders. in infants and children with ards due to different underlying diseases ino can acutely lead to a significant improvement of oxygenation in about % of the cases. the right selection of patients for no therapy and the influence of ino on the survival rate of ards in childhood has to be evaluated in further studies. and pediatric cardiology, university of graz, a- graz purpose: after fontan procedure cardiac output is critically dependent on the pulmonary vascular resistance. even minor elevations of the pulmonary vascular resistance may significantly decrease cardiac output. inhaled no is an effective, selective pulmonary vasodilator in experimental and clinical situations of pulmonary hypertension. the aim of this study is to evaluate the effects of inhaled no on oxygenation and pulmonm , circulation in children after a bidirectional glenn-anastomosis (n-~) or a fontan-like operation (n= ). material and methods: from june t to january children with a mean age of . +~ . (sem) yrs and a mean body weight of . -+ . (sem) kg were treated with inhaled no after glenn-or fontan-like operations. all but one had complex cardiac malformations with single ventricle. all children were mechanically ventilated with an fin > . . inhaled (no) was applied using a rrdcrdproeessor based system which additionally allowed measurement of no/nox using the chemihimniscence method. methemogtobin concentrations were determined times a day. the major indication for postoperative inhalation of no was a high (> mmhg) transpulmonary pressure gradient (tpg--cvp-lap). severe myocardial dysfunction of the single ventricle was excluded by echocardiography. results: the mean duration of mechanical ventilation was . _+ . (sem) days the. mean dose of inhaled no was . -+ . (sem) ppm, the mean duration of no-inhalation was _+ (sem) hours. the mean methemoglobin concentration was . -+ . (sem)%. hemodynamic data and arterial oxygen saturation before inhaling no and minutes later are given in table acute hypoxaemic respiratory failure (ahrf) in children occurs in a heterogenous group of diseases with pulmonary pathophysiological processes ranging from reversible physiological intrapulmonary shunting to fixed structural lung damage. we hypothesized that inhaled nitric oxide (ino), a selective pulmonary vasodilator, might identify those patients with potentially reversible disease, i,e, large response may indicate a greater likelihood ef reversibility and thus survival. a retrospective review of the early response to ino in infants and children (aged month to years, median months) with severe ahrf( with ards). the mean p(a-a)o , pao / fio , oxygenation index (oi) and acute lung injury (all) score prior to the commencement of ino were +_ . , +_ . , _+ , and . +_ . respectively, the magnitude of response to ino was quantified as the % change in oi occurring within minutes of ppm ino therapy. this response was compared to patient outcome data. results. there was a significant correlation between response to ino and patient outcome, kendall tau b r= , , p< . (table) conclusion. in ahrf response to ino appears te define a subgroup of patients with improved outcome compared to nonresponders. we speculate that response to ino may be useful in selecting patients with potentially reversible lung disease for special support therapies such as ecmo. randomised controlled trials are needed to define the role of ino in paediatric ahrf. between may and december , patients (pts) were treated for mas. treatment groups were: group i only : pts; group i conventional mechanioal ventilation (cmv): pts; group ii hfo: pt; group iv hfo+no: pts. therapy was stepwise intensified until oxygenation improved ( i -) ii -) iii --) iv). "high volume strategy" was used with hfo (mawp - cm h ). the initial no-concentration was - ppm, with rapid reduction down to - ppm once oxygenation improved. results: one pt (group it) died of hypoxic-ischemic encephaiopathy (termination of therapy); all other newborn babies survived. in group iv pt and showed barotrauma prior to hfo. pt , and were treated with additional mgci (max. mg serum concentration . - . mmol/i). following the identification of inhaled nitric oxide "no) as a selective pulmonary vasodilator (frostell et al ) [ .+ , + . data are compared to baseline values within each group. *=p< . , **=p< . , ***=p< . l among patients who fulfilled ecmo criteria, improved with no and did not required extracorporeal life support. tltree out of ecmo patients eventually survived. conclusions: m our study low-dose of irthaled no showed a variable effect on oxygenation in newborns with acute respiratory failure. an acute response to no appeared to be correlated with a better short-term outcome and the avoidance of extracorporeal support in ecmo candidates. differently, lack of acute and/or sustained response was associated with death or need for ecmo. although the nature and severity of the underlying disease or the degree of prematurity may play an important role in these patients, we believe lack of acute response to no may be an early predictor of bad outcome, prompting toward alternative treatments such as ecmo or liquid ventilation. *picea s., °bartuli a.,°dionisi-vici c., *dello strologo l., §villani a., §bianchi r., ^salvatori g.,*rizzoni g, °sabetta g. *div. of nephrology, °div. of metabolism, §intensive care unit, ^div. of neonatology. "bambino gesfl" children research hospital. rome, italy. successful prevention of handicaps or death in newborns with ~ depends on rapidity and efficiency of treatment. poor response to nutritional and/or pharmacological treatment requires extracorporeal removal of nh . efficiency and cardiovascular tolerance are often difficult to obtain with peritoneal or hemodialysis in neonates. we report the results of cavhd in newborns with hc. methods: vascular access: femoral vessels. blood flow: - ml/min, dialysate flow: - ml/h. filter: amicon minifilter plusrm(polysulfone membrane; . sq.m.). no ultrafiltrate(uf) production, patients: case with carbamoytphosphate synthetase deficiency (body weight -bw-: . kg) showed hc at day , a relapse of hc occurred at day due to an infectious event. case and (bw: . and . kg), both affected by propionic aeidemia, showed hc at day and day , respectively. plasma nh (~tg/dl) decrease is shown in the complications: transitory ischemia of arterial cannulation limb and transitory thrombocytopenia occurred in case ; surgical repairing of artery after cavt-id was necessary in case ; no cardiovascular instability was observed during cavhd . outcome,'all patients recovered from hc in less than day: case : alive, mild b)iootonia at mos; case : dead after days from cavhd withdrawal for pulmonary hemorrhage; case : alive, normal development at mos. conclusions: ) in newborns with hc, ca~q-id provides good cardiovascular tolerance,high efficiency and quick removal of nh , even without uf production (i.e. only by diffusion). this allows easier management (no need of fluid and electrolyte balance). ) arterial complications seem frequent in neonates treated by cavhd. venovenous circulation could overcome this problem. vb nguyen, m jokie, c leeaeheux paediatric intensive case service, hospital university centre, avenue c te de nacre, caen cedex, france background, the implication of polymorphonuclear neutrophils (pmns) in the physiopathology of children's haemolytic.uraemie syndrome (hus) becomes more and more evident. the purpose of the present study is to role out their impact among other pronostie elements during the course of the disease. patients and methods. diarrheal prodrome and its duration, patient's age, maximal blood nitrogen level, anuria and dialysis time, extra.renal involvements, white enll and pmn counts and thrombopenia duration have been retrospectively analysed in infants with good outcome and in another children with unfavorable outcome. results. neither diarrhoea or its duration, nor children's age, nor blood nitrogen level, nor anuria or dialysis time had any predictive value for the disease evolution in the acute phase of our patients. adversely, extra-nenal involvements was accompanied by severe and complicated courses of the disease (p< , ). the elevation of white cells and pmns (heyon x /i) and pmns (more than x / ) as well as its persistence beyon a week were most frequently observed in complicated forms (p< , , p< , and p< , , respectively). a transient thrombopenia (less than day@ in patients with elevated counts of white cells may be a filrther obvious sign of an unfavorable course of the disease ( < , ). conclusion. the elevated count of white cells and pmns, either alone or associated to one rapid regeneration of platelets, seems enabled to predict an unfavorable evolution of the hus in children. msud results from an inherited impairement of catabolic pathway of branch chain amino-acids. high leucine blood levels may induce acute brain dysfunction. this dramatic complication led us to propose leucine removal procedures as continuous hemofiltration. patients and methods three newborns in acute msud onset were treated by hf, hdf and hd. extracorporeal circulation was performed through a . fr catheter, a circuit with a blood pump (priming volume = ml). patients and procedures characteristics are summarized below in the sucralfate (an aluminium salt of sucrose octa sulfate) is used to prevent and treat upper gastrointestinal bleeding in critically ill patients. with minimal absorption, the potential for side effects is thought to be limited, though aluminium toxicity has been reported in patients with chronic renal failure. these patients may already have had high body stores of aluminium. we report critically ill children with high serum concentrations of aluminium following sucralfate therapy. all had renal impairment. the normal aluminium level is < . gmol/l and in patients with chronic renal failure < . ].tmol/l. none of these patients had known preexisting chronic renal disease. cpb was conducted under deep hypothermia (t,° °c) and cardiocirculatory arrest (cca) or under hypothermia (t,° °c) and low-flow perfusion. continuous holter-electrocardiograms (h-ecg) were recorded from the ilranediate postoperative (po) period on for hours. h-ecg were also recorded prior to the operation and before discharge. following dr were observed: snpraventricutar (sv) and ventricular (v) extrasystoles (es) (> / h), sv and v tachycardia (svt and vt), accelerated junctional rhythm (ajr) and junctional ectopic tachycardja (jet), and nd and rd degree atrioventricular block (avb and avb ). the incidence of po dr was % in the pre-op h-ecg, % on the st, % on the rid, % on the rd po day and % befbre discharge. compared to the pre-op findings, an increased incidence of sves, ves, svt and avb on the st po day was observed, whereas vt and a jr or jet were exclusively observed po. all types of dr were observed up to the rd po day. ty e of dr before discharge was similar to pre-op findings and there was no definitive avb . considering patient groups according to the most frequent isolated op-procedure, the incidence of dr on the first po day was % after asd ii-closure (n= ), % after stthaortal vsd-closure (n=lg), % after correction of a complete avsd (n= ), % after correction of a tetralogy of fallot (n= ) and % after fontan-operation (n= ). incidence and type of dr were not significantly different between groups. longer cpb-dttration and use of cca were risk factors for po ves and vt (p< , and p< , , respectively) whereas use of cca and degree of hypothermia were risk factors for the development of a jr and jet (p< , and p< , , respectively). -our results indicate that po dr after cpb in children m'e frequent but mainly transient. in our series, specific cpb-related parameters are of greater influence than surgical procedure itseif for the development of dr and are discriminant risk factors for particular types of dr. the course of anp, cgmp/anp (as indicator for atrial natriurefic peptide biological activity), and no and no (as indicator for endogenous nitric oxide (no) synthesis) was investigated in i infants (median age months) undergoing cardiopulmonary bypass (cpb). patients were divided into groups according to whether they had (group , n= ) or not (group , n= ) preoperative heart failure (hf) and pulmonary hypertension (pht). group patients had preoperatively significantly higher levels of anp (p< . ), cgmp (p< . ) and no and no (,p< . ) but had significantly lower cgmp/anp (i < . ) than group patients. during cpb, anp was significantly higher in group patients ~< . ). as compared with prebypass values, cgmp/anp was reduced in both groups during cpb (p< . ). cgmp/anp inversely correlated with duration of cpb and aortic clamping time (p< . , respectively). no and no were significantly higher in group than in group patients (p< . ) without any intraindividual change during cpb. from the early postoperative period on anp, cgmp/anp and no and no were similar in both groups. after cpb, anp correlated in both groups with blood pressure (p< , ) and diuresis (p< . ). no and no inversely correlated with pulmonary arterial pressure immediately after cpb ( < . patients after a fontan-type of procedure have elevated central venous pressures (cvp) leading to congestion in the gastrointestinal system and often ascites. purpose of this study was to evaluate whether this causes a different postoperative gastric mucosal ph (phi). methods: we evaluated a series of patients, who underwent cardiac surgery with cardiopulmonary bypass (age: days to years (mean , yrs), weight: . to kg (mean . kg). a commercially available tonometer (tonometics®) for sigmoidal use in adults was inserted into the stomach after induction of anesthesia. the phi measurements were done according to manufacturer recommendations we compared three groups of patients: ) aeyanotic (n= ), among them p with vsd and p with avsd; ) cyanotic (n= ): tof: p, tga: p; ) cyanotic after a fontan-type procedure (n= ). phi were measured at picu arrival and after h. fudhermore we compared lactat levels at these time points. differences between the groups were evaluated with one way anova on ranks with pairwaise multiple comparisons (dunn's method). the relationship between cvp and phi was investigated by regression analysis. results: the median phi for groups i, and were . , . and . at ardval and . , . and . after h respectively. at picu arrival group was significantly (p< . ) different from groups and . there was no significant difference between the latter two groups, after h group was different from group , there were no other significant differences. the median lactate levels for groups t, and were . , , and . at ardval and . , . and . after h respectively. at ptcu arrival group was significantly (p< . ) different from group , after h there were no significant differences. there was a weak negative correlation between cvp and phi: r= - . ; p< . . conclusion: patients after a fontan-type of procedure have lower phi than patients after other cardiac surgical procedures, however, this is only in part due to the elevated cvp and venous congestion. eleven children were investigated months (median) after postoperative mof. iviof was defined as the failure of at least two vital organ systems (kidney, liver, lung, central nervous system) in addition to cardiac insufficiency and high fever. underlying surgical procedure was repair of tetralogy of fallot (n= ), fontan-(n= ) or seuning procedure (n=l). all patients fulfilled criteria for mof in the first postoperative (po) days. six patients needed peritoneal or hemodialysis for days (median) during the po period. one patient showed cerebral infarction due to thromboembolism in the territory of the right internal carotid artery immediately after the operation. the follow-up protocol consisted of extensive investigations of heart-, renalliver-, and lung functions as well as complete neurological and psychological examinations. all patients had adequate cardiac examination. lung function was normal in all but patients who had an obstructive syndrome. only patient showed an isolated decreased creatinine clearance. abnormalities of the liver ftmction tests were only noticed in patients after fontan procedure. severe neurological sequels such as paraplegia (n = ) and diplegia (n-i) were observed in of the patients. the remaining children presented with a delayed graphomotorical and speech development associated with normal intelligence. -in our series the most frequent and severe sequels after postoperative mof were neurological. -abnormal liver fimction tests are more likely to be a consequence of the fontan hemodynamics than a sequel of mof. the optimal dosing schedule of surfactant therapy for the treatment of neonatal respiratory distress syndrome (rds) remains unclear. goal: surfaetant function and the concentration of phospholipids (pl) in tracheal aspirates are compared in a prospective randomized trial involving neonates with rds who received either two or more ( or ) doses of survanta. methods; ventilated neonates < w with rds were treated with survanta oo mg/kg if fio >_ % or mean airway pressure _> , cm hzo, after h a nd dose was given (same criteria), if the support still exceeded the criteria h after the nd dose, the patient was randomized to no extra dose (two}, or to an extra dose of survanta (morel (and a th dose h later; same criteria), pl was measured in tracheal aspirates and corrected for dilution with the urea method. "active" large aggregates and "non-active" small aggregates of surfactant were separated by centrifugation and quantified. surface tension of the large aggregate fraction was measured by pulsating bubble surfactometer, results: neonates were randomized, x two and x more ( x and x doses), gestational age was , ± , w and birth weight ± g. most patients had severe rds with initial ventilation: rate . _+ , , peak inspiratory pressure (pip) , -+ . cm hzo, fio . ± . %. at randomization: rate . ± . , pip . -+ . cm hzo, fio . ± . %, and h after randomization: rate . ± . , pip . _+ . cm hzo, fio . ± . %, without signif, differences between the groups. there was relapse (again fio _> % within h) in group two and t bpd in group more. in total, tracheal aspirates were analyzed. pl was not signif, different before randomization (two . ± . vs more . ± . /jmol/ml), but neither after randomization (two . -+ . vs more . ± ,o /~mol/ml). there was no difference in the % small aggregates (two . ± . vs more . ± . %), the surface tensions (ran/m) were not signif, different (each time two vs more): before randomization . ± , vs . -+ . , in the h after randomization . ± . vs . -+ , , or - h after randomization . -+ . vs . ± . , or - h after randomization . _+ . vs . -+ . . conclusion: neonates who received more than two doses of survanta did not have higher pl, nor a better surfactant function than neonates who received only two doses of survanta. continuation of the trial is necessary to evaluate clinical outcome. may not indicate need for treatment p.c. clemens s.j. neumann university of hamburg, department of pediatrics, klinikum schwerin, wismarsche str.. , d- schwerin. aim of the study: the finding of elevated tsh and decreased t in the newborn usually is classified as "transient hypothyroidism", thus the elevation of tsh is classified as consequence of the lowered t . but on the other hand several data sets show that tsh elevation as well as low t , one independently of the other one, are associated with different kinds of perinatal stress. each of these laboratory deviations, if not associated with the other value being abnormal too, is generally accepted not to be an indication for treatment. from this we conclude, that more pefinatal stress, as in intensive care neonates, may produce tsh elevation as well as low t , but only coincidentially, not the tsh elevation being the consequence of low t , thus not to be classified as "hypothyroidism", thus not indicating treatment. if this hypothesis is right, we should find an association of increasing pefinatal stress with an increasing number of neonates from tsh and t normal via tsh or t abnormal to high tsh and low t . method: in the newborn screening program in germa w we determine primarily tsh, and only in the neonates with elevated tsh, in addition we determine t . thus in our study we asked whether we find an association of increasing perinatal stress with an increasing number of neonates from tsh normal via tsh abnormal while t normal to high tsh and low t . definitions for this study were: tsh elevation = > mu/ (as usual in the german screening programs), t lowered = < p_g/dl perinatal stress score was or or or in dependency of the neonate having stress in none to all of the following three categories: (a) forceps or vacuum extraction or sectio co) birth weight below g (c) at the th day existence of a relevant neonatal disorder (rds, ictems gravis, infection/sepsis, vitium cordis with hemodynamic relevance, severe malformation). results: our data of neonates show a high significant association (chi = , p < . ) of, on one hand, perinatal stress score with normal tsh, versus, on the other hand, perinatal stress score or with high tsh and low t . discussion: facing the background given above, in the intensive care newborn, the constellation of high tsh and low t may be only a coincidential addition of two independent abnormalities. in tbese cases -the high tsh not being the consequence of low t -the classification as "hypothyroidism" is not justified, thus a therapy not indicated. on the other hand of course there exist rare cases with high tsh as consequence of low t thus with hypothyroidism tlms with indication for therapy. unfortunately we have no criteria, that enable a certain discrimination of these two categories thus in respect to the question of therapy or not. conclusion: further research has to be done to learn how to discriminate the coincidential high tsh and low t from the causal constellation of high tsh and low t . until we have certain discrimination criteria we have to treat both groups of neonates. few studies have focused on fa composition of surfactant pc in preterm infants before and after surfactant therapy. methods: tracheal aspirates were collected in venttlated mfants from birth until extubatlon ( / _ /twk ga, .+ g bw). after lipid extraction, t.l.c,, and methylation, fas of pc were quantified by gaschromatography. intralipid a ( . % linoleic acid, : • ) was started h after birth. results: six infants developed respiratory distress syndrome (rds) and received survanta r i mg/kg (sr), all doses within h after birth (ix s r n=l, x s r~ n= , x s r n= ). one child did not develop rds. in alt patients, the patmitate % in pc was ~ % (before sr<=natural composition), increased to ~ % after s r, and remained > % for i h after lx s a, . .+i . h after x, and . .+ . h after doses. in patients, intubated long enough, the palmitate % decreased with a half-life of . _+ . h to a new plateau which was still higher than baseline after week. linoleic acid % was . _+ . (with rds), decreased after s r~ and returned to baseline due to the decrease in patmitate %. thereafter the linoleic acid % increased linearly with . % per h, in patient even up to . %. other fas did not increase after return to baseline. in neonatal medicine the current parameters, arterial oxygen saturation and arterial oxygen pressure, are poor indicators for oxygen delivery and oxygen demand. the purpose of this study was to obtain venous blood samples from the inferior vena cava in stable neonates with respiratory failure and to determine a parameter that reflects more adequately the balance between oxygen delivery and oxygen demand. "l~e study included neonates requiring mechanical ventilation tbr severe respiratory insufficiency. an umbilical venous and arterial catheter were inserted in the inferior vena cava and in the aorta respectively. paired blood samples were obtained at the time that the patients were hemodynamically stable. fifty paired arterial and mixed venous blood samples were analyzed. jnear regression analysis showed the following correlations: in a neonatal intensive care unit adjacent to a delivery room caring for mothers per year, (with a referral of mostly for preterm delivery), virtually every neonate <ls g was seen by the same ophtalmologist, j.o. the incidence of retinopathy of prematurity (rop) was in - of ii cases ( preterms <ls g with % surviving to discharge, and % rop in survivors; % if less than weeks). in - , cases of rop were diagnosed by the same ophtalmologist. were born at less than weeks, of which ( %) survived to discharge, and among those survivors, rop was present in ( %), with rates varying from % at weeks to % at . objective: to compare a method of teicoplanine (teico) infusion using an electrical syringe-pump with a manual injection. methods: infusion of teico was simulated through a standart neonatal i.v. system. the infusion system consisted of an life care infusion pump (abbo'it lab.) with its i.v. set for maintenance intravenous fluid (flow < mi/h) connected to a -way stopcock. an meter extension tubing (vygon lab.) was placed between the stopcock and a neonatal catheter, an another meter tubing (injection tubing) was connected to the stopcock. the volume of the injection circuit was . ml. simulations were realised for weights ( or kg), with a doses of mg/kg and a injected volume of , ml to ml. our goal was to perform a complete infusion in minutes. we compare one method of infusion with an electrical syringe-pump with manual methods: a: teico was infused with a syringe-pump pilot c (becton & dickinson lab.) according to a protocol using ) a priming before connecting the syringe to the tubing (for immediate starting of infusion), ) a programmed volume injected in minutes (the drug volume was greater than the dose prescribed to avoid loss of teico into the syringe), ) a ml wash out was performed over minutes with the syringe pump. b: teico was manually injected in a few seconds in the tubing followed by a ml wash out over minutes. c: idem as b but a nu site valve (medex) was connected to the proximal end of injection tubing to avoid leakage between removal of the teico syringe and connection of the wash out syringe. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at minutes was calculated and expressed as a perventage of the total amount of teico prescribed. results are a mean of to rons. a b c kg . + , % , + . % , -+ . % kg -+ , % -+ , % . -+ % conclusion: with a drug volume injected < circuit volume and a valve, a direct i.v. administration of the drug in the circuit followed by a wash out seems an accurate alternative to drug infusion conbroled by a syringe pump and is easier to perform. doxapram hydrochloride is a central and respiratory stimulant which is used in neonatal intensive care units to treat caffeine-resistant apnoes of the newborn. routinely, doxapram is administered intravenously. oral administration would be much easier but data on bioavailability after oral administration are limited (two studies) and show a large variation. we therefore studied the oral bioavailability of doxapram in preterm infants. doxapram treatment was started with an intravenous loading dose of , mg/kg during minutes, followed by a continuous infusion of mg/kg/h. after h the intravenous administration was changed to continuous oral administration with the same dosage, blood samples were collected h after both the intravenous and oral administration and analyzed by hplc-assay. apnoea rates per hours were listed before and after starting doxapram treatment. the median apnoea rate per hours declined from to after both the intravenous and oral administration. the oral bioavailability of doxapram is between and %, indicating that the oral route can be used effectively in these infants . there were no differences in the decline of the apnoea rate after intravenous versus oral administration of doxapram, infasurf r has been comnared with exosurf r in two studies: one as drodhvlaxis and the other a rescue trial. similar. althouah non-sianificant benefits were found for the natural surfactant. in trials there was a sianificant reduction in dulmonarv air leaks for . : % ci . - . for babies treated with natural comnared to svnthetic surfactants. for trials ( babies~ comdarina natural and synthetic surfactants for rds { comdarina survanta r and exosurf r. and one infasurf r and exesurfr% neonatal mortalitv was sianificantlv reduced (or . : % ci . - . with natural compared to synthetic surfactant treatment. in two further trials different natural surfactant drenarations were compared. reduced oxvaen needs for hours after treatment were found for r r infasurf and curosurf respectively when each was compared to survanta r. andarent lonaer-term benefits from these surfactants were not statisticallv sianificant. further trials will be needed to ascertain differences between various surfactant preparations. introduction bacterial meningitis is a common cause of admission in the paediatric age group, and one which still carries a high morbidity and mortality. these complications are strongly associated with a delay in antibacterial therapy. a significant proportion of these patients require mechanical ventilation; it is in this particular group of patients that survival is greatly diminished. the identification of risk factors for mechanical ventilation associated with bacterial meninges may help improving survival by shortening the delay to icu referral. the paediatdc risk of mortality score (prism) is the most widely used scoring system in the paediatric icu literature; the accuracy of prism on predicting outcome in meningitis has been shown to be poor. aim we aimed to describe our population of patients with bacterial meningitis requiring ventilation, and then to identify predictors of survival. methods this study was conducted at the baragwanath hospital in south africa which is an universityaffiliated institution with end average annual paediathc admission of patients. baragwanath icu admits non-neonatal paediatdc patients per year. a retrospective chart review from january to december of consecutive paedistdc icu admissions with bacterial meningitis was performed. results approximately cases of bacterial meningitis are admitted to the general paediatric wards every year; this constitutes ± % of all admissions. the mortality of these patients is + %. during this time ( m, f) patients ( %) were accepted for icu admission, with a mortality of . %. the median age was months (range days to years). the median delay to hospital admission was hours, and the median delay to icu admission was a further hours. the median duration of tcu stay was hours ( for non-survivors, for survivors). the main presenting features were convulsions ( %), altered mental state ( %), fever ( %), respiratory symptoms ( %), headache ( %), and diarrhoea and vomiting ( %). the most common indications for icu admission were seizures ( %), coma ( %), shock ( %), respiratory failure ( %) and acidosis ( %). in % of patients there was a cardiorespirstory arrest prior to admission. the most common organisms in the csf was pneumococcus ( %), haemophilus influenza ( %) and e coli ( %). the presence of leucopenia (wcc < ), a low platelat count (< ), acidaemia (ph< . ), and the need for inotropic support were strongly associated with nonsurvival. tachycardia and hypotension were not significantly essorjsted with poor outcome, as has been previously reported. discussion early diagnosis of meningitis and prompt institution of antibiotic therapy requires a high level of clinical suspicion. paediatric patients with bacterial meningitis that require mechanical ventilation have a poor prognosis. there is little evidence to suggest that nomsurviva[ can be predicted prior to icu admission, but a rapid deterioration requiring ventilation and inotrepic support with evidence of severe sepsis (low platelet count, leucopenia) is nmost invariably associated with a fatal outcome. the long term functional outcome of these patients make this disease even more devastating; the rote of icu in the management of these patients has yet to be fully estanished. objective and study design: a retrospective study was pertbrmed for all patients diagnosed with hemorrhagic shock and encephalopathy syndrome (hse) during to . soroka medical center is the only medical facility in the southern negev region of israel serving a population of - , residents, consisting primarily of jews and bedouins. results: patients ( bedouins and jews) were diagnosed with hse. main features on arrival included profound shock and coma with con~alsions. active bleeding and/or disturbing coagulation tests with falling heuroglobin levels and thrombocytopenia was noted in every case. all infants developed diarrhea shortly after arrival. elevated urea, creatinine and liver enzymes was noted in all cases. annual incidence tbr inlhnts < year of age was : , for bedouins and . : , for jews. patients ranged in age from - wks and arrived at the hospital late night/early morning ( : am-ll: am), during winter/early spring (november-april). all were healthy prior to admission, with short prodromal symptoms of upper respiratory tract or gastrointestinal infection noted in cases. most infants had markedly elevated body temperature on arrival. a history of overwrapping and/or excessive hearing was obtained in of infants. bacteriological and virological cultures were negative in all infants. one infant died and neurological sequelae were observed in all survivors. the high prevalence of hyperpyrexia during sleep in the presence of negative microbiological results with no evidence of excessive hearing, and the high incidence of rise among a closed, culturally isolated society known to have a high incidence of congenital malformations, may support previous assumptions that hse results from hyqperpyrexia, originating in most cases from a "physiologic" heat induced trigger which starts and peaks during the night in previously healthy infants with susceptible, predisposing genetic underlie. approximately % of hospitalised infants with respiratory syaacytial virus (rsv) infection require mechanical ventilation. our general practice is not to use specific antiviral therapy. we have undertaken studies of rsv-infected mechanically ventilated patients without underlying congenital heart disease or immunodeficiency. study i (n= ): a retrospective review of infants (mean post-conceptual age weeks; median duration of intubation was days (interquartile range - ). blinded review of chest x-rays during the first three days of mechanical ventilation revealed a spectrmn of lower respiratory tract findings from marked diffiase consolidation in all zones without hyper-inflation (n= ) to gross hyperinfiation without consolidation (n= ), with the remaining patients have an intermediate picture (n= ). death occurred only in patients who were at the poles of this continuum ( / consolidation and / hyperinflation). patients at these poles could be differentiated by gender predominance, birth gestation, alveolar-artarial (a-a) oxygen gradient (p< . l), oxygenation index (p< . l), peak inspiratory pressure (p< . ), and intubation days (p< . ). study ii (n= ): prospective audit of infants with the aim of verifying the above differentiation. separating patients based on their early x-rays and a-a gradient we confirmed the above predictable difference in duration of supportive therapy (consolidation v intermediate: ( - ) v ( - ) p< . ). severe lower respiratory tract rsv-infecrion in young infants results in different distinctive partems of disease with characteristic radiological and clinical features, and each has a predictable timecot~se. conflicting reports on special therapy should be interpreted with respect to these observations before making conclusions about the efficacy of any specific treatment. the clinical data of children wich suffered from a severe mycosis between jan. -dac. and wich were treated with amphotericin b in spanish hospitals were collected. mean age was + . years; were mate ( %) and female ( %). the most common underlying diseases were leukemimymphoma ( %) and congenital heart defects ( %). the major pathogens isolated were candida albieans ( %), other candida ( %) and aspergillus ( %). and liposomal amphotericin (la) in ( %). in the ca group, the starting dose was , ~ , mg/kg, reaching a maximal dose of . + , mg/kg after . + days. maintenance time was + days and the cumulative dose: ~ rag. in the la group, the starting dose was . ± mg/kg, reaching a maximal dose of . _+ . mg/kg (p< . ) after + days. maintenance time was ~ days (p< . ) and the cumulative dose _+ mg (p< . ). the reasons for la use were: elective in % of cases, previous renal failure in %, and ca inefficacy in %. hepatic or renal function impairment was two times more frequent in la group than in ca group, the antifungal efficacy was % for ca and % for la. therapeutic failure or toxicity induced withdraw of ca in % of cases, vs, , % for la (p< , ). mortality was not different in both groups ( vs. %), adverse effects were related to ca in events vs, only one in la group (p< , ). the commonest side effects in ca patients were fever ( %), chilis ( %) and nausea ( %). in ca group, cases ( %) developped analitical anormalities related with amphotericin, vs. cases ( %) in la patients (p< . ). in the first group, the commonest serum alterations were hypokaliemia ( %), raised creatinine ( %) and bilirrubin ( %). in the second one, hypokaliemia presented in % of cases (p< . ), raised bilirrubin in % and creatinine in % (p< , ), the antifungal efficacy of la is at least the same of ca. from the clinical and analitical points of view, la is much less toxic than ca. la can be used at a greater dose than ca and is safe in children with renal failure. laurence desplanques -serge gottot -christian dageville d~artement de sant~ publique -facult~ xavier bichat - rue henri huchard paris -france -the french << reaped ~> network was created to implement a nosecomial infections (ni) quality care program in nicu and picu, the first objective was to describe the annual ni incidence rate in each icu population : all patients stayed more than hours in icu. methods : n] criteria were defined by the reaped group according to cdc criteria. all data were collected by a medical and nursing team. all infection data were validated by an external investigator. results : patients were admitted over a months period. % were newborns. ni were identified among patients. the overall ni incidence rate (ir) was . % and . °/ person day (from . to . °/ according to age, lowest rate for newborns). septicemia ( % of ni) and pneumonia ( % of ni) were the two main ni. according to age, the septicemia ir varied from . to . °/oo catheter day (lowest rate for newborns) and the pneumonia ir from . to . °/ ventilator day (lowest rate for newborns). there were very few other infections (uti : %, ir : . °/ catheter day). gram positive cocci were isolated in % of septicemia ( % of them were coagulase negative staphylococcal). gram negative bacilli were isolated in % of pneumonia ( % of them were pseudomonas). % of ni were caused by candida, mostly septicemia. the septicemia and pneumonia ir varied according to unit even after adjustment for age. discussion the aminoglycoside antibiotics are frequently used in newborns for the treatment of severe infection and sepsis due to gram-negative microorganisms. the currently recommended dosage schedule for tobra ( . mg/kg q h) does not take into account differences in gestational or postnatal age during the first weeks of life. we questioned the validity of these recommendations and studied the population kinetics of tobramycin to establish predictive equations that enables the clinician to select the appropriate initial dosing schedule. methods tobra trough (t= ) and peak values (t= ) were taken on day - after birth in newborns. tobra was administered as a -minute intravenous infusion already in an adapted dosage schedule: . mg/kg q h in infants with gas < weeks; . mg/kg q h in infants with gas between - weeks and . mg/kg q h in infants with gas > wks, tobra concentrations were analyzed by tdx-assay, a one-compartment model was assumed and non-linear mixed effect modelling (using nonmem) was applied to the data, a trough level < mg/l and a peak level between and mg/l was required, with the present dosage scheme % of the trough levels were too high and almost % of the peak levels too low. calculations showed that the following dosage schedule should result in optimal levels of tobra. preterm infants gas < wks: mg q h preterm infants gas - wks: . mg q h preterm infants gas > wks: the currently recommended dosage schedules for toeira result in high trough and low peak levels. prolongation of the dosing interval and increasing the amount of drug per dose according to the above scheme will improve tobra level control. since january british clinicians have been conducting a randomized controlled trial of neonatal ecmo. mature infants (>- weeks gestation and birthweight kg) with severe cardiopulmonary failure have been randomized to receive continued care in their referring institution or referral to a designated ecmo centre for further management. we now present the preliminary results which have prompted closure of recruitment to this trial. the final outcome will be assessed as intact survival against death or severe disability at one year of age for all the recruited patients. patients were categorised by diagnosis such as isolated persistent fetal circulation, secondary persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia and by severity of illness at the point of first contact with the clinical coordinators of the trial -judged primarily by the oxygenation index ( before randomization). patients were randomized ( in each arm). hospital outcome data are reported for all patients and year outcomes on t ( survivors). at this stage of the babies allocated to ecmo are known to have died compared to of those allocated to conventional management (rr . ; % ci . - . ; p= . ). fewer deaths have been obsea-ved amongst ecmo allocated babies in all the diagnostic categories used. a % incidence of disability and impah~nent has been observed amongst survivors. this rate is similar in both groups and the survival advantage is not offset by an increased rate of disability or impairment following allocation to ecmo. we consider that these data combined with those available from other studies provide conclusive evidence that the survival to discharge from hospital is substantially higher in patients allocated to ecmo than in comparable infants not so allocated. therefore recruitment to this trial has been closed whist awaiting complete one year outcome data. sigston pe, goldman ap. #keating j. crook r. ~e dj~. great ormond street hospital for children nhs trust, and ~biochemistry department, kings college hospital, london, united kingdom. isoflurane is a safe and effective means of long term sedation in both children and adults in the intensive care setting. the use of isoflurane, by adding it to the sweep gas allows the use of this volatile anaesthetic agent in patients on ecmo, enabling rapid control and weaning of sedation. a potential problem with the long term use of isoflurane is fluoride ion accumulation with the possibility of renal toxicity, the purpose of this study was to assess plasma fluoride levels in patients receiving prolonged isoflurane on ecmo. method: fifteen infants and children (aged day - years, median weeks) receiving ecmo support for either cardiac or respiratory failure were recruited to this study. the patients were sedated with isoflurane as well as intravenous agents (morphine and midazolam). isoflurane was administered ( % - %) via a calibrated vaporiser to the sweep gas, adjusting the level to maintain adequate sedation. blood samples were obtained on a daily basis for plasma inorganic fluoride assay. the relationship between plasma fluoride and amount of isoflurane administered, as %-hours (vaporiser setting in % x hours) was calculated by linear regression. results: the duration of ecmo ranged from to (mean ) hours, during which the amount of isoflurane administered varied from to (mean ) %-hours. blood samples were anaiysed, demonstrating individual peak plasma fluoride levels of . to . #mol/ , mean , p.molli (toxic threshold = gruel/f). the plasma fluoride positively co;related with the %-hours of isoflurane (r = . , p = < . ). conclusion: this study shows that although there is a dose related accumulation of inorganic fluoride ions in patients sedated with isoflurane on ecmq, the peak fluoride levels are well below the suggested toxic threshold. merzel y, lev a, bar yosef g, halbertal m, lorber a ecmo center, picu, emek medical center, israel. the mortality rate of pediatric patients with acute myocarditis is - % according to the severity of myocardial damage. a month old gzrl presented with high fever, respiratory and cardiac failure. diagnosis of acute myocarditis was made and the patient was ventilated with high pressures and fio of . . she required high doses of inotropes. echocardiography revealed a dilated la and lv with severe mr. lvedd was mm and lvsf %. calculated oxygenation index was . she was resuscitated after a cardiac arrest. she was commenced on ecmo (using biomedicus centrifugal pump and avecor oxygenator) at a flow of ml/kg/mm with immediate improvement of hemodynamlcs, oxygenation and pc . resptratory assistance and vasoactive drugs were reduced. the patient was transported by air, on ecmo, to the ecmo cevter. she developed arf and cvvh-d was performed. cardiac fimction started to improve after days. ecmo was discontinued on day . echo revealed lvedd mm and lvsf %. ippv was discontinued on day . on discharge, a month later, her lvedd was mm and lvsf %. she behaves normally for age without neurologic or other medical sequellae. literature search revealed no case of acute myocarditis, as severe, that was treated successfully. survavors of disease this severe usually suffer dilated cardiomyopathy and permanent disability. the use of ecmo allows myocardial rest which prevents long term myocardial damage. introduction ecmo is increasingly used in the care of critically ill newborns. despite the frequent use of betalactam antibiotics in the treatment of these infants there are no data available on the dispbsition of cefotaxime (ctx) and amoxicilfin (am) d ring ecmo. the purposes of this study were to determine the pharmacokinetics of these two drugs in infants on ecmo and consequently formulate appropriate dosing regimens. we therefore studied the pharmacokinetics of ctx ( mg/kg ql h) and am ( mg/kg q h) in term infants on day after birth, blood samples were taken before (t-o) and . , , , , (am) and t h (ctx) after the intravenous bolus injection and analyzed by hplc-assays. . ctx mg/kg q h results in adequate serum levels of ctx in fullterm infants on ecmo, am mg/kg q h results in very high serum trough levels. recalculation based on the known volume of distribution and elimination serum half-life of these infants resulted in the following dosage recommendation: mg/kg q h. persistent pulmonary hypertension of the new-born (pphn) is characterised by rapid fluctuations in pulmonary artery pressure (pap) and a clinical impression of stifflungs. lung mechanics were measured in term infants, mean age . +_ . days who were paralysed and ventilated within the first three days of life. fourteen infants had pphn with systemic or suprasystemic pap measured by echocardiography. in these patients, the respiratory system resistance was . % higher (p < . ) and compliance . % lower (p = . ) during systemic or suprasystemic pap compared to when the pulmonary hypertension had resolved. in contrast, there were no changes in resistance in the infants with respiratory distress syndrome (rds) and no pulmonary hypertension or in the seven infants with normal lungs, where two readings were taken hours apart. the changes in lung mechanics interfered with mechanical ventilation, resulting in a . mmhg rise in paco (p= . ) during pulmonary hypertension. inhalation of nitric oxide ppm resulted in a % decrease in respiratory system resistance and an improvement in oxygenation. the bronchial and vascular smooth muscle was increased by % in postmortem lung samples from eight infants with pphn compared to six age matched post-mortem controls with normal lungs (p< . ). these findings suggest a co-constriction and co-hypertrophy of bronchial and vascular smooth muscle during pphn. anatomically the pulmonary vasculature and bronchi lie in close proximity to each other. thus mediators such as endothelin- released locally may act on both vascular and bronchial smooth muscle to produce the observed vasoconstriction, bronchoconstriction and smooth muscle hypertrophy. prince of wales children's hospital university of new south wales, randwick, n.s.w. australia. introduction an increasing mortality in asthmatic children has been reported. the increased severity of asthmatic illness leads to an increased demand for icu admission, and a corresponding increased need for mechanical ventilation. geographic end environmental factors are thought to be partly responsible for differences in disease sevedty throughout the wodd. for this reason, epidemiological studies from diverse areas are important, risk factors for icu admission, and for the institution of mechanical ventilation should be identified, to optimise icu admission criteria and to avoid unnecessary delays in admitting at-risk patients. aim to document the clinical characteristics of ventilated and non-ventilated asthmatic patients admitted to icu. methods this is a retrospective study of all paediatric asthma icu admissions from january to december . results there were patients admitted to the icu for acute severe asthma in the study period. the male:female ratio was : , the mean age . • . months, the mean prism . - . %, and the mean duration of admission . hours. there was no seasonal variation in admissions. only % ( / ) patients required mechanical ventilation. in % of all patients this was the first presentation with asthma. there were some significant differences between ventilated and non-ventilated patients (see table) . there was a significantly higher incidence of concomitant and nosocomial pneumonias in the ventilated patients ( . % vs . %) as well as segmental lung collapse ( . % vs . %). there were no deaths. discussion the need of mechanical ventilation significantly increases the morbidity of and duration of icu stay of asthmatic patients. younger asthmatic paediatdc patients have a significantly higher risk of ventilation. the need for ventilation is predicted principally from a worsening pco and respiratory acidaemia, which is often independently interpreted by the clinician as respira ory exhaustion. this study has shown that icu admission is important in the management of young paediatdc patients with acute severe asthma and respiratgry fa!!ure. intravenous salbutamoi in the emergency, department management of severe asthma in children. g.j.browne,a. perma,x. phung,m.soo westmead hospital, sydney, australia. it is postulate that if an initial intravenous loading dose of salbutamol is given in severe asthma, a more rapid clinical response will occur, reducing requirements for continued high doses of nebulised salbutamoi with fewer side effects. this double blinded study was conducted in the emergency department of westmead hospital a university hospital in sydney, australia. all children with severe asthma had initial nebuliser therapy ( rag of salbutamol with ml of saline). if asthma remained severe minutes later, they were given a dose of intravenous hydrocortisone ( mg/kg) and either normal saline or salbutamol microgm/kg intravenously. frequent nebulised salbutamoi therapy continued during the initial first hour if clinically indicated. continuous respiratory and haemodynamic monitoring occurred in the first hours. serum potassium and glucose determinations were made at study commencement and hour after intravenous therapy. salbutamol determination was made at study commencement. children remained clinically monitored for the next hours, with their ongoing treatment determined by clinical response. children with severe asthma months to years of age were studied, with given intravenous salbutamol and given intravenous saline. the intravenous satbutamol group (ivsg) showed rapid reduction in asthma severity scale in the first hours, with reduced need for high frequency nebuliser therapy ( _< hourly), occurring . hours.earlier. no clinically significant side-effects were found in either group, although, tremor more frequent in the [vsg. biochemistry and salbutamol concentrations were similar in both groups. the use of intravenous salbutamol (i microgm/kg) in the management of severe childhood asthma is a safe and effective therapy with no significant side-effects and the potential to abort severe asthma attacks in the emergency department. intravenous terbutaline in picu piva j., amantra s, rosso a., zambonato s, giugno k, maia t. introduction: the admission to a picu of children with respiratory failure secondary to an acute obstructive lower airway disease is a common event, especially during winter seasons. these diseases have several causes, but most of them (especially asthma and chronic airway disease) have a good response to the administration of b -adrenergic drugs. objective: to find the dosis of intravenous terbutaline that is safe, efficient and with minimal adverse effects when used in children admitted to a picu with acute obstructive lower airway disease and respiratory failure. material and methods: we study the records of all children that were admitted to our picu during the winter of . only the patients that had respiratory failure and acute lower airway disease and who needed the use of iv terbutaline were selected. the records were divided in two groups: less than months and more than a year old these two groups were compared in the following aspects: the minimal and maximal dosis, and the length of time of use of iv terbutaline, frequency of tachycardia, hypokalemia, and mechanical ventilation. to establish any difference in the two groups we use the t exact test of fisher and x , with p< . , results: during the period of study were admitted patients to the picu, and ( , %) of them used of iv terbutaline. the mean age was . + . month, used iv terbutaline during . + . days ( . to days), the initial rate was . + . p~g/kg/min, and the means of therapeutic dosis was . +l. ~g/kg/min (ranged from . to . ). twelve ( . %) patients had tachycardia art obstacle to the increases in the rate of use of iv terbutaline during any time. mechanical ventilation was necessary in patients ( . %) and ( . %) patients died. the children under year of age used initial dosis of iv terbutaline lower than the children up of year old ( . p.g/ kghnin x . ~tg &g/rain, p< . ), but without difference in the length of use, the maximal dosis, the rate of mechanical ventilation and tachycardia. the frequency of hypokalemia was most common in the group of children under year of age. acute respiratory failure during status asthmaticus may require mechanical ventilation. current therapy includes paralysis, pressure control ventilation (pcv) and permissive hypercapnia to limit pulmonary barotranma and its hemodynamic consequences. asthmatic children exert a significant amount of respiratory effort during exhalation. with paralysis, this expiratory effort is lost. unloading the inspiratory work of breathing while maintaining the patient's expiratory eftbrt using pressure support ventilation (psv), may be beneficial. methods: children receiving pcv (peak inspiratory pressure (pip) = kpa. rate breaths/min) and pco > kpa were switched to psv. children were initially ventilated with psv . kpa and peep = . kpa (servo c). all children received beta agonist therapy, ipratropium and anesthesia with ketamine or inhalational anesthesia, and were breathing spontaneously. respiratory parameters and blood gases are shown be~bre psv, within minutes (start) and when the ph had normalized (during). data are presented as median and range, * p < . compared to before psv. results: children with hypercarbia during pcv responded to psv, normalizing pcos and ph within hours. the mean respiratory rate decreased from a median of ( - ) to ( - ) while the pip was decreased to . ( . - . ) kpa within hours. the i:e ratio also significantly decreased. conclusion: psv permitted patients to active/y exhale while unloading the inspiratory work of breathing. perhaps this strategy shifts the patient's respiratory effort from inspiration to exhalation, thus permitting the child to meet the excess work of breathing caused by bronchoconstriction. maged z. youssef, peter silver, laura nimkoff, and mayer sagv. division of pediatric critical care medicine, schneider children's hospital, new hyde park, ny . introduction: mechanical vemiladon of patients with severe bronchospasm can be difficult, due to poor chest compliance and increased airway resistance. ketarmne is a cormnonly used anesthetic agent that has been shown to have bronchodilator properties. the purpose of this study was to determine ifa continuous infusion of ketamine had an effect on the oxygenation and chest compliance of children with severe lironchospasm who were mechanically ventilated. methods: a retrospective chart review was conducted of pediatric patients in severe bronchospasm who were mechanically ventilated in our picu and treated with a continuous ketamine infusion. all patients were receiving aggressive bronchodilator therapy and adequate sedation prior to keramine. patients were excluded if any new bronchodilator or sedative agents were started within hours of initiation of ketamine treatment. all patients were simultaneously treated with benzodiazepines. for each patient, the pao /fio ~ ratio and dynamic compliance [tidal volume/(peak imp. pressure -peep)] was determined immediately prior to ketamine, and at , , and hours post-ketsmine initiation. data are presented as mean ± s.d., and were a~yzed using one way anova and the multiple comparison method of bonferroni. patients (age . ± . yrs.) received * p< . ketamine for severe bronchospastu during mechanical ventilation in our picu. both . .xto-* * the pao /fio ratio and dynamic . . -.... . compliance increased significantly following initiation of the ketamine infusion (see figure) . the mean ketamine dose was ± mcg/kg/min, and the -, mean infusion duration was ± too-[/ hours. one patient required glycopyrrotate ~' to control excessive airway secretions, and " one patient required an additional dose of o--j i ~-~ ~/me diazepam to control hallucinations after i cessation of ketamine. all patients were t~n~,mr~ *~am~ successfully weaned off mechanical ~l~s ~,~s~on ventilation and discharged from the picu. conclusion: continuous ketamine infusion to mechanically ventilated pediatric patients with refractory broncliospasm results in a significant improvement in oxygenation and dynamic compliance of the chest. reports of adults with status nsthraaticus document significant morbidity and mortality, whereas studies in children have had more varied results. different centers report mechanical ventilation (mv) in to % of admissions, occurrence of pneumothoraces or paeutuomediastinums in to %, and mortality in up to % of patients ~'t . we retrospectively reviewed status asthmaticus admissions to the pediatric intensive care unit (picu) between january and december . seventy-five of these patients were admitted fr~an the emergency department of chla (er admit). the mean length of stay in the picu was . days and the mean length of stay in the hospital was . days. based on patients who had arterial blood analyses, patients had hyperoapnia (pco > ). all patients received oxygen, inhaled albuterol (alb), and cortieosteroid therapy. ninety-five percent of patients also received methylxanthine (mx) therapy. of the admissions, patients ( %) required mv. only of these patients were admitted through our emergency department, whereas the remaining patients were intuhated at outside facilities. twenty-three cases required intr:wenous beta-agonist therapy, either isoproterenol osop) or terbutaline (terb). h~ff of the ea.~es re~%wed were complicated with hypokalemia (k+< . ). c,', ,~lications ofpoeumothoraces or pneumomediastinums were seen in % of ,'r:u~ported patients, but in only % of er admit patients. only % of these were in mechanic.all, )atients. there were no deaths in the review. respiratory mechanics measurements 'are useful in mechanically ventilated children to optimize ventilator settings. nevertheless, the transducers used to measure flow (f) and pressure (p) remain expensive. objective. to evaluate the performances of piezoelectric p transducers ( us dollar) in measuring f and p. methods. we used a previously described monitoring system measuring respiratory parameters [ ] . in this study f was obtained by a differential piezoelectric p transducer (_+ . cmi-i , honeywell) whose sensitivity has been reduced to +_ cmh by an electronic amplification equipment and p by a piezoelectric p transducer (_+ (). cmhzo, honeywell) connected to a grid pneumotachymeter &nt) ffleisch or ). volume (v) ( to ml) obtained by numeric integration off ( . to l/rnin ) and p ( to cmh ) were respectively delivered through a calibrated seringe and an electronical manometer (pic premier) and calculated by the computer. bland and altman analysis was used for assessment of results bias. coefficient of repeatability (cr) was estimated by the standard deviation of repeated measurements of the parameters as calculated in a oneway analysis of variance. results. mean difference (mdi between injected v ( to ml) and measured v using pnt was . ml, sd = . ml. difference and mean v were not correlated. sd of repeated v measurements were not correlated to v. cr was . ml. mdif between injected v ( to ml) and measured v using pnt was lrd, sd = ml sd of repeated v measurements were not correlated to mean v. cr was ml. mdif between injected p and measured p was . cmi-i , sd . cm h sd of repeated p measurements were not correlated to mean p. cr was . cmh . conclusion. inexpensive piezoelectrical transducers can be used to measure f and p and evaluate respiratory mechanics in ventilated children. previous studies have already shown the problem of the reproducibility of pft in preterm ventilated babies. were studied preterm ventilated babies {mean weight gr) in the first week of life in clinically stable condition, measuring flow, airway pressure and esophageal pressure simultaneously. each baby was studied twice with an interval of one hour and each study was done increasing the rate till to inhibit spontaneous breaths. none sedative has been used. only mechanical breaths were analyzed. compliance and resistence were calculated with a computer system using the linear regression method. we expressed quantitatively the intrapatient variability as the percentage of variation of tidal volume, compliance and resistence between the two studies in each baby. then intraclass correlation coefficient test (icc) was applied to confirm qualitatively our results (total agreement = , good reproducibjtity > . ). we h~£ed, an a eept~ble ~efiabirl¢, ~-~r;= '~ . during mechanical ventilation, an air leak (al) and plateau phase duration (pl) may influence dynamic and static compliance (cdy and cst, respectively). this study evaluated the effect of al and pl on two methods of measuring c.dy and est. methods. intubated, ventilated patients in a pediatric intensive care unit were evaluated after obtaining informed consent. patients were intuhated with a cuffed endotracheal tube and ventilated with a serve ( ventilator. cdy and cst were determined using the serve ands~rmedics . objective: evaluate the repercussion in respiratory mechanics and arterial blood gases and the impact of the ventilator adjustments on the auto-peep magnitude. material and methods: the measurement of the auto-peep was performed using an eletronic-pneumatic controlled device with a oclasion valve installed between endotracheal canutla and the ventilator circuit. the d~'ice was connected to a solenoid to detecte the end of inspiratuo phase and thus, the activation of the oclusion valve. the signs of pressure and flow were monitorized using a diferential transducer and it was processed using a pc computer and tmeumoview® software. the stud were divided in phases: phase a. where the ventilator adjustments was performed using the routine of the unit and phase b, where the targets of mechanical ventilation were to minimize the auto-peep. static compliance (crs) was ineasured by the single-breath occlusion technique, using a mean of ten occlusions for analysis. passive respiratory resistance measurements and the tidal breathing flow-volume loops were also obtained., while the ventilatory settings were siguificantly reduced soon atier ecmo was started. before ecmo crs measured in all patienls was . _+t). ml/cmh /kg (mean_+sem). for each patient the ecmo course was divided into four periods, proportional to the duration of the treatment, and the best ~alue of crs in each period was chosen for analysis. as shown on the figure. crs significantly improved (*p< , ) from the second half of the ecmo course in the group of patient that finally were successfidly weaned from ecmo. no change ill compliance was measured in the group of patients who failed to respond to the extracorporeal hmg support our data suggest that compliance measurements during ecmo can be useful togelher with overall clinical evaluation to predict both outcome and duration of cxtracorporeai support in the neonatal and pediatric population. objectives: brain temperature determines the amount of neuronal damage caused by hypoxic insults. thus measuring brain temperature at standardised conditions is in request. we investigated whether brain temperature of neonates varies with head insulation environmental temperature, body activity and time course. patients and methods: we investigated non-invasive brain temperature analogues in healthy prematures tess than two weeks of age in an incubator (gestational age . + . wks; x + sd, weight + g). we measured nasopharyngeal temperature (tnasoph) by a thermistor placed in the nasopharynx via a feeding tube, zero-heatflux temperature (zht) at the temple by a thermistor and healflux transducer, insulated by two pads, as well as rectal and incubator temperatures. patient activity was documented by video taping. measurements were performed during periods of increased insulation ) by turning the head with its measuring site on to the mattress ( ( ) ( ) - ( ) ( ) ( ) ( ) . ( ) ( ) { ) ( ) ( ) - ( ) ( ) ( )i ( ) ( ) ( ) ( ) . ( ) ( ) t ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) web (lmg/kg) at rain ( ) - ( ) ( ) ( ) ( ) - ( ) the vehicle had no effect. paf caused dose dependent rise in ao and pa pressure and reduction in flow to lpa (up to % like the vascular endothelium, the endocardial endothelium (ee) has a significant impact on adjacent myocytes, and may critically alter myocardial function.~ we have previously shown that ee cells are capable of sensing and responding to hypoxia by the release of prostacyclin (pgl). potassium channels in other cell types have been reported to be oxygen sensitive. to determine whether potassium channels modulate the ee hypoxic response, we investigated the effects of three potassium channel inhibitors on hypoxia-induced pg] release from ee cells. methods: ovine endothelial cells were harvested and passaged onto ,~ microcarriers. cells were constantly perfused with normoxic and hypoxic kreb's solution, and with three potassium channel blockers: glibenclamide (gb, #g/ml), tetraethyl-antmonium (tea, ram) and aminopyridine ( ap, i mm), perfusate was assayed for prostacyclin (ria). data were compared by analysis of variance. * p<. compared to normoxic control; # p< . compared to hypoxic control. adrenaline is extensively used for resuscitation in neonates with rds. however, effects of adrenaline on systemic, pulmonary and cerebral hemodynamics have not been defined in newborns with rds. thirteen anesthetized, and ventilated newborn piglets were subjected to repeated saline lung-lavage series while mean systemic arterial pressure (abp), mean pulmonary arteriat pressure (pap), mean left atrial pressure (lap) and mean central venous pressure (cvp), cardiac output and blood flow in the internal carotid artery (ica) were measured. systemic vascular resistance (s~), pulmonary vascular resistance (pvr) and cardiac index (ci) were calculated. sixty minutes after luug-lavage, the adrenaline group (a) (n= ) received adrenaline as a continuous infusion of . lag/kg/mi, while the control group (c) (n= ) received saline. none of the varlables were changed by saline. however, significant increases in abp (p< . ), pap (p< . ), ci (p< . ) and svr (p< . ) were observed after administration of adrenaline, whiie pvr and ica were not modified. mean±sd for abp/pap (p/a), fvr/svr (p/s) and ci (ml/mirdkg) were: ratios of pap/abp and pvpjsvr significantly increased following infusion of adrenaline. these data suggest: ) the cerebral perfusion is preserved during the infusion of adrenaline; ) effect of the adrenaline infusion on the systemic circulation is more pronounced than its effect on the pulmonary circulation in newborn piglets with surfactant deficiency. s demirak~a, ch knothe, kj hagel, j bauer department of pediatrics, justus-liebig-university giessen, frg inhaled no is a short acting selective pulmonary vasodilator. we studied the effects of ppm no and % oxygen during heart catheterization in children (age - years, median years) with heart defects and elevated pulmonary vascular resistance index (pvri) in order to asses the value of no as a tool of decision making for corrective cardiac surgery. patients were eligible for testing when they were more than one year old and had a pathologically elevated pvri in a previous heart catheterization. intubation, 'anesthesia and muscle paralysis were performed in all patients during testing of pulmonary reagibility. calculations of pulmonary vascular resistance and flow were based on the fick method. response to no was assumed when pvri declined more than %, of the patients were responders to no. effects of no and oxygen on pvri, mean pulmonary arterial pressure (mpap) and pulmonary vascular flow (qp) in all responders are described in the table below. cardiac surgery was offered to all responders, and of them were successfully operated. surgery is planned in another patients and parental consent for surgery was not given in one patient. in ebstein disease, during the first days of life, the ability of right ventricle to propel blood to the pulmonary artery is impaired due to high pulmonary vascular resistances. the flow is mainly directed to left atrium through tricuspid insufficiency, right atrium and foramen ovale. to decrease pulmonary resistances and increase pulmonary blood flow, high frequency oscillations, mechanical ventilation, nitric oxide and prostaglandin are required. after few days, a forward circulation is normally established. we cared two newborns with ebstein disease where this approach was hindered by a large pulmonary valve insufficiency. both of them were diagnosed in utero, showing a large tricuspid insufficiency with a non opened pulmonary valve and a ductal left to right shunt. one fetus was hydropic. at birth, blood stream from the ductus arteriosus was directed to the right ventricle through the pulmonary valve insufficiency then to right atrium, left atrium and ventricle, aorta and ductus arteriosus. a low pulmonary blood flow was demonstrated by low mean velocities ( cm/sec). a high reverse flow was seen in descending aorta with a negative flow in the renal artery. both of these newborns were oliguric because of ductus arteriosus steal. pulmonary blood flow doppler evaluation allowed different strategies of ventilation, switching between hfo and conventional ventilation, modulation of pge doses, inhaled pulmonary vasodilators (nitric oxide) and surfactant. the hydropic baby died, the other survived after weeks of intensive care complicated by supraventricular arythmia (wpw). in conclusion, during neonatal period, in ebstein disease, a large pulmonary insufficiency leads to a vicious circle where lungs are excluded, inducing severe asphyxia and high pulmonary resistances. the blood is backward propeled from the aorta through the ductus arteriosus to the right ventricle and atria, then left cavities to aorta. arec must be considered when pulmonary blood flow does not increase despite optimal therapy. guti~rrez-larraya f*, mandoza a*, velasco jm*, zavaneua ( **, gatindo a ~, s&nchez-andrede r, s&nchez jl***, mellon a***, mar f***. pediatric cardiology*, pediatric cardiac surgery**, pediatric intensive care unit***. hospital de octubre. madrid. background: transesophageal pacing (tp) is effective and sate both for diagnosis and treatment of pediatric arrhythmias. material and methods. eleven consecutive patients are included. a tri or quaddpolar or f temporal transvenous catheter with an interpolar distance of to mm was advanced through the nares and positioned to the point with the largest amplitude of atrial deflection, surface ecg and a bi or monopolar electregram were recorded simultaneously, selecting filters when needed ( to mhz). pacing was performed with a programmable stimulator (medtronic ) beginning with ms and increasing ma to and then increasing up to . ms. narula method was selected to diagnose sinusal node disfunction (snd) and overdrive pacing to treat tachyarrhythmias. results. tp was useful in all the patients and no complications were observed: in patients a snd was diagnosed (one needing a definitive pacemaker), in two patients with atrial ratter (ripe ) sinus rhythm was recovered, in one patient with a postoperative junctional ectopic tachycadia we were able to get atrial synchrony with marked bemodinamic improvement, and patients with paroxysmal supraventricular tachycardia sinus rhythm was easily and quickly restored ( of them recquirad repited episodes of tp until pharmacelogycal levels of antiarrhythmic drugs were raised). mean age and weight were months and . kg (one patient had . kg). there was a close relation between height and depht insertion (r= . ). mean stimulation parameters were , ms and . ma. discussion. in experiencied hands tp is an effective and safe way to treat and diagnose cardiac arrhythmias even in newborns. it should be tried before endovenous pacing is stablished and it is faster than pharmacologycal treatment. bailing g., eicken a., sebening w., vogt m., schumacher g., bl~hlmeyer k.; kinderkardiologie, deutsches herzzentrum m nchen, germany to assess the outcome of balloon valvuloplasty in infants with cardiac failure caused by critical aortic stenosis a retrospective study was performed. between and neonates, aged - days (median d), weight .t - , kg (median , kg) with critical valvar aortic stenosis were dilated by balloon (aovp) as the first line treatment. patients received prostaglandin el, needed inotropic drugs and mechanical ventilation. associated cardiac lesions : persistent ductus arteriosus (pda) in patients (restrictive pda in cases), a mitral regurgitation (mivr) in cases ( severe and moderate or mild mivr), angiographic findings of endocardial fibroelastosis (efe) in patients, mitral stenosis (mivs) in , coarctation of the aorta (coa) in , and finally a small musculary ventricular septum defect (vsd) in i patient. vascular approach for ballooning : a. axitfaris in cases ( %) a. femoralis in t ( %) and v. femoralis in cases ( %). the median ratio between inflated balloon and aortic valve diameter was , . dilatation was achieved in all cases. the peak systolic gradient across the aortic valve (pre aovp) ranged from to mmhg (median mmhg) and was reduced to to mmhg (median ; gradient reduction is significant (p < , )). aortic regurgitation (aovr) was absent or mild in , moderate in and severe in patient after aovp. children survived (actual suwival rate: %; early mortalffy: n = ; late mortality: n = ). mid term follow up ( - , years; mean , years) showed an increase of the systolic peak doppler gradient across the aortic valve (median mmhg) but no increase of aovr. re-interventions (re-aovp: n = , commissurotomy: n = , mitral valve replacement n = , resection of subaortic stenosis: n = , resection of coarctation: n = ,vsd-closura: n = ) were performed in patients. rv contractility and pulmonary vascular mechanics(pvm) in immature animal models are poorly underslood. we developed an acute rv injury model to measure rv contractility and pvm in response to commonly used cateehalamines. ten anesthetized piglets ( - kg) were instrumented with micromanometers in the lv, rv, pa, and la. a pulmonary artery flow probe was placed to measure cardiac output(qpa). ultrasonic dimension crystals were sutured to the myocardium and dynamic chamber volumes estimated using shell subtraction methodology. rv injury was induced with - cryoprobe injuries at - to - °c for - minmes each. da at mg/kg/min, db at mg/kg/min, and ep at . mg/kg/min were infused in random order. rv contractility was evaluated by calculating a load independent measure of contractility, the preload recmitable stroke work(prsw), during vena caval occlusions. to describe pvm, input resistances), characteristic impedance(z ), total pewer(tp), and efficieacy f=qimo"p) were measured. measurements were made pre-and post-injury, during infusions, and between infusions. clyoablation decreased prsw ( . _+ . to . + . , p< . ). at the end of the experiment, prsw remained depressed to this level indicating stability of the model. one factor contributing to organ dysfunction for infants undergoing repair of congenital heart defects (chd) is their "inflammatory response" to cardiopulmonary bypass (cpb). this response is characterized by an increase in cytokine release, complement activation and endothelial injury. modified ultrafiltration (muf) is a method for removing tissue water and inflammatory mediators by rapid ultrafiltration followin~ cpb, muf may acutely improve post-operative end organ function. in this study, we evaluated the effects of muf on the pulmonary and cerebral function of infants undergoing cpb for repair of chd. we prosnecrivety randomized infants (.~ mos) to either muf (n= ) or no muf (n= )(control) following correction for chd. the study intervals were ) before cpb, ) immediately after cpb, and ) minutes after cpb. pulmonary function was evaluated by measuring dynamic compliance (cdyn) and airway resistance (raw). for pts (mue= pts; control= pts) exposed to a period of deep hypothermie circulatory arrest (dhca), cerebral metabolism (cmro ) was calculated at each interval using the xe clearance technique for cerebral blood flow measurements and arterial and jugular bulb saturation measurements to calculate cmro . a reduction in cmro has been consistently demonstrated after dhca. the effects of muf on cdyn and on cmro are shown below: p< . vs pre-cpb; # p< . vs post-cpb • p--o. vs. post-cpb this study demonstrates that immediately following exposure to cpb, muf will improve pulmonary compliance. raw was not different between groups. there was no significant difference in hours of post-op ventilation for either group. in those pts exposed to dhca a trend towards better cerebral metabolic recovery compared to control was demonstrated. this is the first technique applied to infants undergoing dhca where cmro after cpb was greater than precpb measm~s. although this may be beneficial to postoperative hemodynamics, ventilatory management and long-term neurologic recovery, more patients and longer follow up will be necessary to verify such an effect. the effects of conventional mechanical ventilation (cmv) on left ventricular (lv). diastolic filling in neonates are not well established. one approach to improve lv filling is the use of cmv to provide a phasic increase in airway pressure {thoracic augmentation). this phasic increase in airway pressure may result in an increase in lv filling similar to that which occurs with cpr. thoracic augmentation has not been evaluated in neonates with ventricular dysfunction who frequently demonstrate increased heart rates. attempts to maintain low peak airway pressures during cmv may result in a prolonged inspiratory time that occurs over multiple cardiac cycles. this may alter lv filling in the later cardiac cycles. to determine the effects of inspiratory time on lv diastolic filling, infants were examined with doppler echocardiography less than hrs after surgery for the arterial switch procedtme. pulsed doppler recordings of the millal valve (mv) were obtained with the inspiratory time adjusted to occur over cardiac cycles ( sec.). a pressure transducer was placed in line with the ventilator, and the respiratory cycle was recorded superimposed on the doppler tracing to provide accurate determination of inspiration and expiration. doppler recordings were obtained from the apical -chamber view and the following measurements were made: peak e and peak a velocities, eia ratio, and deceleration time. compared to the expiratory phase of cmv, the initial beat during the iuspiratory phase of cmv resulted in an increase in mv peak e (. +-. vs . -+ . m/s, p< . ) and peak a (. + . vs . -+ . m/s, p< . ) velocities with no change in mv deceleration times (p<. ). compared to the initial beat during tile inspiratory phase, the third beat during the inspiratory phase resulted in decreased peak e (. + . vs . + . m/s, p< . ) and peak a (. + . vs . + . m/s, p< . ) velocities with no difference in deceleration times. thus, cmv augments lv filling during the initial phase of inspiration. however, as the increase in airway pressure is distributed over multiple cardiac cycles, lv filling falls below baseline levels. these observations indicate that while thoracic augmentation may be beneficial, to optimize lv filling the inspiratory time of cmv must be < cardiac cycles. energy expenditure in pediatric orthotopic liver tranaplantat~on, to determine the actual calorie requirements of critically ill children and evniuate the correlations between measured, stress-p~lictod and repleted energy exponditttm and the severity of illness. des/gn: a prospective, dinlcal study. se~ng: tertiary care pediatric icu in a university hospital. patients: ten patients aged to months with disorders prompting picu admission, including sepsis, respiratory failure, solid organ transplantation, and cardiovascular surgery. inta~entions: all patients were studied within hrs of major surgery or transplantation, or following acute illness. all patienls were severely stressed clinically and all but two were intubated by cuffed tubes, in three of them, still in a stress state, the study repeated on the third day of the disease, energy expenditure mensurements (mee), as well as illness seventy scoring systems, mtfltisystern organ failure scores and various anthropemetric and clinical indices of nutritional status, the stress-predicted energy expenditure (s-pee), the basal metabufie rote (pbmr), the repleted energy (re) and the recommended dietary allowances (rda) were measured or calculated in each patient. multiple regression analysis was used to analyze the data. measurements and main results: although the mean mee was significantly lower than the mean s-pee ( . + kcal/kg/day vs. . : kcal/kg/day, p<. ), it did not differ significantly from the pbmr (mean difference - . kcal/kg/day, range - . to + . kcal/kg/day). the s-pee/mee ratio ranged from . to . , while the re/rda ratio ( . : kcal/kg/day)/( . : kcal/kg/dny) ranged from only . to . . the prism/tiss ratio was not correlated better with mee than the diagnostic category (r~=. vs.. , respectively). the re was positively correlated withthe mee (rz=. , i)=. ) while negative oarrelatian has been found between mee and age, mid-arm circumference, triceps skinfotd and the use of vaseactive agents (r~. , - , -. , p<. and -. resp~lively). concl.m~: if s-pee is used for caloric repletion in the stressed oritic~ly fll el~d, these patients will be substantially overfed by as much as %. although pbmr appears to approximate the mee by ± %, other clinical and nutritional indices should also be ennsidered. objective: to deter .mine..t.he metabpli.c and.nutritional state of mechanically ventilated intants and children m relatmn wlm severity or msease. patients and methods: mechanically ventilated infants and children, median age months (range days to years), were studied. severity of illness was assessed using prism, prism-ii~ and fiss-scores. oxygen consumption (vo ), energy expenditure (mee) and respiratory quotient (rq) were determmed by mdirect calorimetry. total urinary nitroger(tun) and creatinine excretion, levels of albumin and crp were aetermmed in patients. in these patients daily caloric intake and substrate utilization were assessed. they were categorized in subgroups: a partial feeding (recent admission to p cu); b complete feeding. results: mee of the total group (n= ) a) i=intake g/kg/day (% total intake); u=utilization g/kg/day (% total production). nitrogenba]ance was negative in all patients in group a (mean - . -- : mffkg/day) and positive in all but one patient in group b (.mean . ± .d n~g/..kg/day;p= . ). no significant correlations were round between creatinine height index, crp, albumine, jun vs v u /kg conclusions: the mean measured energy expenditure does not exceed predicted resting energy expenditure, but ~ere is a wide range. in a majority ot patients with complete feeding h.igh carbohydrate intake resulted, in high kq and lipogenesis. in patients witla partial teeding the highly negatwe nitrogen'balance suggests that in the early phase of diseasean higher protein intake should be provided. severity of illness scores ann oiocnemicm markers of physiologic stress correlatedpoorly with oxygen consumption. leite,hp; iglesias, s; faria, c; ikeda, a; albuquerque, mp; carvalho, wb pediatric icu -s~o paulo federal university -s~o paulo, brazil objectives: ) to evaluate patterns of use and monitoring of nutritional support in critically ill children; ) to evaluate an education program in nutrition support given throughout the resident physician training in the pediatric icu. patients and methods: records of patients receiving nutritional support during were reviewed. aider this first phase, knowledge and understanding of the role of nutrition support was conveyed to the residents through didactic lectures. in a second phase thedata were reevaluated in children who were given nutrition support in . results: from a total of days ofthempy, the single parenteral route was utilized in , %, the digestive route (tube feeding or oral route) in , %. of this time. a previous nutr~ional assessment was performed in children; no patient had the nutr~on goals set. the nitrogen to nonprotein calories ratio ranged among : and : . only , % of the patients had their estimated caloric needs supplied and this goal was achieved only in those patients who were on enteral tube feeding. patients did not achieved their goals for vitamins. the supply ofoligonleme~s was adequate except the zinc. nutritional monitoring parameters including weight, serum albumin and serum triglycerides were performed in almost all the patients but without uniformity. the reevaluation ofthase parameters showed adequacy of protein and micronutrients supply; however deficiency in nutritional monitoring and infrequent enteral feeding were still detected. conclusion: there were lacks in the implementation of nutritional support, which were partially corrected in the rid phase of the study, although the training of residents may have contributed to give them cognitive skills, it didn't changed policies and procedures as desired. we recommend reinforcement of the education program concerning basic nutritional aspects, and the organization ofa multidisciplinary team in charge of coordinating the providing of nutritional support. plasme free fatty acids (ffa) are the meier energy source for mast tissues. during fasting ffa are released from the breakdown af triglycefides in edipose lissue (at). lipalysis, le. the rote of release o/ ffa, has been megsured in humans by means of stable isotope techniques using labeled pa or glyeerd as traces. no information is avoilob!e io dale on the ro of la. we infused albumin hound u c-pa and u c-la in critically ill infants, receiving kcel/kg/doy of iv glucose end na oral feeding (weight . ,i., kg;, range . - . ; ego : days, range ) and measured simultaneously the ra of pa and la from (he isotopic enrichment of plasma fea by gas chromatography-mass speclrome|ry ai : , : and : hours from tile shod of the infusion. a subcutaneous gluted at biopsy was obtained far fatty acid (fa) composition. we intended to ( ) in fie infants sbjdied atipa ~'os hi her than attla (~p<o.o )' and ihe ra of pa was higher then thai of la (~p= . §). however the ratio el the re's to the respeclive fa in at was higher for la than far pa (*p= . ). in conclusion the ra af la was higher then expected from ~he fa composition of at. we speculate [hat la is preferentially released during tipolysis and its contributuion to the energy metnbolism of the sick infonl could io !orger than what: is normai!y assumed from ihe fa composilion of at and of plasma fea. preoperative starvation can be prevented in infants undergoing non gi surgery by continuing feeds till as long as it is safe to do so. some gi disorders require withholding of feeds for a long period. for these and for infants already suffering from pem~ parenteral feeds are given preoperatively. peroperatively nutrition is maintained by ensuring adequate glucose supply in the infusion fluid and its smooth metabolism. proper placement of feeding tubes are also carried out peroperatively. postoperative early resumption of oral feeds is ensured by new techniques of anaesthesia and pain relief and methods to ensure early return of peristalsis. enteral feeds of pre digested substances and feeds through transanastomotic tubes and through gastrostomies and jejunostomies can prevent starvation in many situations. parenteral feeding is carried out only when enteral feeding is not possible, for example in necrotising enterocolitis~ gastroschisis, short gut syndrome, high enteric fistula and acute pancreatltls. the artedal ketone body ratio (akbr) is established as a valuable tool in the management of adult patients undergoing surgery for severe liver disease.the redox theory emphasises the central role of the liver in preserving homeostasis and the importance of the hepatic mitochonddal redox potential (nad+/nadh) in monitoring liver function and integrity.the akbr (plasma acetoacetate/ hydroxybutyrate) is a measure of hepatic mitochonddal redox status, reduced ratios associated with poorer outcome. the venous ketone body ratio (vkbr) is influenced by peripheral ketone utilisation and therefore thought unreliable in assessing hepatic redox its use has been dismissed as no correlation with the ratio in hepatic venous blood was found. inspite of this. vkbr is used in the diagnosis of lactic acidoses and respiratory chain defects. the objective of this study was to determine the relationship between the akbr and vkbr in a paediatnc intensive care population. children admitted to the paediatdc intensive care unit, with indwelling arterial and central venous lines as part of their routine care, were recruited for the study. the median (range) age was . years ( - . years) with prism score ( - ), simultaneous akbr and vkbr were measured. suppression of ketogenesis was confirmed using a rapid -hydroxybutyrate strip test (ketofilm, genzyme diagnostics) pdor to sampling. the median vkbr . (range . - . ) was lower than median akbr . (range . - , ), there was good agreement between artedal and venous ratios, bland-altman analysis giving a % confidence interval for relative bias of - . to - . . there was a significant correlation between vkbr and akbr r , , p, . (intercept . , slope , ) conclusions; values for akbr tend to be higher than vkbr, however there is a consistent relationship in critically ill children. in paediatdc patients in whom ketogenesis is suppressed, vkbr may be considered equivalent to akbr. this simple test may prove to be a useful adjunct in predicting mortality in cdt{cally ill children. to understand the present status of pediatric intensive care in china, we conducted a survey between october and december, , involving hospitals in provinces and municipalities. the results showed that there were totally icus for pediatric patients, including pediatric icus (picu), neonatal icus (nicu) and pediatric surgical icus (sicu), with total of beds. the physicians to bed and nurses to bed ratios were : . and : . respectively. the average number of equipment per bed was . ventilator, . multi-fnnction monitor and . infusion pump. very few of the icus had portable x-ray machine, biochemical and blood gas analyzers, and hemodialysis machines. the most frequently treated diseases/conditions were pneumonia, intracraniat infections, post-operation and sepsis in picus, and neonatal pneumonia, hypoxic ischemic encephalopathy and sclerema in nicus. pneumonia and respiratory failure accounted for . % and . % of all the diseases/conditions treated in the icus and the mean case fatality rate of respiratory failure was . %. the results of the survey suggest that there is shortage of tcu beds and modern equipment, and treatment is often delayed due to excessively strict criteria for mechanical ventilation. a set of simple, and nationally acceptable criteria for evaluation of severity and cure of the diseases/conditions is urgently required. the medical reports of children were reviewed and each admission was analysed in terms of age, sex, diagnosis, management within the hosp~al, length of hospital stay and type of poisoning. the youngest age was days and the oldest was years. hundred and twelve ( . %) of the children were girls and ( . %) were boys. the most common ( . %) reason of admission was intoxication among all of the cases and the greatest group ( . %) of the poisoned children had ingested medication which was followed by another group of patients ( . %) who had eaten mushrooms. the peak incidence of drug ingestion was salicylate intoxication ( %). forty drug poisoninigs were accidental while was intentional. the majority ( . %) of the cases that committed suicide was between and t years old, and the main cause of suicide was being unsuccessful at school. we conclude that poisoning -especially salicylate intoxication -is still a major problem in turkey and we believe that emphasis on the need to stere all kinds of drugs in a secure place and re-examination of a chin resistant packaging should help to reduce childhood poisoning significantly which is a preventable condition. included were all patients who died in the hospital, except those treated in the neonatal icu (predominantly premature and sga newborns) and those who died in the emergency room. among a total of hospital admissions (excluding the neonatal icu and emergency room), patients died ( . %). of these patients ( %) died in the pediatric icu, ( %) in the ward and ( %) in the operating room. a chronic underlying disease was present in ( %). withholding or withdrawal of therapy was implemented in ( %) children, ( %) died due to failed cpr, ( %) were brain dead and ( %) died following a dnr order. justification for therapeutic restrictions in the patients of the dnr and w/w groups was imminent death in ( %), lack of future relational potential in ( %) and excessive health burden in ( %). withdrawal or withholding of therapy was carried out by extubation in %, vasoactive drugs were stopped in %, and mechanical ventilation was withdrawn in %, analgetics and sedatives were frequently used (in % and %, respectively). hence decisions concerning restrictions of treatment are common in pediatric practice, mostly due to imminent death. patients in which treatment was restricted were characterised by a longer hospital stay, a worse prognosis, a higher frequency of chronic underlying diseases and a lower acute mortality risk. despite restrictions of intensive therapy, most patients were allowed to die in the pediatric icu. background microalbuminuria (mca), a subclinical increase in urinary albumin, reflects glomerular and overall vascular permeability " . an increase in urinary excretion of albumin occurs after burns and trauma. transcanillary albumin escape rate is also increased in response to elective surgery and in critically ill adult patients . we investigated a possible relationship between urinary albumin levels and clinical instability, as measured by pediatric risk of mortality (prism) scores. method we studied consecutive patients (median age of months, range - ). patients whith nephropathies or any abnormality of urine analysis were excluded from the analysis. prism scores, mca (mg. - ) (immunonepbelometric) and urinary creatinine (cu) (mmol.l -!) (jaffb) ( hour collection sample) were determined within hours from admission to the picu. the mca/cu ratio (mg.mmol. "l) was used to correct for urine output variability. diagnoses included respiratory failure ( ), postoperative ( ), neurologic ( ), sepsis ( ), trauma ( ) and miscellaneous cases ( ). pearson's correlation was performed to correlate data. results and conclusions. mean prism score and mca/cu were . ± . sd and - sd, respectively. a significant correlation was found between mca/cu and prism scores (r= . , p< . ). our observations show that, independently of the initial insult, the paediatric unstable patient may have increased capillary permeability, which is correlated with the degree of physiological derangement, as measured by prism scores. microalbuminuria can be rapidly determined since it is routinely used in the management of diabetic patients, it is inexpensive, simple to measure and blood-spearing. therefore, it might have a role in the clinical assessment of capillary permeability and transcapillary albumin escape worldwide the demand for paediatric intensive care services exceeds the supply. in developing countries sporadic access to such services alters expectation of care and can lead to children being either mechanically or handventilated in general paediatric wards. the outcome of children requiring ventilation in a major teaching hospital in india was reviewed.children were ventilated on an adult intensive care unit (aicu) if a bed was available, otherwise in the general paediatric wards. over a year period children were ventilated on aicu with deaths. yearly mortality rates varied between - %. over a month period patients were ventilated on the paediatric wards. of the p~tients over weeks of age died (chi squared .t >p> . ) reasons for the higher mortality rate on the paediatric ward likely include the higher patient:nurse ratio, and more limited resources. a predictor of mortality based on simple physiological observations without the need for expensive blood tests and including chronic health status would be a useful tool. the establishment of a paediatric intensive care unit is proposed to redress the balance of care. to assess the performance of the pediatric intensive care unit of hospital dona estef~nia by an international standard score, the authors did a prospective study of consecutive admissions to the unit during a period of months. mean age was . _+ . months; mean lengh of stay was . + . days. the effectiveness and efficiency were determined by the admission prism. admission efficiency was defined by two criteria: a) mortality risk > % or b) the administration of at least one intensive care unit-dependent therapy. the cumulative observed mortality was . % and the expected mortality was . %, with a standardized mortality ratio (smr) = . . the overall performance of the prism score-based predictive model was found to be good (goodness-of-fit test x [ ] = . ;p= . ). of patients admitted, combining the two criteria (icudependent therapy and mortality risk) an admission efficiency of ( . %) was found, equating to ( . %) of cu days. conclusion: in our study the assessment of the admission efficiency and of the effectiveness of the unit was possible by using the prism score of admission. there was no significant difference between mean values for otiss and ntiss)in level l patients (p= . paired t-test).for level and patients mean value of ntiss was greater than otiss (p< . ). there was a significant correlation between levels using either ntiss or otiss (mean difference level and , level and , ( p < o.oool). conclusions: a new tiss has been developed and used in a picu. nurses were able to accurately score the interventions on their shift. the assignment of patients to intensive care levels correlates with tiss values allowing a quantitative measure of severity. objective : to compare the rate of cerebral palsy (cp) between monochorionic-twins, dichorionic-twins and singletons born at to weeks' gestation. design : two-year prospective cohort study. setting : geographically defined study (region of franche-comt~., france). main outcome measures : type of plasentation was obtained by anatomopathological, or macroscopic examination of placenta and comparison of twins' blood-groups. neurological assessment was performed at two years of age (uncorrected for gestational age) by family doctor (pediatrician or physician), or neonatologist of the icu at tertiary center. sample : of i survivors aged of two years ( % follow-up rate), born between / / and / . triplets and chromosomic malformation were non included. results : thirteen ( %) of the singletons had cp.vs / ( %) of dichorionic twins and / ( %) of monochorionic twins (p= . ). four of the monochorionic twins ( %), / dichorionic twins ( %) and / ( %) nngletons suffer from quadriplegia (p< . ).in a multivariate approach, monochorionic twin placentation was the strongest risk-factor of cerebral palsy (or= . , ic % = a- , p< . ). others risk-factors of cp were : lack of father's profession (or , p< . ), maternal antecedent of abortion (or . , - , p< . ), vaginal delivery (or . , - , p< . ), hyaline membrane disease (or . , . -t , ~ . ). discussion : this is the first population-based study to uplight the role of monochorial twin-placentation as a strong risk factor of cp for premature infants. cp is more severe in monochodonic twins than in other infants. mecanism of cerebrat deficiency is not clear since none of our infants with cp was survivor of an in utero cotwin's death, and none of these infants was exposed to twin to twin transfusion syndrome. were these monochorionic-twins affected by an undiagnosed neurological structural defect that could lead both to prematurity and handicap remains an open question, a vital role of the intensivist is to ensure that knowledge and practice are imparted to trainees in the icu so that patients receive optimal care. teaching effectiveness varies widely leaving gaps in knowledge and practice in the trainee. being an effective teacher should not be a "gift" of a privileged few. the icu provides a fertile ground for using a variety of methods for teaching, e.g. didactic, at the bedside, emergencies, and in the performance ofproeeaures. in this environment, much can be learned. we have embarked upon a program to facilitate this learning process. i) teaching needs to be recognized as the foundation of good clinical care, i.e., patient related, and in its ability to generate discussion and research investigation. ) teaching structurally has many components including the speaker, audience, varying situations, and the message delivered. ) establishment of a program using these components to enhance teaching abilities at all levels, a) evaluate base-line teaching skills initially, b) individualize interventions to improve teaching skills, e) demonstration of learned skills with re-evaluation. this process is analogous to the analysis of a clinical disorder in a patient which, once recognized, interventions are then instituted and then re-evaluated. ) instill the desire to use these attained skills to teach and interest others to teach. teaching excellence should be recognized through awards, honors, and academic advancement. a major emphasis of this program is to provide participants with skills necessary to teach thought processes, decision-making skills (what to do, what to avoid) and implementing appropriate management during stressful emergency situations common to the picu. introduction: many" e-mail based discussion groups exist on the internet to provide medical professionals with a rapidly responsive medium for the international exchange of ideas relating to patient care. several such lists each serve more than a thousand professionals in more than countries, each distributing a dozen or more messages each day to every subscriber. there is very little known about the time being spent by professionals interacting with these lists, and very little known about the impact of the discussions on patient care. we wished to test the hypothesis that these discussion groups provide infortuation which is being used to change the care of individual patients and the general approach to patient problems. methods: in early january a pilot electronic survey was sent to a small fraction (n= ) of the memberships of e-mail discussion groups, picu@its.mew.edu, and nicu-net@u.washington.edu (the full memberships of both. groups (n=t for nicu-net, n= for picu) will be surveyed in early february of ). participants were asked for demographic information, experience and skill level relating to e-mail, time spent with the discussion groups, perceived usefulness of different types of discussions, and the ways in which the discussions were used clinically. the pilot study was analyzed for construct validity by correlating an overall assessment question with a summary of the specific questions. scale reliability was measured by cronbach's alpha statistic. results: the pilot survey response rate was ( %). the majority of respondents were male physicians, with an average age of +_ years, who had completed subspecialty training in intensive care, and were working at a university-affiliated hospital. most had been using e-malt for more than months, and considered themselves moderately adept in that use. % felt that the list helped weekly to keep them informed about current issues and practices in their field(s), and % felt that, at least monthly, they used information from the list(s) that was not readily available in medical journals. overall, % agreed that the list improved their professional competency. when asked to compare the value of months of membership on an e-mail discussion group with more traditional educational media, % compared it with attending a national conference, and % compared it to a journal subscription. cronbach's alpha was . , construct validity testing yielded coeff=. , p <. . conclusior~: internet-based e-mail discussion groups for health care professionals can be an important part of a strategy for maintaining professional competency. despite the very low cost of this medium for most, the value is felt to be comparable to that of t~r more expensive forums for education. further study will include distribution of the full survey in early february of . fronk shann, tony slater, gale pearson and the pim study group we have developed a new score for predicting the risk of mortality in children admitted to intensive care. the score is calculated from only seven variables collected at the time of admission to icu: mechanical ventilation (yes/no), booked admission after elective surgery (yes/no), the presence of any one of specified underlying conditions, both pupils fixed to light (yes/no), the base excess, the pao divided by the fio , and the systolic blood pressure. most scores used to predict outcome in intensive care require the collection of a large number of variables (so many icus do not calculate them routinely), and they use the worst value of each variable in the first hours in intensive care. this means they appear to be more accurate than they really are (about % of child deaths in icu occur in the first hours -so they are diagnosing these deaths rather than predicting them), and they blurr the differences between traits (a child admitted to a good unit who recovers will have a low score; but the same child who is mismanaged in a bad unit will have a high score -the bad unit's high mortality rate will be incorrectly attributed to its having sicker patients). pim was developed in the picu at the royal children's hospital in melbourne, and has been tested in six other picus in australia and one in the uk. objectives: to study the characteristics of the muhiorgan dysfunction syndrome (mds) in children. methods: a retrospective study with all the children with mds diagnosed from january to june is presented. children fulfilled the wilkinson criteria (i). in all of them the number of organs affected and the prims score were determined during the first hours. several groups were performed according to the clinical diagnosis, the hospital of origin and the order of organs affected. results: the subjects studied were an % of the pediatric intensive care unit admissions. of them expired ( %). no differences in age, sex and weight were observed between the children dying and the survivals. the most common causes of mds were sepsis, both nosocomial ( %) and medingococcal (i %) and acute respiratory failure. sixty-fivepercent of the patients were from the hospital wards and the remaining were directly admitted to the pigu from the emergency room. the systems affected were: respiratory ( %), cardiovascular ( %), hematologic ( %), central nervous system ( %), renal ( %) and (hepatic) liver ( %). the organs initially failing were: heart ( %), tung ( %) and central nervous system ( %). the children dying had a larger number of organs with failure than the survivors ( . v,s. . , p< . ).the prmis score was higher in the children expiring than in the survivors ( . v.s. , p < . ). s.mmary: the mds is a common pathology in picu, with a high mortality, the mortality is higher in children with a larger number of organs affected and a higher prism score. sepsis is the most common etiulogy. methods : from june ist to july th , all patients admitted to the pediatric icu were included. the score was measured at day (d ) and day (d ) and we used variables. for each organ system, we defined categories : dysfunction or failure, which we respectively confered or points. results : patients were admitted : newborns, children. were medical and were surgical patients. ( %) patients had two or more organ failure at the admission, ( , %) patients died, which ( %) in the first hours. the mortality rate was the same for children with two or more organ faiiure at d and d : / ( , %) at d , / ( , %) at d . the mean score is different for children who survived or who died : , versus , at d ; , versus , at . when the score is > , the mortality rate is significant. conclusion : in this study, there is a good correlation between the score of severity and the mortality rate but we have few included patients. we need a prospective multicentric study to assess these results and we must compare this score to other scores of severity used in picu. back.qround: injury to the central nervous system is the cause of death in the majority of pediatric trauma victims, studies have identified a wide range of factors associated with poor outcome from brain injury. however, when single features are analyzed, they are not sufficiently accurate predictors. few studies have used a multivariate analysis of these factors and pediatric outcome, methods: clinical and radiographic features of comatose children after traumatic brain injury were analyzed, clinical parameters, the initial cranial ct scan, and demographic characteristics were analyzed for an association with death or vegetative survival at months. a tree diagram in which risk factors may differ within the study subpopulations was constructed using recursive partitioning. results: chitdren with a motor score _< had an -fold increased risk of poor outcome compared to those with motor scores > . among patients with scores of _< , those with abnormal pupillary reflexes experienced a -fold increased risk of death compared to those with normal pupillary reflexes. among patients with a motor score > , an intracranial diagnosis code (no pathology, mild shift _< mm, swelling, shift > mm, surgical mass lesions, or non-operative mass lesions) was highly predicative of poor outcome at months. children with ct findings other than normal or mild swelling had a -fold increased risk of poor outcome. of children with swelling, shift or mass lesions, the pupillary light reflex was associated with outcome. children with abnormal pupils had a -fold increased risk of poor outcome. discussion: a few clinical and radiographic features stratified comatose children into fairly distinct risk groups. information available early after traumatic brain injury in comatose children provides useful prognostic information on the likelihood of death or devastating injury. a retrospective study of children with the diagnosis of epidural hematoma was made during - period. ages ranged between days and years ( % less than year, % between and years, and % older than years), % of them were admitted at the picu. % of the cases were due to falls, % to road traffic accident and % to other causes. on admission gcs was less than in % of the cases and more than in %. diagnosis was made during first hours in % of patients and delayed more than hours in % of them. neurologic impairment was present at admission in % of patients, and delayed in %. even so, % remained without impairment. radiological findings at first ct were skull fracture ( %); epidural hematoma localization was: in the right side ( %), frontal area ( %), temporoparietal ( %) and occipital (t %). associated lesions were: several ( %) or unilateral ( %) cerebral contusions, diffuse brain oedema ( %), unilateral hemispheric oedema ( %) and % showed shifted middle line. four patients died, half of them during the first hours. fully recovered ( . %) and have sequelae of different nature : were left with severe motor disability ( %); at the follow-up t have some degree of neurodisability. next datas keep correlation with death or neurosurgical impairment: only were significative multiple cerebral contusion (p= . ) and brain oedema (p= . ), gcs less than at the admission (p-- . ), shock (p= . ) and remaining cerebral contusion in control ct correlated with death or diasability at discharge. on the other hand, neither surgical drainage volume nor first or highest levels of icp ( cases),nor pupillary abnormalities ( cases) correlated with worse prognosis. conclusion: gcs equal or less than an shock are main factors related to worse prognosis, also multiple cerebral contusions in ct and diffuse brain oedema. the results of a modified gcs were compared to outcome and intensive therapy in children (mean age , t , years) with head and associated injuries ( , % of all cases) of different causes (traffic accidents, falls). the gcs was regularly used inn the course of intensive therapy. according to our own and other experiences the gcs was divided in stages: stage ( - points), stage ( - points) und stage ( - points) palhuiugy wile sp, tdhlg c~'lcb al blood ~ w. sabgcqucntl}. rhc slat,: rerltncd to t tl, iiltlils. the p st,~pem~v~ b}i~g wij!!,:q ! ,:_a!~p!ica!j n~:. ri~;¢ ill the level of sensibflizatjou lo tile cerebn~ anhgrns up to t. -o was flofcd iu i,alicnts. there wa.~ al~ iuclt~a~e ill cerebral vdociij,. ~m d~;'ati a il~ p¢fiphc~ai re~ista/isc of the large ce~'bral ve~ds. neur h;~c ~:yn'.pt,m~at !a~, (s::mno!en~', _r_uscu!~r l~:pot ni& !ryper*'flema) was nbserwed tu lt~ese pal~enls o. cbruc~l ~ nnds. rile ple~c.ut abse~vafion~ suggesl ihal die ~tttdy at" ihe stale ~f hematocr~chcplm/itic bm~ic~ in ckil&en with on emergensy is of abviou.~ !?ece~sib; in co~.te ctin g severe pa~ lo ~-i~mnediately f u wing ne ,:~per,'~fion. background: reconstruction of the heart by three-dimensional ( d) echocardiography provided new information on anatomy of complex congenital heart defects, we assessed the utility of d ultrasound in detecting morphological changes in cerebral anatomy in newborns before and after cardiac surgery. methods: transfontanel cross-sectional ultrasound, scans were obtained in standardized coronal and median sagittal planes. subsequently, rotational scanning was used to acquire the multiple sequential crosssections of the brain. for rotational scanning, a conventional mhz transducer was rotated degrees.scanning took less than one minute and required no sedation, data was stored in the image processing computer which allowed for off-line three dimensional reconstruction of different brain regions.twelve infants aged - (median ) days were assessed before and after cardiac surgery, results: cavity of lateral ventricle, choroid plexus and the periventricular brain parenchyma could be reconstructed in all. accurate estimation of size and volume of lateral ventricle, aqueduct, and other ultrasonographic visible pathological brain lesions could be performed. reconstruction of various brain areas was accomplished in - minutes. the localisation and extension of severe periventricular hemorrhage which was detected preoperatively in one infants was better visualized than in conventional ultrasonography. epicortical and subarachnoidal space could be reconstructed in all and allowed detection of hemorrhage in one case which was not detected by conventional ultrasound. conclusion: d reconstruction of different areas of the brain may provide additional quantitative information on size and volume of the internal ventricle and choroid plexus, and better understanding of the topographical aspects and the extension of intra-and periventricular hemorrhage than conventional cross-sectional ultrasound. introduction: intracranial cerebral blood has been estimated to be % venous, the invasive measurment of venous blood saturation in the jugular bulb provides quantitative information on cerebral oxygen supply and consumption. however, routine oxymetric measurement of blood saturation in the jugular bulb by insertion of a catheter line into the internal jugtdar vein is an invasive procedure which has limited use especially in infants and young children. thus the aim of this study was to investigate the correlation between the non-invasive spectroscopic measurement of rso and the oxymetric determination of the blood saturation in the jugular bulb in infants and children undergoing routine cardiac catheterization.. methods: during routine cardiac catheterization infants and children (age day- year, median , year) the rso was measured continuously using a two chanel cerebral oxymeter (invos a). the sensor was placed in standardized location at the left temporal head side. after the routine oxymetric blood sampling in the superior vena cava the oxymetric catheter was manupilated into the left jugular bulb. after control of the catheter position simultenuous values of the rso were documented. results: over a range of ( - %) sjo , a significant linear correlation was found between the spectroscopic measurement of rso and the oxymetric determination of venous blood saturation in the jugular bulb (r= , , p< , ) and the superior vena cava (r= , , p< , ). no significant correlation was found between rso and the arterial blood saturation in the descending aorta and as well as to the standared hemodynamic parameters. conclusion: meusurement of rso by mrs may provide continuous non-invasive information on cerebral venous blood saturation and thereby possibly on cerebral oxygen supply and consumption in infants and children. these may be of clinical value particulary during and immediately after heart surgery by means of non-pulsatile cardiopulmonary bypass. information on refractory status epilepticus (rse) from developing countries is scarce. we analysed cases of rse admitted over last yrs. the objective was to study etiology end evaluate efficacy of diezepam infusion. median age of the patients was . years irange . months to t . yrs); % were boys. onset of seizures was -t hours (median hours) prior to hespitalisation. the glasgow coma scale score ranged from . (mean+sd + ). the commonest underlying causes were acute cns infections ( / , %; bacterial meningitis, , encephalitis, ) and epilepsy ( / , %). oiazepam infusion in incremental dose (range . - . mg/kg/min) was used in patients over . _+ . days. seizures were controlled n ( %), mechanical ventilation was required in ( %)only, while none had hypotension; % patients survived. thiopental infusion (holus mg/kg followed by . mglkg/min, and increments of . mg/kg/min till seizure control) was used in patients over . _+ . days; seizure were controlled in all, but five patients needed mechanical ventilation, six developed hypotension needing infusion of vasopressoi drugs, out of ( %) died, overall mortality was %, mainly due to acute cns infections (n- ) and prolonged se. the patient was a -year-old gift di~aosed of dov,~'s s~drom¢, tetralogy of fallot. (t.f.) before admission a vasovagal crisis after coughing and vomiting was seen, and she was taken to the emergency room. mother said she had eyanosis in the mucous membranes of the mouth with exercise.on physical examination, she ~as afebrile, normal fundi and neurologic examination was normal. a harsh systolic murmur was hear~ with decrased intensity during bradycardia. chest rx disclosed a decreased pulmonary vascular markings. ecg: synus rhythm, with bradycardia and nodal escape rhyflmas. she was transferred to our picu because of severe h ,pertomc seizure, lost conciousness, and deeembrate poslamng~ ~t cyancx~is. the episode lasted for ~weral seconds, and ceased v~th diazepam. on admission she was lethargy, and neurologlc exammation showed weakness of left leg without babinski, and normal funduscopic. the patient had two episodes of bradycardia and isoproterenol was begun. during those episodes the patient was cyanotic, and the murmur was heard with the same intensity. act scan disclosed a tight parieto-temporai abscess with midline shift, lnmediately after the diagnostic ct, we administered antibiotics, antiedema treatment and it was drained. the abscess culture was negative. a ct control disclosed air and midlme shift. ~ the next two days she had three episodes of h oxia and c'yauosis ceased with o@gen, morphine and propanolol the patient died during a fourth episode. discussion: arrhytmias are uncommon in patients with tetralogy of fallot before surgery. in our case the first diagnosis was sick sinus syndrome vs bradycardia secondary to cyanotic episodes. the incidence of cerebral abscess in children with congenital heart disease (chd) is approximately %. tetralogy of fallot is the most common associated lesion, and is unusual in children under years of age. conclusion: ) brain abscess is a rare complication of patients with cyanotic chd, but should be suggested in patients with °'apparent" sick sinus syndrome. in patients with down's syndrome, t.f.,with cyanotic episodes, and difficult neurologic exploration, a brain ct scan is recommended. guillain-ba~re syndrome (gbs) is an acute autoimmune reaction, directed primarily toward the myelin encasing the peripheral motor nerves= this reaction causes a delay or block in nerve conduction. the presentation often can be very subtle but is followed by rapid loss of neuromuscular power, leading to acute respiratory distress, resulting from weakness of muscles and aspiration pneumonia. there were boys - , , and i i years old with gbs, treated in our icu. two of them due to the respiratory distress were intubated nasotracheally and ventilated mechanically with servo- ooc (siemens-elema, sweden) ventilator. duration of ventilation was i i and days, respectively. plasma exchange was performed in all cases. the numbers of plasma exchange sessions were - in each case. mean amount of plasma exchanged per session was , ml/kg. plasma was substituted with albumin, plasma or saline. the most important aspect of the management of patients with gbs in the icu involves the airway care, prevention and treatment of aspiration pneumonia and the mechanical ventilation if respiratory distress presents. endotracheal intubation should be performed whenever there is evidence of retention of pulmonary secretions, refractory to chest physical therapy, weakness of protective reflexes of the airway, leading to aspiration pneumonia and (or) atelecr~sis. cardiac arrhithmias too, is a main threat to the circulatory stability in gbs. therapeutic plasmapharesis has been shown to be beneficial, reducing the time for weaning from the ventilator and for achieving independent ambulation. however, plasma exchange is expensive and not without significant risks for the patient. some authors find that plasmapheresis is not effective for patients with fulminant course of gbs and blocking of nerve conduction. recent studies have demonstrated that intravenous high-dose immunoglobulin can be equally effective. there were no significant complications associated with plasma exchange. all presented patients survived without residual disability. tetraparesis associated with long-term paneuronium use in an infant. paneuronium is a muscle relaxant used in ventilatory management of patients with respiratory distress in intensive care unit. after the end of sedation some patients were found to have severe tetraparesis. paresis was accompanied by complete areflexia and diffuse atrophy of alt extremity muscles. this neuromuscular complication is caused by prolonged high-dosage pancuronium treatment. in the last years, numerous reports have linked the use of pancuronium bromide with prolonged paralysis, disuse atrophy and areflexia. this side-effect is well known in adults patients but rare in a pediatric intensive care unit. we describe one pediatric observation of tetraparesis after prolonged pancuronium treatment in a -month-old girl, this female infant developed respiratory distress syndrome and was intubated and mechanically ventilated. to decrease chest wall rigidity pancuronium bromide was administered during days. (she received approximately mg of pancuronium bromide). on day the drug was discontinued and the patient had severe tetraplegia and areflexia with normal head movements. electromyograpliy showed absence of any disorder of neuromuscular transmission. this infant showed a recovely of muscles after months. the other causes of peripheral neuropathies were eliminated. electroencephalograms and head scans were normal. the recovery pattern observed in our patient correspond to the process of regeneration after axonal degeneration. it is suggested that these neuromuscular complications were caused by prolonged high-dosage pancuronium treatment (associated with cortieoid and aminoglucosides). polyneuropathy syndrome in adult lc.u. appeared in literature in and is extremely common in long stay cases. the etiology of these disorders remains elusive. it is tempting to ascribe them to administration of drugs (muscle relaxants, steroids, aminoglycosidea), plolonged immobility, malutrition, sepsis and ischemia associated with reperfusion injury. to our knowledge there is only one case report of similar condition in a children i.c.u. (pascucci ) we present a serie of previously healthy children, aged months to years, who admitted in i.c.u with respiratory failure and who following weaning from m.v, remained in profound diffuse hypotonia with proximal and distal muscle weakness for various length of time, recovery of muscle strength occured in a week or months {the longest i months), all children, except one, - days before admission developed symptoms of either respiratory or upper airway infection with fever. on admission viral and bacterial cultures were positive in cases (haemophilus influenze, herpes virus). during treatment patients became septic. muscle histological and neurophusiological investigations have not been done. considering the multifactorial nature of the aquired nmd in adult critically ill pts, is impossible to attribute the muscle weakness of our pts to any specific cause, in conclusion, our findings suggest the need for further investigation of nmd in critically ill children treated in i.c.u. a van esch, ha van steen~l-m , ir ramtal, g derksen-lubsen, idf habbema. febrile status epilepticus (fse) is a prolonged and serious febrile seizure. little is known about the outcome of fse in neurologically normal children. this survey involved patients between months and years of age who had visited due to their first fse, the sophia children's hospital during the period of january till december . patients with a history of neurologic disorders were excluded. patients were identified, % were male. the cause of the fever remained unknown in % of the cases. in all case the fse was generalized and it most frequently occurred at night ( %). the mean age at fse was t. years ( . - . ), the mean temperature . °c ( . - °c). the mean follow up time was . year. twelve children ( %) had neurologic sequelea. the neurologic sequelae varied from speech deficit ( case mild, v - year delayed; case moderate > year delayed) to severe retardation and epilepsy ( cases). speech deficit was detected after a mean period of months (range - ), age, gender, temperature, family history and time of onset were no significant risk factors for neurologic sequelae. duration of seizure [rr . ( . - . )] and more than two drugs to treat fse (rr . (t. - . ) were related to neurologic sequelae. we recommend that fse children should be followed for at least a year to detect possible speech disorders properly and start early intervention. unusual presentation of myasthenlg gra%qs ibtza e. modesto ,v~ abe~gochea a, sanch]s l all, go l varas k folgado s, garcia e. p. .c.u. la fe, valencia. spain case report: the patient was a -year-o!d gift transferred to our pic because of severe respiratory failure. the patient, convaleseem of ehiekenpox, came into contact with horse manure previous afternoon. in the morning, she was lethargy, and irritability, with poor finding, and ~ an episode of coughing, cyanosis and acute respiratory failure after mucous vomiting when she was drinking milk. on admission she had severe respiratory distress, respiratory acidosis, and the sat was %. she was mtubated without difficulty, and was transferred to our p.i.c.u. physical examination reveals stable hemodynamies, pupils equal, round, reactive to light, normal fandi, and muscle relaxation. crusted vesicles diseminats~d. rhonehi over both lungs. hepatomegaly (+) and splenomegaly (+). ~lhe urine, hematologic, and c.s.f. laboratory findings were normal. c.t. scan of the brain, e.e.g., and ekg. revealed no'abnormalities. rx chest disclosed a retrocardiac atelectasis. speci~ts of stool and blood were obtained for cultures and study of c. botul#num toxins. pending receipt of these results, a broad-speotmm antibiotic and acyctovir was begun. the initial differennal diagnosis consisted of laryngospasm associated with aspiraqlon, botulism, and postmfecfious varicella encephalitis. after hours, weatm~ was begun. the neurologic examination showed a low modified glasgow coma ~ale (mgcs), generalized hypotouia and muscle weakness. these data suggested three diagnoses, posfnfecfious encephalitis, residual neuroumsoaar blockade, and excessive doses of sedative and analgesic drugs. after hours she regained skeletal muscle poxver and ufltlcient respiratory effort, the mcgs was acceptable, and blood gases were normal. she was given n~-tigmine and atropine, and her tr~ma was extubated. an acute respiratory failure ocurrs ram. after. chest radioga'aph disclosed a left inferior lobe atelectasis. after hours weaning begun~and the same episode w~as seen. at this point her mother stated that the girl showed weakness of the eyelids or extraneular muscles. it suggested myasthenic syndrome vs ~-barr syndrome. c. botul#num toxins were negative, chotinesterase level ~as normal. edrofoinum test ~as positive. anti-acetyleholine receptor antibodies were negatives. e.m.g. confirmed myasthenia gravis (congenital vs juvenile serenegative). pyridostigmine was begun and the trachea was extubated without complications. conclusion: din the differential diagnosis of weamng failure we must consider ~c gravis~ )myasthenia gravis could resemble encephalitis, because of low ocs, overall if is triggered by viral infection. )in some diseases (this case) gcs could not he an aemuate index of mental state. a burguet*, a menget*, e monnet**, a gasca-avanzi*, c fromentin*, h allemand**, jy pauchard*, ml dalphin*. * r animation infantile potyvaiente chu st jacques besancon cedex. ** d~padement de sant publique besancon cedex, france, objective : to point out that strabism is) of one-year-old premature is a good predictor of a poor neurological outcome at two years of age. design and setting : two-year prospective cohort study and geographically defined study (region of franche-comte, france). main outcome measures : neurological assessment was performed at one and two years of age (uncorrected for gestationnal age). a mailing questionnaire was sent to the famity and fuu-filled by thefamily doctor (pediatrician or physician), or neonatologist of the icu at tertiary center, s was diagnosed at one year of age by the examinator but s was not used to diagnose cerebral palsy (cp). sample : of survivors ( %) evaluated at one and two years of age. results : correlation of one and two years neurological evaluation is weak (kappa= . ). correlation of s at one year and cp at two year is fair (kappa= , ). the goal of this paper is to review evidence related to hypothesis that the "waiting" axons and cells of the transient subplate zone may participate in the structural plasticity of the human cerebral cortex after perinatai brain damage (kostovic et al, metabot brain res : , t ) and to correlate this phenomenon with different forms and mechanisms of structural plasticity. it is our basic assumption that all lesions occuring during cortical histogenesis will lead to more or less pronounced structural reorganization. here we show that various components of the subplate zone participate in several forms of the structural "plastic" responses in the human cortex: modification of convolutional pattern, changes in size of cytoarchitecturat areas~ columnar reorganization, dendritic and synaptic plasticity. the etiological factors which induce lesions and subsequent plastic changes act via the following pathogenetic mechanisms: * disturbances of radial unit formation (rakic); * changes in ingrowth of afferent fibres; * changes in the rate of normally occuring reorganisational events, depending on the critical period for a given histogenetic event. in the present study developmental lesions (localized perlventricular leukomalacia and haemorrhages) were demonstrated by ultrasound in live-born infants ranging between to weeks of gestation. in younger infants ( - w) who died shortly after birth, examination revealed lesions of the white matter with the preservation of the subplate zone. in infants who died one week of more after the lesion, we have observed localized micropolygyria, cavities, condensed layer vi -subplate zone, and columnations of the cortical plate. these changes are less prominent if the lesion occurs after diminishment of the subplate zone (after w). since in the fetal cortex the subplate zone serves as predominant source of growing fibers, transient neurons, trophic factors and contains cellular substrata for migration, this zone is the most likely candidate for major types of structural plasticity. in conclusion, cerebral cortex of the low -birthweight infants is more susceptible to the various lesions but shows vigorous structural plasticity and conspicuous functional recovery due to the growing, transiently located neuron at elements. the mortality due to meningoccocal sepsis is high in spite of important progress in emergency and intensive care medicine. during the last decade multiple scoring-systems have been developed in order to establish a therapeutic approach and to evaluate the final outcome of a meningococcal infection. different clinical and biological data (shock, ecchymosis, peripheral wbc and platelet count, coagulopathy, acidosis, meningism, etc) are taken into consideration and the importance given to these data depends on the scoring-system used. a review of the different scoring-systems is given and a clinical case is presented. we report the case of a year old male, who was transfered to our icu hours after onset of temperature and skin rash. the parents described a fast deterioration of his condition. the boy presented wide spread ecchymosis, high temperature, no signs of meningism, circulatory insufficiency and shock, coagulopathy and low peripheral wbc and platetet count. disseminated intravascular coagulopathy developed promptly. the glasgow meningococcal septicemia prognostic score (gmss) was used and the obtained score reached the highest level ( / ). this corresponds to a % mortality. the patient required mechanical ventilation for days. at admission he received human albumine, fresh frozen plasma, dexamethason, dopamine, dobutamine and a continuous infusion of adrenaline. antibiotical treatment consisted of ceftdaxone. the evolution was favorable and the infant fully recovered. retrospectively the gmss was compared to other meningococcal scoring scales which gave the same mortality ( %). we conclude that the scoring-systems are important to evaluate the seriousness and to assess the therapeutic approach, but they should be used cautiously even when % mortality is predicted by several risk evaluations scoring-systems. the aim of this study was to assess the haemodynamic status on admission and the critical care management of children presenting with meningococcat infection. this was a retrospective study of the charts of consecutive admissions. mean age was . years (+/- . ). the average duration of symptoms prior to admission was . hours (+/- . ). on admission . % were hypotensive, . % had clinical signs of haemodynamic instability and . % of cases that had a blood gas analysis on admission had a metabolic acidosis (bases excess < - .q): the mortality rate was . %. % of patients that died were hypotensive on admission and all had a metabolic acidosis. of the survivors . % were hypotensive on admission, % had clinical signs of haemodynamic instability, % required invasive pressure monitoring and . % were ventilated and received inotropic support. this study demonstrates that at the time of presentation with meningococcal infection children had a high incidence of established haemodynamic instability. successful management of this infection is dependent on early presentation and initiation of therapy and on aggressive support of the cardiovascular and vital organ systems. dept. of intensive care medicine and dept of infectious diseases, our lady's hospital for sick children, crumlin, dublinl , ireland. jude. pediatric intensive care unit, ch&u, lille-france. more than % of children surviving sip (defined as purpura with shock) have snli. objective. to search for a specific hemostatic profile in children with snli. patients and methods. between may and march , children with sip were admitted to our picu : ( . %) died and ( . %) ranged in age from to months (mean : ) survived, of them ( . %) with snli (defined as the need of a surgical procedure). in survivors, two hemostasis studies (between h and h , and h later) included the determination of coagulation factors (routine tests), protein c (pc : amidolytic activity, biogenic), total protein s (ps : elisa, stago), c b binding protein (c bbp : laurell's technique, stago), antithrombin (at : chomogenic test, stago), and plasminogen activator inhibitorl (pail : chromogenic test, biopool). three severity scores were determined at admission : french group of pediatric intensive care, gedde-dahl, and crp. statistical analysis used the wilcoxon's test. results. at admission (lst sample) severity scores and at , pc, ps, c bbp levels were not different between the group with snli and the group without snli ; quick time ( - % vs ± % ; p = . ), vti+x ( . % vs - % ; p = . i) and pall ( - ui/m! vs . ui/ml ; p = . ) were lower in the group with snli. on the nd sample there was no difference between the two groups. kinetics of hemostatic abnormalities was not different between the two groups. conclusion. in the literature, intravascular coagulation (dic), low fibronectin and at were identified as predictors of snli, and a negative correlation was found between the mean size of the skin lesions and pc activity, at , and total ps. in this series, apart from dic, there were no specific hemostatic abnormalities that support the use of treatments such as pc, at , and pail antibodies administration to prevent snli. further studies including more children are needed. the aim of study was to investigate the efficacy of intravenous immunglobulin with enriched igm content pentaglob/n /biotest/. in our pediatric intensive care unit ten septic children /group i/-their average age , years /sd:o, /, of them with gramm negative and one with gramm positive blood cultures, and two with unindentified bacteria-were treated with basis sepsis therapy and pentaglobin. the application of pentaglobin was as follows: , ml/kg loading dose for one hour, followed by a continuous intravenous infusion , - , ml/kg/hour depending on body temperatura /lanser scheme/ for - hours. another ten septic patients /control-group ii/the mean age , years/sd:o, /, their blood cultures were gramm negative bacteria , positive , and the bacteria was not indentified in two cases -were treated with only the basis therapy. results: the duration of intensive treatment decreased from an average , days /sd: , min -max days/ to , days /sd: , min -max days/ in the group treated wit pentaglobin. the difference was significant /x p< , /. in the group i nobody died, but three in the group ii. conclusion: the pentaglobin therapy can improve the efficacy of the basis therapy of sepsis. sinus bradycardia after an episode of sepsis is a rare symptom complex decribed in children with hematologic malignancies. we present a case of postsepsis bradycardia following severe typhlitis and septic shock in a year old boy with relapse common all. blood and ascitic fluid specimen grew clostridium species and pseudomonas aeruginosa. at surgery there was a necrotic gangrenous terminal ileum and cecum, requiring ileocecal bowel resection with ileostoma. while clinically recovering from sepsis he developed bradycardia for hours. extensive diagnositic procedures was given and the heart rate slowly increased to normal range of age. postsepsis bradycardia in children with hematologic malignancies after an episode of sepsis is self-limiting and after careful differential diagnostics warrants an expectative attitude. nitrate level is known to be enhanced during sepsis. serum nitrate is the stable metabolic end-product of endogenous nitric oxide generation. nitric oxide has demonstrated to be a powerful anti microbial final mediator and also a key molecule driving to the lethality of one of the most common complication of sepsis; the endotoxic shock. such facts prompted us to investigate the possible diagnostic and/or prognostic value of monitoring serum level in high risk, presumptive and confirmed sepsis patients. additionally we have explored the usefulness of this mediator as index of therapeutic response. in our study it is demonstrated that there is an important relationship between nitrate level and the occurrence of neonatal sepsis. septic newborn group showed fold higher nitrate level than that of healthy control group. in addition, the group of patients with high risk of sepsis which finally became septics, exhibited fold higher nitrate level at - hours before the first symptoms appeared, when compare with those who did not develop sepsis. however in the presumptive sepsis group, there was no difference between the patients which finaliy ,&'ere considered septics and those which not. in all septic cases, after days of a successful therapy with antibiotics, the level of nitrate diminish fold. our results suggest the utility of monitoring nitrate as index for the diagnosis of neonatal sepsis. the potential benefits of exchange transfusion, plasma exchange, and haemofiltration have all been described in children with overwhelming sepsis. however, little hard evidence exists to prove the benefits of any of these techniques. i have treated five patients with plasma exchange (pe), having been asked to see all these patients at a point when it was felt death was inevitable. two of the patients had staphylococcal, two meningococcal and one enterococcal septicaemia. all patients showed a dramatic haemodynamic improvement following pe with improvement in blood pressure, reduction in inotrope requirement and improvement in tissue perfusion. three patients survived. one of the patients with staphylococcal sepsis and both of the patients with meningococeal sepsis had developing gangrene of the limbs which showed remarkable reperfusion with pe. in two of the patients measurements of cardiac output (co) and systemic vascular resistance (svr) showed ~a reduction in co and a rise in svr over the course of a pe despite the reduction or cessation of vasoconstricting inotropes. many believe haemofiltration is of value in septic shock. a trial with a no treatment limb is difficult to achieve. i believe we now have enough evidence to justify a controlled trial of haemofiltration versus plasma exchange in patients with septic shock and unstable haemodynamic status whilst on inotropic support. during the next several days, cough and chest pain suggested pulmonary embolism confirmed by radiologic evaluation. echocardiographic examination showed multiple thrombosis of the superior vena cava, right atrium and ventricle and pulmonary artery. estimated protein c level was . % (normal range - %); identical deficiency was found in patient's mother and elder sister. cvc was removed, and alter -month heparin therapy and supstitution of protein c with fresh frozen plasma, there was almost complete thrombolysis of the great vessels and cardiac chambers. we conclude that invasive diagnostic and therapeutic procedures in such patients may result in higher risk for severe thrombosis at unusual sites, and numeuos further complications bronchopulmonary dysptasia (bdp) is a chronic pulmonary disease of preterm and term babies treated with mechanical ventilation for respiratory problems of different origin and requiring oxygen therapy days after birth. bpd is a disease affecting the growth and development of pulmonary tissue. such pulmonary }esions heal by squamous metaplasia leading to scar formation and fibrous tkssue r~growth, the pediatric intensive care unit makes the survival of babies w~h very low birth weight ( - g) possible. with the increase in their aulyival, the number of complications in low birth weight babies increases as well. bdp is a very serious complication. therefore the importance of early diagnosis and treatment of bdp must be stressed in order to reduce the consequences. babies with bdp must be under medical suveillance for at least years as the disease needs at least that long for complete resolution. tn the icu of pediatric department at madbor teaching hospital: during the past two years ( - ) newborns were treated with mechanical ventilation. the neonatal and postnatal death rate of all newborns admitted to our icu was , %o.ln the two years from to , newborns were admitted to our icu ( %~ of all newborn babies at maribor teaching hospital), with birth weight - g. in the icu, the survival of these babies and parallel to it the number of complications is increasing. during the mentioned -year period, babies with very low birth weight ( - g) survived: in and in t . in - %, first or second stage bdp was treated,there was no case of third of fourth stage bdp. the treatment consisted of eary removal from mechanical ventilation, oxygen therapy~ intensive treatment of infection, volume and caloric intake contro}, corticosteroid treatment throught weeks with decreasing doses, diuretic end antioxydant therapy. the children are to be reevaluated at the age of and months and again at i and years. oeure j van der, markhorst do, haasnoot k department of pediatrics, pediatric intensive care unit, free university hospital, amsterdam, the netherlands. case summary a %-month . kg girl of african origin was admitted to the pedfatric irtensive care unit with pneumonia and progressive respiratory irlsuffjderey. she was intubated and ventilated by pressure regulated volume controijed ventilation (servo c, siemens, soma, sweden). maximum conditions were inspiratory minute volume . l, peep cm h~o ahd % ~. chest x-ray showed bilateral interstitial consolidation. material obtained by broncho-alveolar lavage showed preumocystis car}nil htv-serology (elisa and westerll blott) and p -antigerl were positive, confirming the diagnosis of pediatric aids. she was then treated with high dose co-tllmoxazoie, penthamldine, z{(~ovudire and steroids iv. because of thee x-ray features, high need for o ( %, pad mm hg), not responding to elevatiofi of peep (max cm h=o) and pao /fio = < (s ). m acute respiratory distress syhdrome (ards) was diagnosed. because conventional ventilation (cv) failure, hfo-v ( ooa, serisor medics,yorba linda, ca) was initiated. starting mean airway pressure (map) of cm h~o was based or map of the cv, oscillatory pressure amplitude (dp) of was, at ii~itial frequency of . hz, adjusted ur~til chest wall vibrations were visible, it was required to raise map to cm h and dp to before optimal lung volume and ventilation were achieved and need for o reduced within hours, this was monitored by frequent blood-gas analysis and chest x-rays. map and dp could slowly be reduced, after a good response the first day, gradually demand reduced and the patient could be weaned from the ventilation. map, dp, fi and oxygenation index (map x pa ~jfio ) are shown in table i. chest x-ray follow-up showed gradually improving lung features, with marked improvement of aereation. after days hf -v she could be succesfully detubated when a map of cm h was acmeved. results : sianificant increase in ventilato~ rate and mean airway pressure was noticed after the change to savi. no differences in oxygenation, co partial pressure and systolic, diastolic or mean blood pressure between imv and savi periods were noted. in infants however an improvement in pao /p .ol/ and decrease in paco was observed after the switch to savi. these babies had a lower initial a/a oxygen tension ratio and required higher initial ventilator rate /p<o. / in comparison to the rest of the studied patients. conclusion:infants with low a/a po ratio who need high initial ventilator rate are likely to obtain benefit from savi.. fumimare hatori, haruo uchida, masao katayama, and rika muto department of anesthesia and critical care medicine chiba children's hospital, chiba city, japan. purpose: this study was made to find out whether the heat and moisture exchangers (hme) was effective enough to humidify in the respiratory management for children. patients: the study population consisted of patients who were provided with artificial airway. they were divided into the two groups: ii with heated humidifier (a) and i with hme (b). methods: hme could be used for those without pulmonary complication and with less leakage around the endotracheal tube. in both a and b groups, (i) we have measured relative humidity, temperature, and absolute humidity at the endotracheal tube connector. for these measurements, humidity sensor system was utilized. ( ) any troubles and complications caused by the artificial airway were investigated. results: (i) in group a, we confirmed the mean values as the relative humidity of . %, the temperature of . ~c, and the absolute humidity of . mg/l. in group b, they were . %, . °c, and . mg/l respectively. no difference was noted between the two groups as to the relative humidity, but the temperature and absolute humidity were lower in group b with a significant difference (p< . ). ( ) in neither of the groups, any respiratory complications such as obstruction or stenosis of the artificial airway were noted. in pediatric icu, hme can be used without any problems under given conditions. titei: objective: evaluate the precision, reproductibility and aplicability of a new device to measure auto-peep in pediatric patients during mechanical ventilation. material and methods: it's an electromc-pneumatic eontolled device with an oclusion valve and a pressure monitor installed between endotracheal canulla and the ventilator circuit. the measurements were performed with a sollenoid conected with to the ventilator to detect the end of inspiration phase and the actwation of the oclusion valve. the signs of pressure and flow were moniturized using a difere~rtial transducer and it was processed using a pc computer and a pneumoviaw® software. the auto-peep also displayed in the ventilator pressure monitor. results: we submitted children with neuromuscular disease or respiratory distress in this study. the incidence of auto-peep was %, with variability between , to cmh . all the measurements were performed times to verify the precision and the reproduetibility and evaluation of the pressure and flow curves. conclusion: the device is low cost, easy to use and can be used without the pneumotacograph. the auto-peep measurement can be done during mechanical ventilation with time cycled, pressure limited and continuous flow, the most commom ventilator used in pediatric patient. resistance was modeled by endotracheal tube (ett) sizes ( . , , , ), and compliance by test lungs ( and ml/crnh ), for each resistance -compliance arrangement, we measured tidal volume (vt) at various frequencies, peak to peak (p-p) and mean airway pressures. results vt increased when ett size increased with all ventilators in accordance with fredberg results (jap, ; : - ) . the maximum vt delivered was smaller with the hfv-babyiog than with the ohf or the sm a at a given frequency (figure on the left). increasing p-p resulted in a linear increase in vt delivery in the - % range of maximum p-p (figure on the right). hfv-babylog didn't provide significant vt increase when p-p was set above % and vt deliven/decreased when mean airway pressure decreased. --i ~ sm a a number of ventilatory parameters had been analyzed with russia-produced monitor humitemp htm (servisinstrument j,-s. co) in newborn infants with rdsn of t-iv stages on cmv, cppv, imv, and cpap steps using respirators of various kinds (stephan-staxel, bear- , newport rezee, sechrist). parameters investigated were: temperature of inspired mixture (t), relative and absolute humidity (rh and ah, respectively), static compliance (c), expired tidital volume (vte), expired minute volume of ventilation (mve). the monitor read these parameters in following ranges; rh-from to %; ah-up to mg/i; mve-up to . i/mini vte-from to ml; t-accurate to %; c-from . to t ml/cm h . continuous monitoring time ranged from to hours, it was noted, that during this time the monitor and transducers had no malfunctions, and it's using didn't require additional calibration, it was found, that humidifiers mr and mr (fisher, paykel) couldn't maintain parameters t and ah continuously (these values varied from , to . c and from , to . mg/i, respectively, when heating regulator position was unchanged). changes of parameters c depended clearly on cppv conditions and rdsn severity (with rdsn of stages i-ii c value ranged from . to . ml/cm h ; and with stages iit-tv-from . to . ). tn newborn suffering from rdsn of stages ii-ltl and ill-lv with pip> mbar, fi > , , peep= - mber, c-from . to . ml/cm h , effectivity of exosurf therapy was studied. in newborns in - hours of therapy pip decreased to . - . , and c increased to , - . ml/cm h . in newborn infants with aad > mmhg and c from , to . mltcm h positive effects of exosurf on lung compliance were not observed. in newborns the monitor had revealed decreased of c (from . - . to , - . ml/cm h ), manifested clinically by pneumothorax. in general, monitor htm made possible; ), to estimate the adequacy of cmv-parameters and regimes in newborn infants; ). to select optimal t and ah values in the respiratory outline in dependence on lung damage severity and infused volume; ). to reveal rdsn severity; ), to optimize indications and adequacy of surfactaot therapy; ). to diagnostieate the air leakage syndrome; ). to effects to some agents (broncholytics, spasmolytics); ). to obtain objective indications for imv/simv and cpap regimes. albano communication is an important aspect of human development and existence, and an inability to vocalise can be a problem in ventilatordependent patients. we present our experience with speaking aids as a means of enhancing verbal communication in four ventilatordependent children in our paediatric intensive care unit. the age of the children ranged from months to years, and the period of ventilation ranged from months to months via a tracheostnmy. they require continuous flow generated pressure limited or control ventilation at rates of - bpm. the reasons for ventilation include tetraptegia following a shrapnel injury; tetraplegia following congenital cervical spine damage; tetraplegia following atlanto-axial subluxation; and critical illness polyneuropathy following adult respiratory distress syndrome from prolonged ventilation for a severe head injury. the first three patients have passy-mnir one-way speaking valves and the final patient has a bivona foam cuffed tmcheostomy tube with a talk attachment in view of recurrent aspiration. an improvement in quaiity of speech has been shown by independent assessment. we will review the present literature on this subject and discuss the advantages and disadvantages of these two types of speaking aids in the light of our experience. the prognosis of antenatally diagnosed cdh is closely related to the degree of ph. there have been attempts to correlate antenatal or postnatal criteria to mortality: none have been demonstrated to be predictive of lethal ph. the aim of this retrospective study was to determine whether antenatal or early postnatal data could correlate with the findings of post-mortem examinations. patients and methods: between july and july , cdh patients have been antenatally and postnatally managed at our institution. twentythree infants underwent a post-mortem examination. ph was assessed by using the lung weight to body weight ratio (lw/bw) and the radial alveolar count (rac). antenatal results: cdh diagnosis was made at weeks of gestation (wg) ( - ). twenty-eight patients had a left sided cdh, had a right sided cdh, and one had a bilateral cdh. herniated organs were stomach none (n= ), or liver alone (n= ), or both stomach and liver (n= the patient was a -yenr-old girl with chronic renal insufficiency see~ to renal dysptasm, two months before admission a kidney trar~ptant was performed. one morah later she showed acute graft rejection with serum ereafinine (cr) level of . mg%. the rejection was unreslxmsive to an increased steroid dosage, and okt was begun with resolution of the rejection. one week arer, new rejection episode was seen marestxmsive to an increased steroid dosage, and transp~ ~s performed five days before admission to our ptc. hemedialysis and peritoneal dialysis (p.d.) each other day, was indicated (g.r.f.< ml/rnin). four days before admission t ~ rose to °c. "lhe diagnosis of opporttmistic pneumoma was made on the basis of tach ,pr',e~ hypoxi~ and diffuse interstitial infiltrates. senma ~ was positive for cytomegaloviras (cmv), and stool culture for c albicans. pentamidine, ganciclovir (dhpg), arai-cmv gamma globulin, eritromicine and amphotericin b was administered. on admission in our picu, trachea was mmbated, (a-a) o gradient was , paofffio~: , lung injury score > with peep level of cm hzo. she had normal fiver function. during te next days she had fever and developed ards. bal was negative. p.d. was of little efficiency. we adjusted pentanfdine, and dhpg doses for severe renal failure, with supplements after hero, sis, and at~rp.d.. during ~ next days she was afebrile, and the chest became radiologlcally normal. after ten days on menhani~al ventilation (mv.), the patient was extubated. cr. level was . rag%, (a-a) oz gradient was , and paoyfioz was , the patiem was discharged with chronic ambulatory p.d. discussion: opportunistic pneumonia is a major complicalaou in imm~romised children, specially after kidney tvansplaraafion. c m.v. infection can result at~r okt administration. in the treatment dhik} dose must be adapted to the degree of renal insu~cieney, with supplements after hemedialysis, and after pd. pneu~y~tis cann# tmeumov~ is ehemeterized by ventilafion-perfusion mistmaeh, decreased pulmonary compliance, hypoxia arld elevated (a-a) oz gradient, with diffuse interstitial infiltrates. in our ease bal was negative. although we did not find the etiology the prevoclons eombh~ation of arairmcrobiat therapy, along with m.v., and supportive measures were the most effective trealme~. conclusion: ) in patients with severe renal failure and life-threatening infections, we must co~ider drug adjuslments. ) in our patient we gave dhpg supplements at~r pd. with excett~at results, although p.d. was of little effiele~. introduction: endotracheal intubation and mechanical ventilation have become an important treatmem for many diseases accompanied by respiratory failure. with the frequent use of this treatment modality, an increasing number of complications associated with endotracheal intubation have gained clinical significance. material and methods: a transversal study was realized to find the prevalence of pulmonary aspiration with endotracheat tubes in infants and children. aspiration was assessed by applying two dyes (evans blue, er)¢rosine sodic) on the tongue and searching for the dye during suctioning in the endotracheal aspirate. the factors, that potentially have influenced the aspiration, including weight, age, sex, cause of respiratory failure, main pressure airway (map), level of consciousness, presence of swallowing and body position were evaluated. all the variables studied had their association with aspiration tested by chi-square method with relative risk considering a confidence interval of %. the results were adjusted by multivariate analysis. results: the overall prevalence of aspiration was . %. among all children who aspirated, compared to those who did not, there was a statistically significant difference in the presence of swallowing (p= . ). the odds ratio to aspiration in the presence of swallowing was . (t. - c.i. %) and the relative risk . . aspiration was not significantly affected by sex, weight, age, cause of respiratory failure, map, level of consciousness and position of the body during the ventilation. conclusion: the endotracheal intubated children frequently aspirate as intubated adults and that preventive measures are ineffective. the presence of swallowing movements is the main risk factor to aspiration of oropharingeal content in intubated patients. clinical features and shortterm outcome skling, rp gie pneumonia is the second most important cause of death in young south african children. the clinical features, intensive care course and outcome of children being ventilated for pneumonia in the developing world is unreported. aim: to describe the clinical findings, aetiology and shortterm outcome of children younger than months with pneumonia requiring ventilation. the data of all babies under the age of six months with a lower respiratory tract infection admitted to the paediatric icu for ventilation were prospectively collected over a period of months. tracheal aspirates and blood specimens were submitted for viral and bacterial cultures. results: forty-seven babies aged to days were ventilated for pneumonia. twenty-six infants had been born prematurely; t had been ventilated during the neonatal period and had bpd. the median duration of symptoms was day, the most common being cough, tachypnoea, apnoea and cyanosis. five babies ( %) died. the mean duration of ventilation was days (range - days) and of ward stay after icu discharge days (range - days), blood euttures were positive in children ( %). viruses were cultured in children ( %). conclusion: ) fifty-five percent of children below months requiring ventilation for pneumonia were premature infants, of whom % had been ventilated during the neonatal period. ) the median duration of symptoms prior to admission was day. ) ninety percent of the children survived and were discharged from hospital. ) viral pneumonia was responsible for % of the admissions. mechanical ventilation and atrial natriuretic factor release ulloa santamarfa, e, p rez navero jl, ibarra de la rosa i, espino hernladez m, velasco jabalquinto mj, frfas p rez m. picu. reina sofia children's llospital. c rdoba. spain. mechanical ventilation effects on renal function decreased diuresis and natriuresis due several factors including anf. several studies have demostrated anf released due increaasing pressure in right atrium. on the other hand, mechanical ventilation, overall peep modality, inhibits peptide release althougt cvp increased is found. this study was designed to demostrate anf stimulation is due rigth atrium stretch which be higher during mechanical ventilation instead of atrium pressure. we desing a prospective study including patients, age range months- years with congenital heart disease. all of them were admitted at pediatric intensive care unit after extracorporeal surgery and were assisted by mechanical ventilation. hemodinamic state was stabilized in all patients and nor renal neither neurological diseases were found. after hours with mechanical ventilation, plasmatic levels of anf were measurement, pvc, pericardical pressure were assessment; all patient were sedated with midazolan and paralized with neuromuscular blocking agent; mechanical ventilation technique was as follow: imv between and , tidal volume and fi o enough to mantain respiratory parameters in normal range. afterwards, at least twentyfour hours in spontaneous breathing, the study was made again in each patient. atrial stretch was assesssment according to following equation: transmural pressure= cvp -pericardial pressure. cvp were significantly higher with mechanical ventilation than when the patient was breathing by himself. ( . +__ . vs . + . mm hg; p< . ). however, transmural pressure during mechanical ventilation were lower than during spontaneous breathing ( . +__ . vs . +__ . mm hg; p < . ) equal, plasmatic anf levels were lower during mechanical ventilation ( . + . vs . + . pg/rnl; p< . ). in conclusion, anf secretion decreases during mechanical ventilation, even with cvp higher. anf release would depend on atrial stretch meassured by transmural pressure, lower in patients with mechanical ventilation and it would not depend on atrial pressure. the paediatric intensive care unit shaikh zayed hospital, lahore is an acute care area devoted to the care of critically sick children upto the age of years. in a bedded unit with limited equipment, constant care is ensured by the presence of at least one nurse aed one doctor round the clock. in this setup we have the facility to ventilate - children at one time, between sep. and dec. , out of patients admitted to icu, ( . %) were below yr of age, while ( %) were below month of age. life support was discontinued in ( . %). total mortality was ( . %), major mortality was in - month age group ( . %), and month to month ( . %). majority of the patients were of sepsis ( . %), cns disorder ( , %) followed by respiratory problems ( . %). it seems therefore that the major indicatiou for ventilation was overwhelming septicemia leading to multiple organ failure, rather than purely respiratory problems. high frequency oscillation (hfo) in the therapy for ards in pediatric patients requiring aggressive conventional mechanical ventilation (cmv) -routine or experimental mode ef pre ecmo therapy. fedora m., nekvasi~ r, vobruba v., srnsky p,, zapadlo m. dpt. critical care medicine, nicu and ecmo center, university children's hospita! brne, nicu of university hospital prague, czech republic. introduction: pediatric patients ( males, female, average age . months, average body weight , kg) with severe ards ventilated with aggressive regimen of pcv or prvc were connected to hfo (sensormedics ) as the last "rescue" therapy due to uncontrollable respiratory failure before intended ecmo. in the course of hfo of them were given no in the concentrations of - p.p.m., were subjected repeatedly to surfactant replacement therapy (alveofact). results: ecmo was needed in no patient, patients survived, patient was disconnected from the ventilator because of brain death in spite of conspicuous improvement of oxygenation and other parameters, some relevant parameters hours before and hours after starting hfo are given in table ~ in all the cases, the disconnection from hfo was carried out through the simv regimen, never directly to cpap. table : the levels of blood gases, oxygenation index (oi), aado ,map,fio and pao /fio ratio hours before and hours after starting hfo. conclusion: although none of the patient had to be subjected to pediatric ecmo, hfo should be carried out only in workplaces having the immediate possibility of using this method in the case of hfo failure. speculation: should not hfo be used ir pediatric patients with ards earlier than aggressive cmv? can hfo ce considered standard, not experimental method of therapy? refractory hypoxemia in premature patients is characterized in a persistent elevation of pulmonary vascular resistance, with right to left shunt through the ductus arteriosus and or foramen oval. we report the case of a vlbw patient (ga w, bw g) who present a severe hypoxemia related to hyaline membrane disease and a pulmonary and systemic infection to group b streptococcus, refractory to conventional ventilatory support and surfactant therapy, associated to hemodynamic failure falling in ecmo criteria used for term infants. a rescue therapy with hfov (sensor medics a) is decided at h of live, the table resume the patient's evolution before and after hfov. at w of postgestational age the patient present a fio of . with a chest x ray compatible with a cld type l at discharge no oxygen requirements was needed and actually he's doing well. conclusion: hfov, using an adequate alveolar recruitment strategy, was effective in the rescue of a severe hypoxemic respiratory failure with a rapid off of ecmo criteria entry in our vlbw premature patient, during the united nmioffs embargo ~nst yugoslavia the prevalence of the ast}nnafic ~acks in c~dldren aratsed. the mo~t common causes have beem dramm~e worsening of life standard, ecom~c disaster in global community, gr~ number of refugees from the other parts of former yugodavia. it wm obviom that mcio-ecoumnical conditions took a part in the exacerbations of previously known cldldhood asthra~, ~av~ of micro-and m~mclimaflc changes, psychosocis] and emotional cryses, lack of medics-m~nts for p~ve~on and tl~rspy of acute asflanatic attacks. about % of d-dldv~ tmslod in our picu for these year~ exp~dvncod ~vcr~ attack for the flint time iu ~jzeir lifts. it has been cu~ ~%~ children in mspir~ry picu of our hos~mt. the scut~ revere attack (more ~asn ~/o of hight clinical score) was detected in % of all children admitted with respirak~ problems. from tl~ mmlysss we exclu&d: bmncldolifis, ~i anomalies, ~eve~ i~ccqions. concerning our drug supplies (which wc~e reduced), we started our therapy by administration of oxygen, ~ta -ago~dst inhalations (but sometimes we had the solution for jet nebulizcm only for o~e inhalation per p~cnt), mwinophyllin and mefl~ylpr~ini~done in/ravenously. % of ih~ asthmatics needed repea~ doses of muinophyl~n pinch.ally, tnch.,ding the fluids. the bronchodilak)r msponm was poor ~r~cl slow, hospital stay in picu was for days and for days in other units sl~rwsvds. tim ~ of their stable condifio~ was hard at borne (or refugees camps), without p~ventkm, so they came bsvk to hospital for morn than times in % of cases, dtrdng ~e je last motlfl~s file dtustion improved, concerning tim drugs supply for prevention, and we hope that these lifc~restening conditions wouldd~ introduction: the incidence of ards is increasing as survival of critically ill patients is higher. the application of new therapeutic modalities have increased the survival rates in (ards) adult patients. objective: to study the therapeutic efficacy of new tleamlents in children with ards material and methods: a retros~ctive study was conducted from to . children with severe ards, (lung severity score > , ) (r), aged days to years, were included. the diagnosis were as follows: interstitial pneumonitis, non interstitial lung infection, with lung aspiration and with clinical sepsis. patients had different tipes of cancer and to suffer inmunodeficiency disease, the first subjects (group t) were treated with conventional measures. from october of new therapeutic modalities were introduced, including: less agressive ventilatory support, postural changes (prone to supine) in subjects, administration of corticosteroids in patients, rfitric oxide in , pe~ssive hypercapnia and administration of exogeans sarfactant in one, pao /fio , d(a-a)o , oxigenation index (oi) and the score of respirator), severity disease were similar in both groups. the two groups evolntiou was compared. results: -ten patients died, from group i and from group ii ( % v.s. : %,ns). -the evolution time, either to exitus or weaning from ventilatory support was higher in group ii ( . v.s. . days in group i, ns), -the incidence of barotrauma was observed in subjects ( . %), from group i and from ii. of these patients % expired. -during the course of the disease, ( %) patients had more than one damaged organ. only in one subjet mof was considered to be the main cause of death. the majority of the patients expired because of their respiratory disease, although, % of them met criteria of mof. -fifty percent of the subjects were infected at the time of death. stmmry: a trend toward a higher survival rate is observed in the subjects receiving the new modalifies therapeutic intervention (corticosteroides, postural changes and permissive hypercapnia). our results are not significative,probably because of the small number of subjects studied. a new doubleaurae~t two-stage et-tube (dl-ett) was desig~aed and tested in the rabbits with acute king injury under conventional mechanical ~entilation_ ventilation efficiency of dl-ett was emrrpared with that of canveniionally t~sed single lumen et-tube (sl-ett). meth~s: dl-ett was specially made out of two sl-ett. vertical crosssections at the distal end of two et-tube (td _ rmn portax) were adhered with each other to form a tracheal stage lumen wifu id . mm the two remained uncut parts of the tubes corlntithted the oval s~ge with two separate imnens. dl-ett and sl-ett were randomly applied to five adult paralyzed rabbits with acute lung injury (by . nffkg oleic acid. iv). a bird inter vetffttator (bird products corporation) was used for time-cycled pressure-limited ventilation at /min of respiratory rate, ern h of peak i_~piratory pressure, l: of ire ratio, ljmin. of flow rate and . of fich. peak inspirntory pressure, mean mrway pressure, posi ve end-expiratory pressure at tip of et-mbe and bemodynamics were measured and recorded continuously. arterial blood and expired gas were measured ~by avl blood gas analyzer) after each stabilization t.~iod of minntes. _analysis w~as by prated t test. result: dl-ett acaltety improve cos removal at all amman. pa(?oz was decreased by t . +_t. (p< . l) and physiologic dead space fraction (v~zvt) reduced by % +- . % (p< . t), compared with dl-ett. there were no significant change in arterial oxygenation. conelus|on: the double-lumen two-stage et-tabe significantly increases ventilation effmiency with simple operation in rabbits v, ith acute hmg injury, lts availability may influence future clinical management of ~ennated patient~. this ~muly was fimded by the science and technology. commiuee of beijing municipality. analis of hemostasis alterations on different coagulation cascades in children with septic shock has shown that coagulation disorder character is dependent on lung affection rate. the initial manifestation of the respiratory distress-syndrome (rds) are characterized by the obvious activation of blood thrombin potential, moderate coagulopathy and not sharply marked endoteliosis, the witlebrand's factor (wf) increase tot - %. progress in the clinical picture of "shock lung" leads to chronometric and structural hypocoagulation with potential hypercoagulation in "mix-test", high level of firbin derivative, thrombocytopenia with thrombocytopaty and the wf increase to ~ %, terminal stages of the rds, as a rule, are characterized by potential hypercoaguletion absense, depletion of at-lit and plasminogen, prevalence of antithrombin and antiaggregating activity, obvious endoteliosis (the wf to increase - %). the arteriowenous difference according to index of the thromboelastography (teg) in the rds ill-iv rates was , % less than in the - rates, disorder of lung filtering ability in severe rds is confimed also by minimal arterio-venous difference of activated euglobulin lyses (ael) in children with the rds ill-iv rates is only , %, while the patients whit rds i-i rates have the ael-activity in arterial blood , times as much than in venous blood. the use of then allows to determine the potential hypercoagulation rate, the at-ill level and fibrinogen quantity during the anticoagulant therapy and also the character of the x-factor activation and thrombocytic hemostasis. the effective therapy component of septic genesis rds in children is the controled coagulation method with the use of the individual selected heparin doses in according to desagregants, kryoplasma, proteolisis inhibitors and trombolytics. it is necessary to avoid the heparintherapy for children with the rds complicated with producting coagulopaties and termal phases of blood disseminated intravascular coagulation (dic). bronchoseopy has been used for evaluation of the potential problems of the airways and for investigation the bronchial specimens for diagnostic purposes. regent technical advances result in performing this procedure at the bedside manner and in critically ill patients. we have performed hronehoaeopy during last three years on pediatric patients with respiratory problems, in % of cases the opentube hroneh seopy was performed (for diagnostic as well as for therapeutic reasons) and collected secretions or bioptic material were examined. the indieatiuns were: acute upper respiratory problems, chronic wheezing, inspiratory strider, tracheal or bronchial bleeding, chronic eongh, retractable atelectssis, severe pulmonary infections, lymph node perforation in lung tuberculosis and soquells like bronehiectssis and fibrosis. our results were: anatomical malformations in %, mueosal oedema with chronic inflammation and thick secretions in %, easuos masses in %, granulation tissue and purulent secretions in foreign bodies and bronehieetasis in %, and only % of eases were normal finding. our exlxdenees pointed that this invasive procedure in carefully selected patients has important role in establishing the diagnosis and in the- introduction: tbg has been a useful investigation in the management of ventilator-dependent infants in our experience. one ml of contrast was hand ventilated into the respiratory tree via their nasotracheal tubes and their anatomy and dynamics demonstrated on radiological screening. case descriptions: three infants who were difficult to ventilate requiring high airway pressures, high peep and a significant oxygen requirement had tbgs. the ages ranged from to months. two cases were complicated by complex cardiac lesions. in all cases there were frequent episodes of desaturation, where hand ventilation proved difficult and various intermittent lobar collapses occurred. microlaryngobronchoscopies (mlb) performed on the infants by experienced paediatric ent surgeons failed to identify the airway problems. more than one mlb was frequently done. concern about introducing contrast into the airways of infants with limited cardiorespiratory reserve combined with an uncertainty about how much extra intbrmafion would be gained often led to a delay in investigation. when performed these fears proved groundless, the anatomy and pathology of the airways were demonstrated in full and the correct therapeutic plan started. in two cases tracheostomy and peep producing patency of bronchomalacic segments allowed weaning to low levels of ventitatory support. in one case tracheal reconstruction was undertaken and in the cardiac cases the respiratory component of the ventilatory dependence was fully assessed. at the age of months, a baby boy with a history of minor respiratory problems, was admitted to hospital with an upper airway infection and severe dyspnoea. shortly after arrival at the icu he had a total airway obstruction. after intubation there were still difficulties to establish a normal gas exchange, and he was tranferred to the regional picu. ct scan and bronchoscopy verified a congenital tracheal stenosis affecting the whole trachea except the upper mm below the vocal cords. the diameter was estimated to less than ram. an unsuccessful attempt was made to dilate the extremely rigid stenosis with a balloon. after the procedure he had a respiratory and circulatory arrest, and he was put on ecmo as a bridge to surgical correction. after stable days on ecmo, surgery was performed during ecmo with a tracheal homograft transplantation. immediately after surgery, ecmo was discontinued. a silastic dumont type stcnt was inserted inside the homogra~, and a nasotracheal tube was placed inside the stent for assisted intermittent mechanical ventilation. repeated bronchoscopies were performed to remove granulation tissue and secretions. at months of age, the stem was removed with an endoscopic procedure. however, the trachea was still soft and collapsable, and another silicon stent was placed inside the trachea for another months period, after removal he had some respiratory problems and he was treated with nebulized salbutamol, mcemic epinephrine and steroids. he was discharged from the hospital at months of age and his condition is now stable. this is the first procedure of its kind in sweden. it was accomplished by international and multidisciplinary collaboration. ecmo may be a bridge to corrective surgery and long time stenting may be necessary in the postoperative period. post mtubation laryngitis ( pil ) is still a frequent complication, occurmg in l - % of intubated patients. inhaled racemic epinephrine has for long been used as an accepted therapy, but this drug is not always available. the authors undertook a randomized, double-blind, placebo-controlled trial to determine the efficacy of inhaled l-epinephrine(le) in the treatment of plu in the period between july/ and may/ , patients were submitted to endotracheal intubation for ventilatory support. atter the extubation procedure patients were considered for enrollement if they met the following criteria: clinical signs of laryngeal estridor and a downes and rafaelly score for upper respiratory obstruction equal to or higher than patients with primary upper respiratory disease were excluded all patients enrolled reeieved either inhaled l-epinephrine % or normal saline. dexametasene ( , mg/kg/day) was given to all patients in both groups. after inhalations, au patients were monitored for a period of - minutes and monitoring included cardiac and respiratory rate, mean arterial blood pressure, arterial blood gases and the dowries and rafaelly score. statistical analysis included, qui-square with the fisher correction test and the z-test for paired variables. thirty eight patients ( , % ) met the criteria for enrollment, to the le group and to the placebo group.there were no significant differences in both groups in regard to age, sex, initial score ( , x , ) and endotracheal tube diameter. the period of ventilatory support and tracheal intubation was significantly higher in the le group ( , x , , p = , ). the follow-up score showed a significant drop only at minutes after the inhalations (p = , ). re-intubation due to laryngitis, occured in patient of the le group and in of the placebo group with no statistical sxgnificance (p = , ). no difference was observed on the monitored hemodynamic variables during the minutes, except for the mean arterial pressure at minutes, being heighar on the placebo group (p = , ). we concluded that, although the l-epinephrine group showed a trend in better scores post-inhalation and fewer re-intubations due to laryngitis, the results were not statistically significant. we especulate that the period of intubation may have affected our results. similarlly there were no differences in the incidence of adverse effects between both groups. objectives:to evaluate the complications of endotracheal intubation in children with upper airway obstruction due to epiglottitis or croup. methodes: during a year period ( - ) all patients with epiglottifis or croup were reviewed to determine the complications of endotracheal intubation, especially upper airway obstruction due to granulomas. results: patients were reviewed. in children (mean age . years) with epiglottitis the mean duration of intubation was . days ( - ). no complications were seen. in patients (mean age . years) with croup the mean duration of intubation until the first extubation was . days ( - days). elective extubation was performed if an airleak was present or after days without airleak but in the absence of fever and obvious secretion. reintubation was not necessary in children ( . %). in this group the mean duration of intubation was . days ( - ). in patients ( . %) reintubation was necessary because of severe upper airway obstruction due to granulomas. mean duration of intubation until the first extubation was . days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . there seems to be a difference in duration of intubation between these two groups with croup, however it is not significant (p > . ). all the patients with granulomas could be successfully extubated after microlaryngeal surgery, with a mean intubation period of . days ( - ). revealed no complications, where as endotracheal intubation in children suffering from croup showed a high incidence ( . %) of granulomas. however laryngeal steepsis and other serious complications were not sesn~ patients ( days averagely] was obviously seen in ~he peak =one of fl, f resonance and in the zone of high freq,-~ncy :r, ~;~e composition while cases( day~ average;y] :~bowed no abnormality both clinically and isryngoscopica!~y. / patients with catheter placement for more than week~ end p~tie,~ts for less than weeks had t;~ryngeal abnormal change in their larynges,abnormal changes of sound spectrogram were all seen in patients with placement for mope than weeks. our data suggest= ca] the complication of endotracheal intubation was increases with increasing length of time of catheter placsm. entjbut aeriuoa complication is rare i (b] the time limit of pernasal endotraoheal catheter placement is weeks within which the procedure is • comparatively safe and effective means for maintaining e tong term artificial airway. in a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) we diagnosed tbm as an apparent dilatation of the trachea and main bronchi ih four premature infants on continued mv for respiratory distress syndrome (rds). the infants were three boys and one girl with gestational age (ga) - weeks and body weight (bw) - g. mv was provided by bourns cub time-cycled and pressure-limited ventilator to attain normal gas tensions. no jet ventilation was used. chest radiographs were reviewed for a complete evaluation, and for the evaluation of the airway. after the intial subjective diagnosis of tbm, the width of the tracheal and main bronchial air column was measured at the lower level of the first and the third thoracic vertebal body it , t ) and near the carina; the width of the main bronchi below the carina was also measured. in all infants, tbm became apparent close to the lh day, that is, after - weeks of mv. therefore, for the time period from birth to the th day the following ventilatory parameters were reviewed and analyzed: ( ) the percentage of total ventilation time when more than % o concentration was required, ( ) the peak inspiratory pressure, ( ) the positive end-expiratory pressure, and ( ) the duration of high frequency ventilation ( - breaths per minute). also noted were the apgar scores ( and min after birth), the duration of hypotension (systolic bp below mmhg) and circulatory instability, the presence of systemic or tracheal conatal or later infection, the duration of mv, and the final clinical outcome. the records were also reviewed for other possible pertinent data. rigid respiratory endoscopy in children fraga j, amant a s, piva j, nogueira a, palombini b. introduction: the respiratory endoscopy is an important procedure to diagnose and treat many airway's diseases in children. although have had advances in radiologic investigation exams and pulmonary function tests, the direct anatomic visualization of airway is important to the management of many respiratory problems. objective: evaluation the respiratory endoscopies performed with a rigid bronchoscope in a pediatric reference hospital. material and methods: we study the records of all children that were submitted to respiratory endoscopy under general anesthesia from march to march . age, sex, clinical to indicate the procedure, diagnosis and complications of endoscopy were registered. results: three hundred and fifty six respiratory endoscopies were performed. the most common indications for endoscopy were strider ( %), suspected foreign body ( %), atelectasis ( %) and difficult tracheal extubation ( %). the most frequent diagnosis were laryngomalacia ( %) and subglottic stenosis ( %) in the glottic and subglottic areas, and foreign body ( %) and tracheomalacia ( %) in the tracheobronchial area. normal endoscopy was performed in ( %) of the children. only three slight complications of the endoscopy were observed. two patients presented bradycardia during the exam, and the third need tracheal intubation due to post-endoscopic subglottic edema. conclusion: the rigid endoscopy in children is efficient and has no serious complications. near drowning; indicators of acute and long term prognosis bernardien t.mj. thunnissen t, reinoud j.b.j. gemke , loes veenhuizer?, krijn haasnoot , a.johannes van vugh department of pediatrics, ~wilhelmina children's hospital, utrecht, sophia hospital, zwolle, and ~free university hospital, amsterdam, the netherlands. in this retrospective study factors that affect short and long term prognosis after submersion were analysed. all patients that were admitted to a tertiary pediatric icu between january i, and january i, were included. of patients, aged - years, died in the icu, one after hospital discharge. survivors and non-survivors showed significant differences with respect to central temperature, pupillary reactions, arterial ph, pediatric risk of mortality (prism) score and therapeutic intervention scoring system (tiss) upon admission (p < . ). non-survivors more frequently required mechanical ventilation, bicarbonate administration and active reheating. ards was seen in patients ( %), invariably within hours after admission. no patients with cardiac arrest on" admission snrvived without sequelae. hypothermia appeared to have no protective effect on hypoxic damage. survivors with persistent sequelae _> months after discharge had significantly higher prism and t ss scores (mean and , respectively) than those with complete recovery (mean and , respectively). long term cognitive problems were present in / survivors ( %) and emotional disturbances in / ( %). in conclusion, a concise number of clinical and laboratory parameters, representing acute severity of illness, are important prognostic indicators for survival and health status of children after submersion. there were ( %) bronchoscopies, and ( %) were oesophagoscopies.the average age was , years for bronchoscopies, and years for oesophagoscopies. the outcome of the patients was good. no complications were observed. extraction is recomended in every symptomatic patient. orphenadrine is an anticholinergic drug mainly used to decrease symptoms of parkinson disease. orphenadrine has a peripheral and central effect and overdose can result in athetoid movements, convulsions, cyanosis, coma, arrhythmias, shock and cardiac arrest. physostigmine is a specific antagonist of the peripheral and central effects and can be a useful antidote. we report the case of a two and a half year old female who was transfered to our icu for general convulsions. the little girl had, three hours before admission, accidently ingested rag of orphenadrinehydrochlodde (disipal®), which was her grandmothers anti-parkinson medication. three hours after ingestion she presented neurological signs: confusion, unstable walking, and periods of aggression. generalized tonic-clonic seizures appeared who were rebel to administration of multiple anti epileptica but ceased after iv administration of diazepam and endotracheal intubation and ventilation. an episode of ventdcular tachycardia responded well to the iv administration of tidocaine. the levels of orphenaddne in the serum were high at admission ( pg/l) and were present in the blood up to hours after ingestion. high serum levels are, in the literature, associated to a high mortality rate. physostigmine was administered three times at a . mg/kg dose in the first hours. we decribe the noted effects of physostigmine on the different symptoms. the patient survived and could leave the icu after one week. in conclusion: orphenadrine poisoning is a very complicated medical problem associated with high mortality. in severe intoxication, the benefit of physostigmine more than counterbalances its side effects. objective: to define the optimal volume of dilution for endotracheal (et) administration of epinephrine (epi) design: prospective, randomized, laboratory comparison of four different volumes of dilution of endotracheal epinephrine ( . , , and ml of saline) setting large animal research facility ofa universi~ medical center subjects and interventions: epinephrine ( . mg/kg) diluted with four different volumes ( , . . and i rot) of normal saline was injected into the et tube of five anesthehzed dogs. each dog served as its own control and received all four volumes in different sequences at ieast one week apart. arterial blood samples for plasma epinephrine concentration and blood gases.were collected before and . , . . . _ . . , . . , . , . , and minutes after drug administration. heart rate and arterial blood pressure were continuously monitored. measurements and main results: higher volumes of diluent ( and i ml) caused a significant decrease of pao , from :!: tort to ±i torr, compared to the tower volumes of diluent ( and ml), from ± torr tu +_ torr (p< . ). these effects persisted for over minutes. mean plasma epinephrine concentrations significantly increased within seconds following administration for all the volumes of diluent. mean plasma epinephrine concentrations, maximal epinephrine concentration (cmax), and the coefficient of absorption (ka) were higher in the ml and ml groups. the time interval to reach maximal concentration (tmax) was shorter in the ml and ml groups. yet these results were not significantly different. heart rate. systolic and diastolic blood pressures did not differ significantly between the groups throughout the study. conclusions: dilution of endotracheal epinephrine into a ml volume with saline optimizes drug uptake and delivery, without adversely affecting oxygenation and ventilation. the aetiology and outcome of paediatric out-of-hospital cardiac arrest was studied during a -year period in southern finland served by physician staffed emergency care units. the files of prehospital patients less than years old without palpable pulse and spontaneous respiration were analysed retrospectively. fifty patients were declared dead on the scene (dos) and resuscitation (cpr) was initiated in patients. the sudden infant death syndrome was the most common cause of arrest ( %) in the dos patients as well as in patients receiving cpr ( %). asystole was the initial cardiac rhythm in % of the patients in whom cpr was attempted. eight of the hospitalised patients were discharged, of them with mild or no disability, with moderate disability and one in vegetative state. in multivariate analysis the short duration of cpr (< minutes) was the only factor significantly associated with better survival. due to various aetiologies the survival rate from prehospital paediatric cardiac arrest is quite low. on the other hand, hypothermic near-drowning victims seem to have a relatively good prognosis. duration of cpr less than minutes was the best predictor of intact survival, our study supports the previous findings of the importance of early and effective resuscitation efforts for establishing ventilation and perfusion on the scene. in our system well trained physician staffed emergency care units are able to provide immediate and effective als on the scene. on the other hand, these units also appear to be able to refrain from resuscitation when the prognosis is pessimistic. objective: to assess the normal ,gastric intramucosal ph ~hi) by tonometry in healthy children patients and methods: twelve healthy children ( males and females) with age rmaged from months to years scheduled for minor plastic or urologic surgery. children were previously medicated with midazolam ( . mg/kg) and atropine ( . mg~) both i.m.. anaesthetic induction was standardized with -n ( %) administered via facial mask and increased halotane concentrations (up to %). all patients got an endotraeheal tube after iv. administration of femanile ( mcg:jkg) and vecuronium ( . mg/kg) or suxametonio ( mg/kg), pmaesthesia was maintained with o -n ( - %) and isofluorane ( . - %). during surgery, children needed mechanical ventilation and the others maintained spontaneous breathing. ekg, heart rate, blood pressure, and pulse oximetry were moniterized. after anaesthesia, a sigmoid tenometry catheter (tonometrics, inc.) was inserted in the stomach of the patients by direct visualization with laryngoscope and magyll clamps. children were all maintained normoventilated and with normal cardiorespiratery variables. cadet's balloon was £~led with . ml of saline. thirty minutes after the insertion rrd was extracted and rejected, just afterwards the remanent . ml was extracted and immediately analyzed. simultaneously an arterial gasometry by puncture was performed. gastric phi was calculated by the henderson-hasselbalch's equation using the pco obtained from the tenometry catheter and the bicarbonate value obtained from the arterial gasometry. results: average gastric phi was . -i- . , range ( . - . ). objective: demons~ating intramucesai ph (phi) alterations during transport of patients from operative room to pediatric intensive care unit (picu), material and methods: phi measurements were performed with gastric tonometer catheter in t patients undergoing cardiac surgery with cardiopulmona d" bypass (cpb), there was mate and female, the average age = yl ra, average weight = , kg, average time of cpb = rain. the measurements were made at the end of the surged' and when the patients had arrived in the picu statistical aualysis: average and ~andart deviation and test "t" student. objetive: to asses the efficacy of gastric iatramucosad ptt (phi) and arterial lactate levels to evaluate splacalc tissular perfusion in an experimental model of intestinal ischemia. suneets ~nd methods: twelve piglets weights t - kgs. undergoing orthot~ie liver trasplantation. the intestinal ischemia was induced by aortic damping. tonometry catheter (tonometrics inc.) w~s placed in the stomach after artaesthesia and ot intubation. phi ~s determined times and lactate levels was determined fi times in stages: i) pre-ae~hepatic stage (twice: before surgery and before aortic clamping ); ii) end anhepatic stage (only phi): iii) reperfusion stage (a , , and minutes). the phi was derived from application of the henderson-hassdbach formula using the pco value from the tonometer and the arterial bic~rbonate. all pipets received raaitidiila before sttrgery. values of phi above , and lactate levels between and mg/dl were considered nortrm. the results were statistically anaj.izated with anova and bonferroni tests. results: the phi was normal on pre anhepatic stage (> , ) and lactate levels were slightly increased ( , +_ , and , ± , mg/dl ns) . in relalion to we-anhepatics values, phi decreased signncatly at the mid of anhevatic stage ( , _+ , vs , _+ , p< , ), phi remain low in stage iii, at rain ( , + , p< , ) and min(g -+o, p< , ). arterial lactate levels increased significatly in relation to levels in stage i, at rain ( , _+ , p< ,o ) arid rain ( , ± , p< , ) of reperfusion stage. there is a slight improvement on phi and lactate ievels at and t rain althought the differences did not reach significance. cnmments: phi and arterial lactate levels propperly reflect hypoperfusion on the experimental model of acute intestinal isdlemia. b~kground : the paediatrie gallbladder diseases generally described are calculous ¢hol~tstitis, cystic duct obstruction, congenital anomaly of the biliary tract, and inflammation. in the neonatal period, noulithogenie gallbladder disease could be also due to erythroblastosis or hyperalimentation. obieetive : we describe an other type of disease affecting the gallbladder in neonates thought to be related to their vascular vulnerability. methods : four patients with abnormal gallbladder ultrasound not related to classical observations were included. we have studied and reviewed the biological and clinical data, the ultrasound findings and their evolutions. results : four patients, to ~.k-old neonates ~ffth a birthweight be~,een , and , kg, were intubated and under total parenteral nutrition for to days. none of them were symptomatic on repeated clinical evaluations. one newborn developped hypotensien on umbilical bleeding at hours of life. in two cases, signs of cholestasis were discovered : the total bilirubin level has risen to mg/dl; the direct bilirubin level was , mg/dl while the urina were dark and the ~o~,ls :mcolour~. the c~mplct~ ~crology as a!! the culvare~ remained negative. the ultrasound explorations were atypical : in the four eases, an initial increasing broad and thickness of the wall of the gallbladder with an hyperecbogenie inside content, which was not sludge, was discovered. in three eases the images resolved in ten to fifteen days. in one ease, an asymptomatie thrombosis of the vena portu which remained patent was discovered. in this case, at one month, the ultrasound showed images encountered in chronic ebolecystitis and, at one year, the gallbladder appeared atrophic. none of them underwent surgery. conelusiou : the gallbladder diseases are multifactorial. besides the prematurity, the infections, the total parenteral nutrition, the premature neonate is exposed to vascular vulnerability affecting also the gallbladder and this may explain our findings. progress in prognosis of pts with b-nhl had followed the use of multimodality chemotherapy (ct). with the prolonged survival, there are comlications due to myetosupression & desease process. the syndrome of neutropenic enterocolitis (ne) is one of the ominous problems because ofpts increased susceptibility to infection & overwhelming sepsis. this material included neutropenic pts ( - years) with the stages iil& iv of b-nhl who were treated with the modifired bfm- (mtx g/m in -h inf.); males, females. seventeen episodes of ne were observed & only after the first courses of ct ( of after tst, %; of after nd, %). the symptoms existed to days. wbc ranged from to in l~tl (median, ). the first signs of ne were directly correlated to the beginning of the neutropenia & the recovery of neutrophils led to the disappearance of abdominal recovery of neutrophils led to the disappearance of abdominal pain. the conservative treatment included gastrointestinal tract decompression, broad spectrum antibiotics initially, volume & electrolyte substitution, nutritional support, correction of acid-base balance, symptomatic treatment. sixteen pts were treated nonoperatively, died. on autopsy the transmural bowel necrosis due to thrombosis of branches of a.mes.sup, was found. the bowel perforation occurred in one patient, he was undergone laparotomy & hemicolonectomy & survived. we conclude that ne is a frequent complication in neutropenic pts with the st. lii& iv of b-nhl. it occurs after the induction courses of ct. close observation by surgeons, oncologists & pediatric intensivists is mandatory. conservative treatment is effective & more preferable until leucopenia resolves. operation is necessary only for those.with perforation. near infrared spectroscopy as a tool for evaluation of intestinal perfusionpresentation of an animal model. c. scheibenpflug, p. buxbaum and a.m. rokitansky the recent development of and investigations in the so called near infrared spectroscopy ( nirs --transcutanous emission and simultaneous registration of intensity of spectralcolours depending upon modulations of tissue perfusion ) enable physicians to measure and qualify organ perfusion and nowadays is mainly used to control cerebral as well as skeleton muscular blood flow in trauma patients at intensive care units ( icu ). today intestinal perfusion, hypoperfusion , cell damage caused by reperfusion injury, bacterial and toxin translocation are serious problems in critically ill patients at an icu. paediatric intensive care physicians put major concern on intestinal perfusion, which for. instance gains more and more importance, especially in the neonatal period for example as an etiologic factor for necrotizing enterocolitis. we established an animal model, in which we measured intestinal perfusion by nirs under various invasive and noninvasive conditions. methods and results will be referred. for preliminary conclusion we propose near infrared spectroscopy ( nirs ) also as a potent diagnostic tool to determine early intestinal malperfusion in order to prevent lethal outcome. fm'ther investigations in animals as well in paediatric iritensive care patients should be done to estimate our efforts. introduction: following the acute phase of necrotising enterocolitis (nec) starvation of the gut for a period up to weeks is a generally accepted treatment modality in many centres. objective criteria to refeed these patients are hardly available. recently the double sugar test has become available as a parameter for (ab)normal gut permeability ~' . aim of the study: to evaluate the changes in permeability of the small bowel in patients with nec and controls before introduction of enteral feeding. methods: a lactulose! rbarrmose (i/r) test was performed in two groups. group was studied - times within a -week period of starvation (n= , mean gest. age , range - weeks). in group seven different control patients were studied (mean gest.age , range - weeks). the test was performed by giving a patient after at least a hour fast ml/kg bodyweight l/r solution and determination of the /r ratio in a -hour urine sample by chromatography. results: objective: to evaluate the prognostic factors in the response to nitric oxide (no) in children with acute respirator/ distress syndrome (ards) and/or pulmonary hypertension (pht). patients and methods: critically ill children received no inhaled for ands and/or pht treatment. patient before and after cardiac surgery ( cardiac transplants), with bronchopneu~onia, multiple trauma, sepsis and cardiorespiratory arrest. patients showed /j~ds and pht, in with associated ards. we analyzed age, sex, diagnosis, pao , pa /fi , oxygenation index, pht, shock, and sepsis as prognostic factors and response factors to n . results : after no administration oxygenation did not improve in patients ( . %) and pht did not diminishe in one children ( %). patients survived ( %), / ( . % with /d%ds) and / ( %) with pht. the four patients with isolated pht survived , and the patients with pht and ards dead. patients after cardiac surgery presented less mortality ( . %) than the rest of patients ( . %). patients with shock presented higher mortality ( . %) than the rest of patients ( . %). there are no differences in response to no in respect of sex, age, diagnosis, shock, and sepsis. survivors showed higher increase of pao /fi . ± . to no than non-survivors . ± . (n.s). patients with pht showed higher increase in pa /fi to no administration ( ± . ) than patients with ards ( . ± . ), (n.s), but patients with ards showed a higher increase in !, ± . , than patients with pht . ± (p < . ). patients with pa /fi < i showed less increase in pa /fi , . ± . , than the rest of patients . ± . (n.s) conclusions: i. mortality of isolated pht treated with no is less than patients with ap~s. patients with shock and those with pht and ards showed higher mortality. . we have not found any clinical or analytical factor to predict clinical response to no administration. patients showed ards, and severe pht after cardiovascular surgery, in with associated ards. we registered respiratory assistance, blood gases, pao /fi , the oxygenation index (oil, and mean pulmonary pressure/ mean systemic pressure (pap/sap) before and after no inhalation. we measured continuous concentration of no and no by electrochemical method (noxbox, bedfont, airliquide). results: no administration improved oxygenation mean pao from ± tm~g to i ± ~g (p < . ), mean pa /fi fr<xa ~ to £± (p < . )and i from ± to ± (p < . ). patients did not improved with no administration. the oxygenation improved in the first five minutes and the best oxygenation was achieved with - ppm. there is no significant change in pac . pap/sap diminished from ± % to ± % ( p< . ), in one patient there is no response. the no administration was maintained between ~ minutes to days. the effect of no on pulmonary pressure and oxygenation was maintained without change during all the time it was administrated. n concentration were always less than ppm y metahemoglobinaemia less than . %. there are no side effects secondary to no administration. patients survived ( %). concluaions:l.administration of no improves oxygenation in children with ~/eds and diminishes pht after cardiac surgery. .no effect is fast and maintained during the evolution. high frequency oscillatory ventilation in combination with inhaled nitric oxide g~thberg sylvia, md, edberg k e md, phi), dept of paediatric intensive care, children's hospital, s- g teborg, sweden background: for man), years severely sick infants with congenital heart malformations or acute lung disorders have died due to pulmonary hypertension, hypoxia and multiple organ failure. today there are several therapeutic facilities coming up for these infants. ecmo progranunes have been introduced in severul centres as well as improved venlllatory techniques, as high frequency oscillatory ventilatior~ (hfov), which provides adequate ventilation with less risk for hmg injury.. in , the endothelium derived relaxing factor was identified as nitric oxide (no), and extensive studies have sho~-a that inhaled no reduces pnimonm o vascular resistance and improves oxygenation in hypoxic infants with pulmona~ hypertension. material.. from july to january , we have treated severely hypoxic children with combined ttfov-no. seven were newborn, with cdh, one with mas, one with irds, one with paediatric ards due to rsv infection and one with poor oxygenation atler open heart surgery. were between month and years and all had ards of differentorigin but one who was hypoxic after open heart surgery. method: hfov was given by means of sensormedics a oscillatory ventilator to patients, and dr~ger babylog was used in one case. mean airway pwssures varied from - cm h . oscillatory pressures varied from - cm h and ventilatory rates from - hz. fi o varied from , - , . no was administered by nomius classic. no and no was measured in the inspiratory limb with an electrcchemieal device. noconcentration varied from to ppm and the no -concentration between - , ppm. methemoglobin was never more than , % (average , ). duration of treatment varied from to days. combined trealment with hfov and inhaled no improved oxygenation and carbon dioxide elimination in out of treated childretl patients died, due to their underlying congenital heart disease, one of asphyxia due to rsv-infection and one of cdh with progressive hypoxia and multiple organ failure. combined treatment with hfov and inhaled no improves oxygenation in severely hypoxic children. treatment should be slarted early to reduce the risk for chronic lung injury following barotranma and high oxygen concentrations. we speculate that the combined hfov-no may reduce the use of ecmo, and that it may improve outcome in ceotres where ecmo programmes are not introduced. apart from its vasodilative properties nitric oxide appears to act also in physiologic immune defense. intracetlular concentrations of no synthesized by macrophages are in the range of above those produced by vascular endothelium. we investigated the bacteriostatic effect of nitric oxide at concentrations used during inhaled therapy for pulmonary vasodilation in neonates. ten different strains of five species were used (staph. anrens, staph. epidermidis, strop. group b [gbs], e. coil and pseudomenas aeruginosa), which are ~e most often tracheally isolated bacteria in mechanically ventilated premature infants and neonates. we compared bacterial growth of cultures applying three different concentrations of nitric oxide ( ppm. ppm, ppm) m the growth of the same strains in room air for a duration of hours. no bacteriostatic effect was demonstrable at no concentratioes of ppm. e. coil showed decreased bacterial growth at ppm and ppm, however without reaching statistical significance (p= . ). at nitric oxide concentrations of i ppm staph. epidermidis and gbs grew significantly less as compared to colonies of the same strains in room air. no effects were found regarding the growth of staph. aureus and pseudomonas aneruginosa. we conclude that nitric oxide has a selective bacteriostatic effect on some of the most often trachealb, isolated bacteria in premature infants and neonates. this effect appears to be dose-dependant and occurs in the upper range of dosages used with inhaled no therapy. further research is required in order to examine the mechanisms of action as well as specific interactions between different strains of bacteria and nitric oxide. the no,box monitor (bedfont, kent, uk) is used to monitor nitric oxide (no) and nitdc dioxide (no ) during no administration in ventilated neonates. according to the manufacturers specifications the monitor can be applied in cases where airway pressures range from to mbar. we investigated in-vitro the accuracy of the no monitor in a range of ventilatory conditions. using a dr~ger babylog we ventilated an artificial lung. no was administered { ppm no in % nitrogen) with a mass flow controller to the inspiratory tube, at a distance of cm from the y-piece. the no target value was set to ppm. the ventilator was operated in both cpap and ippv modes at different settings. the no sampling tube was placed on two different locations; in the inspiratory tube dose to the y-piece; in the expiratory tube haft way between the y-piece and the ventilator. the no-monitor was ca)ibrated with ppm no at mbar. fig. and show the sensitivity of the no-monitor for respectively static pressure (cpap) and pulsatile pressure (ippv) with the sampling tube located in the inspiratory tube. fig. shows the resur for pulsatile pressure with sampling in the expiratory tube. we conclude that the accuracy of the bedfont no-monitor is dependent upon airway pressure and sampling site, the latter possibly caused by incomplete mixing, pressure and no are linearly related when sampling occured further away from the administration site. based on this study we suggest to place the sampling tube in the expiratory tube. during neonatal care the clinician should be aware of varying inaccuracies depending on the respiratory pressures. hypothesis: availability of therapy with inhaled nitric oxide (ino) decreases ecmo use in patients referred .to a tertiary care hospital for treatment of respiratory, failure unresponsive to conventional therapies. background: at children's hospital of wisconsin (chw) treatment for patients who have failed conventional treatment for respiratory failure, sometimes called "rescue" therapy, has included ecmo since and high frequency oscillatory ventilation since . ino has been in experimental use at chw since may of i and has resulted in the perception of a decreased need for ecmo therapy in those patients referred for rescue therapy. this study was designed to tbst the validity of that perception. study type: retrospective cohort. methods: the medical records of all patients referred to chw from /lj to / / for rescue therapy for severe respiratory failure were included in the chart review. data were collected regarding diagnoses, illness severity, hospital course including interventions and complications, and outcomes. exclusion criteria w~ere the finding of structural heart disease or congenital diaphragmatic hernia as the basis for hypoxemia. qualification for ino treatment included an a-ado - or oi ~- for two hours or -> for twelve hours and echocardiographic demonstration of persistent pulmonary hypertension of the newborn. patients were classified into two groups based on the availability of ino at the time of their hospitalization. results: in the time period of the study, patients were referred for possible ecmo therapy. twelve patients greater than weeks old, with congenital diaphragmatic hernia and with congenital heart disease were excluded from this analysis, leaving patients for study, ino availability reduced ecmo use from of ( %) patients in the ~ino unavailable" group to out of ( . %) patients in the "ino available" group, p=& by fisher's exact test. the fact that the two groups were composed of patients of similar severity of illness is reflected by comparable rates of ecmo and ino rescue therapy ( % vs. %). conclusion: by providing an alternative rescue therapy, ino has reduced the need for ecmo in this group of neonates referred for respiratory failure. introduction: true hepatnrenal syndrome (his) is defined an acute renal failure {arf) in the presence of severe liver disease without other known causes of renal failure. hrs is frequently seen in the course of hepatic cirrhosis• in children, cirrhosis is rare; however, arf can be seen in combination with aseites and liver dysfunction• we describe patients with hepatic dysfunction and aseites in combination with ar~ and abnormal sodium-water handling, leading to the diagnosis of hrs. pathophysiology: three factors are considered in the pathogenesis of hr~: i) hepatic dysfunction, ) deranged hemodynamics, including abnormal blood pressure, reduced effective arterial blood volume and abnormal blood flew distribution, and ) neuro-humoral dysrsgulatiom, including elevated levels of aldosteron, renin, angiotensin-ll, ade, vasodilatim nitric oxide and vasoconstrictor peptide endothelin-l. the main pathogenetic feature is decreased cortical renal blood flow, decrease of glomerulur filtration rate (gfr), vastly increased sodium retention, uliguria, and azotemia. treatment: therapy is based on counteracting sodium and fluid retention by highdose aldosteron antagonists and loop diuretics, improving renal perfusion by lowdose dopamin, and strict restriction of fluid and sodium. interventions as paracenteals of aacites or n peritoneo-systemic shunt are associated with high morbidity and poor outcome in children. reversal of hem by conservative measures can only be attained at early stages of hrl liver transplantation is the only definitive treatment that can reverse ere at advanced stages. patients: the described patients developed severe ascites with insidious renal dysfunction and abnormal sodium-water handling during admission at picu and fullfilled clinical criteria fur hrs. treated according to the cited principles, all patients showed improvement of gfr, with increased natriuresis and gradual decrease of ascites. eventually, renal function normalised completly. conclusion: ere deserves greater recogmitimn in the picu population; diagnosis can be suspected on clinical criteria. with this increased awareness, therapy tun be instituted at an early phase, with better prospects for recovery. positive outcome of hem depends on early recognition of the clinical picture, understanding of the pathophysiology, and early institution of consistent treatment. mtx is an antimetatxflite widely used as chemotherapeutic agents. high dose ivitx (i to ~m ) administered as a prolonged intravenous infusion (over - hours), is often used to treat malignant paediatric diseases. major complications of this treatment are myelosuppression, orointestinal mucositis, dermatitis and impairment of anal function. we report two cases of mtx overd~age occurred in two children ( -year-old. month-old) t~ted for acute lymphoblastic leukaemia. they were treated by cavh and the mtx bhk~d levels rapidly decreasedavoiding multisystemic involvement. establishment of alkaline diuresis and monitoring of plasma mtx levels during treatment is essential to prevent nephrotoxicity. however. leuco',cnn rescue may not prevent the development of potentially lethal toxicities in patients with mtx concentrations persistantl} exceeding t mm. in theses cases, em'ly treatment of mtx intoxication may pm~cnt myelosuppression and reducerenal damage. the goal is to lower the concentration to below mmoll, at which time rescue agents aleme would be expected to be cllcctive. respective indications of these remo',at mctny.:is are still discussed : hacmt~ialysis t~ eharc(~l haemoperfusion should be prolx',sed for massive and acute intoxication. however, rebound has been reported after combined hcmodialysis and hemoperfusion. exchange transfusion may be proposed as a treatment for prolonged and moderate intoxication. peritoneal dialysis is an incflbedve method for remo~ al of mtx. cavh was used in our icu. cavh is a simple method for blood purification and n':dy iluid control. use of cavh was never be reported in this indication to our knowledge. simplicity, rap~d application and gco.l clinical tolerance are the main advantages of this technique. the technique presents ~peclal advantages in terms of low priming volume of extracorporeal circuit, low blood flow, low rate heparinisation. our results show a decreaseof plasma mtx concentration and a rapid reduction of halfqite of elimination (t hours over the period of cavh). moreover, we didn't delec~d rebound after stopping prc,xedure. small size of the i:ratients may present sometime special problems, but these technical problems can be overcome, no severe complication (needing, inlection) were observed during filtration, in summary, aggressive intravenous fluid hydration and alkaliniaation of the urine coupled with careful monitoring of renal function and plasma mtx concentrations during and al'tcr infusion along with lem~overin rescue has reduced the inndcace of life-threatening toxicity after highdose mtx. however, some mtx inu>xication still occurred, leading to se~em toxicity, particularly nephrotoxicity. in these cases, we think that cavh (or cavhd) is a reliable, rapid method without rcix~und increase in plasma mtx concentration or important adverses effects compared to other procedure removal. gouyon jb, germain jf, semama d, pr vot a, desgres j preliminary limited data suggested that hemofiltration and hemodiafiltration may be valuable in some neonates with decompensation of maple syrup urine disease (msud). venovenous hemofiltration (vvhf) and hemodiafiltration (vvhdf) were performed with a new neonatal hemo(dia)filter (miniflow , hospal) on anesthetized rabbits infused with branched-chain amino acids (leucine, isoleucine and valine) and c~-keto-isocaproate. the bcaa and aketo-isocaproate blood levels were close to those previously observed in neonates with msud when extracorporeal blood purification was required. vvhf and vvhdf performances were assessed with two different blood flows (qb = . and . ml/min). vvhdf was performed with dialysate flow rates (qd = , , . , . and . l/h). thus, each animal was submitted to successive procedures. within each studied period, clearances of the bcaa were strictly similar. bcaa clearances obtained by vvhf were similar to ultrafiltrate rates (respectively, . - . and . - . ml/min at high and low qb ; p < . ). the ~x-keto-isocaproate clearances obtained by vvhf were . - . and . - . ml/min at low and high qb (not significantly different). whatever qd value, the vvhdf procedures always allowed higher bcaa and c~-keto-isocaproate clearances as compared with the corresponding v'~hf period with similar qb. bcaa clearances obtained by vvhdf with a . l/h dialysate flow, were . - . mljmin and . - . ml/min at iow and high qb, respectively. the concurrent a-keto-isocaproate clearances were . -,. , ml/min and . _+ , ml/min. at both qb regimens, bcaa clearances provided by vvhdf were markedly higher than values previously obtained with peritoneal dialysis in human neonates with msud. the management of renal failure in the newborn is difficult. when dialysis is instituted peritoneal dialysis (pd) is usually the technique of choice. this is can be problematic and impossible in some patients with pre-existing intra-abdominal pathology. continuous arterio-venous haemofiltration (cavh) has been described in infants but sick preterm infants are not able to support the circuit. i have devised a means of having pumped haemofiltration in small/preterm infants (phis/pi) and describe its use in nine patients ranging in size from to gms for periods of to days. vascular access was achieved through or guage cannulae in either a peripheral artery and a central vein or through two central veins. blood was pumped out using an ivac infusion pump and through a gambro fh haemofilter. a second ivac pump was used to remove haemofiltrate from the filter and a third to infuse replacement solution. removal rate was set to give a clearance of mls/min/ . sq.m and blood flow rate set to between and times the removal rate. heparin was infused into the circuit to prevent clotting of the filter. biochemical and fluid balance control was achieved in all infants. guaranteed fluid removal allowed the administration of full nutritional support. four patients died when treatment was withdrawn because of an untreatable underlying problem. one recovered renal function but died some weeks later from unrelated problems, three survived and recovered renal function and one patient is still on treatment. this system allows a secure means of achieving fluid and electrolyte control in the preterm infant. the use of this technique may allow haemofiltration to become as applicable to preterm infants as it is to older children and adults. unibrtunately, children often receive no treatment, or inadequate treatment for pain and painful procedures. this prospective, multicentric study focuses on the efficacy, safety and side effects of novalgin (metamizol sodium) for this indication. patients and method: novalgin was administered to children, aged between - years, with acute, postoperative or procedural pain. novalgin ( - mg/kg) was given - hourly iv or im respectively, in some cases ( ) in combination with opioids (tramadol , piritramid , butorphanol ). the pain relief was assessed by six-step verbal rating scale (vrs) from to , vital signs were monitored, the side effects, that occured were recorded. results: pain relief was good (vrs less ) in children - . % of study patients. novalgin was very well tolerated, only one patient had adverse reaction -hyperpyrexia following intravenous application of the drug. discussion: novalgin (metamizol sodium) is safe and effective drug in the management of acute pain in children with low incidence of side effects. obie~qve: a prostx~tive study comparing simultaneous, indepeadent ratings conducted by intensi~ sts using an american (comfort) and an european chartwig) sedation scale for mechanically ventilated pediatric patients. measurements and results: the study comprised observations in mechanically ventilated pediatric patients (aged days to years) in a pediatric intensive care unit (from march to january . each patient was sedated by his/her managing physician with opiates, benzodiazepines, barbiturates, used isolated or in combination. each observation consisted of a -mid period of oly~ervatien of the patient in his or her pediatric icu bed, after each observation, the comfort (analyses dimensional physiologic and behavioral subscores -range to paints) and hartwig (analyses dimensional behavioral subsenres -range to points) were performed by the intensivist. we established the comfort scores ~ correspanding to adequate (range to ), excessive (range to ), and inadequate (range to ) sedation; and, hartwlg scores z correslxmding to adequate (range to t ), excessive (range to , and inadequate (range to ). statistical mmlysisj: agreement rate (kappa) and p <. was considere d s!l~nificant. comfort ( . %) ( , %/ ( . %) hap, twig , ( . %) ( . %) ( . %) to the comfort score, the average for adequately sedated, inadequately sedated, and too sedated was . +- . , z _+ . , and a.+_l , respectively. and to the ha~twig scorn, the average for adequately sedated, inadequately sedated, and too sedated was . :k-' . , . -&l , and . l- . , respectively. conclnsion: in our study there were no significantly statistical difference when you apply a more complex scale (conff'ort) or a less complex scale (hartwig) to assess the sedation of mechanically vemilated pediatric patients. the application of local and intravenous morphine infusion after surgery of urinary tract eva nemeth , m.d. semmelweis medical university , first oepartment of paediatrics , budapest , hungary in±roduction:continuous analgesia with morphine may be ~egaroed as a safe and effective method of pain relief during postoperative period. subjects and methods: children /mean age . years/ underwent elective ureteroneoimplanta±ion were randomly selected to receive either morphin intravenously of lo ug/kg/h /group one/ or bladder morphineinfusion ug/kg/h /group two/ after surgery. all patients were prospectively evaluated during their s±ay in the postanaesthetic care unit. cardiac and respirafory rates,blood pressure,sa ~,degree of alertness,pain perception and complaints of the paticnto ~cr~ recorded hourly. pruritus,nausea and vomiting,voiding difficul-±ies,sedation,dysphoria were systematically sough and quoted. statistical analysis was performed by chi square test. results:postoperative analgesia was the same in the two groups,but side effects were less in the bladder morphine group,because of the lower se morphine concentration.the differentes weren't significant in two groups. conclusions:the administration of bladder morphine infusion is a safe and effective method in children. objetive: compare the evaluations of sedation level made by physicians and nurses with the visual analog scale (vas) and the comfort scale (cs) in pediatrics patients receiving difforents modes of intravenous sedation. material ~ method." file evaluations were made by an attending physician and nurse with the vas and by another physician (always the same) using the cs. the observations were divided following the sedation mode: one drug (fentanyl or midazolan), two continuous drugs, one continuous and one intermi~ent drug and two intermittent drug (fentanyl and midazolan). the groups were compared using the t-student test. the groups also were compared between the percentual of agreement of the evaluations of sedation level made by physicians and nurses with the cs and vas using the x . results: we didnk find any statistical difference between the observations made by physicians and nurses with the vas in the differmts modes of intravenous sedation, the average of the observations using the cs betwom one drug and two drugs modes didnk exhibit also statistical difference. the observations made by physicians mad nurses using the the vas when compared with the cs didn't show statistical difference between the sedation level. we found statistical difference only in percentual of concordance of sedation level between physicians and nurses when compared the one and two drugs modes of sedation. conclusion: we didn't find differences in the observations made by physicians and nurses in the sedation level, only in concordance pereentua/ of observations when compared two modes of sedation. the observations using the cs (more complex) didnk show differences when compared with the vas. effects of age, concurrent administration of other pharmacologic agents, and disease [cardiac(n= ) & pulmonary(n= )] on the pk & pd of b were evaluated in volume overloaded infants aged days- mo (n= ). single doses of . , . , . , . , . , , , . , . & . mg/kg iv were given over - min after baseline evaluation. age was used as a continuous vadable to determine its effects on the variability in the pk & pd of b. values for pk parameters were compared between patients in cardiac and pulmonary disease groups. hierarchical multiple regression analyses were used to determine the effects of age, disease and other pharmacologic agents on the variability of bumetanide excretion rate (ber) and pd responses, e.g. urine flow rate (ufr) & electrolyte excretion. cit, cir & cinr increased with age (p< . ) while t, decreased markedly in the first monthe of life (p< . ). ber normalized for dose increased with increasing age. patients with pulmonary disease exhibited significantly greater clearance and shorter t~= (p< . ) than those with cardiac disease whereas vd~ was similar in both groups. the administered dose of b was the primary determinant of ber but increasing age also contributed. penicillin antibiotics decreased ber. dose response curves for ufr and electrolyte excretion were similar between disease groups. more of the variability in ber and pd responses could be accounted for in the pulmonary group than the cardiac group but this was not statistically significant. conclusion: the pk of bumetanide were influenced significantly by age and disease. differences in pk between patients with pulmonary and cardiac disease were primarily due to differences in total clearance. age and the administered dose of b were positive determinants of ber and pd responses while penicillin antibiotics had a negative impact on both, once b reached its site of action, no differences in pd responses were detected between disease groups. the pharmacodynamic effects of bumetanide were evaluated in volume overloaded infants (n= ) aged days- months. single doses of . , . , . , . , , , . , . , . & . mg/kg iv were given over - rain. bumetanide concentration in blood (n=l ) & urine (n= ) samples were quantified by hplc. baseline urine samples were collected over - hours prior to drug administration. determinations of urine volume, electrolytes (na ", k +, ci, ca ++ and mg++), creatinine and osmolality were performed before and at - , - , - , - , - and - hours after bumetanide dosing. changes in urine flow rate and electrolyte excretion were plotted as a function of bumetanide excretion rate which was considered the effective dose of the drug. peak bumetanide excretion rate increased linearly with increasing doses of drug and showed no evidence of approaching a maximum. time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. urine flow rate and electrolyte excretion increased lineady up to a bumetanide excretion rate of approximately #g/kg/hr and either plateaued (urine flow rate) or declined at bumetanide excretion rates > #g/kg/hr. bumetanide had no detectable effect on serum electrolyte concentrations, conclusion: maximal diuretic responses occurred at a bumetanide excretion rate of about ;~g/kg/hr. higher bumetanide excretion rates produced no increased diuretic effect. peak bumetanide excretion rate of about #g/kg/hr corresponded to bumetanide doses of . - . mg/kg. neonates using an electrical syringe-pump. authors: tr~luyer j.m., sertin a., bastard v., settegrana, c., bourget p., hubert p. background and objective: many problems can be observed with drug administration by i.v. route, especially in neonates. so we evaluate different protocols of teico delivery using an electrical syringe-pump. methods: we simulate infusion of teico with a syrlnge-pump (pilot c, becton & dickinson lab.) trough d standart neonatal i.v. system. for weights ( or kg) we used doses of teico ( mg and mg/kg) and a dose volume _< . ml. our goal was to perform a complete infusion in minutes. the infusion system consisted of an life care infusion pump (abbott lab.) with its lv. set for maintenance intravenous fluid (flow _< ml/h) connected to a -way stopcock. an meter extension tubing was placed between the stopcock and a neonatal catheter. an another meter tubing (injection tubing) connected the teicoplanine syringe to the stopc, ock. the volume of the injection circuit (from the syringe to the distal part of the catheter was . ml methods of injections were assessed: a: injection of the predetermined volume of teico in minutes with no wash out. b: idem as a but the teico was injected in minutes, followed by a wash out ( ml / minutes). c: twice the required volume was introduced in the syringe and the volume to infuse was programed in minutes, followed by a wash out ( ml/ minutes). d: ]dem as c but a priming was performed before connecting theteico syringe to the tubing. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at minutes were calculated. the results are a mean of to runs and expressed as the percentage of the total amount of teico prescribed. a , % , % b % , % c a % , % d , % % conclusiom for accurate and reliable intermittent drug infusion with a syringe pump it is mandatory to use a precise protocol of administration and to take in account ) a priming (for immediate starting of infusion), ) a drug volume greater than the dose prescribed and a programmed volume injected, ) a wash out of the tubing (with a volume ~ , x volume of tubing injection) caz is an antibiotic with activity against the major pathogens responsible for neonatal bacterial infections. we previously reported the pharmacokinetics of caz in preterm infants on day of life which showed that the clearance of caz increased with increasing gestationat age (ga). mean serum half-life of infants with gas < wks was . h. we wanted to investigate the effect of postnatal age on caz pharmacokinetics, we therefore studied caz pharmacokinetics on day - of life in preterm infants with gas < wks. caz ( mg/kg) was administered as an intravenous bolus injection. blood samples were coilected before (t = ), and . , , , , and h after the caz dose and analyzed by hplcassay, the pharmacokinetics of caz followed a one-compartment open model. during newborns with complex congenital heart defects requiering either htx or palliative staged single ventricle repair were admitted to our hospital: hlh n= , unbalanced cavsd, tga with hypopl. rv and hypoplastic aoa. tga with hypopl. rv, sas and dextrocardia. /i children had been admitted with cardiogenic shuck and mukiorgan failure due to intermittend closure ofductus arteriosus; in / stabilization failed. parents were informed about the known and unknown risks of the always palliative surgery; in cases parents denied further therapy. one pafiem with hlh underwent orthotopic htx at the age of month after the ducms art. had been stunted in the newborn period. month later he is still in favourable condition and without any sign of acute organ rejection. / underwent first stage of palliative single ventricle repair: norwood -op. ( ) ( n= ), damus-kaye-stansel -procedure ( ). the clue to adequate postoperative management was to archieve a balanced distribution of flow to systemic and pulm circulation, that is to protect the single ventricle from volume overload and to guarantee sufficient oxygenation and pulmonary development as well. with the centralvenous sato at about % provided maintaining the arterial sato at about _+ % is corresponding with a qp/qs of : . using modified bt-shunts of . mm resp. a central anrtopulm, shunt of mm in one case l severe puim. hypertension, surgery at weeks of age ) there was no excessive pulm. blood flow and no need to increase pvr with inspired co . one child ( norwood at weeks, preexisting pnim_ edema ) developed severe pulur hypertension and parenchymal pulm. dysfunction after prolonged bypass and multiple transfusions due to intraoperative bleeding: hypoxemia could be managed successfully by implanting a second shunt of mm hh later and temporarily using prostacyclin and no; at sternum closure dd later the second shtmt was banded to ram. follow-up ranges - month: all children are at home being assigned for second stage operation at about month of age. establishing clinical practice guidelines has become increasingly important in the current health care environment. significant effort has been focused upon development of post-operetive critical care pathways. however, benchmark data upon which such pathways should be based has not been well reported. length of mechanical ventilation (lmv) and length of stay (los) for children following cardiac surgery, for example, is poorly described. we prospectively recorded the lmv and los in patients who underwent cardiothoracic surgery between / / to / / . only patients who belonged in any one of five categories of congenital heart disease (ventricular septal defect _+ other septal defects (vsd), atrioventricular (av) canal, tetralogy of fallot (tof), transposition of great arteries (tga), and single ventricle physiology (fontan)) were included. eight non-survivors were excluded from the analysis. all patients were admitted to an intensive care unit cu) post-operatively where mechanical ventilation was managed by pediatric intensivists. lmv was defined as the period from post-operative admission to planned extubation. length of stay (los) was defined to be from le from the icu. cytokine patterns during and after cardiac surgery in young children. especially in children, cardiac surgery with cardiopulmonary bypass (cpb) can cause a systemic inflammatory response. this process is thought to be mainly a result of inflammation induced by surgery and exposure of blood to an artificial surface, and of reperfusion injury during weaning of bypass. complement activation, degranulation of granulocytes, induction of free oxygen radicals, endotoxemia and release of cytokines, are important contributing factors. we studied cytokine patterns before, during and after cpb in young children admitted for complex surgery or for septal defect correction. in the first group, significant amounts of il- and il-lra could be detected preoperatively. these findings could reflect the already existing hemodynamic dysregutation. in both groups, cpb procedure upregulated the circulating pro-inflammatory cytokines il- / , but not il- b. at the same time, il-lra became detectable. therefore, we suggest that in these patients the production of the anti-inflammatory cytokine il-ira was not induced by the preceding acnvity ot pro-inflammatory cytoidnes. during cpb, we noticed a sharp decline in the capacity of the leucocytes to secrete il- / . the ex-vivo production of il-lra however, was only slightly attenuated. we conclude that there is a differential regulatory pathway for the induction of il- / and il-lra. in addition, we studied the influence of dexamethasone administration on the cytokine pattern. administration delayed the appearance of il- / and il-ira in the plasma, interestingly, it did only interfere with the ex-vivo production of pro-inflammatory cytokines. the latter supports our hypothesis that production of il- / and of il-lra is regulated by two independent pathways, ( %) of pts. % ofpts < months of age developed metabolic alkalosis as compared with % ofpts > months of age.the infants with metabolic alkalosis received more citrated blood products and furosemide. following cardiac pulmonary bypass the highest ph-values and be-values were observed - hours and - hours, respectively. ii. prospective study: metabolic alkalosis was registerd in t children ( %), of those < month ( %) developed metabolic alkalosis and % of those elder than monms.durmg the postoperative course patients younger than months developed the highest ph-and base excess values after and t hours, in the subset of the older patients maximum ph and base excess was found after and hours, respectively. in one case the top level ofph-value exceeded . , the base excess + mvalb. conclusion: children undergoing cardiac surgery with cardiopulmonary bypass often develop metabolic alkalosis.in contrast to previous reports, we did not observe an association between metabolic alkalosis and mortality, nor greater frequency of cardiac arrythmias or prolonged mechanical ventilation. in context with decreasing serum lactate levels, our data show positive correlation of metabolic alkalosis with postoperative improvement of liver function. respirator, mechanics and weaning outcome in children undergoing cardipvascular surgery. vassallo j., cernadas c., saporiti a., landry l., rivello g., buamsha d., rufach d., magliola r. mechanical ventilation (mv) and acute respiratory failure are common events in children unergolg cardiovascular surgery (cvs), the development of new techniques helped to measure some of the main respiratory mechanics (rm) in a non invasive fashion. our goal was to evaluate the predictive value of these measurements in weaning (w) outcome in these patients, patients and methods: we prospectively evaluated children considered clinically to be ready for w with < kg and > hs mv. patients with diaphragm paralysis and those who failed w because of upper airway obstruction were excluded. before patient extubation the following measurements were recorded during spontaneous ventilation (cpap/t piece) using the cp neonatal pulmonary monitor bicore (lrvine, ca): total respiratory system static compliance (cssr) and resistance (rts), rapid shallow breathing index (rsbi). maximal inspiratory negative pressure (pi max) was measured using an unidirectional expiratory valve. threshold values predicting w success (ws) were: cssr > . ml/cm h , rts < cm h /l/sec, rsbi and pi max > - cm t . w failures (wf) -patient reintubation within the following hs, these values were compared between w success and failures using fisher exact test. an apriori level of statistical significance was chosen at p < . . considered, an increase in tnf-a levels is observed after cardiac surgery (p< . ) with a return to previous values after hours (p< . ). hours after cpb, similar values are observed in groups ii and ill, but there is a further increase in serum tnf-a levels in group i when compared with both other groups (p< . ). we found no statistically differences in any other moment. there was a significant correlation between serum tnf-o levels determined hours after surgery and cpb duration (p< , ). conclusions: cpb in childhood provokes a significant increase in serum tnfa levels, in newborns the inflammatory response is maintained hours after surgery. this enhancement of serum tnf-e levels indicates the existence of a relevant inflammatory response in these patients. introduction: cardiac surgery appears to induce a systemic inflammatory response. we have investigated the behaviour of il- i~ and il- before and after cardiac surgery. patients and methods: we studied serum il- and il- levels from children with congenital heart disease ( boys and girls), aged from days to years, undergoing open heart surgery, before cpb (d we found no statistically differences in the il-i levels in the different groups and moments. there is a significant increase in il- immediately after surgery (p< , ) with similar levels hours after cpb and a significant decrease (p< . ) hours after cpb. preoperatory il- levels were higher in the groups i and tl than in group i (p< . ). hours after cpb serum il- levels in group were significantly higher when compared with group (p< . ). conclusions: cpb in childhood induces a significant transient increase in serum il- levels, strongly relevant in newborns. cpb was not associated to a significant modification in serum il- levels. thus, cpb in childhood induces a dissociated behaviour in the proinflammatory il- and il- & pathways. obiective, to evaluate the effects of amg receipt on the clinical condition during the first hours after birth (t ), the morbidity and mortality in immature outborn neonates. methods. we studied outborn neonates with ga to wks, admitted during the years to . eighteen neonates exposed to amg (ga: , +lwks, bw: _+ g) and neonates did not (ga: , _+ wks, bw: _+ g). results. amg-exposed neonates compared to those not exposed had lower incidence of apgar score at min _< ( % vs %, p<. ), lower incidence of ph t < . ( % vs %, p<. ), decrease need of bicarbonate ( % vs %, p<. ), lower fio (fio min> : % vs %, p<. and fio max > : % vs %, p<. ), lower incidence of intubation ( % vs %, p<. ), lower requirements of surfactant ( % vs %, p<. ) and lower mortality ( % vs % p<. ). there were no differences between the two groups for the following parameters: type of delivery, hypothermia hypoglycemia and anemia during admission, hypernatremia, hypotension (map< mmhg), need of dopamine and or plasma , incidences of ptx pda sepsis nec severe rop major ivh (plus pvl) and bpd and duration of intubation. conclusions. the main beneficial effects of amg receipt on the immature outborn neonates were the decrease of mortality and the decrease of surfactant need. there was no effect of amg receipt upon other severe morbidity in this high risk group of neonates. premature babies are very sensitive on homeostatic disturbances, and often develope intracranial haemorrhage (ich). ultrasound scan of the bram shows four grades of ich: -grade i -only periventricular hyperechogenic areas -grade ii -haemorrhage ham the lateral ventricles -grade ili-dilated lateral ventricles -gtrade iv -intracerebral haemorrhage. the purposes of this study were: to show the incidence of ich in premature babies and its correlation with the gestational age, . to determine the severity of ich . to present the outcome &those babies. in the study were included premature babies successively-born at the department of gynecology and obstetrics before gestational week (g.w.) and grouped in three groups: less than g.w., - g.w., - g.w. to all of them was performed ultrasound scan of the brain. results : . the incidence of ich hi premature babies is % and there is ingh level of correlation with the gestational age: -babies born before t~ g.w. have % incidence of ich and graduated : i grade - %, ii grade - %, iii grade - %, iv grade - % -babies old between - g.w. have incidence of % : i grade - %, i[ grade - %, iii grade - %. -babies older than g.w. have incidence of %: i grade - %, ii grade %, iii grade - % . sixty of premature babies have died and it is . % lethality. in all died ilffant was confirmed the grade of ich diagnosed by ultrasotmd scan of the brain. d. maksimo~ c. z.braiko~ic, n.vunjak. p. ivanovski ( ~iversi~, children's hospital. belgrade, yugosla~, ia infantile intracranial hemorrhage is the most frequent and serious manifestation of late hemorrhagic disease of the newborn caused by ,,~tamm k deficiency in earl?,, ti~fancy. in the last two years, we recorded five cases of infantile intracranial hemorrhage due to "dtamin k deficiency, despite routine prophylax~s (intramuscular vitamin k, mg) , with bpieal clinical presentation: age was - days (average days): vomiting, poor feeding, lethar~'irritabiljty, palor, bulging t ntanelle and convatsiones were present in most cases.two patients developed signs of hemorrhagic shock, with hemoglobin level less than g. . in ~ f \qi level was less than % of predicted value. there was no evidence of head trauma or liver disease in none of patients. four inlants were breast fed, while one, who had diarrheal disea.se, was on adapted milk formula. routine therapy wa.s given (including vitamin k and fresh frozen plasma). two patients were discharged with no sequellae, one developed posthemon'hagic hydrocephalus as a complication and two patients died. late hemorrhagic diseo.se of the newborn is sill/ a significant cause of morbidib' and mortality in earl ' infancy, despite different approaches to prophylaxis developed in recent years. background: neonatal hearing screening in at risk newborns can detect % of the children with a congenital hearing loss. automated abr hearing screening (algo- ) has been introduced for healthy newborns. the aim of this study is to test the validity of this algo- screener in at risk newborns in a neonatal intensive care unit. subjects: at risk newborns (median gest.age: . wks, median birthweight g) selected according to the criteria of the american joint committee on infant hearing. interventions: algo-i automated abr-hearing screening at a level of db was performed in the neonatal intensive care unit. when bilaterally referred, further audiologic screening and/or therapeutic intervention took place. when passed uni-or bilaterally, children enrolled in a) a nation wide screening programme (ewlng) at the age of months and b) in a half yearly follow-up programme in which hearing and speech-and language development were observed according to egan an illingworth. results: screening without disturbance from ambient noise or from routine technical equipment was possible in the incubator, even during nasal cpap therapy. ( %) newborns passed algo- screening. ( %) did not pass bilaterally. of with a congenital rubella died shortly after screening.in of bilateral congenital hearing loss of -> db was confirmed. of the newborns passed were still alive at the age of year. ewing screening was performed in of ( , %). / passed, of had passagere conductive hearing loss, in / no further investigation was performed. all children enrolled in the i/ yearly follow-up programme had normal speech-and language development. in this study all at risk newborns with bilateral congeni "tai hearing loss were detected with algo- screening. screening results showed no false negatives at follow-up. the algo- infant hearing screener can be used as an valid automated abr-screener to detect hearing loss in at risk newborns in a neonatal intensive care unit. gancia gp, bruschi l pnlito e, ferrari g, rondini g -divisione di patologia nc~matate e turapia intensiva -irccs policlinico s. mattco -pavia, italy latrogenic esophageal perforations (iep) in preterm and term infants are seldom reported in litteraturc, in association with difficult endotracheal (et) intubation (with or without stylets), insertion of gastric tube, and pharyngeal suctioning with stiff catheters. crieopharyngeal muscle spasm caused by instrumentation may also lead m a narrowing of lumen, with increased risk of local injury. we report iep observed in intubatcd, mechanically ventilated newborn infants ( male, female, all outborn). a common feature of iep was inability to pass a nasogastric (ng) tube into the stomach, mimicking e~)phageal atresia.~se : birth weight (bw) (i g, gestational age (ga) wk, sepsis. before admission to n cu, the baby underwent multiple et inmbations, because of inappropriate securing of et robe. bloody secretions in pharynx were observed. the endoscopy showed a large lesion at the end of proximal third of the esophagus, case : bw g, ga wk, rds. chest x-ray (cxr) showed a retrostcrnal air leak: the ng tube was stopped }~etwcen d and d and soluble contrast was seen in upper mediastinum.case : bw (/g, ga wk, rds. the endo~opy showed an esophageal lesion. cxr showed a paravertebral route of ng tube and a right pneumothorax.case : bw (i g, cz ,.v!:. rd c. ~!,'.::;;: ::':'_'rvt!~' s l" ~k':.rvrx. cwr, d,,,,vs ~,,mr~e, ~n rhe upper mediastinum and abnormal route of ng tube through a false passage. surgical intervention is needed in case of mediastinitis or mediastinal abscess: conservative management included broad spectrum antibiotics, total parenteral nutrition, antireflux therapy and, if necessary, drainage of air leaks. enteral feeding has been stopped lor days and cautiously resumed after radiographic study. [x~cal sequelae and death are uncommon, but iep occur in newborns with high risk of death due to prematurity and other diseases. in our patients, et intubation has been performed by experienced personnel: therefore the lack of skills in resu~itative procedures is not always the main factor of iep. prevention of iep requires appropriate materials (et tubes, laryngoscope blades, suction catheters), and procedures (positioning of the infant with correct neck estension, firm et placement). sedation and pain control may help to prevent the muscle spasm. aggressive treatment has improved the tong-term outcome of extremely low birth weight neonates (elbw) but it has also increased the chances of iatrogenic lesions. reviewing the charts of our neonates we observed a high number of vascular injuries. from to , neonates were admitted to the neonatal intensive care unit (nicu); of them were elbw ( . %). studying the charts of these elbw we observed cases ( m - f) with vascular lesions ( . %). mean gestational age of these patients was . weeks (rain -max ). mean weight at birth was g . mean weight at diagnosis was g ( - ). in the same period patients with vascular injuries were reported in the neonates over g ( . %). the injuries observed in elbw group were: arteriovenous fistula ( bilateral) at femoral,level, carotid lesion and limb ischemic lesions. aetiology was in cases by venipuncture, in one case umbilical catheter and in the case of carotid lesion a wrong surgical maneuver. no general simptoms were observed. the vessels were repaired with microsurgical technique in six cases: the carotid lesion and five arteriovenous fistula; one case was solved with thrombolitic drugs; an amputation at knee level was required in one case after a long period of medical treatment. the last neonate with an arteriovenous fistula was only observed for parent's will. at follow-up (clinical and by ecodoppler) out of neonates presented normal vascular function without sequelae. from our experience elbw neonates have more chances than older neonates to develop iatrogenic vascular lesions. we advocate an aggressive microsurgery and/or medical treatment to obtain good results and prevent late sequelae. a retrospective comparison between natural surfactants l.j.i.zimmermang m.c.m,van oosten. dept. pediatrics, div. neonatofogy, sophia children's hospital/erasmus university, rotterdam, the netherlands. aim: retrospective comparison of alvofact (in ) versus survanta (in ) as rescue treatment for neonatal respiratory distress syndrome (rds). methods: both surfactants were given at an initial dose of mg/kg (except for alvofact mg/kg for mild rds grade mi). repeat doses were attowed (survanta mg/kg, alvofact mg/kg) up to a maximum of mg/kg, all parameters and outcome criteria were strictly defined beforehand. the initial response (good,mild,no response,relapse) to surfactam therapy was defined on the basis of the decrease in fio . results: there were no signif. differences in patient population and initial parameters: ga ( . +_ . vs a _+ , wks), birth weight (t _+ vs -+ g), severity of rds (grade ill-iv: . % vs . %), apgar scores, cord blood gases, initial ventilatory settings. in ' however, the initial surfactant dose was administered earlier than in ' ( . -+ . vs . _+ . hrs postpartum, p= . ). although the average total cumulative dose was equal in ' and ' ( . -+ , vs . _+ . mg/kg), more doses of alvofact were given compared to survanta { . _+ . vs . _+ . , p=o.o ) and more patients in ' received more than two doses than in ' ( % vs % of patients). there was no difference in the incidence of non-putmonarycomplications. aivofact ( there was a better initial response to survanta and a better respiratory outcome in : in the group < g the duration of ventilation was half in , and in the group >~ og the duration of extra o need was half in as compared to . we speculate that the main reason for this difference is the earlier and initially higher dosing used with survanta compared to that used with alvofact which was given in the same total cumulative dose but over a larger time span. background: e×ogerlous sur&ct~t raplacem~t treatmem has become rou~ne k~ the t~eatme~t of respira~"¢ dim'~ syndrome (i~ds) of pr~e~tur~, wh~eas its effica w th odi~ respiratory diseoses is sdi being wader mvesugatio~. objective: "eac~ mt ereat isto report ottr results of prospect/re, non-randomized "re~-o.e" study oe suffact~t replacement in outhom premamae infa~t~ with rds reruirmg me~aical ventilatioa (nfv). p~tien~ and metho .s: from j-aly to june , / ; ( %) out~ ~¢ infaats, at a mesa age of z , horn's ( boys, ~rls; ~ gestafioan age -+ . weeks, mera~ birth weight _+ g, ~ . i" at minutes) with rds, requiring mv, received bov~e-suff~amt (survanta, ros~/aboti, laboratotie~ columbus, ohio) eadotracheally, as was recomm~aded by maaufacturer. as the c,~:ttrol group o~bom premature infants (ot~ of ; %, admitted with rds from euiy to eune ) were saelected ~d who did not receive surfaaam, compared with ~hctant ~'oup they were admitted for treatmeat e~'li~" aft~" daliv~:y (at the age . :: . hours vs. . +- hours), but they did not diff~ in othe~ baseline dam'a~eri~cs at ~ti~ion. entry crkeda for ~¢fa~aut ~hcadou were fractional i~firat o~ oxtgem r~emeats -fio > . - . , ratio au-lerlal to alveolar oxygea pre~are~ao ~ao < , ~ad oxyge~at,~ i~.dex -ol > . primary o~comes were deter~caned by ~hanges m exs'ge~ab, c~ ~r~d vmtilatic~ ~ the following variable~; ( ) fi'aaic~ of i~spired oxtge~ (fio ); ( ) mesa nnvay presmzre (map) ( ) pag ~ao ratio, ( ) oxyge~ion index (oi). commo~ comphcadces of prem,musty ~d con~ol mechamcal v~ati]al~on (pater dumas merios.s, intracr~nlal haemcrn:hage, air leak, br onchop ulmrmm'y dy~pl~a ~d death) were reg~ded as sec~d,~y outcomes. r~suas: in warfactaat group we observed slg~ .c~t improve~aeat (p< . ) in oxygea~thia md veaatilation at hours all~ e~try k~to the m~dy in compari~ion to nons~fa~m" group. compa~on of secondao' outcomes in ~ts with p,.ds showes table l we did not observe ~y major acute hfe fl:u-eattming complicatlola,s m sxlrlhct~mt grou~ tr/lmediately after stu'~actsmt rcplacemev_t therapy. the duramm of mechmucal ven~ation ~ad oxygen lreau~ent m survivals of both groups did not dafter gmficautl y a-ore ead~ other. condusion: l!a premature mthats with rds treated with surfaaaat replacemeaat therapy we observed decrease m mc~de~ce of tme'~m~o~oraces add de~th (p< . and p< . ), whe~e~s m othe~ observed variables thee was uo ,igmfi~t d~=ecce infectious complications during the therapy of respiratory insufficiency in neonates with birth weight less than g in the course of yearsretrospective study. zitek infants on cmv, cppv, and imv were administered exosurf in dose of - mg/kg twice endotracheally (see table) . in newborns ( . %) hours after surfactant admin fi value decreased by . %, and after hours -by . % compared with initial value; pip and peep values decreased by - cm h and - cm h after hours, and by - cm h and - cm h after day, respectively accompanied by mean decrease of aado from , to . mmhg, qs/qt decrease from . to . % (see table) . mean time of cmv, cppv was . days, imv- - hours, cpap - - hours. respiratory therapy in newborns ( . %) was complicated by pneumothorax (bilateral -in infants chorioangioma is a rela~ively rare placentai malformation associated with considerable mortality and morbidity. a chorioangioma can be regarded as an arterio-venous shunt in the circulatory system of the fetus. this causes volume loading eventually resulting in cardiomegaly and high output cardiac failure. a female neonate (gest age wk, birth weight g, - . sd) was born with an apgar score of and after and rain respectively. the placenta showed multiple chorioangioma. ultrasound of the heart showed a hypertrophic cardiomyopathy. she developed severe hypertension ( / mm hg), treated with nitroglycerine and nitropruside. finally blood pressure decreased when enalaprillic acid was given ( . mg.kg ). we measuered the activity of the renin-angiotensinsystem. an elevation in renin-angiotensin system is shown probably to compensate for the low resistance circulation before birth, hypothesis: the instantaneous cut off of a large arteriovenous shunt did not result in a fast downregulation of the renin-angiotensin system resulting in hypertension. hypertension should be added to the list of complications of chorioangioma of the placenta. the authors studied cases of children's septicemia with blood culture yielding staphylocucetts aurens. the age of patients varied from months to years ( , % from years downward), % of the children caught their disease in the hot season (may to october). the deaths also occured in this season: , % ( / ). following were the anatomo-dinical lesions. -skin %, muscle , %, bone , %, joint . %. -viscera : lung %, heart . %, cerebrum . %, kidney . %, fiver , %. -simple lesion skin-muscle-bone joint: %, no death in this group. the concomitant lesions of the soft tissue,bone-joint and viscera : % with one viscera, % with two viscera, % with three viscera and % with four viscera. -bone lesion : mainly on the long bones ( % on the tibia, % on the femur, the remainder being the mandible ( ) and the humerus), inflammation of' the hip joint was the main one. -i,ung lesion had forms pneumatocele ( cases), bronchopneumonia ( cases), pleural effusion ( cases), multimicroabcess bursting into the pleura ( cases), most multimicroabcesses were lethal : / ( , %), -heart: all thethreelay~rs got le@~r~, % had or layers alrected and death ensued. -cerebrum : the meninges had three forms of lesions purulent meningitis ( cases), obturafing embolns of brain vessels ( cases) and cerebral abcess (one case). the characteristic clinical sign was paralysis and meningismus, phlebothrombosis of eavcrnous finus ( cases)was mually ther~sultofalxil vdfi:h burst there were cases of death with lesion of the meninges and cases of obturating embolns of brain vessels. -the main sign of lesion of the kidney was a change in the components of urine: % got proteinuria, % had leucocytes in their urine, % had erythrocytes in their urine, the urea in their blood increased (over rag%) in . % of cases.the lesion of the kidney seemingly had little relation to death. seven cases of ictertts due to an increase of direct bilirubinemia and a decrease of blood-albumin. -the biological characteristics of the pathogen staphylococci showed that all the isolated specimens had positive coagulaza ; the specimens from the dead patients were less semiti~e to, mad ~t to mali~ overag death rate was . % ( / ). the fungal infection to fusariun species in immunocompromissed child have been reported in the literature with a rare, severe and high, mortality rate in spite.of the use of antifungal drugs. we report a case of successful treatment of a severe disseminated fusariun infection in a ll-year-old boy with acute lymphocytic leukemia (lla-l ), after use a chemotherapy followed by absolute granuloeytopenia. the patient developed fever, skin lesions, pneumonia and fungaemia. fusariun species was cultured from the blood, necrotic skin lesions and lung secretion. the child developed multiple organ system disfunctiou in spite of use broad spectrum antibiotcs and antimycotic therapy needing. uci during days. the patient receive suport treatment (mechanical ventilation, inotropie d~.ugs, diuretics, imunestimulants, blood components, a broad spectrum antibiotes and antifungal agents). we absorved a gradual recovery in the white blood cell count and regression on the sites of infection. the association of preeoce diagnostic and the terapentic with increase in the white blood cell count was the most important in a successful treatment. a year old african-american child suffered a severe pulmonary injury in a house fire. initial survey revealed % total body surface burns, soot on the face, and bloody endotracheal secretions. initial chest radiograph revealed diffuse, bilateral infiltrates. severe respiratory failure with an oxygenation ratio of rapidly developed. he developed a pneumomediastinum and subcutaneous emphysema. although transient improvement occurred with inverse i:e ventilation and surfactant, he became more hypoxic (sac as low as %) and acidotic. on day post injury, he was placed on venc~venous extracorporeal life support (ecls). on ecls day he was decannulated. chest radiograph on ecls day showed an opacity in the left chest. ultrasound of the left chest was consistent with atelectasis rather than pleural fluid. flexible bronchoseopy failed to reveal any obstruction in the left lung. a computed tomography (ct) seen of the chest, which was performed after decannulation, revealed a large loculated collection of fluid in the left, anterior chest. under ct guidance, a f cope loop catheter was inserted and cc of thick blood was removed, follow-up ct performed immediately after this procedure revealed minimal change in the size of the fluid cavity. over the next hr, we instilled urokinase , units over minutes every two hours. a minute dwell time was allowed before draining the fluid. repeat ct scan done at the end of the urokinase infusion showed a marked decrease in the size of the fluid cavity. act scan was not performed prior to decarmulation because the ecls circuit tubing was too short to allow appropriate positioning of the child in the ct scanner. after a ct scan revealed loculated pleural fluid, a simple drainage procedure was diagnostic but inadequate treatment. we were able to successfully dissolve the thrombus after hr of urokinase therapy even though the thrombus was > days old. we suggest that large loculated plenral thrombi which develop as a complication of ecls therapy may be successfully managed with urokinase infusion. introduction: haemorrhages, particularly intracranial, are major complications experienced in - % of neonates treated with extracorporeal circulation. an induced thrombocytopenia and impaired platelet function play a key role in the increased bleeding tendency observed in these patients. the aim of the present study was to establish a dose-respons curve for the effect of a synthetic protease inhibiting agent, nafamostat mesilate (fut- ), on platelet membrane glycoprotein density and platelet activation during experimental perfusion. methods: two identical extracorporeal life support (ecls) circuits were primed with fresh, heparinized human blood and circulated for h. four different concentrations of fut- ( . mg/l blood/h; . mg/l/h; . mg/l/h+ % bolus at the start of the perfusion and & mg/l/h+ % bolus) were used in different perfusion experiments. a total of eight paired experiments were performed. platelet count, plasma betathromboglobulin levels and platelet membrane density of glycoprotein ib and lib/ilia were followed as well as plasma concentration of haemoglobin. results: a protective effect of the agent on platelet count, plasma concentration of btg and platelet membrane gpib could be observed during the first hours of the perfusion when a bolus dose was added. no positive effect could be recorded with the two lower doses used. plasma concentration of haemoglobin was higher in all the fut-circuits compared to the control circuits. conclusion: the addition of a bolus dose of fut- at the start of the perfusion seem to induce a protective effect on platelets during the first hours of perfusion. extracorporeal membrane oxygenation (emco) is a form of invasive cardiopulmonary support that can provide imporary physiologic stabilisation in reversible circulatory failure and or respiratory failure. we reviewed our expierence with extra corporeal membrane oxygenetion in children aged day to year between and . two neonates was succesfully decanulated, but died - well after decanulation due to septic complictions. one child years old, one neonates died on day and day" respectively while still on emco. complication which were and encountered were heavy bleeding in case (child), (neonate) and raceway rupture in case (neonate). problems which are specific developing countries like indonisia are: high cost ( . us for days) difficulty in transportation (transporting intubated baby) from the orgin hospital, lack of knowledge and understanding of the primary physician and nm-ses and difficulty organizing in hours emco team. resnratory mon tor/ng in picu z,zjvkovic, s. mihailovic, o, tosev respiratory monitoring in pediatric intensive care unit picu) provide the importartt informations for understanding of the pathophysiology of the clinical signs, aid with the diagnosis, and assist in therapeutic management and predicting prognosis. pien in children's hospital for ~flmonary diseases and tuberentosis remained for the t~s't two end a half years relatively limited for diagnomic tools and therapeutic regimens, mostly because of the poor fmnaeial suptx~rt. the number of children admitted for aurae asthmatic at.lzek~ severe pneumonias, bronehiolitis, complicated pulmonary tuberculosis, foreign bodies and exacerbations of ehronit'. pulatonary diseases was t . for all patients the respirator' monitoring system means: physie~d examination, ehe~ x rays, capillary bltxxl gas mmlyses (vevv few ehiktren experienced itwasive arterial blt~.~'i gases), noninvasive oxyntctry, measuring of the vital capacity in coopo-able patients, as~d capnography. later on, after the imtial critical illness, a complete hmg fimction tests was performed, as well ,~s bronehoscopy in selected eases, (~lr experience revealed that abotrt % of ehil&en heos suecessthl outcome, without s~lllens , instead they had been tremted in limited conditions. ']'he rest of our patients were previously diagnosed ~s ettronie pulmonary patients, with high risk score system ibr having seqnells 'llae mortality rate were , %. the continuous blood gas monitor, pasatrend (biomedical sensors, ltd., high wycombe, bucks, england) has the capability of measuring ph, pco , and po via an indwelling optical absorption optodelclark electrode sensor that is placed through an intra-arterial catheter. we evaluated the accuracy of the sensor in radial and femoral locations in critically ill pediatric patients. methods: the simultaneous values of ph, pcoz, and po recorded from the paratrend monitor were compared to values measured by standard arterial blood gas analyzer (coming , ciba-corning diagnostics, medfield, ma). criteria for the elimination of data points included a core vs. sensor temp. gradient, and sensor pulled back beyond accepted insertion distance. mean time of monitoring per sensor was hours (range . - . hrs). mean time of radial monitoring was hrs (range . - . hrs) and of femoral monitoring was . hrs (range . - . hrs.). linear regression and bland-altman analysis for bias and precision for each parameter were calculated. results: a total of patients (age range weeks to years) had paired samples of ph, pens, and poz made by the sensor and blood g&s analyzer. the range of measurements were ph . - . , pco, . -i . t(n r, and po - torr. the paratrend monitor demonstrated accuracy that is comparable to the accepted standard of blood gas analysis in a group of critically ill pediatric patients manifesting wide variation in ph, pen , and poz..this technique appears m be very useful especially in the extreme values of the parameters measured. funding provided by biomedical sensors. understanding of pulse oximetry d.semple, l.e.wilson. royal hospital for sick children, edinburgh, eh lf, scotland, uk. pulse oximetry is a useful, non-invasive monitor, routinely used on the itu and increasingly often on the general wards. we used a questionnaire incorporating questions on the theory and clinical uses of the pulse oximeter to assess understanding of pulse oximetry in medical and paramedical staff doctors indicated grade, speciality, pulse oximetry tuition and neonatology experience. doctors, itu nurses, t medical students and physiotherapists completed the questionnaire. some confusion existed between the principles of pulse oximetry and transcutaneous oxygen measurement. wide variations in the lowest acceptable saturation in fit children were seen ( - %), with around % of respondents in all groups accepting values of % or less. some potentially serious mistakes were made in the evaluation of oxygen saturations in the clinical scenarios. there were widespread variations in correct responses at all grades of medical staffing. nurses scored well on more clinically-orientated questions but relatively poorly on theory. only % of doctors (mostly senior grades) had received tuition in putse oximetry. neonatology rotations appeared to confer little additional knowledge on pulse oximetry. few doctors and nurses receive tuition in the use of pulse oximetry a significant proportion of nurses and doctors, of all grades, exhibited a lack o{" understanding of the principles of pulse oximetry. this may result in unsafe use of the equipment and put patients at risk. one can see from the table that blood composition in uv and ua differens in some characteristics, and similar in sgp magnitude. venous-asterlal gradients "gas functiomals" between uv and ua represent the measure of difference in this characteristics. the gradient cari be positive, zero -order or negative and change both in value and in sign but not reach apo (positive) and apco (negative) in absolute significance.minimization of "gas functionals" deviations atom the zero is achieved due to"mutual replacement acts" between po and pco in uv and ua blood. we suggest that presented tests can be useful in full evaluation of gas exchange in newborns. (pap) in the context of pulmonary hypertension is oft desired but rarely achieved. inhaled nitric oxide (no) has been shown to produce this desirable effect, but is relatively difficult to administer or monitor. we wondered whether np, chemicaily related to no but more stable in solution, would produce similar physiologic effects when administered in the convenient modality of nebulization. methods: piglets were anesthetized, mechanically ventilated, and surgically instrumented. systemic blood pressure (bp), pap, and cardiac output (co) were monitored continuously. after postoperative stabilization, . % nac} nebulization was begun, and pulmonary hypertensiorr was induced by reducing fio from . to . . the piglets were monitored for minutes during this hypoxic phase, next, without altering fio or ventilator settings, np ( mg/ml, dissolved in . % nacl, flow ipm) was substitued for . % nacl in the nebulizer circuit. np was nebulized for mins. results: during hypoxia, pao fell from to mm hg. pap rose during hypoxia from to torr (p< . ). ,^fhile bp and co did not change significantly. pap fell during nebulized np in each piglet, (mean apap = to torr; p< . ; mean reduction of hypoxia-induced rise in pap = %; range: to %; p < . ). pvr/svr fell by % during np nebulization (p< . ), while bp and co did not fall significantly ( to tort; to mllkg-min), the reduction in pap began within minutes of the onset of nebulized np, and appeared to reach a plateau by minutes. no tachyphylaxis to nebulized np was noted. nebulized np did not significantly affect pap, bp, or co under normoxic conditions. conclusions: ) like no, np selectively reduced hypoxia-induced pulmonary hypertension without altering systemic bp, ) unlike no, np can be administered by nebulizer, a technique familiar to virtually all health-care providers, and potentially adaptable to both intubated and non-intubated patients. } nebulized np may be beneficial in clinical contexts where inhaled no is impractical. dang phuong kiet and nguyen xuan thu examining cases of purulent pericarditis with various clinical forms treated by surgery, the authors drew the following experiences for their diagnosis. t. clinical factors. purulent pericarditis appeared like a cardiac tamponade in a septicemia due to staphylococci with dassieal symptoms: severe dyspnea, tachycardia, faint heartsound, big liver, prominent cervical vein ; rentgenography of the chest showing enlargement of the cardiac silhouette, a diminution of ventricular pulsations, ~i clear lung field. by an emergency operation, ml of diluted blood were drained. purulent pericarditis and pleural effusion appeared at the same time but at first tile symptoms of purulent pericarditis were masked by the predominant symptoms of plearal efihsion. after the pleura was drained, its pus was no more, the general state was relatively stabilized but there still were big liver, dyspnea, enlargement of the cardiac silhouette while central venous pressure increased. purulent pericarditis appeared late. in the first stage (about weeks) there was no suspected sign. later on gradually appeared such symptoms as dyspnea (during serum transfusion for instance). central veinous pressure also raised. the heart chest diametre increased at first (up to - %) then decreased (down to below % ) but the liver kept on swelling together with the particular changes of electroeaediegramme. now the pericardium had no more pus but get fibrous (up to ram) thus constricting the heart and its main arteries ike pick syndrome). . diagnostic values of electrocardiograms : common signs of ecg related of these purulent pericarditis were: a diminution of voltage, a widespread elevation of the st segment, the tf wave flattened and inverted. however, what should be stressed was : the diagnostic values of an electrocardiogram for purulent pericarditis was mainly in the dynamics of their signs: in the first week, the voltage diminished corresponding to a pericardium containing pus, while the st segment went up then seemed parallel to the fibrosis of the epicardium, the liver swelled, the central velnous pressure increased, the heart/chest dimension ratio decreased, the st segment went down, the t wave became more flat and inverted. between and neonates, aged - days (median ), weight , - kg (median , ) with critical valvar pulmonary stenosis were scheduled for balloon dilation (psvp), children ( %) were on pge and ( %) needed mechanical ventilation. after stepwise dilation a final balloon : pulmonary valve (pav) ratio of % ( - ) was achieved, there was a significant correlation (p< , ) between an adequately sized balloon and freedom of reintervention. two valves could not be passed, four neonates underwent surgical procedures (brock n = , commissurotomy n = ), two children ( %) died of sepsis. / patients ( %) were successfully palliated by psvp in the first month of life. the rv : systemic pressure value fell from % ( - ) to % ( - ), complications included transient dysrhythmias, transient hypoxia, vessel occlusions;- right ventricular outflow tract perforation. in / patients follow up data is available. the residual systolic peak doppler gradient over the pav on the last out patient visit ( - months after psvp) was - mmhg (median ). four children needed repea.ted psvp to months after the initial intervention. conclusion: psvp of critically ill newborns is possible. the risk of mortality is relatively low. psvp in neonates with an adequately sized balloon is a challenging alternative to surgical treatment. post hypoxic-ischemic (hi) reperfusion induces the formation of non protein bound iron (npbi), leading to production of the reactive hydroxyl radical. it was investigated if the ironchelator deferoxamine (dfo) could reduce free radical production and improve neonatal myocardial performance after hi. severe hi was produced in newborn lambs and changes from pre-hl values were measured at , and min post-hi for (mean) aortic pressure (mean pao), cardiac output (co) and stroke work (sw). left ventricular (lv) contractility and co were assessed by measuring lv pressure (tip-manometer) and volume (conductance catheter), using inferior caval vein occlusion to obtain slope (ees) and intercept of the end systolic pv relationship (v ). npbi, reduced and oxidized vitamine c ratio (vcred/ox) and lipid peroxidation (mda) were measured from sinus coronarius blood. lambs received dfo ( mg/kg i.v.) immediately post-hi, control lambs (cont) received a placebo. results: mean pao was stable, co and sw decreased up to and % respectively in cont as compared to pre-hi. in both dfo-groups co and sw remained within the normal range. ees and v decreased in all groups post hi, but did not differ between groups. npbi and mda were higher at min post hi (p<o. ), vcred/ox was lower at min post-hi (p<o.o ) in cont as compared to dfo-group, indicating more oxidative stress in cont. conclusions: dfo reduced the oxidative stress of the heart and prevented co and sw to drop, suggesting a positive effect of iron chelation on the myocardium after h{. from we published reports with analysis of performance of the heart as a whole organ.while analysing the heart performance as a whole, we recognize three block in it located intrapericardially: l."atrial"block -left (la) and rigth (ra) atriums; ."aorta-pulmonary" block-aorta 'bulb (a) and pulmonary artery(pa); .ventricular "three-chambered" block (vb) consisting of: -left (lv) and right (rv) myocardial chambers, both frith blood outflow into "aorta-pulmonary" block vessels, and -spongy (venous) myocardial chamber with the blood outflow through coronary sinus (cs) and thebesiau vein (tv) into "atrial" block. the following conceps are introduced for vb functions assessment "common" systole and "common" diastole of "three-chambered" vb. the process of normal "common" vb systole: -begins with blood ejection from vb spongy chamber into the "atrial" block; -continues with blood outflow from rv and lv into "aorta-pulmonary" block wi~ venous minimums -x-coiiapses -~btmation iu "a~riai" block; -completes with "three-chambered" vb general emptying. at this period the following blood volumes are transferring: -two-from rv and lv(their stroke volumes)into"aor~o-pulmonary"block; -two-from "spongy" chamber .into "atrial" block; -two-from systemic and pulmonary veins into "atrial" block during the process of so called "systolic" membrane suction (at pulling atrio-ventricular valves into rv and lv chambers as blood ejects out of them). it appears to be the regulation of blood inflow to "atrial" block by blond outflow from "three-chambered" vb into "aorto-pulmonary" block. objective: to evaluate the efficacy and complications of transpyloric enteral nutrition(ten) in critically ill children patients and methods~ from june to january children (i boys and girls), aged from days to years (mean l. ± . years) were treated with ten. patients were included after cardiac surgery, with acute respiratory failure, and after cerebral surgery. the indication of ten was mechanical ventilation in patients and failure of nasogastric nutrition in patient. children ( %) had previously received parenteral nutrition. and i fg enteral tubes was inserted into duodenus through nasogastric intubation en patients and by endoscopy in patients. rx and ph determination were used as methods to control tube situation. children received adapted formula, caseine hidrolisate, and enteral formulas. (in patients the nutrition formula was changed during ten). patients were supported with mechanical ventilation during ten, received midazolamperfussion(range to mcg/kg/min), fentanyl (i - . mcg/kg/h), and vecuronium ( . - . mg/kg/h). resulte: ten was used during to days (mean . ± . days). mean maximmnvolume ad~iniateredwas ± ml/kg/day (range ) .patients with midazolam, fentanyl and vecuronitml tolerated ten similar than children without sedatives. complications were diarrhoea patient, abdominal distension and/or important gastric fed residuals patients. pulmonary aspiration or respiratory complications were no registered. ten was ended in one patient due to diarrhoea, in due to change to oral or nasogastric nutrition, children continue yet with ten and was discharged of picuwith ten. conolusion: ten is an useful method of nutritional support in critically ill children with mechanical ventilation and/or nasogastric intolerance. introduction: the enteral nutritional support of the critically ill child may reduce the morbidity and mortality by attenuating, the hypermetabolic and catabolic response, decreasing the gut translocation and the septic complications, improving the bowel mucosa integrity and the wound healing. the aim of this study was to show the safety and tolerance of en. methods: we enrolled consecutive patients admitted to our unit from may to december , mean age . years (range imonth to i years). the prism, mechanical ventilation, inotropic use, opiates and other drugs were recorded. the en was delivered by continuous infusion across a polyuretane tube.we kept the patients head elevated °, and we used cisapride routinely. the gap betweeen admission and the en beginning, average time to meet the nutritional objective, en duration, selected formula, patients outcome and complications were recorded. results: prism groups were - = patients; - = ; - = ; - = ; - = . two patients with mof (multiorgan failure) died. % needed mechanical ventilation.the average time elapsed from picu admission to initiation of en was . days (range to ) and the average duration of the en was . days (range to t ). the average time to meet the nutritional objective was days (range to ). the selected formula were: lactose free infant formula in patients, elemental diet in , pediasure in and jevity in . we recorded vomiting in patients, diarrhea in and constipation in . none of them forced the en suspension. we didn't recorded any case of ~spiration or pneumonia. we found no relation between drugs, selected formula and complications. we think that en may be a safe and well tolerated procedure at the picu setting. generation of free radicals in iipid emulsions used in parenterai nutrition (pn) has been described recently. this seems to be due to high polyunsaturated fatty acid content. we studied lipoperoxidation status and antioxidant parameters presurgically and through the postoperative period ( days) in a group of twelve children (ranging from months to years of age), who underwent heart surgery and received nutritional support with pn. malondiaidehyde (mda), an end product of lipid peroxidation was used as a marker of oxidative stress. it was determined by the yagi spectrofluorometric method. antioxidant activity was measured with an assay based on the inhibition of spontaneous autooxidation of a brain homogenate, and vitamin e in serum by the technique of hansen and warick. erythrocyte mda release fonowing incubation in hzo in vitro was used as a functional measure of tissue vitamin e levels. data were compared using one-way variance analysis. there was not significant differences in the plasma mda production among the values obtained before surgery ( :t: . nmol/ml), postoperative pre-pn ( . +_ . nmol/ml) and through the course of pn ( . : . nmol/ml). levels of vitamin e previous to surgery were , : . #g/ml and decreased to . _+ . #g/ml at hours post-surgery before starting pn. while receiving pn, concentrations of vitamin e increased progressively up to + . l #g/ml (p = . ). pre-surgicai plasma antioxidaut activity values ( :i: %) dimiuished in the first postoperative day ( _+ . %) and then showed a clear increasing tendency, directly correlated with that observed in vitamin e levels. the measurements of the maximal percentage of mda release of erythrocytes in vitro, showed an inverse relationship with plasma vitamin e levels and with the plasma antioxidant capacity: preoperative . + . % and postoperative descending from . + % to _+ . %. our results indicate that during surgery and within hours postsurgery, a decline in antioxidant defenses occurs, in the postoperative period, while patients are on pn and taldng into account our obtained data: the unaltered mda values, the rise of plasma vitamin e levels, the recovery of both functional erythrocyte membrane antioxidant protection and the plasma antioxidant activity, they do reflect that during the intravenous administration of lipid infusions, oxidative damage does not occur, probably due to the addition of vitamin e to pn solutions in order to avoid autooxidation of lipid emulsions. garnitine is one of the essential nutrient in the diet of newborn infants. mother's milk represents the natural eamitine source for the newborn infants. we studied enteral earnitine intake in premature infants eutrophic (eu) and hypotrophic (hy), fed with mothers milk trough consecutive days-from fifth to tenth day of life. mean gestational age was (range - ) weeks for eu and (range - ) weeks for hy. birth weight was ranged - g for eu and - g for hy (p < , ). breast milk carnitine concentration was , i.tmol/i in mothers milk delivered eutrophic babies, and singnificant higher mean coenetration , l.tmol/i, of hypotrophic premature infants (p< , ). breast milk earnitine concentration was ranged between , - , ~moi,'l, and daily carnitine excretion was between , - , p.mol/i, mean , +- , i p.molll. the daily mean carnitine intake was from - , mgkg/d, in eutrophic and , - , mg/kg/d, in hypotrophic premature infants, in milk volumene intake from - mllkgld., the results of this study suggest that premature infants should be fed with own mothers mitk in eady neonatal pedod in attempt to prevent camitine deficiency. keto-acids and parenteral lipid admlnistration. castorina m., antuzzi d., ricci r., rendeli c., polidori g. pediatric intensive care unit -catholic university -roma (italy). some metabolic studies have suggested that the administration of mediumchain tltgticerides (mct) might induce a marked increase in ketone body concentrations; the aim of this study is to evaluate the effective ketogenetic risk of infusing mct emulsions in total parenteral nutrition (tpn). two groups of seriously infected children were examined: a- septic infants were given to tpn with a % of long-chain tryglicerides ( lct). b- septic infants, in wich the lipid source in tpn consisted in a - mixture of lct and mct. the children in the different groups showed similar severity and therapeutic scores (prism, tiss, ~, f~ , f~ ); the lipid intake was the same, corresponding to - . g, ckg bodyweight/day. in all patients a sample of urine was taken six times a day for the whole time of tpn the urine samples were screened by the diphenylhydrazone test, and the ketoacids excretion was confirmed by a chromatography. the urinary excretion of -keto-acids equivalent to p-ohphenyl-pymvate (mcg/ml urine) is summarized in the no significant increases in frequence and/or in severity of acid-base disturbances were found in all studied patients in consequence of the lipid infusion. the patients of b-group showed a lower excretion of -ketoacids. the c~-keto-acids excretion was ever unsignificant and seemed to be correlated with the illness severity more than with the lenght of the tryglicerides chain. this observations let us suppose that the mct, at employed doses, can be safely administred also in childen with metabolic acidosis and/or serious illness. reye syndrome cayetano heredia hospital, lima, peru five patients with reye syndrome were studied; included were those diagnosed from january to march and treated at cayetano heredia hospital. the age of presentation varied from z. to months. the syndrome occurred more frequently in males ( / ); the time of illness at the presentation varied from to lo days, and the following features were found: fever ( / ), akeration in mental status ( / ), seizures ( / ), gastrointestinal illnesses (diarrhea) ( / ), and respiratory insufficiency ( / ) --in this case ventilator)-support was needed, in all cases hepatomegaly, intracranial hypertension, hypokalemia hyponatremia, metabolic acidosis, hyperammonemia and elevation of hepatic enzymes were found. coagulation blood tests were abnormal in three patients. cerebrospinal fluid (csf) showed hypocellularity in all cases (less than cells/ram ). the cultives were negative, and the final diagnosis was confirmed by hepatic biopsy. no deaths were due to reye syndrome. a contribuhon to the study of reye's syndrome the aulhors analysed records of patients meeting all the clinical, biochemical and anatomic criteria put forward by hutrealoch~ and samaha ( ) who were ireated at the emergency and resusdlation depammlt tithe ipch in years. the average age of the children was years (the ~umgest monks and the driest year~ most of lhon ( / ) came from lhe countryside to lhe lmfia~ willfin hours of file oulbreak. a few days previously the patients w¢~ld have fever (some of ahem wilh diarrhea or cough) ,,rod vomit then rapidly fidl into coma and c~nvuksien. they ~me to the imtia~ with the signs of typical increased inlracranial pressure ( stages - according to lovejiy for most cases) but the liver was unllkely big. the main biocheafical dmnge of the blood was acute hepatic thilure -the bllod glucose decreased : (ha the aver~ , n~% ( ) ~ not measured in five cases (glucose a"aces). -the blood ammonia ino~ased riven to microg/dl fin lhe average , n = ) -the percentage of p~in was low, in the average , % (n-- ), % at the lowest (a case ofmekaa lasling five days was ctwed with vitamin k). -got and gpt enzymes increased - times (n= ) besides, tht~re was decompcmated addt~is with lhe average valnes ph = . ; pcoz = ~ mmhg and eli = - ~ ~, (n~). the charadaislic dumge in the ¢~'ebrospinal fluid was a low glucose tx~acenwalien h the average of k mg/dl ( cases of glucose it'aces) ; meanwhile protein decreased in the average of mg/dl ( cases below mg/dl). besides ~here was no inflammatory lesion ~tion) : very serious brain oedona and fatty degeneration of live~ scatteredly or parllally.microso~ically (biopsy and necropsy) in file brain appeared bright space around blood arteries and glioma extended v'lrdmw -robin space, with no inflammatory reaction. liver.-the sa~dure was intact there was no " "mtlammal~s ' cell, the kupffer cells did not show hyperplasia but show a heterogenous deg~nerafion~eart: also showed a fatty degencralion in some areas of the myocard eellkidney: the ihtty degenerati~l scattetedly in the tubular cell. pano~as:fatty degeneration scattetedly in file pancreatic cell. two cases of liver biopsy for lhe rid lime (check before leaving file inslitute) found that fatty degeneration was r~tta~ nearty ff~pletely. the exact muse remained unknown. objectives: to analyse whether there exists serum and urine electrolyte disorder in children with respiratory failure, methods: we have made prospective study of children in our icu during a month period, electrolyte concentrations were measured in serum and urine collected during hours (sodium-na, potassium k, chloride-ci, calcium-ca, magnesium-mg and phosphorus-p). results: average values in serum were: na . +/- , (rv: - ) mmol/i, k . +/- . ( . - . )mmol/i), cl . +/- . ( - ) mmol/l, ca .t +/- . ( . . )mm /i), mg . +/- . ( . - . )mmol/i. average electrolyte levels in hours urine were: na . ~/~ . ( - )mmol/day. k . +/- . ( - )mmol/day, ci . +/- . ( - )mmol/day, ca . +/- . ( . - . )mmol/day and p . +/- . ( . - )mmol/day. conclusions: average serum ci and ca levels were decreased in children with respiratory failure. in urine, average k, ci, ca and mg levels were decreased and urine p concentration was increased. we concluded that serum and urine electrolite disbalance may be expected in children with respiratory failure. the nurse is going to kill me! (icu syndrome) anita duvndam ~, sonia v.d,sluis ~dpt. of pediatrics, div. pediatric intensive care, sophia children's hospital, rotterdam dpt. of pediatrics, div. pediatric tntensive care, juliana children's hospital, the hague. content description: this presentation will provide the critical nurse with background information concerning the identification, the prevention and management of the critical ill child who has developed the icu syndrome. the results of a questionnaire concerning the occurrence of icu syndrome on a picu will be presented. behavioral objectives: at the end of this session the participant will be able to: . describe four clinical symptoms of the tcu syndrome, . identify major sources of picu environmental stress, . discuss nursing's unique role in helping the child to cope with the icu syndrome, . discuss nursing's unique role in preventing icu syndrome. content outline: the icu syndrome is a situation in which the individual is not able to deal with changes in observation and interpretation of both quantity and of patterns of sensory perceptions. in other words the borders between the inner and outer world becomes unclear for the person. the exact incidence of the icu syndrome in the critical care setting is unknown, we have limited knowledge of the occurrence of the icu syndrome in critical ill children. yet critical ill children in our hospitals sometimes show the symptoms of icu syndromes. to be able to identify the occurrence of icu syndrome we developed a questionnaire. the thesis of the questionnaire was: does the icu syndrome occur in critical ill children in the age between three and ten, who have been intubated and/or ventilated in a picu? eighteen questionnaires have been send out to parents of critical ill children in two hospitals. the response was percent. conclusions: . most of the children were anxious (n= ), showed regression (n= ) or had sleeping problems (n-lo) during the stay on the picu. . children showed the same problems after discharge. . there is no relationship between environmental factors and symptoms of the tcu syndrome during the stay. . there is no relationship between preexistential behavior and symptoms of the icu syndrome during the stay. because the lack of a scientific definition for the icu syndrome in children and good criteria for diagnosis, we were not able to get an answer to our thesis. more research is needed. continuous veno venous haemofiltration (cvvh) was adopted as a first line renal replacement therapy in our paediatric intensive care unit (picu) some three years ago. ~/he process of introduction and development of cvvh proved to be an exciting challenge for nurses as indeed it was for the whole multidisciplinary team involved. we have successfully used cvvh in the treatment of over infants and children, weighing between - kg. the range of conditions treated is ever increasing. to date we have not only used cvvh for patients in renal failure and fluid overload, but also to gain biochemical control in tumour lysis syndrome-and metabolic disorders. other distinct patient benefits in comparison with more conventional means of renal replacement therapies are that, it is a continuous controlled treatment being extremely effective in creating 'space' for nutrition, which is especially important in the fluid restricted, catabolic patient. of paramount importance in providing this level of service is the education and training necessary to impart the skills and knowledge for nurses to become expert practitioners in this field. we now have a teem of highly advanced practitioners who have developed their nursing skills to provide even more holistic care for their patients. this group are embracing new challenges and responding positively to the developing service whilst expanding their knowledge base. this paper will discuss the advantages and disadvantages of cvvh as we have experienced, relating i t to the wide variety of patients we have treated. we wish to share how cvvh has become an accepted role of the picu nurse and how the service has been successfully implemented. integrated care pathways (icp's) define the optimum course of events in the care of a patient with a specific condition, within a set timescale. aims and methods: icp's and case management (cm) were introduced to evaluate and improve clinical practice. icp's were developed for patients undergoing surgery for atrial septal defect (asd) ventricular septal defect (vsd) and fallots tetralogy. they were based on the median experiences of the last patients. patients have been managed using icp's. results: analysis of variation from the icp's shows a reduction in the following potentially avoidable causes of variation: delay in extubation has been reduced from % to %, and patients ( %) were extubated earlier than the median. prolonged stay on the intensive care unit (icu) has decreased from % to %, and patients ( %) were discharged to the ward a day earlier than the median. the number of patients receiving inadequate post operative analgesia has decreased from % to %. delayed feeding after operation has been reduced from % to %. unavoidable delays in extubation and discharge from icu occurred in patients ( %) because of haemodynamic instability" or lung problems. cm utilising individualised pathways for these patients has reduced variation in care which can improve patient outcomes. pathways have been developed for other conditions and it is anticipated that approximately, % of patients will be treated using an icp revision of icp's results in continuous evaluation and improvement of the care provided, conclusions: the use of icp's and cm has improved patient care and decreased avoidable delays and variations. the future development of other icp's, combined with a case managed model for selected patients, is seen as a viable method of continuously improving patient care. this paper is a retrospective audit of children who received continuous veno venous haemofiltration (cwh) whilst on the paediatrie intensive care unit (picu), data was collected over a month period from may to january . the girls and boys were aged from day to ½ years (median ½ years) and weighed between , and kg (median . kg). length of admission to picu was to days (median days). sepsis syndrome was diagnosed in cases: of these had bowel necrosis and meningoceccal disease. eight patients had an underlying haematological, oncolngical or immune disorder. the remaining children had inborn errors of metabolism ( ), nephrotic syndrome ( ), or cardiac failure ( ). cvvh was instituted for a variety of reasons. muttiorgan dysfunction was present in % of patients, % had acute renal failure, . % tumour lysis syndrome, . % uncontrollable metabolic acidosis with hyperammoneemia and % required fluid management. treatment was continued for between hours and days (median ½ days). haemofiltration was successful in achieving its desired effect in all except one patient. . % of children with haematological, ontological or immune disorders died despite successful haemofiltration. survival was higher in cases of septicaemia ( . %), nephrotic syndrome ( %) and errors of metabolism ( %). overall mortality was . %. this was attributed to the severity of the underlying disease process rather than the effectiveness of cvvh as a renal replacement therapy. asynchronous defibrillation and synchronized cardioversion deliver direct currents of high amplitude through the chest, to stop ventricular fibrillation or to convert life-threatening arrhythmias. since the human body is partially conductant, it should be possible that after a brief delay of time, a derivation of this monophasic defibrillation pulse is measurable in regions of the defibrillated body, other than the traject between anodal ("sternum") and cathodai ("ape~;") paddles. one could also estimate that health care personnel in the immediate environment of defibrillatoty shocks, are always at risk to possible electric injury. accidents might occur when health care personnel do not stand clear from the patient during firing and create an additional electric path from this patient through their own body. most likely, the nonisolated parts creating a transversal eiectric path, will be the hands of the caretaker. since defibrillation generates touch voltages up to v and - a in ved, short delay's ( to millisec), the total body resistance during skin to skin or skin to paddle contact, is calculated to be as [ow as ohm (percentile tank for the entire population). an experimental protocol was developed to evaluate the conducted currents during defibrillation. mature pigs with a weight of up to kg. were used as animal models. the:,, had barbiturate anaesthesia, inotropic support with dobutamine at l micmgrams/kg bodyweight and all had a sinasat rhythm at the begining of the test-rounds. synchronized defibrillation at j (approx. . j/kg) and asynchronized -at j (whenever ventricular fibrillation or ventricular tachycardia occurred), were attempted, through latero-lateral placed and firmly pressed defibrillation paddles and/or adhesive multi-function electrodes. gel pads were choosen as contactmedium to cross the skinpaddle barrier. subdermal electro-myography needle electrodes were put at different parts and regions of the pig's body, but not between the paddles. these electrodes were coupled to a resistance device of ohm and a measuring computer. we measured monophasic and low current pulses up to , a during the defibrillation burst. thus conducted currents are high enough to produce accidental electric shocks when additional electric paths are created by the caretaker. "llaese are usually harmless, but in some "worst case" (wet or transpiring hands, rings,...) or in association with defectuous equipment, peak currents might be harmfull, and can produce pain, bums, apnae or cardiac (transient or persistant) arrhythmias. maria skogbv. karin mellgren, lars-g ran friberg, g sta mellgren, hans wadenvik. g teborg, sweden. bleeding complications in extracorporeal circulation is partly due to perfusion-induced platelet dysfunction. the aim of this study was to evaluate an in vitro model for investigation of platelet function parameters in an extracorporeat system. study: two complete extracorporeal life support systems were perfused with fresh heparinized human blood for hours. piatetet membrane glycoprotein changes, platelet granule release and platelet count were followed. eight paired experiments were performed. one of the circuits was perfused by a roller pump (polystan) and the other by a centrifugal pump (biomecicus), other components were identical. results: a continuous increase in glycoprotein (gp) ib-negative platelets was seen in both circuits. a marked increase of plasma beta-thromboglobulin concentration and a decrease of the intracellular pool of serotonin was observed, indicating a marked release of alpha as well as of dense granules. the plasma concentration of glycocalioin increased in parallel with a reduced platelet surface expression of gpib, suggesting that the loss of gpib is caused by proteolysis rather than by a downregulation of this receptor protein. conclusion: hours of ecls perfusion induces pronounced platelet degranutation and causes changes of important membrane receptors. this is in accordance with clinical studies, suggesting that our in vitro model does mirror the platelet exhaustion observed in a clinical reality. no significant difference was observed between the two pumps. the purpose of this study was to examine signs of distress exhibited by several patients following the discontinuation of opioids and benzodiazepines (o & b) in a -bed pediatric intensive care unit. the authors compiled a list of all cases of possible withdrawal reactions reported by nurses in the study setting over a one-year period. five cases were selected for study in terms of their wide diversity of relevant circumstances. the cases were examined through a retrospective chart review. data pertaining to analgesic and sedative administration, along with nurses' reports of behavioral distress, were transcribed and coded. a remarkable pattern of behavioral distress was clearly associated with discontinuation of o & b. cessation of benzodiazepines was associated with severe distress. these reactions were characterized by various combinations of crying, irritability, tremors, grimacing, gagging, vomiting, or feeding problems. some of these persisted in spite of large amounts of bolus drug administration. these signs were manifested for to days following cessation of o & b. these findings demonstrate that the rapid weaning of o & b infusions, sometimes following short-term therapy, can cause severe withdrawal reactions. the particular course that a specific patient will follow will likely be modulated by underlying manifestations of "icu psychosis" and unresolved pain and emotional distress. hermana tezano mt, pilaf orive j, latorre garcia j, lizarraga azparren ma, lopez bayon j ucip hospital de cruces. bilbao. spain a female child, one year old, was referred to our unit from another hospital because she had ischemic syntomsjn her right forearm wich started three days before. she had ~i downs syndrome and fallot's tetralogy with a systemic-pulmonary by-pass. nine days before the admission in our hospital she was undergone to a cardiac catheterization by arterial and venous femoral punctures with no incidences. on the admission to the picu her forearm was cold and pale with absence of cubital and radial pulses and slow capilary filling. treatment with heparine was started unsucessfully in the firsts hours, so uroquinase was added that later was changed to rtpa plus brachial plexus blockade. by the time me arterial tlux became more and more evident (doppi~) il bccuute aiat) evident a regional aedema witch made necessary a fasciectomy &the wrist. she also developped necrotic delimitted areas that included her first and fifth fingers. she was discharged from the picu after days and a week later she went to the operating room where an amputation of the distal phalange of the fifth finger was made. the etiolgy of this ischemic picture can't be attributed to the catheterization itself, but probably it should be due to some attempts in arterial puncture in its course, attempts that could be guess by the little marks noticed at the elbow flexure when she was admitted. long maintenance of cardiovascular funtion by assisted ventricular device with membrane oxigenator hermana tezanos mt, pilar orive j. latorre garcia j, lizarraga azparren ma lopez bay n j. ucip. hospital de cruces. bilbao. spain a little girl of three and a half years came to the intensive care unit from the operating room. affected of great vessels transposition with a pulmona~' banding corrected vith rastelli technique, it became impossible to discharge her from the by-pass circulation. it was assumed that this factt was due to a transient myocardial disfunction dfter the surgeon x~ent through the technique and found no wrong step in it. at the picu admission she had an ejection fraction belox~ % (echncardiografy), and was manteined on veutricular assistance with a circuit consisting ofa plate's membrane oxigenator, a bio-medicus pump and pvc rubber tubes, with monitoring of pulmonary', right and left atrial pressures. initially she needed a ventncular support of . l/min with dopamine. dobutamine and adrenaline; gradually the ejection fraction rose to % aliowing a decrease in the mechanical and inotropic support. the organic function ,.'.-as preserved but x-ray of the thorax showed images of pulmonary aedema with an increase in the needs until a fi of . . even though she was placed in a transplant program, she was remouved when the ejection fraction rose to % on the lth da of the evolution. there were no signs of infection (profilactic coverage). on the fifhteen postsurgery day. with a good cardiac sound and an ejection fraction of at least %. it was considered the withdrawal of the ventficular support, but unsucessfully despite the increase ofinotropic drugs, so she died. we think that our patient is a good example of the posibiti~ to mantain x~ith ecmo during a prolonged period of time a potential transplant receiver without major complicatios. joan wierema; ma )an mourik. sophia children's hospital, department of pediatric surger,j, rotterdam, the netherlands. the success of an ecmo program is heavily determined by the organizational structure and the daily availability of both well trained nurses and physicians. until now there is no general guideline to determine the optimal training schedule to set up an ecmo program. objective: to evaluate the set-up of an ecmo program in an area without direct availability of perfusionists of cardiothoracic surgeons. description of the progress: during the preparation of the ecmo program which started november , different phases are identified. first phase, acquisition of experience by training abroad of one physician, staff member of the icu, physician acting as a fellow and one icu nurse with theprimary task to serve as an ecmo coordinator and train the nursing start. in the second phase animal experiments were performed by paediatric surgeons, staff physicians, fellows and nurses. third phase, start of the actual ecmo program, priming by one trained nurse and ecmo fellow, daily care of the patient by nurses, icu nurse taking care of the patient related activities, ecmo trained nurse taking care of the circuit. fourth phase, transition of the tasks for priming the system from the ecmo fellow to the ecmo nurse and changing daily care for the ecmo patient now including the circuit by trained icu nurse with special legislation for ecmo. ongoing training of to nurses working for at least half a year in the icu. during an ecmo run direct contact between the ecmo nurse and one of the staff members; patient data: in a year period neonatal ecmo cases were performed with an overall mortality of %, ranging from over % in meconium aspiration to % in congenital diaphragmatic hernia. in other patients pediatric ecmo (age range month - months) mortality was %. conclusions: ecmo can be established without perfusionists or cardio surgical back up once a predetermined training schedule is available, resulting in comparable results with the international ecmo registry both for neonatal as well as for pediatric cases. mechanical ventilation at home makes normal development of the child with chronic respiratory failure possible. the parents must be encouraged to accept the treatment at home; therefore, they should be enabled to take care of their children all by themselves and the continuous professional support has to be offered to them. it must be stressed that the nurse is the link between the diseased child and his family introducing them into the process of the medical care at home. all the equipment needed for the mechanical ventilation of the child at home (ventilator, suction device, pulse oxymeter, oxygen tanks) has to be provided before the child is discharged. it is paid by the national insurance company. the maintainance service workers will make the necessary installations available and they will renew oxygen and compressed air weekly. the ventilation assembly must not interfere with the childs activities. the related dispensary and nursing service should be notified of the child's condition and the list of the required material (suction tubes, cannulas, desinfectants etc.) has to be made. our experience is so far -from the nursing and medical point of view -satisfactory, however the social status of the parents needs further regulations, omphalocele. mourik m, sophia children's hospital, department of pediatric surgery, rotterdam, the netherlands. in patients with (giant) omphalocde operative closure is impossible due to the lack of intra-abdominal space and a variable degree of pulmonary hypoplasia. consequently conservative treatment allowing epithelialization is the treatment of choice with a high risk of infection and/or sepsis due to a sometimes very long stay in the icu. this conservative treatment consists of daily application of an antibiotic containing powder on the cele which is covered by sterile gauzes. furthermore the enteral intake is started as soon possible. objective: to evaluate whether this treatment renders a high risk for serious infections. patient characteristics: in a year period patients with a giant omphalocele were admitted; mean birth weight g ( - g) mean gestational age . ( - weeks). overall mortality ( %). patients had to be ventilated for a median duration of t days ( , - ). results: patients were discharged at the mean of days following birth ( - ) following complete epithelialization of the omphalocele. following the initial stabilisation period parents were involved in daily care of all patients even during artificial ventialation. enteral intake was started at a median of days ( - ). colonization of the omphalocele was observed within - days in all patients. although infectious periods were observed at regular intervals, sepsis was the primarily cause of death in only of the patients who died, in conclusion: nursing care to prevent sepsis in patients with (giant) omphalocele is feasible for a long period of time and can be performed with simple measures, since june , we have been using nasal cpap in the treatment of respiratory disorders in newborn infants (severe apnea syndrom, tachypnea, hyaline membrane disease). in newborns presenting hyaline membrane disease, we have used cpap and administered surfactant therapy to premature babies out of . clinical data were : mean ga : . + weeks. mean bw : + g. mean administration time was hours. before administration, mean fio was . + . , mean pao . + . kpa and mean a/ao ratio . . all babies were intubated for administration of surfactant (curosurf) and were extubated after half an hour to hours after administration. this treatment failed for seven babies and they were ventilated by oscillation ventilation ; all babies survived. complications : we have observed pneumothorax in cases and cerebral hemorrage. mean duration time of nasal cpap was hours for the babies without assisted ventilation. nurses in charge of babies with nasal cpap should be aware of neonatal care, of the possibility of surfactant administration and of complications during this type of treatment. therefore nurses should know very well the use of nasal cpap, the monitoring during this treatment, the fixation of the system on the baby, nursing of the babies during this treatment and finally should take care of the baby physical and psychological well being. as a conclusion, nurses in intensive care neonatal units should know the possibility of treatment of rds by nasal cpap and should be aware of baby-nursing. emco in the postcardiotomy infan_t : a simplified circuit and reduced management grillet lsabelle, bosson christa, goelz andrea, helmer pascale, icu nurses, tschaut rudy perfusianist aldo castaneda institute, clinique de genolier, suisse to improve postoperative survival of infants with repaired cardiac tessions but severe residual cardiopnlmonary dysfunction, emco was used in infants, ranging in age from l days to months and in weight from , kg to , kg. diagnosis included tga / intact ventricular septum ( ) (both subiected to rapid arterial switch operation because of unsuitable lv function) and tga +vsd ( ). "['he emco circuit included a sarns roller ump, a medtronic minimax plus hollow fiber oxygenator and tubing ( / - / inch) with bioactive surfaces, an arterial canula fr., venous canulas : right atrial fr, left atrial fr., an air oxygen mixer and a sarns heater. the act was kept between - sec. after the infant was connected to emco by the surgical team and the perfusion technologist, the patients were being cared for and controlled exclusively by the cu nurse assigned to the patient and the physician on call for the icu, pump flows of - ml / kg / mln were targeted to insure an adequate urine output, a brisk capillary fill and physiologic left and right atrial pressures. sodium nitroprusside was used to control systemic hypertension while all other inotropic drugs were discontinued. inspired oxygen fraction on the ventilator was reduced to , at a respiratory rate of - breaths per minute. body temperature was maintened close to normal. when the heart started to eject again, inspired oxygen was increased to about , . the preparation for weaning from emco was done by the icu nurse: including oxygen fraction and ventilator rate. weaning from emcowas coordinated by the medical / surgical team and the perfusion technologist. the duration of emco in the patients ranged from to days. three patients ( %) were saccessflly weaned from emco. one of the three died within hours from neurologic complications, unrelated to the emco. the other patients ( both with tga + vsd ) are long term survivors and are doing well. neither the survivors nor the patients who died bad hemorrhagic complications, despite the fact that of the were placed on emco because of failure to wean from cardiopulmonary bypass. the simplified emco circuit worked reliably throughout this experience and no complications occurred nor could any shortcoming be ascribed to the use of this reduced, cost effective management team. years of praciical experience wiih exiracorporeal membrane oxygenation (echo) -the viewpoint of the nursing siaef monika schindler in a training program was started for the introduction of echo in the kinderklinik of mannheim/germsny. years later ( ) the first european echo patient, a days old newborn baby, ~as treated successfully in our institution. with echo, more treatment modalities ~ere available after failure of conventional therapy in eases of severe lung diseases like meeonium aspiration syndrome, congenital diaphragmatic hernia, sepsis/pneumonia, primary persistent pulmonary hypertension of the newborn and -in infants and children -ards (acquired respiratory distress syndrome) due to multiple underlying illnesses. in the first ards patient, a years old girl, was treated successfully ~ith ecmo in mannheim. until now patients (age: i day - years) were treated with echo in our institution; additional patients were transferred to us from other institutions for therapy with echo, but could be treated ~ieh alternative moda]ities of therapy like improved conventional ventilatory support, high frequency oscillatory ventilation (hfov) and inhaled nieric oxide (no), unexpectedly the more ~ide-spread use of hfov and no -also in other ~ntensive care units -did not lead to a reduction of the echo frequency in our hospital. due to this long ecmo practice, which is helpful in many critical situations, a certain routine came up in the nursing staff of our intensive care units; but ecmo continues to be a maximum strain for all co-workers and implies an high personnel and material/financial-expense. but in our opinion the improved survival rates in severe respiratory failure-( % in neonates and % in infants and children, estimated survival rates under continued conventional management: < %) by the use of echo justifies this expense, even in times of less financial support for public health. • analyse the differences between each urdt. method : ni criteria were defined by the rt~a ped group according to cdc criteria. all data were collected by a nursing and medical team. data vere dealed with epi info software. all u-dections data were validated by an external mvestigatol : patients who stay more than hours in an icu were included over a months period. % were newborns, % infants and , % children. ni were idenlified among sll patients, the overall ni incidence rates was , % and , person day, septicemia was the first cause of ni ( %). staphylococcus epidermidis were isolated in % of septicemia cases. pneumonia was the other main ni ( %) with gram negatwe bacille isolated m % ( % of them beei,ng fseudomonas) accordmg to age, the septicemia mcidence rate varied from , ~., to . %,, catheter/day and pneumonia incidence rate from , %, to , % ventilation/daywith the lowest rate for newborns. : this survey was possible thanks to the collaboration between laboratories, bacteriologist, physicians and nurses, and allowed each concerned unit to work together in~tead of every one in his own field. 'lhe results of this survey bring changes in attlhades and empower the different team work the next step is to analyse the ditferent nurses procedures of indwelling central venous catheter in each unit ar)d implement a ni quatity care. program in all nicu anti picu. v~,~jl~j~'v~y : new born in~ra-v~ nous drugs ~md lheir pr~taration mcounter a lot of risk ~)f utters, due to inadapted conditionn~ng to podia)eric and minimal amount injec~.~d, th~ study t~ed to evaluate degrees of do.~age er~o~ dye tt) dru~ preparaek, n i~ nc,:,~atol~gy and to come out w~th ~ method of dihttion able to reduce risk to minima (errors _< %) at the ~eme t~me, ¢o~,~x-tueaces on cost were studioj methnd~ : amikacine was choosen because this antibiotic is regularly ~,~l in neonatology unit and its dosage is easily used by standardiaud method, amikacine doses ( , mg doses and , mg doses) were prepared" by nurse~ form mg for m) vial. each dose w'a~ diluted to obtain mi volume, tallowing usual ward method, for each dilution, amikacine con<entrati('m and it,s volume was measured and used equipment for preparation wa~ regi~tred. "first s utj(m" were prepared diluting ~t'~ mg amikacine pouder inn ) ml glucnse solution bag (viaflex baxter bag with transfer cap), from tho~e "first solution" doses at mg and doses of ~ rng were prepared, amik~cine coc, cenir,)tmn for each preparabon and their volume were measured, ai,~n ntttl~,ber of seringe were tounted. first soiuhon staeiiity was conrroieo aher one week conservation at + '>c. amjkacine concentration were measured by fluorescence process (tdx abbott) after sample dilurion. on a mg/l sample, tovhnical reliahility show~ > ~ % of result mpmductlon and < % of variation due to dilutions. results : when amikacine injection werv pro.pared from araikacme /) mg for mt vial > % do~ge, ermr~ were found in / cases ; ~ % in ,t ,to cases. if preparation is done from amikacine "~it'st soltltion", les.--concenvr~tcd, it i~ more preci,,,e and only one dosage error ~ % ( , %} is found in eli studied doses. in add)inn to )hal if doses were wep,m-'d from one "first soiatiol~' bag, the cost economy sl~ouid b~" of fr~, and ii dos~$ were prepared tram the same bag the saving mtmey should be o{ i its .cencluslon : .ur survey shows th~t h' ntu)nato|ogy the u~ of a "first sohation which can be kept fi~r one week is enable to reduce dosage erroes and i~ co,~tsavmg, regarding [,v. admimst'rahon method the survey is still on, introduction: so-called vein of galen m~iformations ale rare in~racranial embryologycal anomalies, repl~senti~g tess than of symptomatic intracranied artefiovenoas l~alform~tions. the spontlneous prognosis is ~s~u~lly fatal, because of cardiac frilure due to left-to-right shunt thrq~ugh the fistula. recent developments of new techniques of treatment of the malformation and its cardiac consequence have led to a revolution in the practical approach of children w~th galen malformation. our fukfose is to contribute, with our persoaal series of s newborns and infal~ts admitted in our unit after endov~,scular embolization, to a better management of these children. such a management requ!res a rnultidisciplinary approach. intensive care are required prior to embollzation for patients with cardiac failure or cardiogenic shock and after cmbolization in order to insure cardiac and cerebral hemodyna.mic stabilities. this overlooking suppose for the nursing team to understand: prior to embolization : heart failure and cardiogenic shock. after cmbolization : evaluation of neurological and hemodynamic consequences of this proccdure, without forgetting the nursing and psychologic aspects, in concl'iision, this last ten yerrs, these new approaches give to the patients and their famitiy a good reason to hope a total recovew, in our exl)erience, the global mortality is % aad % of children #j-e neurologically normal after embolizafion, ii ii~ i ~ii i ii i i l i iiii~ i ~i iii i background: venous oxygen saturation (svo z) reflects the residuai oxygen after tissue oxygen extraction and represents the relation between tissue oxygen supply and demand. we studied svo and arterial lactate during progressive isovolemic anemia to assess the relation between svo and tissue hypoxia. subjects: ten - day old anesthetized ventilated piglets sao and svq were measured continuously by a fiberoptic catheter (oximetrix, abbott lab.) in the carotid and pulmonary a~epy tissue hypoxia was confirmed by a reduced vo, and an increase in lactate. conclusion: svo reflects better a reduced dp obtained by progressive anemia surfactant replacement improves gas exchange in early-stage adult respiratory syndrome (ards) [ , ], but not in late-stage ards [ ] . we report the first case of successfull treatment of ards after repeated instillation of surfactant.a ten year old boy, weighing kg, presented with hemorragic shock. biphasic-positive-airways-pressure ventilation was performed (evita ii, dr~ger, germany). he had recieved nine units of packed red blood cells and underwent surgical exeresis of two bleeding gastric ulcus. post-operatively, a cardiac arrest required cardiopulmonary resuscitation for three minutes. hemodynamic status was subsequently stabilised. the chest-radiograph showed infiltrates of both lungs without signs of cardiac failure. on the third day, the patient became severely hypoxic with a pao /fio ratio of . gas exchange was not improved by high ventilator settings. peak inspiratory pressure (pip) and ventilatory rates were cmh~o and breaths/min respectively. inspiratory:expiratory time was : and the positive end expiratory pressure (peep) cmh . after increasing the peep level to cmh , we instilled over minutes, mg/kg of porcine surfactant (curosurf, serene france), in two equal volumes in both main bronchus,the spo~ rose to % within rain, the fie could be reduced to . . twenty four hours later, gas exchange worsened again (pao /fio ratio ). we increased the peep from to cmh , and instilled a second dose of surfactant ( mg/kg). again, fie could be reduced within minutes (spo ; fie . .). the patient was weaned from the ventilator and extubated on the tenth day. follow-up at four month showed normal lung function.we demonstrate improvement in oxygenation after repeated exogenous surfactant administrations. we assume that in early-stage ards, surfactant may potentiate shunt-reducing effect of peep as it has been demonstrated in experimental model of ards [ ] , and allow decrease in fie . in case of secondary deterioration, we think that a second dose of surfactant should be administered. . weg jg, balk ra, tharratt rs, et al. ,lama : : - . . spragg rg, gillard n, pdchman p, et al. chest t : : - . . haslam pl, hughes da, mcnaughton pd. et al. lancet : - . . huang yc, caimulti sp, fawcett ta, et al. jappl physiol : - % (ref) . the aim of this study was to verify these data: patients/~lethods: all pts admitted to our multidisciplinary nicu/picu in were included if they were in respiratory failure recruiting conventional mechanical ventilation (cmv) with peep >_ and 'fig -: % or high-frequency oscillation ventilation (hfo) with mean airway pressure _> t cm h for or more houm. diagnosis, maximal ventilatory parameters, barotrauma, organ/ system failures, mechanism of death and glasgow oulcome scale (gos) and months after study entry were prospectively collected. results: patients were admitted to the unit, o whom required mechanical ventilation for a mean duration of . days. overall mortality was %, patients fulfilled study criteria. survivors had gos , pts with preexisting neurological impairment survived with gos . neonatal diseases included hyaline membrane disease ( ), meconium aspiration syndrome ( ) and cardiovascular surgery ( ), pediatric diseases included bacterial ( ) and viral ( ) pneumonia, aspiration ( ) and cardiovascular surgery beyond the neonatal period ( ). - ) . patients and methods: cefotaxim was used as a prophylactic agent in patients in life threatening situations (e.g. multitrauma, neurosurgery atc.). more than % children required cefotaxim for the treatment of severe infections (epiglotitis, meningitis, sepsis, pneumonia mainly in immunodeficient and neutropenic patients) in monotherapy or in the combination with the other antimicrobial agents. results: cefotaxim as a prophylactic drug was successful in all cases ( %). the effectivity of treatment of infections was . % ( patients). the change of antibiotic therapy required patients ( . %). patients ( . %) died, but only in of them ( . %) the obduction confirmed infection. conclusion: we conclude that cefotaxim is very effective and safe antibiotic and represents "golden standard" in the treatment of severe infections in childhood. in order to improve nursing quality, we recently adapted nursing care to the "five nursing functions" (activities of daily living, accompagnment in crisis, treatment, prevention and research) as described by the swiss red cross in accordance to the new educational guidelines of the european community, the aim of this study was to document complications of "treatment nursing function".methods: all treatment complications were prospectively collected by the nursing and medical staff. the nursing staff included patient (pt) name, time of occurence and exact description of complication, proposal for prevention and information of parents. the medical staff reported type of complication together with pt information, diagnosis, medication, treatment and interventions, outcome and referral, all complications were discussed in monthly meetings including nursing and medical staff.results: from january until december , pts were admitted to the picu/nicu for nursing days ( % of total bed occupancy). pts needed endotracheal intubation for an average of . days and pts required nasal cpap. complications in pts were noted ( per pi): inadequate check-up of equipment ; accidental extubation ( in intubated pts); bedsores ; false drug dosing ; wrong drug ; umbilical bleeding ; wrong transfusion setup ; nasal septal necrosis ). there was no mortality due to these complications. exact documention of treatment complications and their meticulous discussion within the medical and nursing staff may improve "treatment nursing function". however, documentation and evaluation of nursing within all "five nursing functions" will be nessecary in order to achieve optimal nursing care. cardiac output determination by thermodilution, using iced injectate has been shown to be valid and reliable in pediatric patients. it has been demonstrated in adult patients that there is no difference in cardiac output values when using room temperature injectate as compared to iced temperature injectate. the purpose of this study is to examine the effect of injectate temperature on cardiac output values in pediatric patients. our study consisted of sixteen pediatric patients who had oximetric thermodilution catheters in place after cardiac surgery and who had cardiac output determined using both iced and room temperature injectate. with each patient, cardiac output was measured once on the day of surgery and again the following day. in each case cardiac output was measured using both iced and room temperature injectate. statistical analysis included a two-way, repeated measures analysis of variance for each individual injectate administered and no significant differences were found in cardiac output. no statistically significant differences were found between groups with regard to the order of injectate administration or volume of injectate used (i,e., or cc's). the correlation coefficients between groups for cardiac output measurements at each injectate administration time, and for the average measurements across times, ranged between . to . (p < . ). preliminary data analysis suggests that cardiac output measurements for children are not effected by the temperature of injectate. a lenghty stay at a paediatric intensive care unit will always have sideeffects on a child's well-being and will put a high strain on the parents. in order to minimize the side-effects longterm intensive care unit opened in at the childrens' hospital. admitted children are all ~ongterm-ill and technically-dependent and the ventilatory support can alter from a tracheostoma to cpap or portable volume ventilator. nutritional support is applied by gastrostomies. a homelike atmosphere surrounds the children, they share a dormitory, a living-room and a dining-room the main purpose is to send the child home with or without technical equipment. this can only be implemented by giving structured education (theory and practice) to all categories involved. the multi-disciplinary team consists of one anaesthesiologist, head nurse, clinical specialist, rn nurses, nurses, one habilitation doctor, one social worker and therapists. twenty-four patients have been admitted to licu during these six years. length of stay was from one day to four years. four are presently staying at the trait. the assessment of pain in children ( - yrs) is still difficult, because children of this age have limited language and cognitive skills. to standardize the assessment of postoperative pain and distress in the intensive care unit an observational mstrument was needed that met several criteria. it should be easy to use in daily routine care. be suitable for the i.c. situation, and in children of - hrs of age. the comfort scale, an observational instrument designed to assess distress in infants in i.c. units, met these criteria. to accommodate the use of the comfort scale in the i.c. units and in research, nurses should be trained to use the scale. an additional requirement was that the inter-rater reliability should be sufficiently high, (cohen's kappa > . ). objectives: ) to introduce the comfort scale in the i.c.u.; ) to examine whether this instrument can easily, be incorporated into routine care; ) to investigate the inter-rater retiabtlity. methods: the comfort scale is an -item instrument specifically designed for use in pediatric i,c, units and contains both physiological items (heart rate, blood pressure) and behavioral items (e.g., alertness behavior, calmness/agitation, body movement, facial expression respiratory response, muscle tension). the observation period is minutes. the scale is supplemented with an item on crying tbr children who are not mechanically ventilated. groups of t.c. nurses were trained by means of video's and observations at the wards. after the training, each nurse completed scores with other nurses, after which the cohen's kappa was computed. when the kappa's for the items met or exceeded our . criterium, a new group of nurses was trained. results: to date, nurses have been trained. nurses find the comfort scale easy" to administer and a valuable addition to routine care in the i.c. unit. the cohen's kappa's were higher than . for all items that the inter-rater reliability was high. the comfort scale is feasible in postoperative care in the i.v. and is considered a valuable instrument to improve and maintain high postoperative quality of care in the i.c. unit. introduction:children with neuro-muscular disease are believed to have a higher resting energy expenditure (ree), because of their increasedwork of breathing.the influence of nocturnal nasal mask ventilation on energy metabolism and nutritional state of these children has not been studied so far.objective:l,ls the ree inereased? . s there an influence of nasal mask ventilation on the ree? .what is the nutritional state? .what is the estimated total energy expenditure(ete) in relation to the caloric intake? methods:a pilot study of patients( - years) .the following measurements were performed:l.anthropometry. .bioelectric impedance- .ree was measured by indirect calorimetry during the day (in bed) with and without nasal mask ventuation,ree was compared with predicted ree according to schofield(pee), .caloric-intake and activities were recorded during hour before measurement. .total energy expenditure was calculated as follows:measured ree x estimated activity factor. results:tin all children weight for height was too low, <p . .aii children had a low % of fat. .according to the healthy group, ree is not increased. ,nasal mask ventilation lowered ree in patients, in patient we measured a clear decrease.conclueion:l.anthropometry and indirect calorimetry were helpful in evaluating the nutritional state. .there is no increased ree,in t patient there is clearly effect of nasal mask ventilation. .when caloric intake was related to ree and level of activity patients had too low caloric intake. .the influence of nocturnal nasal mask ventilation and nutritional assessment should be evaluated longitudinally. increasing awareness that the neonate can percept pain and suffer following surgical procedures, has major impact on pain management. in our unit continuous morphine infusion (t /~g/kg/hr) was introduced from january as a standard medicatton following surgical procedures. before morphine was given as a bolus (i.m., i.v., rectal) of /~g/kg up till four times a day. repeated gifts of morphine were only gwen following observation by the nurse that the child experienced pain. aim of the study: to evaluate pain management before and tbllowing introduction of a continuous morphine infusion for postoperative pain in our icu. patients and methods: term born babies with isolated oesophageal atresia and tracheo-oesophageal fistula were included in the study. the total amount of morphine (/~£/kg/ hours); number of days morphine was given; duration of artificial ventilation was evaluated in a case control study. res ults: - - central venous catheters (cvc) have been increasingly used also at our picu, university medical centre ljubljana. besides advantages, the cvc has brought numerous risks of complications; the catheter sepsis occurs most often and can be fatal for the patient. for example, in we dealt with children aged - years or in other words . cvp per a child treated at our picu. a specialized unit for preparing parenteral natrition started to function in the university medical centre pharmacy in . after that we equipped a special room for preparing other necessary infusion mixtures and organized a team of nurses -"catheter nurses".their tasks comprise: managing cvcs, replacing and installing infusion systems and mixtures made at pharmacy, preparing drugs and some necessary infusion mixtures in special room, permanent training and co-operation with related disciplines, pharmacy, epidemiology, microbiology, etc. all registered nurses at picu have been trained for this work. the routine is as follows: in the morningafter the doctor's visit, we first check the cvc and change the dressings; according to the nurse's observations, the doctor decides whether there is a need to remove or replace the cvc. if the catheter site is inflamed, swollen, or purulent, a swab is taken for microbiological culture and the area cleaned. in case of systemic infection signs, cvc has to be replaced, blood culture taken and the infection treated with antibiotics. the dressings are always changed by two tmcatheter nurses together. afterwards the infusion mixtures for the next hours are prepared for each child. the infusion mixtures which will not be used immediately are kept on + °c; before application they are, of course, warmed to at least room temperature. finally the "catheter nurse" supplies the cvc with new infusion mixtures made at our pharmacy. our observations show that such work requires responsibility and is demanding; but our pemanent care lessens the number of complications. thus the described scheme fulfilled our expectations. perl- perative management of neonates with hypoplastic left heart syndrome muir warren, blondel maryse, foltz rhonda, farine martine, icu nurses, the aldo castaneda institute, clinique de genolier, switzerland both the pre-operative and post-operative physiology of patient with hypoplastic left heart syndrome is critically determined by the puhnonary-tosystemic resistance ratio. a high ratio results in minimum volume work for the right ventricle but is at the expense of important hypoxemia. a low ratio is reflected in minimum hypoxemia but an unfavorable increase in excess ventricular volume work. a resistance ratio of approximately results in an arterial oxygen saturation of % - %, a qp/qs of , and ventricular volume work only twice normal. this latter physiology appears best for oxygen delivery and systemic perfusion with tolerable volume work. carbon dioxide (co ) in the inspired gas is known to increase pulmonary vascular resistance without significantly influencing systemic resistance in the range of to tort partial pressure. hyperventilation with no co in inspired gas decreases pulmonary vascular resistance. thus, managing co may be useful to modulate the pulmonary-to-systemic resistance ratio, in the tast months, patients with hypoplastic left heart syndrome were managed by a norwood procedur e. patients with endotracheal entubation pre-operatively had co added to inspired gas to modulate the pulmonary-to-systemic flow ratio. patients had co added to inspired gas post-operatively. all but patient had characteristically large pulmonaary-to-systemic flow ratio with oxygen saturation mean % preoperatively, even in those patients receiving co , co was accompanied by elimination of metabolic acidosis pre-operatively. the most comlnon partial pressure of co added post-operatively was torr. po ranged from mmhg to mmhg. all surviving patients developed a metabolic alkalosis ( mean) when treated with co . there were deaths, one from drug toxicity, one from excessive post-operative hemorrhage, two from sepsis or mocardial insufficiency. only one patient benefited from catecholamine support which can increase systemic resistance unfaborably. in this experience co was felt to be an important adjunct in some patients pre-operatively and most patients postoperatively to faborably modulate the critically important systemic-topulmonary flow ratio, to maximize oxygen delivery and systemic perfusion, while minimizing excessive right vantricular volume work. key: cord- -ak pq authors: nan title: th european congress of intensive care medicine athens - greece, october – , abstracts date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: ak pq nan objectives: evaluate the levels of tnf, il- and pai-i in different moments of the ards and the possible relationships among them. methods: septic patients with ards were studied. also significant differences for: tnf, pai-i and il- in septic patients and both evaluations of ards with control gropup; pai- between septics and nd evaluation in ards, and between the ist and nd evaluation in ards; il- between septics and both evaluations in ards; and il-~ in both evaluations in ards patients in relation to mortality. conclusions: i) elevations of tnf, pai-i and il- , with clinical signs, are suggestive of infection; ) the persistent and progressive elevation of pai-i with any clinical criteria may suggest evolution to ards; ) due to its own kynetics, il- takes part later in the acute phase, its levels being related to the magnitude of the injury in the tissues. objectives: the influence of long-term volume therapy with different solutions on plasma levels of circulating adhesion molecules was studied. methods: according to a randomized sequence, patients with sepsis secondary to major surgery exclusively received either hydroxyethylstarch solution ( % hes, mean molecular weight (mw) , daltons, degree of substitution (ds) . ) or human albumin % (ha) for volume therapy for days. plasma levels of circulating (soluble) adhesion molecules (endothelial leukocyte adhesion melecule- [selam -i] , intercellular adhesion molecule- [sicam -i] , vascular cell adhesion molecule- [svcam -i] , and p-selectin ) were serially measured on the day of admission to the intensive care unit (='baseline ' value) and during the next days. results: selam-i, sicam-i, and svcam-i plasma levels were markedly higher than normal at baseline in both groups. in the hes-patients, selam-j decreased to normal range, whereas it further increased in the ha-group (from • to • during the study period, sicam-i and svcam-i plasma levels remained unchanged in the hes-patients, but further increased in the ha-group (from • to , • sgmp- increased significatly only in the ha-group ( • to • only pao /fio was significantly correlated to plasma levels of adhesion molecules. conclusions: sepsis is associated with markedly elevated plasma levels of adhesion molecules indicating endothelial activation or damage. by long-term volume therapy with hes, these levels remained unchanged or even decreased, whereas volume therapy with human albumin did not have any beneficial effects on soluble adhesion. central venous catheters are frequently used in the care of the critically ill patient. the incidence of catheter related sepsis varies in the literature. we investigated the occurrence of contamination and sepsis compared to results of the epic study as part of quality assesment in our intensive care unit. from january until august all removed central venous catheters were examined for microbiological culture. the patients who showed signs of sepsis were also registered. the results of the contaminated catheters and septic patients were compared with results from the epic study. during the month period , patients were hospitalized on our intensive care unit. central venous catheters were examined for microbiological culture. specimens appeared to be possitive ( %). patients showed clinical signs of sepsis. the incidence of sepsis due to contaminated central venous catheters was / ( %). the incidence of sepsis due to the presence of all central venous lines was / ( %). the microorganisms responsible for the sepsis syndrom were : stapylococcus aureus (n= ), escherichia colt (n= ), others (n= ). in the epic study the percentage for sepsis on the icu was . % for the netherlands and . % for europe. despite a high number of positive culture from removed intravascular lines, a low percentage of sepsis was seen compared to results of the epic study. we recommend routine bacteriological culture of all removed central venous lines and recommend to look at colonization and sepsis due to intravascular lines as a measure of quality control in the intensive care unit. objectives: prognostic assessment of simplified acute physiology score (saps) in granulocytopenie patients with septic shock (ss). methods: the medical records of admissions to an intensive care unit (icu) of granuloeytopenic patients with ss are reviewed. fiftytwo patients had haematological malignancies. seven patients had aplastie anaemia. patients were categorised as survivors (discharged from icl and non-survivors (died in the icu). saps index was calculated for patients daily during their stay in icu. all patients were severe granulocytopenic (total white cell count less than , ] ] ). results: five patients ( , %) were discharged from icu. fifty-four patients died in icu. non-survivors had saps on admission higher than survivors ( . + . and . + . , respectively, p< , , mann-whitney u test). no patient with a saps greater than survived. mortality among the patients with saps from to was , %o. the evolution of ss was rapid. the mean stay in icu among non-survivors was only hours. an analysis of the saps index on admission of non-survivors showed an inverse correlation with the duration of their stay in icu (r=- , , p= . ). all survivors recovered from granulocytopenia. they had normal white cell counts at the time of discharge from icu. there was inverse correlation in survivors between saps and white cell counts, when these parameters were evaluated daily. however, the saps index alone cannot be considered to be on individual predictor factor of mortality. patients who had failure of the malignancy to respond to chemotherapy and who had persistent granuloeytopenia died in icu despite saps index on admission and recovery from ss. conclusion: saps index greater than , failure of the malignancy to respond to chemotherapy and persistent leueopenia all point to a poor outcome of granulocytopenie patients with ss. introduction: antipyretics sometimes are used for fever control in febrile neutropenic patients with hematological malignancies(hm). we observed a dramatic fall of blood pressure(bp) and development of septic shock(ss) in some of the patients who received antipyretics. aim: to clarify can antipyretics provoke ss in neutropenic patients with infection. methods: retrospective review of medicat records of neutropenic(wbc < , / )patients with hm, admitted to the intensive care unit for ss, was performed. there was selected group of patients receiving antipyretics shortly before a fall of bp. results: there was a definite causal relationship between receiving antipyretics and fall of bp in from patients. all patients had fever due to infection and had normal level of bp before receiving antipyretics. hypotension developed within minutes up to , hours after administration of antipyretics. three patients received , g of metamisol and one , g ofparacetamol per os. in all cases we observed dramatic diaphoresis and the temperature fall to subnormal level ( . + . ~ accompanied'by hypotension. but in - hours the fever was coming back without blood pressure elevation. the fluid replacement was controlled by central venous or wedge pressures. there were required + ml colloid and cristalloid solutions for volume loading. in spite of fluid administration the hypotension persisted and all patients required inotropic therapy. only one patient survived and is alive now. conclusion: it seems to us that our data offer to state that antipyretics administration can initiate ss in febrile neutropeuic patients with infection. objectives: to assess the agreement between cardiac output (co) measured by odm t and by other methods used in icu patients. methods: we prospectively studied adu t patients requiring hemodynamic monitoring with a pulmonary artery catheter. an esophageal doppler monitor provided measurements of co (odm), stroke volume and flow time (ft) used as an indirect evaluation of patient's volume status. patient hemodynamic status was evaluated by a modified fast response pulmonary artery catheter (baxter health care corporation, santa ana, ca), allowing co measurements by thermodilution "d) and an evaluation of right ventricular ejection fraction and end diastolic volume (rvef and rv-edv). in the last six patients co was measured by transthoracic echocardiography (echo) and oxygen consumption was measured by a deltatrack ii metabolic monitor (datex) allowing co calculation according to the fick formula (fick). the agreement between methods measuring co and their reproducibility, were evaluated by bland and altman analysis. results: agreement between co measurements is expressed as bias (d) and % limits of agreement (l of a = d_+ sd . td-fick - . - . to . fick-echo . - . to . there was no correlation between ft and rv-edv. conclusions: although co measurements by odmil had the best reproducibility, the limits of agreement between the four methods tested were unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of co measurement in the icu. phd, a. paltzev, v.bajbikov, b.dobryakov d.sc., a.ostanin phd, o.leplifia phd, h.chernykh phd munieip. hosp. n l, n ; inst. of clin. immunol., novosibirsk, russia objectivies: efficiency of native cytokines used in the treatment of patients with severe surgical infections has been studied. methods: for two years patients were treated with cytokine mixture (ssp) obtained by arterio-venous perfusion of swine spleen and contained the following cytokines: il- , il- , il- , tnfa, ifny, gm-csf. results: ssp intravenous infusions were shown to accompany with mortality decrease from . % to . % in patients with abscessed pneumonia and lung abscesses and from % to % if disease course was complicated with sepsis. in patients with purulent peritonitis and sepsis efficiency of ssp was decreased due to endotoxieosis. thus, we used adoptive immunotherapy with mnc activated in vitro with ssp or recombinant il- . intravenous infusions of such cells resulted in transformation of a pathologic process from destructive into productive one. moreover, clinical manifestations of sepsis were controlled in % and mortality was decreased from % to %. conclusions: the use of eytokines themselves as well as cytokine-treated lymphoeytes permits to control the disease and leads to the mortnlity decrease owing to stimulation of host defence mechanisms. background: although red blood cell transfusions (rbct) are used to increase oxygen availability in septic patients, several lines of evidence suggest that rbct may actually worsen tissue hypoxia. thus, rbct may negatively influence outcome of septic patients. objectives: to determine the association of ) rbct ; ) number of units transfused; and ) mean age of the units transfused on the first day of transfusion with mortality of critically ill septic patients. methods: we prospectively identified patients who met strict criteria for sepsis syndrome (ss) seen in the icu of st. paul's hospital from to and excluded patients who died in the first days after the onset of sepsis. we recorded clinical characteristics, multiple system organ failure score, and apache ii at onset of sepsis. then, we retrospectively recorded the total number and age of rbc units transfused during the first days after onset of sepsis. overall -day mortality was %. results: the main results are shown in the table. the mortality of patients who received rbct was nearly double the mortality of those who did not receive rbct even after adjusting for severity of illness using apache ii. objectives: gastric mucosal acidosis is frequently observed in patients with sepsis. the aim of this study was to determine whether volume infusion using pentaspan| decreases abnormal gastric mucosal pco (pico ) in patients who have sepsis syndrome (ss) who have already been resuscitated using clinical endpoints. methods: we prospectively identified patients who met strict criteria for ss, had a pulmonary artery catheter and a gastric tonometer in place, and pico > mmhg. pentaspan| ( ml) was infused in rain. measurements of hemodynamics, hemoglobin, arterial lactate, blood gas analysis, and pico were performed before and repeated miff and hr after pentaspun| infusion. we calculated the pico -arterial pco' difference (pico -paco ) and phi (using henderson-hasselbach equation). anova was used to assess statistical significance. results: all patients werereceiving adrenergie drugs. map was : : mmhg and lactate . : : . mmol/l. pentaspan| increased ci by % (p< . ) but did not change pico ( and increase m oxygen o* wery were simimny achieved in both groups. nevertheless, epinephrine was associated with a lactic acidosis and increased laetate/pyruvatemia ratio (l/p) that evoke a dysoxia rather than a metabolic effect. an higher gastric mucosal pco in the ep group compared to nor-rob suggests the hypothesis of an anaerobic production of co in favor of a splanchnic hypoxia. in both group, arterial ketone body ratio that reflects hepatic mitochondrial redox state, compared to a control group without shock was decreased but increased between and hours after restoration of arterial pressure. the association norepinephrine-dobutamine seems to be better for splanehnic circulation than epinephrine and should be used for dopamine resistant septic shock. moreover, the increase in arterial pressure with nor-dob improved gastric mueosal ph and hepatic mitochondrial redox state and argue to reconsider arterial pressure as a significant goal for resuscitation in septic shock. conclusion: significantly higher malondialdehyde and ghitathione levels and glutathione-peroxidase activity in group ns at the end of icu stay were related to mortality these findings indicate an increased generation of free oxygen radicals together with increased anfioxidant activity in this group and sapport the employment of antioxidant interventions in critically ill patients. oblecfives: to determine the role of nitric oxide (no) in the mechanism of septic shock induced by isolated limb perfuslen with recombinant tnfcr methods: we have measured tnfr~ and metebo~ites of no in patients with signs ot septic shock following treatment with isolated limb perfusion for nonresectable soft tissue tumors and melanomas of a limb. perfuslen was carried out with melphalan (burroughs wellcome) and recombinant tnfcr (boehringer). tnfc~ was determined by specific radiometric assay (medgenix diagnostics), nitrate and nitrite were measured with a modification of the guess reaction ~. results: results are shown in the table. conclusions: during isolated limb pedusion with recombinant tnf~ very high levels of tnfcr were measured in arterial blood in patients. they all showed signs of severe sepsis syndrome with shock from vasodilafion, probably due to leak of recombinant tnft~ from the peduslen circuit to the systemic circulation. tnfc~-induced vasodilation was not accompanied by a rise in serum no-metsbolites. our findings do not confirm the widely accepted theory, mainly based on animal experiments, that genera• of no is the key pathogenefic mechanism in septic vasodilafion , nor that tnfrt invariably induces forreafion of no. the precise mechanism of shock in these patients remains to be elucidated. references: . moshage h, kok b, huizenga jr, jansen plm nitrite and nitrate determinaiions in plasma: a critical evaluation. clin chem : / . . moncada s, higgs a. the l-argioine-nitrio oxide pathway. n engl j med ; : - ec is a commonly used for prolonged, stable animal anesthesia. noting that the hypotension after iv lps was attenuated by ec, we hypothesized ec also protects against lps toxicity. sprague-dawley rats received ip saline (s), thiobutabarbita mg/kg (tb), or varied doses of ec, followed hours later by bolus mg/kg iv lps. -day survival is shown below: group: s tb ec( . gmikgi ec( .sgm/kg) ec(i. gm/kg) alive (n) t ~ total (n) s s "signiflcant;y different from all other groups, p< . s / rats given lps followed hours later by ec ( . gm/kg) also died. additional rats were treated with s (n= ) or gm/kg ec (n= ) followed by mg/kg lps, then sacrificed at hours. blood glucose (bg, mg/dl),.hematocrit (hct), leukocyte count (wsc/mm~ platelet count (pltxl ~/mm ), bicarbonate (hco, mg/dl), gross bowel hemorrhage (bh, - scale) and lung myeioperoxidase activity (mpo, ~vmirvgm wet lung) are shown below ( we conclude that ec reduces the lethality and multiple organ toxit;~ty of lps. its diverse effects suggest asite of activity upstream from the cytokine cascade. these results are important for studies of lps which may use ec anesthesia and may have potential in the therapy of septic shock. [zo = hz impedance (z; {dyn.sec.cm " }); zl = first harmonic z; zc = characteristic z; z ph. = t'trst harmonic phase angle {radians}; f, #, * at least p < . between fio . and . , fio . and fio . &no - . _+ . - . _+ . # - . + . m - . + . * - . + . * - . + . * - . _+ . * in hyperoxia, compared to dogs at the same q, minipigs had a higher ppa ( + rnmhg versus + mmhg; p < . ). hypoxia increased (ppa-ppao) at all levels of q by an average of mmi-ig in minipigs and mmhg in dogs. inhaled no inhibited hypoxia-induced (ppao-ppa)/q changes in both species. conclusions: we conclude ~ that the minipig is an animal model of elevated pulmonary vascular resistance and impedance, and ~ that hypoxia-induced alterations in pvz spectrum are due to changes of resistance in small arteries. objectives: ) to determine the toxicity of ng-monomethyi-larginine (nma) administered by intravenous bolus to patients with refractory septic shock. ) to investigate the biologic activity of nitric oxide synthase inhibitors in septic shock. methods: from august to january , thirteen patients with vasopressor refractory septic shock received nma intravenously in escalating doses from to mg/kg. results: no hepatic, renal, gastrointestinal, or hematologic toxicity was observed at doses of nma as high as mg/kg. significant biological activity was observed at all dose levels consisting of increased blood pressure (systolic blood pressure from . mm hg + . to . _+ . s.e.m., p= . , systemic vascular resistance ( + to + dyne.sec/ cm s, p=. ), and a decrease in vasopressor requirements. the magnitude and duration of these effect were dose dependent. decreased cardiac output ( . _+ . to . _+ . i/min p=. ) and increased pulmonary artery pressure ( . _+ . to . _+ . mm hg; p=. ) were also observed. no significant effects on heart rate, pulmonary capillary wedge pressure, or central venous pressure were observed. four of patients survived for more than days, patients died of cancer complications (all patients had maintained blood pressure for h on nma) and patients died of complication attributable to septic shock (mods, ards, dic, refractory hypotension), and patient was unevaluable. conclusions: no adverse clinical effects have been observed in patients receiving bolus doses of nma as high as mg/kg. the increased pulmonary artery pressures observed in septic shock patients is further augmented by nma and may limit the dose which can be administered by intravenous bolus. other schedules of drug dosing may attenuate this effect. glucose-insulin-potassium (gik) solutions have been shown to improve cardiac contractility and increase oxygen availability in experimental and clinical settings of septic shock. several mechanisms have been proposed to explain these effects including a direct improvemeut of the energy balance by glucose, a direct influence of insulin on cardiac performance or an increase in intravascular volume due to the hyperosmolarity of the solution. to explore the role of hyperosmolapity, we compared the effects of gik to those of a isoosmolar hypertonic saliue solutiou in endotoxin shock in dogs. methods : the study included mongrel dogs ( • pentobarbitalanesthetized aud mechanically ventilated with air. thirty minutes after the intravenotls administration of mg/kg of e. coli endotoxin, the dogs were randomized to receive a ml/kg infusion in rain of a hypertonic ( mosm]l) solution iucludiug either a mixture of glucose % with u insulin and meq kcl/l (glk-group ) or hydroxyethyl starch . % in naci . % (hes-group ). in each dog, a . % saline infi~sion was continued to maintain the puhnonary arlery occluded pressure at baseline level. hemodynamic, blood gas aualysis and laboratory data were collecled at baseline and miu, rain, rain, and nunutes later.. results : eudotoxin administration was followed by a fall in mean arterial pressure (map) aud cardiac index (ci) and a rise in blood lactate levels. resuscitation with either gik or hes hypertoaic solutions resulted in similm increases in map, ci, oxygen delivery and left ventricular stroke index (table ) . we conclude that during resuscitation from endotoxic shock the use of gik solutions is not superior to hypertouic hes solutions. the higher blood lactate levels observed in the dogs receiving gik can be attributed to the glucose metabolism. , for group , for group ) were drawn and immediately analysed at ~ using the abl radiometer for po , pco and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the ps at ph= . , pco = mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood, as was the ps "in vivo" (i.e. the ps at the patient's value of ph, pcoz and temperature), using siggaard-andersen's algorithm. the data were compared by the one-way anova test and by the t-test for paired and unpaired samples. results: the mean resulting values (in mmhg) with the statistical differences are shown in table i. in addition, the time series analysis shows the mean ps~st values as statistically below the psin vivo" in the septic patients while the opposite is shown for the cardiac patients. no differences in the time analysis are demonstrated for the second group. a possible clinical significance may be drawn from these different behaviours. objectives:toxemia degree and humoral immunity condition have been studied in patients aged from to with progressive course of sepsis and polyorganic insufficience. methods: such toxemia and humoral immunity findings as lencositlcindex of toxication (lii), level of oligopeptides of the middle molecular mass registered at the wave length of nm(mmi) & nm (mm ), distribution index (id), immunoglobulins a,m,g, concentration of circulating immunocomplexes (cici & cic ) and also some clinical and biochemical findings on the , , day after the operation serve as criteria for treatment effect. results: it was founded that in intensive therapy and detoxication, level of lii is successively decreased from . ~ . to . +. on the -th day after the operation. true decrease of the level mm from . ~. to . +. un & optimal density and increase of distribution index from . to . are argued. conclusions: in studlng the dynamics of the immunoglobulin's spectrum and the true increase of immunoglobulin g level from . +. g/i to i . +. g/i on the -th day after the operation simultaneously with the decrease of cic from . ~ to . ~ . (p . ) were founded. some stages of the investigation true increase of lymphocytes from . + . % to . + . % was noted and it appeared to be a favourable prognosis finding for disease outcome. high correlation dependence between bacillus-and segmentonuclear neutrophils and immunoglobullns g & m (r=. -. in p<. ) was discovered and it also showed positive dynamics of the course of the disease. a year old male patient was admitted to the icu with severe paraquat poisoning. treatment consisted of gastic lavage and oral administration of fullers earth. because of very high plasma levels hemodialysis together with charcoal hemoperfusion was started within one hour after admission. this treatment was further continued by continuous veno-venous hemofiltration in order to remove the circulating paraquat and also circulating cytokines. nevertheless patient s condition worsened necessitating artificial. ventilation and hemodynamic support. patient died hours after admission of acute multiple organ failure due to paraquat poisoning. serum levels of paraquat were determined by colorimetric method (table) . levels of interleukin (il ) and (il ), tumor necrosis factor (tnf-alpha), interleukin i receptor antagonist (il ra) were determined both in plasma and ultrafiltrate ( q~!ectives : evaluate in critically ill patients the effects of tow-dose dopamine on gastric mucosal blood flow (gmbf) using laser-doppler flowmetry, a continuous non invasive method of assessing microcirculation. methods : patients requiring both mechanical ventilation and pulmonary artery catheterization for multiple trauma (n= ), ards (n= ) and pancreatitis (n=l) were included. in each patient, the laser-doppler (ld) probe was inserted through a naso-gastric tube. the ld signal is proportional to the number of red blood cells moving in the measuring volume and the mean velocity of these cells. when the ld signal was satisfactory, an aspiration was created into a catheter which was fixed in parallel to the ld probe, to maintain the tip of the probe against the gastric wall at the site of measurement. data (systemic hemodynamic parameters and gmbf) were obtained at the end of a rain resting period (baseline), then min after dopamine ( mcg/kg/min) infusion, and finally rain after the end of dopamine infusion (recovery gmbf _+ (perfusion units) gmbf ~a% vs baseline) * p < . vs "baseline" and "recovery". conclusions : ) despite a slight increase in co (+ %), the dramatical increase in gmbf (+ %) with dopamine, strongly suggests a selective vasodilator effect of low-dose dopamine on gasaic mucosal perfusion. ) laser-doppler flowmetry appears a promising method to assess gastric microcircalation in critically ill patients. increasing evidence suggests that the activation of inos is the final common pathway for vasodilation in human sepsis associated with endotoxic shock. activation of the cellular immune system induces the excessive release of the pteridines neopterin (n) and , -dihydroneopterin (nh ) by human macrophages/monocytes. besides the well established diagnostic value of pteridines in several inflammatory diseases, it is speculated that these substances per se exhibit biochemical functions. thus we hypothesize that pteridines can modulate inos gene expression in vascular smooth muscle cells (vsmc) in vilro. cdtured rat aortic vsmc from female wistar kyoto rats were incubated with n ( pm), nh ( ilm), lipopolysaccharide (lps, ~g/ml), and interferone-~/(ifn-~/, u/ml) for h, respectively, inos gene expression was measured by competitive reverse transcription polymerase chain reaction. the results are summarized in the table. the present study demonstxates a neopterin induced increase in inos mrna expression at the transcriptional level in vsmc. while coincuhation of cells with n + lps resulted in an additive effect on inos gene expression, n + ifn- seem to have a more than additive effect nh did not alter inos mrna synthesis, but it suppresses the lps as well as the ifn-yinduced augmentation of inos gene expression. we speculate that this pteridine-mediated modulation of inos gene expression is involved in the regulation of the vascular tone in endotoxic septic shock. the relationship of sepsis and coagulation abnormalities is well known, mainly in severe sepsis and septic shock. still farther, the extreme expression of hemostasis abnormalities (disseminated intravascular coagulation) in sepsis, has been extensively described. we studied the changes in several coagulation and fibrinolysis markers in septic patients, trying to correlate them with the evolution of the sepsis phenomenon, with an emphasis in its early stages, where therapeutic intervention might be more drastic. in patients, with sepsis, with severe sepsis and with septic shock, as well as in healthy volunteers (control group) we measured : platelet (ptl), coagulation markers [fxii, fvii, fviii, fvw, fibrinogen (fibr) we conclude that all parts of the coagulation system are gradually changed during the evolution of sepsis phenomenon , even in the earliest stage of sepsis. the expression of an inducible nitric oxide (no) synthase (inos) plays a major role in the pathophysiology of septic shock (ss). inhibition of inos could therefore be of therapeutic value. however, such an inhibition has been shown to be detrimental, increasing tissue anoxia (and end-organ damage), possibly through the simultaneous blockade of constitutive nos (cnos). thus, selective inhibition of inos might be more suitable. we evaluated the effects of l-canavanine (can), a more potent inhibitor of inos than cnos, in an animal model of ss. method: in anesthetized rats, catheters were placed in the femoral vein and artery. rats were given an iv bolus of lipopolysaccharide (lps, mg/kg), at baseline (to). after h (t ), rats received at random an infusion of either can ( mg/kg/h; can group, n=l ) or an equivalent volume of . % naci ( cc/kg/h; nac group, n= ), giyen over h (t -t ). a third group (sham group, n= ) received . % nac in place of lps, and then was treated like the nac group. mean blood pressure (mbp), blood lactate and nitrates (no ) were measured each h. glucose, creatinine and asat were also measured in rats (n= in each group). the can _+ * + "t . + . "~ . +_ . "t + " + " *p< . can vs naci ?p< . vs sham can suppressed the hypotension, reduced the hypoglycemia and hyperlactatemia, and attenuated the biological signs of renal and hepatic dysfunction induced by endotoxemia. these effects were associated with a lesser elevation of blood no , confirming a partial inhibition of inos. conclusion: l-canavanine attenuates the hemodynamic and metabolic consequences of endotoxemia in the rat. these effects may be related to a partial inhibition of inos. they contrast with the deleterious effects described with non selective inhibitors of nos. l-canavanine could become a new tool for the treatment of septic shock. rocalc tonin :marker of sepsis, ii~flammaiiur% t~ boifi .cheval*~ jf.timsit*, m.assicot**, b.misset*,/.carlet*, c.bohuon** saint joseph heap, paris**biochemistry institut g roussy, villejuif, ce bi~)l~i~ttectives_: high serum levels of procalcitoaln (proct) have been shown to be ~ss-ocinted with bacterial infection. however, few data exist about the ability of proct to differenciate septic shock and shock from other origin in which an activation of intlmmamtory mediators has been also demonstrated. methods: thirteen patients with bacterial septic shock (ss), patients with non septic shock (nss), patients with bacterial infection without shock ( nf) and icu patients without shock and without infection (control) were compared for proct levels at dayl, , , , . patients were classified blindly and independently fi'om proct results. twelve patients were excluded because any classification was impossible due to mixed pathology. proct was measured with ebemoluminescenee (brahms diagnostica-berlin). results: dayl, proct levels are significantly different between the four groups. dayl proct levels are correlated with saps (p= . ), infection ( . +_ vs _+ ,p= . ), shock ( _+ vs +.- ,p= . ), death at day ( _+ vs _+ ,p= . ). when shock and infection are introduced in multifactor &nov& only infection remains correlated with day proct levels ( = . ) in patients with shock, dayl proct levels are correlated with saps, infection and death at day , but not with arterial lactate levels (p= . ), white blood calls (p= . ) or fever (p= . ). proct levels remain higher i~i septic shock patients at day , and ( figure) . i c edpsion: procalcitonin levels in the first three days of shock are differen[" between septic and non septic shock patients. in patients with diseases known to induce acute an inflammatory process, procaldtonin seems to be a marker o~ infection. obiectives-to evaluate the effect of endotoxic shock on the distribution of blood flow between the mucosal and the muscular layer of the intestinal wall. methods: in fasted pigs, mean aortic pressure (map, mm hg), cardiac output (co, ml/min-kg),superior mesenteric artery flow (q sma, ml/min.kg), and phi, where measured before (control) and after i.v. endotoxin ( gg/kg). the blood flow to the mucosal and the muscular layer was measured in regions (proximal jejunum (pj), mid-small intestine (mi) and terminal ileum (ti)) by colored microspheres, using adjacent samples in each region. the muscular layer was separated from the mucosa by blunt dissection, and the flow determined independently in each layer. results: endotoxin with fluid resuscitation induced the expected decrease in map ( . _+ . vs . -+ . , p< . ), and phi ( . !-_ . vs . _+ . , p< . ), with a constant co ( _+ vs _+ , p= . ) and qst, aa ( . _+ . vs . _+ . , p= . ). the results of regional pertusion are presented in the table. (flow in ml/rain g of tissue; mean _+ sem ; * p< . vs control by two-way anova) conclusions-these data indicate that the mucosal flow increased during septic shock. they suggest that a decrease in phi may be due to hypoper~usion of the muscular layer or to metabolic alterations within the mucosa, despite a % increase in flow. acute increase in wbc count (from a mean of lo.oo mm a to o /mm~), between the rd and the th day of therapy. there was a decline of the wbc count to an average of about . mm a after decreasing the daily dose of the medication to mcg there was no increase in tile absolute number of the eosinophils during the whole course of the medication. there was a slight decrease in the c complement between . to . g/i. normal values . to . g/i there was no change in c values. conclusions : an early increase in wbc count was observed ( rd day) without subsequent increase in the number of immature types from bone marrow, probably due to the mobilization of wbc from the periphery and this increase was dose dependent. there was a slight decrease in c fraction of complement, probably due to the consumption of this fraction in the process of opsonization. no adverse effects of the medication were observed, during the treatment with the above dose. these data sugest that cm csf may be a useful complement to tile main antimlcrobial treat,nent ~ of septic [cu patients. objectives: as part of a large multicentric, placebo-controlled, randomized clinical trial investigating the effects of interleukin- receptor antagonist (ii-lra) in the treatment of severe sepsis and septic shock, this substudy evaluated in dem.il the acute hemodynamic effects of ii-lra in patients who were invasively monitored. methods: in a total of evaluable patients in whom vasoactive support was little altered, hemodynamic measurements were performed at baseline (twice), and i hour, h, h, h, h, and h after the administration of mg/kg (n= ) or mg/kg (n= ) of i - ra or the corresponding placebo (n = ). / patients ( %) were treated with adrenergie agents and / ( %) with mechanical ventilation. data were analyzed by a kruskal-wallis test. results: during the study, there was no significant difference with time or between groups in arterial pressure, cardiac filling pressures, cardiac index or left ventricular stroke work (figure). burmester, "~ man and h. djonlagic medical university (internal medicine, "cardiology, *'microbiology) and "**southern city hospital, lfibeck, germany obiectives: evaluation of the incidence of bacteremia and sepsis in patients with nontyphoidal salmonella (s.) infections, specification of risk factors, need of icu treatment, clinical course, and mortality in the group of the patients who developed septic complications. methods: data of all patients with microbiologically proven s. infections hospitalized in the medical university of lobeck and in the southern city hospital of l beck from to . results: within the observation period s. was isolated from the stool cultures of patients. in patients (g m, f, median age yrs) s. could be detected in blood cultures ( s. enteritidis, s. typhimurium). in addition, in of these patients s. was also isolated from other specimens (urine, liquor, and tissue fluids derived from abscess punctures). in all patients with positive blood cultures the clinical course of s, infection was complicated: ? patients developed mof (acute renal failure, ards, hemodynamic instability, dic) and required icu treatment for at least up to days, of the patients died. the predisposing disorders in the patients with s. bacteremia were (n=): aids ( ), immunosuppressive drugs ( ), chronic alcoholism ( ), malignancies ( ), none ( ). septic complications in patients with nontyphoidal s, infections are relatively rare (in this study < % of all hospitalized patients with microbiologically proven salmonellosis) but severe (mortality of approx. %). patients at risk for a complicated clinical course are predominantly those with predisposing disorders but occasionally also patients without evidence for an underlying disease. age (yr) + + death (n) duration of shock (h) + + noradrenaline (rag/h) , _+ + temperature (~ , + , + pvr (dynxsecxcm - ) + + co (ljmin) , _+ , , + , lactate (mmol/l) + , , + interleukin- (pg/ml) _+ + interleukin- (pg/ml) , _+ , , + , tnf-alpha (pg/ml) , + , + neopterin (nmol/l) , + , + crp (rag/l) _+ +_ pro-ct (ng/ml) , + , , + there was no positive correlation between serum lactate levels, degree of shock, hypoxemia and pro-ct positivity. pts with septic shock of bacterial origin entirely developed hyperprocalcitoninemia, whereas pts with cardiogenic shock, who expired within h did not. however, in late cardiogenic shock (> h) all pts developed fever of unknown origin and consecutive hyperprocalcitoninemia. these data suggest bacterial inflammation and/or mucosal translocation of bacterial products in pts with prolonged cardiogenic shock. the use of a loading dose of quinine ( . mg/kg base in h) is recommended in previously untreated patients (pts) with sfm, particularly in multi-drug resistance areas. this protocol is difficult to validate, since the viability of microorganisms is not assessed routinely in parasitology laboratories. objectives: to examine the evolution of parasite viability during the early phase of therapy of sfm. methods: from / to / , pts with sfm (who ) treated with iv quinine for less than h were included prospectively. blood samples were collected at o, , , , , and h viability was assessed by culturing parasitized red blood cells in the presence of h-hypoxanthine, and radioactivity was determined at h by scintillation counting. viability was expressed as the percentage of radioactivity compared to the initial sample. plasma quinine was determined by liquid chromatography. tile ratio plasma quinine (pmol/ )xlo /icso for quinine (nmo]/]) was called the parasiticida/ index. results: pts were included, • saps . -+ . . the initial parasitemia was t. + . %. complications of malaria were coma ( pts), shock ( pts), renal failure ( pts) and acute lung injury ( pts). all strains were sensitive to quinine (icso -- nmol/ ). in pts who were not given a loading dose, parasite viability increased by and %, with concomitantly low quinine levels ( and #mow] at h); pt died. in pts that received a loading dose (serum quinine at h = . -- . ~mol/]) a marked decrease of parasite viability (by +_ % at h) was shown. viability was inversely correlated with plasma quinine (r=. , p-.o ) and parasiticidal index (r=. , p-.o ). conclusions: even with fully sensitive strains, the use of a loading dose of quinine seems warranted in severe falciparum malaria in order to reach rapidly adequate plasma quinine ]evels, necessary to inhibit significantly parasite viability. l nkka, e ruokonell j takala. critical care research program, department of intensive care, kuopio univ hospital, finland objective: to determine the incidence of positive blood cultures, their microbial subgroups and to evaluate the outcome of icu patients with different bacleremias. material and methods: we analysed all positive blood cultures in consecutive admission to a university hospital icu in - and the icu and hospital survival of the bacteremia patients. during these years patients had positive blood cultures that were considered as clinically relevant, excluding colonizations or contanfinations. results: patients with positive blood cultures had an icu survival of . % (vs. , % in all icu patients) and six month survival of . % (vs. . % in all icu patients). the most common bacteria were enterobacteriaceae ( , %), staphylococcus aureus ( , %) , coagulase negative staphylococci ( . %), pseudomonas ( . %) and slieptococci ( . %). obiectives: to evaluate prognostic factors and mortality in consecutive patients (pts) with hiv infection and septic shock. methods: from - to - , records of consecutivepts with septic shock (crit care med , : - ) admitted to the icu were reviewed retrospectively. results: among pts with septic shock admitted during the study period, had hiv infection- of whom had aids-(gr. i) and were hiv-negative (gr. ill. ten gr. ii pts ( %) were irnmunosuppressed because of neoplastic or immune dlsease. mechanica] ventilation was required in % gr. i and % gr. ii pts in gr . i pts ( %) a multivariate analysis demonstrated that hiv infection and sap i were independently predictive of death in pts with septic shock. ~onclusions: evidence of increased mortality, number of organ failures and higher severity scores (saps i does not take into account immunosuppression) is demonstrated in hi v-positive pts, infection with hiv appears to be an independent prognostic factor in pts with septic shock. the frequency of opportunistic infections (often responsible for delayed diagnosis and treatment) may contribute to the poor prognosis in this population. obiectives: to determine interleukin (il)-i levels in plasma of patients with sepsis and septic shock. to analyze the relationship between plasma il- and the proinflammatory mediators, tumor necrosis factor-aifa (tnf) and il- , the underlying severity of the disease and the evolution of patients with sepsis. methods: we studied critically ill patients ( men, women; - years old) in three diferents groups. group i: patients without evidence of infection, group i : patients with sepsis and with septic shock (group iii). we measured plasma il-lo, tnf and il- levels in the first hours of diagnosis. severity of illness was estimated with the acute physiology and chronic health evaluation (apache ii) scoring sytem. results: plasma levels of il- were higher in group iii (median, pg/ml; range, - pg/ml) than in group ii (median, pg/ml; range, - pg/ml; p <. ) and group i (median, pg/ml; range, - pg/ml; p <. ). median il- concentrations did not differ among patients who survived (median pg/ml; range, - pg/ml) and those who died during the overall follow-up period ( days) (median, ; range, - pg/ml); but patients who died in short-term (< hours) with catecholamine-refractory hypotension showed the highest concentrations of il-io (median, pg/ml; range, - pg/ml). in patients with bacteriemia ( %), levels of il- were higher (median, pg/ml; range, - pg/ml) than in those with negative blood culture (median, , pg/ml; range - . pg/ml; p< . ). there was a good correlation between plasma il-io concentration and levels of tnf (r= . ; p < . ) and il- (r= . ; p < . ). the correlation between levels of il- and the apache ii score was significant only in the septic shock group (r= . ; p <. ). conclusions: in septic shock, il-io and proinflammatory citokines are released in high concentrations. the significant correlation observed in patients with septic shock between il- levels and apache ii, short-term death and bacteriemia can possibly be explained by the massive inflammatory response in septic shock with fulminant course. intensive care department -calmette hospital - lille -france. in septic shock, inadequate splanchnic blood flow may play a prominent role in the pathogenesis of multiple organ failure. measurement of gastric phi has been propose to evaluate tissue oxygenation in splanchnic organs. objectives: to compare gastric phi values with hepatic icg clearance, an index of liver blood flow and function ; to determine if one of these two methods could be proposed to assess the entire splanctmic peffusion in septic shock. methods : patients (age : • years ; saps ii : • were prospectively investigated (septic shock : bone criteria). following parameters were collected during hours : systemic hemodynamic parameters (swan ganz catheter a h -ref computer -baxter lab.), calculated systemic oxygen transport (do ), oxygen consumption (vo ) by indirect calorimetry (deltatrac datex lab.), gastric intramucosal pco (pco ss) and phi (trip -ngs catheter -tonometrics lab.) and plasma disappearance rate of icg (pdr dye) (femoral artery fiberoptic/thermistor catheter , cold z computer -pulsian medizintechnik, germany). correlations were performed using a linear regression. elevated in all days with the highest value in second and third days of treatment. nonsurvivors had higher values of these parameters than survivors but differences did not reach statistical significance. another trend of changes were observed in selectin p (gmp- ) concentration. in all patients concentrations measured were elevated but in survivors after not significant decrease this parameter in second day another one had simmilar values. in patients who died we noted significant decrease in third day (p < . ) whereafter prominent increase, significant after seventh day, in comparison to third day value and value in survivors group. icam- concentrations in all patients reached high levels and in nonsurvivors after four day of treatment significant increase in comparison to survivors we found. conclusions: multiple trauma complicated with sepsis induce rapid elevation of concentrations of il- , il- and increased expressior of adhession molecules (selectin e, p, icam- ) measure of icam- and selectin p concentration determine lung injury severity and prognosis as to health and life. (clp) .pathophysiology of cip is unclear, but changes in regional bloodflow may be a ~ignificant factor. nerve blood flow (nbf)is reduced in rat models of hemorrhagic shock (g),but no information is available in sepsis. we studied the comparative effect of acute endotoxemic shock {etx)& h on perfusion of rat sciatic nerve. methods: male sprague-dawley rats were anesthetized with pentobarbital (ip), instrumented with a tracheostomy, carotid arterial & venous catheters and mechanically ventilated (fi = . ). the left sciatic nerve was surgically exposed. monitored variables included: a) mean arterial pressure (map,mmhg) ,b) nbf (ml/ o g/min) by laser doppler flow meter,c) nerve internal arterial diameter (id ~ m) by video image shearing and splitting method. after stable baseline measurements were obtained, acute hypotension was induced by randomly assigning the rats to etx ( . b , difco) in saline at mg/kg or h. both interventions produced % reduction in map within min., which recovered to baseline values spontaneously in etx group, & by reinfusion of heparinized withdrawn blood in m. data were analyzed by linear regression, two-way repeated measures analysis of variance followed by bonferroni-t method. experimental stages were:( )baseline, ( ) mid-point of map reduction; ( ) nadir of hypotension, ( )midpoint of map recovery, & ( ) after stable recovery of map. both etx & h induced shock result in similar reduction in nbf consistent with lack of autoregulation in peripheral nerve vessels independent of etiology. since cip is primarily associated with sepsis, it is not likely that acute reduction in nbf alone causes cip. direct & indirect neurotoxic effects of mediators of sepsis need to be evaluated. .':_.~::::o o:oc ., objectives : evaluate the relationship between il- , a cytokine which inhibits tnf, production and protects mice from endotoxin toxicity, and the other proinflammatory cylokines, tnf~, il and ils in severe sepsis and septic shock. methods : twenty-eight icu patients ( m, f, mean age + y) were studied as soon as they developped a severe sepsis (n = ) or a septic shock episode (n= ) as defined by a conference consensus in ( ). tnf~, il , il s and il- plasma levels were measured by immuno-radiometrie assays from medgenix (fleurus, belgium). lc mean and range. results : the comparisons between cytokine levels in severe sepsis versus septic shock were made using the logarithm of the value in order to normalize the distribution of data, and student test. il- plasma levels were higher in patients with septic shock than in patients in severe sepsis. there was a significant correlation (p < . ) between il- and tnf a (r= . ), il- and il~ (r = . ) and il- and il s (r = . ) as well as between il- and apache n score (r= . ). patients who died (n = ) had il- levels higher than patients who survived but this difference was not statistically significant ( pg/ml vs . pg/ml; p> . ). conclusions : during severe sepsis and sepsis shock, il- seems at least to follow the same evolution (increase in plasmatic level) with the severity of sepsis as the other cytokines. reference : ( ) crit care med ; : - . objectives: to evaluate the effects of steroids on hemodynamics and mortality in septic patients with konwn levels of cortisol concentration. methods: retrospectively we analyzed data ofpatients with documented septic shock who received steroids after assessment of adrenal function. in all patients hemodynamic parameters as well as the necessary vasoactive medication were assessed, before and hours after corticosteroid medication. immediately before administration of corticosteroids adrenal function was evaluated with cortisol levels before and after synthetic corticotropin ( . mg). finally we studied mortality. we defined a positive respons on corticosteroids as an elevation of map of at least mmhg and/or a decrease in the necessary vasoactive medication of at least % within hours. adrenal insufficiency was defined as a cortisol level after stimulation of less than nmol/l. results: of patients were found to respond to steroid medication, did not. mean cortisol levels before and after corticotropin were • and • nmol/l in the responder group (rg) and • and • nmol/l in the non responder group (nrg). in the rg out of ( %) were found to have an adrenal insufficiency, in the nrg out of ( %). in the rg -weeks mortality was . % (l out of ), the overall mortality % ( out of ). mortality in the nrg was % ( out of ) (p < . ) and % ( out of ) (p < . ) respectively. conclusions: in patients in septic shock there is a beneficial effect of steroids in case of adrenal insufficiency, but also in a subgroup with normal adrenal f{unction. obiectives: intercellular adhesion is a critical step in the accumulation of leukocytes. postischemic cardiac lymph has the capacity to stimulate icam-i. in the coronary microcirculation neutrophils can be trapped and in many cases obstruct capillaries, previously we found that troponin t (s-tnt) a marker for myocardial iechemia, was increased in septic patients. the aim of the study was to follow slcam- and s-tnt levels continuously starting at the beginning of sepsis. methods: patients were ingluded in this institutionally approved study after relatives had given their informed consent. all patients were included within hrs following the beginning of sepsis. blood was drawn every hrs in the first ;~ hrs, after hrs, followed once per day for days. s-tnt, icam- , elam (elisa's, boehringer mannheim inc, r&d systems ltd.) arterial and venous blood gases were determined, an ecg and a complete hemedynamir measurement including cardiac output were obtained. all patients received adequate volume and catecholamine therapy (norepinephrine, dopamine, dobutamine; median (range) . ( . - . ), . ( . - ), . ( . - . ) pg/kg/min, respectively). statistical analysis: wileoxon signed rank-sum test. . ( . - . ) . patients had s-tnt levels > . pg/l. of these died, whereas only of patients died with s-tnt values < . pg/l (p= . ). all patients that died had elevated sjcam- levels ( ilg/l:cut-off ) whereas in the survivor group only % had elevated icam- levels (p= , ). conclusions: increased slcam- and s-tnt levels were found during early sepsis in the majority of patients, a high sicam- and s-tnt value was associated with a higher mortality. the research of the noninvasive haemodynamic monitoring accelerated recently all over the world. the aim of our study was to test whether the changes of the haemodynamk parameters measured by impedance cardiography (icg) were corresponded to clinical changes in septic patients. investigations were performed on critically ill postoperative septic patients (their multiple organ failure score was - /with icg monitor. in cases the investigation~ were performed in septic shock. the measured parameters were: heart rate (hr), mean arterial pressure (map), cardiac output (co), peripherial resistance (svr),preejection period (pep), and ventricular ejection time (vet). these parameters were measured during - hours in every minutes, depending on the patients cl~tnical condition. results: at the septic patients the hr and the co ]~reased. in septic shock the co was significantly higher the svr lower than in the septic group. in the hr there was no difference between the two groups. in septic shock noradrenalin influenced more effectively the measured parameters than dobutamin. conclusion: the trend of the measured icg parameters correlated with the clinical changes of septic patient's state. the noninvasive haemodynamic monitoring by impedance cardiography helps the planning and leading the adequate intensive therapy of these critically ill septic patients. to evaluate the development of sirs, sepsis and septic shock in hospitalized patients with fever, a prospective study was performed on patients using previously defined criteria. methods: normotensive patients with fever (temperature > . ~ axillary), admitted to the department of internal medicine were evaluated for the existence of sirs during the first three days of the study and sepsis at inclusion. during a follow-up period of days the patients were daily evaluated for the development of sepsis or septic shock. results: most patients ( %) had or developed sirs within the first three days, patients ( %) did not. sepsis was present in % at inclusion. in patients with sirs, % did not progress to sepsis or septic shock, % progressed to sepsis (mean interval . • . days), and patient (< %) directly progressed from sirs to septic shock. in patients with sepsis, % progressed to septic shock (mean interval . • . days). sepsis was preceded by sirs in %. septic shock was preceded by sepsis in % and by sirs in %. conclusions: % of patients with fever in an internal medicine department develop sirs, or sepsis. furthermore, progression from sirs to sepsis or septic shock is poorly predicted by fever or sirs. nevertheless, all patients with septic shock were preceded bysirs or sepsis. taken together, this may indicate a severity hierarchy of the syndromes. however, fever, sirs and sepsis are relatively poor indicators of development of septic shock. this supports further research on additional predictors of septic shock. b. m.manuylov, v.b.skobelsky (moscow) in recent years sodium hypochlorite (sh) has been successfully used to eliminate pyo-septic complications. moreover, the mechanism of the sh effect on the immune system has not been sufficiently studied. the aim of the present investigation was to study the mechanism of sh effect in inflammatory pulmonary diseases. patients with double pneumonia were subjected to the evaluation. sh in the concentration of mg/l in the volume of - m / hours was administered by drop infusion into the central vein. to evaluate one of the defence systems the leukocytes activity by the chemoluminescence technique was studied. in all the patients baseline secondary immunodeficiency which was indicated by the decrease in the luminescence level was established. even hour after the sh administration the leukocytes activation exp-ressed by the enhancement of their chemoluminescence . - times was observed. this supports the available findings that accumulation and liberation of the oxygen active forms (ol'oh, ' , h ) are accompanied by the increased phagocytosis, i,e. the signs of "the oxydation explosion" testify to the favourable sh effect on the course of inflammation processes. the use of sh permitted to decrease the percentage of lethality in double pneumonia by % in the intensive care unit over the year. at the same time, excessive activation of free radical oxygen may be a damaging factor. therefore, precise individual control over the choice of concentration, dosage and the preparation administration rate is required. prospective, double-blind, placebo-controlled, trial of atiii substitution in sepsis r. a. balk objective: pilot study to evaluate the efficacy and safety of atiii substimtion therapy in patients with sepsis. efficacy assessed using change in mortality or organ failure/dysfunction. adult patients meeting a definition of sepsis and cared for in a tertiary care academic medical center in chicago were identified and prospectively randomied to receive either atiii (kybernin p) or placebo in a double-blind treatment protocol. all other therapy and patient management were under the direction of the patient's attending physician. all patient's were followed for days and the organ dysfunction/failure were scored using published scoring systems (jordan et al crit. care med. , goris et al arch. surg. , kuaus et al ann. surg. colldusions:wha~ we met the shomaeker objectiv% the mortality and the pro~os[s were i~ttc*. those criteria were obtained with file tradititmal t~ctor likr doht~mme, hut c.~vh ~,as ca in~aertam measure. they ac~s smxergically in the optimizatic~l of the fell vmtrictdar work index, tad fimdameatally cavh seox~s to have an impo.aat role in the better respiratory ev-altmtioa, leaving yet the possibility to coltrol the flui& r althou~l eomproved it's not aec~pt~xl file importmlce h* the diminution, of the sepsis modiat~lrs llke fnt and il- with h~wmotiltrafi(al, stopphlg the evolution to nmltiorganic failure mid de~easethe mortality. with ours clhlicals results, we could saythat cavii in multiol~atlie disfut~oa septic patieats, se~r~ to be an c xilna] supoa or troatmeat maesure. of anaesthesia and intensive therapy, medical university of prcs, p~csf hungary. objectives: since some biological effects of bacterial endotoxin require an interaction between the lps molecule and a serum factor(s), we hypothesized that lps-induced no production and cgmp accumulation in vascular smooth muscle cells (vsmc), a mechanism ~thought to underlie cardiovascular collapse associated with septic shock, is modulated by serum factor(s). methods: cultured vsmc from rat aorta were challenged with e. coli lps for - hours either in the presence or absence of fetal calf serum (fbs), and no production was monitored by radioimmunoassay determination of cgmp content of hci extracts. results: in the absence of serum, o ng/ml lps was required to increase cgmp levels, whereas the presence of % fbs shifted the lps concentration curve i times to the left. similarly to fbs, human serum also potentiated lps-induced cgmp accumulation. in contrast to lps, serum had no effect on cgmp accumulation elicited by sodium nitroprusside, a no releasing agent, suggesting that the sensitivity of vsmc to generate cgmp in response to exogenous no is not modulated by serum. heat inactivation (> ~ min) but not removal of small molecules (< , d) from the serum by dialysis, reduced the potentiation of cgmp accumulation by serum. time course studied indicated that serum is required within the first min of lps exposure to increase cgmp levels. to investigate whether the effect of serum is specific for lps, we treated the cells with increasing concentration of interleukin -~ (il-i). % fbs shifted the il-iinduced cgmp responses five times to the left. conclusions: our study suggests that lower concentrations of e. cell lps and il-i require a heat labile macromolecule in the serum in order to elicit no production. this factor is present in the human serum and it may play a potentially important role during no synthesis induction in vsmc. objective: to evaluate the factors of acquisition and the outcome of methicillin resistant staphylococcus aureus (mrsa) bacteremia in an intensive care unit (icu). methods: all patients in which bacterermia due to staphylococcus aureus developed > hours following admission to our icu, during a year period ( january through january ) were reviewed. patients (pts) were included, mean age , y (sd , ), saps , (sd , ), mac cabe ( and ) %, mortality directly due to sepsis %. pts had mrsa bacteremia and methicillin susceptible staph. aureus (mssa) . both groups were compared using the chi square (with correction of yates), fisher's exact, student's t or wilcoxon test. results: there was no statistically significant difference between mrssa and mssa regarding at age ( , + , vs , + , ) , saps ( , + , vs , + , ), use of vancomycin ( % vs %), mechanical ventilation ( % vs %), number of days (d) before the drawing of the first positive blood culture (median d, range - d vs median d, range - d). more mrsa than mssa pts had previous use of nonsteroidal anti-inflammatory drugs (nsaid) ( % vs % p< , ), central venous catheter infection due to staph.aureus ( , % vs % p< , ), but previous use of antibiotics was not significantly different ( , % vs %). the outcome of the bacteremic pts was not statistically different: saps at the first day of bacteremia ( , +_. , vs , + , ), severe sepsis and septic shock ( % vs %), persistence of the bacteremia ( % vs %), mortality directly due to bacteremia ( % vs %). conclusion: previous use of nsaid, infection of venous central catheter are more frequently associated with mrsa bacteremia. thus, similar to others studies (hershow infect control hosp epidemio ; : - ) , these results do not indicate that mrsa is associated with increased virulence. objectives: to closer definition of mosf formation mechanismes in nosocomial sepsis (ns) the complex clinicobiochemical, microbiological, immunological, functional exaroination of cases with ns had been done. methods: examination of cellular and humoral immunity, nonspecific immunologic reactivity, systemic and hepatic circulation, microbiological examination of blood,electro-and echocardiography, sonography and computer tomography of chest and abdomen organs were obligatory. autopsy findings of dead cases had been analized. results: in cases ( , %) opportunistic pathogen microscopic flora ( staphylococcus anreus,staphylococcus epidermidis, staphylococcus saprophyticus) had been found out in blood inoculations. in cases ( %) side by side with destructive process in lungs the bacterial endo-and myocarditis with blood circulation failure had been determined.in cases ( %) simultanious lesion of three organs (heart,lungs,liver) had been found. morphologic examinations of dead cases ( %) internal revealed involvement of them in mosf-syndrome.hyperplasia of adenohypophysis;sclerosis of adrenal glands cortical layer;perivascular brain oedema,paralysis of brain capillaries and plasmorrhagia, cerebral thrombosis and cerebral abscess,necrobiosis of epithelium tubules of the kidney,pletora of hepar, fatty and granular degeneration of hepatocytes had been found.atrophy of white pulp and hyperplasia of red pulp, supress of lymphoid tissue, plethora and formation of infarctious had been found in spleen. mentioned changes in spleen were indispensable in ns. conclusion: in ns spleen can not secure it functions to support and appropriate detoxication potencial of organism,elimination of microbes,toxines,antoallergenes. insolvency of immunological link of antimicrobic defence is the starting mechanism of mosf developmentin ns. %neviere, jl. chagnon, b. vallet, d. mathieu, n lebleu, f. wattel ] ept of intensive care, hop calmette, lille, france ~everal studies have described tiypoperfusion of intestine during sepsis. owever, it is unknow whether the mesenteric blood flow is associated with nucosal hypoperfusion. additionally, the effects of resuscitation on the ntestinal microcirculation remain controversial. bjectives : to describe the effects of endotoxin in a porcine model during ~hock and resuscitation. ~ethods : ten pigs ( kg) were anesthetized and instrumented for "neasurement of cardiovascular variables. gastric and gut oxygenation vere assessed by intra-mucosal ph and microvascular laser doppler lowmetry. after baseline data collection, a minute intravenous infusion )f escherichia colt (serotype h , sigma, st. louis, mo) was begun ~t a rate of pg/kg. an infusion of either saline at . ml/kg/min (group ; n= ) or saline and dobutamine at a rate of pg/kg/min (group ii; n= ) vas begun mn after the end of the endotoxin infusion. tesults : to td t ~ fl w fluid ioadin,q alone sfyras d, k perreas, e douzinas, k spanou, m pitaridis and c roussos critical care dpt, evangelismos hosp., athens univ, school of medicine. obiectives: much controversy exists concerning the beneficial effects of cvvh on sepsis. we studied the effects of cvvh application on septic patients with reference to the following parameters: i) survival rate ii) cytokines' removal and iii) timing of cwh onset. methods: patients with sepsis (criteria according to accp/sccm, ) underwent cvvh as soon as they developed renal failure or dysfunction (urinary output< ml/ h, cr> . mg/dl and bun> mgd'dl ). specimens were collected: blood samples before cvvh and therafter both blood and ultrafiltrate (uf) samples on , and hours. cytokines tnfa, i - and ii- were measured by the immunoassay method in all specimens (uf and plasma -p) and sieving coefficient ([uf]/[p]) and h solute mass transfer of tnf and i - were calculated (v h x [uf] ). the apache ii score before cvvh onset, the duration of icu stay and the timing of cwh application related to the sepsis onset in days (ta) were recorded.with respect the mortality two groups were formed, i.e. group a (survivors) and group b (non-survivors) . the morbidity period in days of those septic patients who died in the past year and were not subjected to cwh (group c) was compared to that of group b. results: group a included pts and group b pts with mean+sd age ( _+ vs _+ , ns) and apache scores( _+ vs -+ . , ns). the mean ta-+ sd was . + vs -+ , p< . . the mean_+se morbidity period of group b vs group c was _+ vs _+ . p< . . the mean values of cytokines are presented in the following figures. the sieving coefficient for tnf was . and for i - was . . the solute mass tranfer was -fold the actual plasma content at a given time. . o conclusions: i) early application of cvvh seems to favourably affect the outcome of septic patients, ii) cytokine plasma levels do not decrease although cytokine removal is substantial, iii) it seems that cwh application in sepsis of any stage helps to buy time for further treatment. the most commonly monitored variables in shock stages idclude : arterial pressure, heart rate, central venous pressure, pulmonary artery wedge pressure and cardiac index. with vigorous therapy it is possible to bring these values back into the normal range in both survivors and nonsurvivors. therapeutic goal in septic shock stages is to maximize the values of cardiac index, delivery (do ) and consumption (c ). objectives: the main purpose of this article is to determine the relationship betwee~ delivery an consumption as a sign of hypoxia. fifteen patitents with septic shock were treated with intention to maximize the value of ci,d and v . we compared the levels of these parameters between the survivors and nonsurvivors and found no significant differences after hours. high levels of do and v may not guarantee against tissue hypoxia in early stage of septic shock. zjar~iic, dj janjic, lj. gvozdenovic, a.komareevic. t.petrovic, &marjanovic, institute of surgery, novi sad, yugoslavia objectives: evaluation and mutual comparison of clinical signs, laboratory data and microbiological monitoring in the patients with burn sepsis. method: retrospective analysis of the recorded data of all burn patients treated in our department between january and december . specially attentions were given to data considering wound infection, positive haemocultures, positive urinocultures and characteristics of septic state. results: out of patient there were ( , ~) adults and ( , ( ~) children. almost two thirds of the patients ( - , ~) were males. the predominantly cause ( , ~) of children's burns was scalding b~y hot liquids and flame burns ~ , ~) in adult patients. the most frequdntly species isolated from surface swat~ were pseudomonas aeruginosa ( " in adult patients) and staphyloccocus epidermidis ( , % in children). in only five patients ( , ~ the haenmcultures were positive -pseudomonas aeruginosa was isolated in three and staphyloccocus aureus in two patients. urine infection was diagnosed in , % of all patients. the treatment protocol included use of imipenem and polyvalent pseudomonas vaccine again~ pseudomonas aeruginosa and vancomycin and aminoglycosides against staphylococcus aureus. total mortality rate in this group of burned patients was , ~, but the mortality rate caused of sepsis was low (i %) . conclusions: early detection of any signs of wound infection and symptoms of septic state is a foundation for prevention and treatment of burn sepsis. the burn sepsis could be reliable detected by continuously monitoring the patient's status and by systematic microbacteriological monitoring of the burned patients. hyperdynamic vasoplegic septic shock p.f. laterre, p. goffette, j. roeseler, j.p, fauville, a. poncelet, p. lonneux, m.s. l~eynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. splanchnic ischemia is described as a common feature of septic shock and could determine the development of msof. therapy such as noradrenaline (na) aiming at improving blood pressure is expected to worsen splanchnic ischemia by its vasoconstrictive effect and subsequent reduction in intestinal blood flow. ob[ective: evaluate the effect of na on splanchnic blood flow. material and method : in a patient admitted for variceal bleeding, ards and sepsis with positive blood culture, a fiberoptie catheter was positionned in the portal vein after recanalisation of its portosystemic stent shunt. blood pressure (bp-mmhg) , ci, svr, do (vigilance ~ baxter), v (indirect colorimetry), arterial, mixed venous and portal vein blood gases, phi were determined before (to) and during (t ) na infusion ( , to , hcg/kg/min.) . changes in splanchnic flow were assessed by changes in portal oxygen saturation (sp ) and arterio-portal oxygen saturation gradient (sao, -spoe laterre, ,lp. pedgrim, th. dugernier, v. delrue, ph. hantson, p. mahieu, m.s. reynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. aim of the study : prospective determination of plasma levels of in patients with ss and their correlation with the type of microorganism and outcome. material and methods : in patients (pts) with ss and severe sepsis, plasma levels of tnfti, ill-b, il and il were determined every hours for days and on day after fulfilling the criteria of ss and severe sepsis. results : in pts, sepsis was caused by a gram (-) microorganism, in pts by a gram (+) and in pts no microorganism was identified. there were survivors ( %) (s) and non-survivors ( %) (ns) . cytokines profiles and levels were not different between gram (+) and gram (-) sepsis. ill-b levels were seldom elevated whatever the group studied. tnfot and il- were significantly higher in ns than in s ( objective: to evaluate the effects on the nitric oxide synthase inhibitor l-n~ hcl ( c ) on myocardial performance in human septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion >_ .i ]tg/kg/min with a map _< mmhg. cardiovascular support was limited to na _+ dobutamine (db), c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t = ); and at the end of treatment (t = ) with c . conclusions: c can restore systemic vascular tone in patients with septic shock enabling na therapy to be reduced and/or removed. the ci tends to fall whilst lv performance is sustained over time. c is a novel vasoacfive agent for the treatment of septic shock, which is undergoing further clinical evaluation. laterre, f. thys, e. danse, j.p. pelgrim, e. florence, z roeseler, m.s. r eynaert. dept, of intensive care, st. luc univ, hospital, brussels, belgium. therapy aiming at improving blood pressure and cardiac index in septic shock (ss) might have deleterious effects on regional blood flow. objectives : compare the influence of volume loading (vl), dobutamine (dobu) and noradrenaline (na) on sushepatic oxygen saturation (shoe) and svoe-sho, gradient in treated ss. material and methods : in patients with ss, ci (thermodilution) , doe, svo,. sho,, svoe-sho e gradient and lactate (l) were determined before (to) and after (t ); vl, dobu and na. results: in patients with treated ss, tests were performed (vl n= ; dobu n= ; na n= method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion ~> . ~g/kg/min with a map _< mmhg. cardiovascular support was limited to na + dobutamine (db), c was administered for up to h at a fixed dose-rate of either i, . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at h from the start of treatment (t = ); and at the end of treatment (t - ) with c . conclusions: c is a novel vasoactive agent that can sustain map in patients with septic shock, enabling na support to he reduced and/or removed. there is a tendency for the ci to fall during treatment, which may be reflex in response to the increase in systemic vascular tone. c is a promising new therapy for septic shock, which will now be evaluated in a randomised, placebo-controlled safety and efficacy study. k. guntupalli objective: to evaluate the acute effects of the nitric oxide synthase inhibitor l-n~ hc ( c ) on selected indices of organ function in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . [xg/kg/ min with a map _< mmirlg. cardiovascular support was limited to na + dobutamine. c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. indices of organ function were assessed at baseline (t = ); at the end of treatment (t = ); and h after treatment (t = ) with c . results. -median values (* assessment made at h or when c discontinued). conclusions: there was no appareut dose-dependent adverse effect on these indices of organ function either during or after exposure to c . the plmelet count tended to fall whilst creadnine appeared to increase over time in all dose cohorts. this novel and promising therapy for septic shock will now be evaluated in a randomised, placebo-controlled safety and efficacy sludy. pharmacokinetics of c in patients with septic shock preliminary results z. hussein, b. jordan, c. fook-sheung, k. guntupalli objective: to evaluate the pharmacokinetics of the nitric oxide synthase inhibitor l-n~ hc ( cg ) given by continuous infusion for h in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . ~tg/kg/min with a map _< mmhg. cardiovascular support was limited to na • dobutamine. c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. plasma was collected from each patient over a h period and analysed for c . pharmacokinetic parameters were derived from plasma concentration-time profiles using non-compartmental pharmacokinetic analysis. results: the (cm~ -maximum plasma concentration; auc -area under curve; cl -plasma clearance; v,, s -steady state volume of distribution; t'/ -plasma elimination halflife). conclusion: the pharmacokinetics of c in patients with septic shock are dose-independent at infusion rates up to . mg/kg/h. at higher rates, clearance of c decreases without any marked change in volume of distribution. c metabolism may be partially saturable at dose-rates above . mg/kg/h. obiectives: investigate the effect of the no synthase inhibitor, l-nt-methylarginine hc ( c ) on the haemodynamics and survival rate in a conscious mouse model of endotoxin shock. methods: female cd- mice ( - g) were instrumented under gaseous anaesthesia (isofluorane, %) and connected to a swivel tether system for continuous monitoring of blood pressure and drug administration. results: after h recovery, endotoxin administration (e. col• :b , - . mgkg - i.v.) elevated the plasma concentration of nitrite/nitrate (nox) and caused a progressive fall in mean arterial pressure (map) from + to + mmhg (n= , p< . ) at h, with a survival rate at h, h and h of %, % and % respectively. c administered as a h continuous infusion ( mgkg-th -t i.v., n= ), h after endotoxin, inhibited the elevation of plasma nox and attenuated the fall in map from + to + mmhg (n= ) at h, with an improved survival rate at h, h and h of %, % and % respectively. conclusions: this study suggests that overproduction of no is involved in the hypotension and mortality characteristic of septic shock. inhibition of no synthase using c represents a novel and promising treatment for septic shock. cultures of e.coli ( , %) and candida( , %) were olso received from autopsy material of children;p.aeruginosa,unspored anaerobes,proteus sp.,s.aureus,b.pneumonia were found in the few cases. in adults the spectrum of bacterioflora was mo~ re limited speaking about the number of species and cultures. in generalized forms of bacterial pyo-septic pathology a wider specific spectrum of causative agents was revealed usua fly with associations. e.coli and k.pneumonia played the leading role in children as well as in adults. in general,k.pneumonia ( , %cultures) and common e.coli( , %)prevailed according to the date of microbiological investigations of authopsy material in pyo-septfc pathology in . objectives: .in spite of all clinical exertion sepsis is still the reason for high clinica! lethality. this study is characterizing the group of patients which survived a septi~ shock. methods: during a period of months all surgical patients on icu were registrated prospectively, more than parameters for each of them were documented'daily in a paradox file. results (see table ): of patients fulfilled the criterion of a septic shock (r. bone, ) , of them died at the lth day, while the surviving group of patients stayed almost days at icu. obiectives: to compare the effects of and % pentastarch solutions to a human albumin solution on oxygen delivery (do ) in septic patients. methods: this stud}, included septic patients with fever (t > ~ tachycardia flqr > /rain), tachypnea (rr > /min) or mechanical ventilation, leukocytosis (wbc> /mm ) or leukopcnla (wbc< ()/mm ) and a clinical source of infection, who required a fluid challenge. in each patient the pulmonary arterial occlusion pressure (paop) was < mmhg. patients were randomized to receive ml of % albunun (n:i ), hydroxyethyl starch (hes -mw /d.s. . ) % (n: ) or t % (n=i ); patients were also treated with adrenergic agents. results cardiac index (c ) increased significantly only in % lies (table) hemoglobin (hb) decreased significantly at min in the same group. there was not significant change in oxygen delivery ( do ). baseline ci alb . :: . (l'min/m ) hes % . = . hes % . polyneuropathy of the critically ill (pci ) is a well recognized complication, acquired in the course of severe illness. we undertook a prospective study, to estimate the severity, extension and time of onset of pci in a selected group of patient with established septic shock ( bone's criteria ). all patients received inotropic circulatory support and were mechanically ventilated. none received relaxants or aminoglycosides. pci was diagnose<by clinical investigation and by emg, and repeated weekly ( axonal degeneration ). after days ( day = onset of septic shock ) in % of the patients pci was demonstrable. after days % of the patients had pci. there was a strong correlation between pci and other mof and between pci and encephalopathy ( eeg ). we conclude that i. pci is a common complication after septic shock. . pci develops early in the course of illness ( % after days ). . pci can be considered as a part of mof, suggesting a common pathogenesis. objectives: we addressed two questions: ) can serial measurements of vapco and avph also reflect the onset of tissue hypoxia during endotoxemia? ) are whole body changes in vapco and avph associated with parallel changes in regional circulation? methods: in anesthetized, mechanically ventilated dogs exhaled gases were sampled for determination of oxygen consumption (vo ). a catheter was positioned into the pericardial cavity to induce cardiac tamponade. ultrasonic flow probes were placed around superior mesenteric, left renal and left femoral arteries, and the corresponding veins were cannulated. group l served as control (n= ), group (n-- ) received mg/kg of endotoxin. thirty min later, tamponade was induced to gradually reduce do . results: systemic do crit was higher ( . _+ . vs . + . ml/kg.min, p < . ) and critical oxygen extraction ratio (o ererit) was lower ( . +_ . vs . +_ . %, p< . ) in the endotoxie than in the control group. meslenteric and femoral do crit were higher in the endotoxic than in the control group ( . _+ . vs . _+ . mlll g tissue.min and . _+ . vs . _+ . ml/min, respectively, both p< . ). regional o ercrit were lower in we endotoxic than in the control group (mesenteric: . _+ . vs .i_+ . %, renal: . + . vs . -+ . % and femorah . -+ . vs . _+ . %, all p< . ). vapco and avph followed a similar pattern in both groups, increasing slightly before do crit was reached, but dramatically wh,en do fell below do crit. in the presence like in the absence of endotoxin, systemic and regional do crit calculated from vo , from vapco , or from avph were similar; do crit was also significantly higher in the mesenteric and the femoral beds of the endotoxic than the control dogs. systemic and regional do crit could be calculated from the blood lactate levels only in the control group. conclusions: during an acute reduction in blood flow i) vapco and avph can reflect hypoxic threshold in the presence like in the absence of endotoxemia. ) alterations in organ oxygen extraction capabilities induced by endotoxin can be reflected by regional changes in vapco and avph. objectives: enhanced nitric oxide (no) release has been incriminated in the vasodilation and myocardial depression characterizing septic shock, but the administration of no blockers has yielded equivocal results. the present study explored the systemic and regional effects of a no donor linsidomine (sin-i) during endotoxic shock. methods: anesthetized dogs received endotoxin ( mg/kg iv), followed min later by a saline infusion to keep cardiac filling pressures constant. oxygen uptake (vo ) was derived from the expired gas analysis. regional blood flow was measured by an ultrasonic flowmeter (transonic). results: the control endotoxie group (n= ) maintained low arterial pressure and systemic vascular resistance. the dogs receiving a continuous infusion of , , ~ug/kg.min of sin- starting min following initial fluid resuscitation (each dose for h), had a higher cardiac index ( . -+ . vs . _+ . l/min.kg, p< . ) and lower systemic and pulmonary vascular resistance than the control group ( -+ vs -+ and -+ vs -+ dyne.sec/cm , respectively, both p< . ). arterial pressure and pulmonary artery pressure were not influenced. sin- significantly increased the mesenteric blood flow from -+ to + % of baseline levels and renal blood flow from -+ to -+ % (both p< . ) but did not influence femoral blood flow. the relative blood flow was increased in the mesenteric bed (at all doses), and reduced in the femoral bed (at highest dose). systemic oxygen delivery, vo , oxygen extraction and blood lactate levels had similar course in the two groups. conclusions: in fluid-resuscitated endotoxic shock dogs, the no donor sin- increased cardiac index without deleterious effects on arterial pressure, and increased splanchnic blood fl w. objectives: sepsis syndrome is associated with the release of a variety of inflammatory mediators, such as interleukins, tumor necrosis factor and platelet-activating factor (paf). administration of paf, a naturally occuring phospolipid, to laboratory animals has been demonstrated to resullt in pathological changes that closely resemble those found in sepsis. in addition, paf antagonists of various origins have been demonstrated to attenuate cardiovascular collaps and to protect against lethality in endotoxemia. in the present study the efficacy and safety of the paf-antagonist tcv- g was investigated in sepsis syndrome patients. in addition, the putative inflammatory parameters tumor necrosis factor (tnf), interleukin il) - il- , and soluble (s) e-selectin were measured in both tcv- and placebo treated patients. metho.~a randomized, double-biind, multi-center study was undertaken to compare the safety and efficacy of intravenously administered tcv versus placebo (takeda chemical industries ltd., osaka, japan). tcv- was used as add-on to conventional therapy in the treatment of patients with severe sepsis and septic shock ( . mg/kg body weight intravenously over hrs, twice a day for one week). day mortality was registered, as well as vital signs, laboratory parameters, hemodynamic parameters, apache ii score and mof score. plasma samples for the determination of inflammatory parameters were collected twice a day for one week. the study was approved by each institutional review board and written informed consent was obtained for each patient. results: a total of patients were included in the study. one patient had to be excluded as a result of protocol violation of the remaining patients patients were randomised to receive tcv- and to be treated with placebo. there were no significant differences between the treatment group with respect to age. gender, and apache i~ score on admission. however, admission levels of il- and il- , considered to reflect severity of disease, tended to be higher in tcv treated patients: . . vs . ng/ml for il- (p. ) and . vs . ng/ml for il- (p. ) in tcv- and placebo treated patients, respectively. a remarkable difference in survival, however not significant, was observed at day i.e. the end of tcv treatment (mortality: out of in the tcv group and out of patients in the placebo group). the inc;dence ui ~-,~verse events, 'n both treatment groups were comparable. plasma il- and plasma il- levels tended to decrease more rapidly in tcv treated patients compared to controls (p=. and p=. , for il- and /l- respectively) conclusions: tcv- is safe as add-on treatment in sepsis syndrome patients. the data presented indicate that tcv- may enhance survival of sepsis syndrome which will be assessed in a phase ill study. objective: oxidation of lipids by free oxygen radicals playes an important role in sepsis. an important source of oxygen radicals is the respiratory burst of phagocytic leukocytes, especially~ polymorphonuclear leukocytes. clinically the hallmark of sepsis is the capillary leak, which is mediated in part by oxyradicals. the adult respiratory distress syndrom (ands} represents the most studied capillary leak phenomenon in sepsis. methods: in ii patients (df,~m, aged - y.) with verified septicemia had been included in this study. beginning from day oxidisable lipidautoantibodies (club), ~opterin and crp were determined in the patients serum and compared against the apache ii score during the days - . patients, f and m died @u= ring their stay at the icu, of them in less than h~urs: after admission. at the begin surviving patients showed olab values between - %, non-survivors between - %, com= pared to neopterin values of - m~ol/l in survivors and - ~mol/l in non-survivors. apache ii score didn t show any difference. during the following days olab sbowed an in= crease in survivors, while in non-survivors olab stayed equal or showed a decrease. no difference between both groups was found in neopterin, crp and apache ii score. as result we conclude, tbat lipidperoxidation playes an important role during septicemia. olab as a marker of this process are predictive for the outcome of patients. obiectives : to evaluate the influence of cardiopulmonary bypass ongastrointestinal transit. meth~xls; gastrocoecal transit time (gtt) in consecutive children on day after uncomplicated open heart surgery was compared to gtt in children after closed heart thoracic surgery and to healthy controls. gtt was measured by hydrogen breath testing, using lactulose (o, g/kg in a % aequous solution) as nonabsorbable marker. exspiratory hydrogen content was measured using a electrochemical system (stimotron). patients in both groups had continuous infusion of morphine and midazolam and were comparable in respect to catecholamine dose. children with a history of toddler's diarrhoea and children with elevated central venous pressure were excluded. results: gastrocoecal transit was delayed in all patients after cpb, no transit was achieved within minutes in / . after closed heart surgery gtt was delayed (+- ) min vs. (+- ) compared to controls, but transit was achieved in all aptients within rain. mean dopamine dose was , mcg/kgmin after cpb and , meg after closed heart surgery.. conclusions: after uncomplicated cpb gastmcoecal transit is extremely delayed. the degree of delay is not explained neither by the use of analgetic and sedative drugs neither by the use of catecholamines. factors directly related to cpb (e.g. low flow perfusion, hypothe,mia) may be responsible. these findings are of limited clinical relevance in ancomplicated cases. in critically ill patients delayed enteral feeding may contribute to infectious complications. studies of therapentic measures to accelerate gastrointestinal transit therefore are warranted. neonatal ecmo -czech experience. nekvasil r., penkova z, vasek l., plier p., bobula a novotna e., pavlicek v., hnilicka m. nicu and ecmo center brno and dept. pediatric surge ', children's hospital brno, czech republic. introduction. in spite of the fact that neonatal ecmo has been gradually considered a standard method of solving uncontrollable respiratol t failure in newborns in most countries of the western europe, the introduction of this sophisticated method in countries of the former communist block meets a lot of problem. material methods. in the course of two years, only newborns, b.w. - g, were reffered to neonatal ecmo because of uncontrollable respiratow failure. at the admission the average values of oxygenation index were + , and aado , -+ , kpa. results. newborns ( %) died shortly alter" admission or during transport without possibity to further is newborns ( , %) were treated using high-frequency ventilation (hfo or hfjv), one for conspicuous airway resistance paradoxically with low-frequency ippb. all ventilated newborns survived. ecmo was applied in newborns ( , %) and of them survived the mortality rate of group mentioned was %. conclusion. the fact that in the czech republic ( mil. population with natality rate of about . newborns/year) only small part of patients was reffered to neonatal ecmo has a number of causes. the most important are: unacquaintance of prognostic and indication criteria at forwarding workplaces and the aversion of neonatologist to all new.therapeutic interventions. last but not least, a negative role is also played by current change of health service systems when, under the influence of health-service insurance companies a newborn in serious condition given only a standard intensive care in primary and secondary nicu is literally "the golden calf", and therefore these workplaces either do not send him or send him too iate ~o an ecmo center. stndy aim: urfactant, which is being applied into the lungs for treatment of respiratory distress syndrome, can reach the circulatory blood system by absorption. it refinances local fimctiun of macrophages and lymphocytes and increases the accumulation of nentrophils into the hmgs this eunld influence the local acute phase reactiml in the hmgs after surfactant application. "ilia aim of the stud), was to investigate the influence of oatural and artificial surfactaat onto the acute phase reaction and the blood elottiog system. material :and methods: a) measurement of tnf-a, - , ltb and thromboxane b release in whole blood: each of . ml hepariaised blood of healthy adult volunteers was iucubated lbr hears with eillier ill ug/ml lps, mg/ml b&,ine smfactant (alveulhct/themae), rag/nil artificial surfactant (exosurf/wellcome), og lps + i mg/ml bovine surfactant or i ug lps + i mghal artificial sorfactant, tleparinised bhx-,d without additions was used for controls. ' e concentration of e)lokines and eicosanoids ".van measured semiquantilatively by eijsa or eia (dimmva/hamburg) after ceatrifagalion, b) measurement of platelet aggregation: each of . ml haparinised hltxxl of healthy adult vohmteers was inculmled lbr hours with eilher aghnl i,ps, i mg/ml bovine surfactant (alveafact/thomae), i mg/ml artificial snrlhctant (exosurf/wellcotne), it} ug lps + i mghnl bovine snrfactant or ug lps + i mg/ml artificial surfaetant, tlepminised blood withont additions was nsed for controls. platelet aggregation in whole blood was measured by impedance in the aggregometer (g~nstaedt). c) measurement of the dotting activity: citrated bleed of healthy adult w~lunlccrs was mixed with difl'ereul couccalrations of imvine or artificial snrfactant fad then prolhrombiu tiaras and imrlial thrmnlx~plaslia filues were ineasnrcd. for measurement of the prokoagulatioo acfivily the reagent in the qnick test was replaced by surfaclant. results: dependmlt on the dose both surfactants stimulated the release of - but not or tnf-a io wlmle blood. "illere was no suppression of the lps-indaeed eytokine-release. both surfaclants did not directly influence the extrinsic blood coagulation system, while both activated the inniasie activity dependant on the dose. platelat aggregatiun was slightly stimulated by bovine snrfactunt and strongly inhibited by by artificial surthctant. in comhinafion with . ~ both factors showed no difft.'renca to lps ahme.'fhe reltu.tse of eiconasnid~." was stimolated more by artificial surfactant then by bovine surfilctant with regard to the cyehmxygelmse (thromboxsne b ) and the lipooxygenase (lencotrieae b ) pathways. conclusion: we cooclude: ) i:lovine as well as artificial surfaelant stimulate the cellular inmnn]e response. ) bovine as well as artificial surfnctant activate the intrinsic ctmgnlation cascade. ) bovine surlilctant stimulates platelet aggregation, artificial sar-fijctant inhibits platelet aggregation.. introduction: although the use of modem noninvasive methods like measurement of tope , tcpco or san leeds to an carly infonnation about pathologic alterations of the gas exdmage of ventilated patients, these methods cannot replace invasive bloodgas analysis. a new noninvasive method to monitor the capillary gas exchange is the reflection spectrophotometry. to record reflection spectra with a ldgh sensitivity on the surface of tissue we eonstnmted a special mierolightgnide photospectronmter (empito). this spectrometer enables the investigation of local helerogenities of llbo and lb content, capillary flow rate and oxygen uptake rate. aim of the study: ) to compare the sousitivity and specifity ofthe empilo with other non-invasive method~ of monitoring the gas exchange in neonatal intensive care patients. ) to investigate the possibility of obtainiug infonnations about the local nptake and the venous as well as arterial satnration. patients and methods:we investigaled non-selected patients of oar pediatric intensive care unit. for coulinnons monitoring we conslracted a special sappert to fix file end nf the microlightguide+ during the investigation tope , tcpco and san were measured by standard methods. "fo investigate the local tisslm oxygen uptake we recorded spectres within minutes by moving the lightgnide over an described area of the skin of the patient. 'lhe reselting i(gx) l ibo vahms were sorted by a software package. on the assumption that the low values correspond to the tibo value of the veaons ends of the capillaries and the high values to those of the arterial ends we ) it is possible to gel infonnations about the local o -uptake and arterial saturation ia the peripheral tissue by photoslg'ctroscopy. ) in combination with noninvasive pl i-measorement it seems possible to reduce withdrawal of blood for invasivn bhmd gas analysis. objectives:improve ventilation,tissue oxygenation and acid base balance among extremly low birth weightand premature infants. methods: fourteen cases were s~udied,their gestational age ranged from( - )ws.continnous positive air way pressure was applied to six cases at peep level from ( - )cm h o through nasal pronge,(group i),the other cases were managed as routine,(group ii).blood gases, tcpo ,tcco ,resp.rate,depth and pattern were monitored for assessment of tissue oxygenation and ventilation, results: our rasults showed that early application of cpap improve ventilation among ( . %)of cases,while ( . %)of cases need imv.the cases of group ii need imv among ( %)of the studied cases during the second or the third day of life. conclusions:-this preliminary study showed the import-............ ance of early application of cpap before the onset of respiratory distress syndrom to improve spontaneous ve ventilation,tissue oxygenation and to gecrease the risk of intubation. comparative assessment of pediatric intensive care; a national multicenfre siudy. reinoud j.b.j. gemkc, gouke j. bonsel , the dutch picasso (pediatric intensive care assessment of outcome) study group. twilbelmina children's hospital and utrecht university, utrecht department of clinical epidemiology, academic medical center, : amsterdam, the netherlands the performance of all ( ) pediatric intensive care units (icus) in the netherlands ( tertairy and non-tertiary) was analyzed in an open prospective muiticenter study. effectiveness of care was defined as the ratio of observed to prism-score derived expected mortality aenee, standardized mortality rate). efficiency was determined by objective criteria (mortality risk > % or administration of at least icu-dependent therapy)'. consecutive admissions aged < years old were included. overall, observed and expected mortality were in good agreement (p > . ). between hospitals, crude mortality showed wide variations (mean . %, range - %). however, in each center, observed and expected mortality were similar (mean ratio . , range . - . ). in tertiary care centres, severity of illness corrected mortality in high-risk patients was less than in non-tertiary care centres; paradoxically, in low-risk patients the opposite was found. probably the large proportion of low-risk tertiary care patients suffering from severe, incurable chronic disease, explains the higher mortality in this group. this indicates that simultaneous assessment of circumstances of dying and of long term morbidity in similar future studies is imperative. the average proportion of efficient icu days was %, however large variations between units were found (range: - %). in conclusion differences in mortality rates among pediatric icus were explained by differences in severity of illness. high efficiency rates in combination with adequate effectiveness, found in several centres suggest that admission and discharge decisions might be improved by a better selection of high risk patients requiring icu-dependent therapies, especially in less efficient centres. objectives: previously published studies showed that serum lactate levels correlated with outcome of severe ill adult, 'we hypothesized that critically ill newborns are often incurred hypopeffusion manifested by elevated lactate levels. these initial blood lactate levels should be related to nicu outcome. design: prospective study with ethical comfnittee approval. setting: the -bed neonatal intensive care unit of a university hospital material and method: a total of consecutive outbem newborns admitted to nlod from , . to ., . were enrolled to the study. babies who died or were discharged from the unit within hours of treatment were excluded from the study, mean birth weight was g (+/- r), mean gestatational age was weeks (+/- . wks), mean age at the admission was h (+/- hi. multiple (~_ j organ system failure occurred jn . % of babies at the admission./~tertal lactates were measure/at the admission, among - hour and - hour of n[c'lj therapy. outcome was defined as a mortality and length of nicu stay. results" survival rate was . %, mean length of nicu stay for survivors was . days (+/- . day). we found high lactate levels at the admission in . % babies (~ . % with levels above . retool/i). the mean arterial lactate concentrations for nonsurvivors were signiftcahtly higher than for survivors durin~ consecutive da~ as follows: objectives: the purpose of our research was to analyze the frequency of bronchial asthma (b.a.) exacerbations in pregnant women and health status of infants. methods: the research was based on the epidemiological investigation and prolonged observation of pregnant women with b.a. during the gestation period. remission of b.a. before the pregnancy in excess of years was recorded in patients ( . %), patients ( . %) reported a - year remission and patients ( . %) had a remission lasting less than months before they became pregnant. results: seven patients ( . %) developed medium attacks in the second half of pregnancy, four patients ( . %) experienced light attacks of b.a. asthma attacks were most frequently caused by acute respiratory diseases and stress factors. in two cases with grave manifestation of b.a., the pregnancy ended in abortion within the first - weeks due to the frequent and heavy choking attacks. to fight b.a. attacks, five patients used adrenomimetics (salbutamol, becotid) in sprays, six women were administered theophyllinum and salbutamol in the form of tablets during - weeks. a significant portion of pregnant women with b.a. ( %) exhibited frequent complications during pregnancy (toxemia, late gestosis, threat of miscarriage). our findings prove that babies born from women with b.a. of domestic and pollen origin had a low body weight ( - gr), functional immaturity and chronic antenatal and intranatal hypoxia twice as often as the infants born from healthy women without allergic background. conclusions: preventive treatment of women with b.a. prior to pregnancy is required to maintain a stable remission of the disease, which is a key to having healthy children delivered by mothers suffering from b.a. introduction. intracerebral hemorrhage (ich) is a common event in human prematudty, affecting about % of newborns weighing below g who are born before weeks of gestation, however, little is known about the pathogenesis of ich with exception of the prematurity of the brain itself, (birth) trauma, and asphyxia. the postischemic production of oxygen free radicals (ofr) dudng reoxygenation as a cause of brain damage has been demonstrated in animal research. since almost all preventive antioxidant activity of plasma is associated with ceruloplasmin and transferdn we investigated the association of such iron-oxidizing resp. iron-binding proteins and ich. we could demonstrate significantly reduced levels of both, iron-oxidizing and iron-binding proteins, in premature asphyxiated newboms pdor to development of ich. an increase of suparoxide after hypoxia in the presence of iron ions facilitates the formation ofthe highly reactive hydroxyl radicals. our data support the theory that ich may be caused by ofr, which can damage any sensitive tissue including growing endothelial cells. the estimation of transferrin-saturation and measurement of ceruleplesmin levels might help to identify an infant at dsk before the onset of ich. with the new medos | hia-vad | cardiac assist system the missing tool in the armamentarium of cardiac surgeons is available in two pediatric sizes: i -ml and -ml pump volume. the right sided pumps are % smaller for biventricular use. between february and may we implanted this assist system in children. the indications and demographics are indicated in the following table (left ventricular assist device-lvad, right vad-rvad univentricular vad-uvad, post cardiotomy cardiac failure-pcf, dilated cardiomyopathy-cmr bland white garland syndrome-bwg, tetralogy of fallot-tof, hypoplastic left heart syndrome-hlhs). objectives: evaluate tile effeci'of inhaled nitric oxide (no) as puhnona] t vasodilating agent ill tile posloperalivc period after correclion of congenital heart defects in infant. patient n.l: kg, lnonlhs, down syndrome undenvcnl rep~fir of atrioventricular septal defect (avsd). after surgery the puhnonary arlcry pressure (pap) slowly rose to tile syslemic dcspilc tnaximal eonvcnlional fllerapy (fentanyl mcg/kg/h, hypocapnia of mmhg and metabolic alcalinization). no was delivered into tile inspiratory branch of!be breathing circuit at ppm, and the gas aoalyser for no and no (polylron dmger) were situated at the espiratory branch, a rapid dccrcasc of pap io i/ of systemic was obtained with a dramalic improvement. no was continued at ppm for six days and the baby was exlnbated if! days after surgery and discharged from the icu days after. patient n. : . kg, monlhs, onderwen! repair of avsd. the day after surgery the systemic oxygen salnralion was % wilh a pap at % of systemic. two hours of c wenlional therapy failed o improve ihc patient and no administration was slarled at ppm. so dramatically incrcased to %, but the pap dropped only to % of syslemic. nevertheless ihe clinical conditions improved and the no administration could be reduced at ppm in the following days. she was extubaled days after surgery and discharged from the icu days after. patient n. : kg, 'ears. underwen| hearl tral~splantalion for congenital heart disease with moderate hypoplasia of pulmonary arlcrics. at the end of cardiopulmonary bypass the transpnlnlonary al~erio-venoas gradient yeas higher than mnfflg and we speculaled !hat w'ls due to a degree of puhnonary vasocostrictiont. the nsnal dose of no was otilised, however no significant modilicalion of pulmonary pressure or systemic oxygen saluralion was noled, and after h no was discontinned. tile palienl was carried io the icu with maximal inotropic support, extubated after d;b's and disclmrged from the icu after days. in all patient no major adverse effect relaled to no admilfistration ",','as holed. conclusion: in our experience no ms a pulmonary vasodilaling agent is effective and easily adjustable to tile palienls requiemenls, however its use remains limited ill those palienl ill whoin tile alnonll! of fixed inlllllojliify vascular resistance is predominanl. we report the use of ecmo support in two unusual cases of severe tracheal disruption in which it had become impossible to achieve adequate ventilation. case : severe tracheal laceration due to aspiration of a share forelan bodv: a previously healthy month old toddler was referred for ecmo following aspiration of a porcelain foreign body (with razor sharp edges) which had become embedded in the right mainstem bronchus with massive extrusion of air. this was removed on veno-arteda[ ecmo support, as the patient was unventilatable prior to bronchoscopy due to ongoing airieak. ecmg was continued after bronchoscopy to permit airway healing without the presence of an endotracheal tube. unfortunately, an extensive pulmonary haemorrhage on day of ecmo necessited re-exploration of the airway. this revealed a posterior tracheal tear from the cricoid to the middle of the right lower lobe. following repair the patient was left on ecmo support together with high frequency oscillation ventilation (hfov), the latter being used to minimise potential aideak and maximise alveoli recruitment. ecmo was weaned after days ( hours) -the patient was extubated weeks later. case : tracheal wound dehiscence due to seosls -tracheal transelant on ecmo: a month old infant with a c[inically significant congenital long segment tracheal stenosis and left pulmonary artery sling underwent resection of the stenosis, followed by primary reanastomosis. this was complicated, days later, by severe mediastinitis and complete dehiscence of the anastomosis. an autologous pericardial patch was used to repair this, however, the tracheal wound again dehisced days later making mechanical ventilation impossible. in view of ongoing sepsis and a severely disrupted trachea ecmo was the only possible form of support. following resolution of the local sepsis ( days) a definitive procedure in the form of a tracheal homograft (transplant) was undertaken on ecmo. the patient was managed on ecmo and hfov for a further days, the hfov being used to optimize rapid lung inflation. unfortunately this patient died months after weaning from ecmo due to complete disintegration of the homograft, which was not deemed reparable. conclusions: ) ecmo can be used in the acute management of oxygenation when there is major airway disruption making mechanical ventilation impossible. ) hfov was a useful adjunct in aiding recruitment of lung volume on ecmo in these two patients. backoreund: persistent pulmonary hypertension of the newborn (pphn) consists of a heterogenous group of diseases ranging from transient reversibte pulmonary hypertension to fixed primary malformations of the lung (primary pulmonary dyspfasia-ppd). inhaled nitric oxide (ino), a selective pulmonary vasodilator, has been proposed as a treatment for severe pphn. obiective and methods: ino was administered to near term neonates with severe persistent pphn, oxygenation index > and echocardiogrephic evidence of pulmonary hypertension, in order to further determine the clinical role of ino in the treatment of pphn. the response to ino was also analysed retrospectively to examine whether this could be of diagnostic value in differentiating at an early stage patients with reversible from fixed causes of pphn results: twenty one of the patients studied responded to the initial trial of no ( ppm x minutes), as defined by a greater than percent improvement in pad as well as a fall in the el to < . these patients were continued on ino therapy, with patterns of response emerging: pattern babies (n= ) continued to show a sustained response to ino and were successfully weaned from it within days -all survived. pattern babies (n= ) failed to sustain their response to ino over hours, as definded by a rise in the el > . six survived, five with ecmo. pattern babies (n= ) had a sustained dependence on ino for - weeks. all three died and lung histology revealed severe primary pulmonary dysplasia (ppd). patients with ppd (pattern ) not only required ino for longer periods of time than did the sustained responders (pattern ), but also required significantly higher doses of ino we report on the air transport of paediatric intensive care patients. these transports fall into three categories: ) retrieval of critically ill neonates and paediatdc patients referred for either ecmo or inhaled nitric oxide (ino) (n = ). one patient was transferred on ind. mean transfer time . hours (se + . hrs). ) long distance international transport using chartered aircraft (n = ). the indications for these transfers included both urgent retrievals for cardiac surgery and semi-elective transfer of stable patients back to their referring unit following treatment in tertiary centres. mean transfer time . hours (se + . hrs) ) long distance international transport using commercial aircraft (n = ). indications for transfer were either semi-elective retrieval for tertiary treatment or the return of stable chronically ventilated patients to their referring hospitals. mean transfer time hours (se _+ .fhrs, longest hrs). the transport team consisted of a paediatric intensive care doctor of at least registrar grade and a registered sick chidrens nurse with intensive care experience. the administrative components of the transfer (ambulances, airlines, customs) were managed in collaboration with companies specializing in air ambulance transfers. outcome: all the patients were safely transported to their destination without mortality or morbidity. complications durino transfer ir~lv~; ) patient complications -semielective endotracheal tube change and central access needed in the only patient brought to the commercial aircraft by the referring hospital (all others retrieved directly from referral hospital), seizure in patient with known encephalopathy, severe cyanotic spells in patient with fallots tetralogy who was retrieved for urgent surgery for this indication ) mechanical compfications -ventilator failure, incubator battery failure, oxygen regulator failure -all occurred with equipment sent from referral hospital, this was unfamiliar and unchecked by our transport team -it was not the decision of the transfer team to use this equipment on this single occassion. ) administrative complications -confiscation of incubator battery by airport security police, excessive delay by custom officials ( hours) in the airport. the incidence of such problems were felt to be low and unpredictable. in conclusion: mechanically ventilated paediatric patients can be safely transported on both chartered and commercial airlines. these transports are best accomplished by trained intensive care medical and nursing staff with the backing of an air ambulance organization competent in arranging the necessary administrative details. it is essential to use your own equipment and to retrieve the patient _directly from the referrin(] hospital to minimise ootential complications. our experience with anaesthesia for paediatric electromyography _w_._pla_ti_k_a_n_o_v, r.eousseff, k.pavlova, d.marinova dpts. of anaesthesiology and int. care and clinika] neurophysiology, med. university, pleven, bulgaria ~)_b_j#~ti_v~. to t~st a " heavv sedation " regimen of anaest-es~a for the purpose of paediatric electromyography d#s~gil~ non-randomized,non-blinded human trial in the seting of an uriiversity hospetal. _m_a_t_eri_a_is_a_nd_ m_e_th_od_s_. children,asa i-if,median age years,range - who undervent eleetrcmyography required anaesthesia. they recieved low-dose ketamine + i~iazepam or midazolam via musculary route( children,age - yrs,ketamine , mg/kg, diazepam - mg total dose ) or per os ( children,ketamine - mg/kg,diazepam , mg/kg or midazclam , - , mg/kg ) _resu_l_t_s. - minutes after medication a state of heavy sedation with weak spontaneos and stimuli-provoked movements was achieved in all children, that lasted - minutes and allowed adequate needle emg and nerve conduction investigation. children recieved additional , - , vol.% halothane during the placement of the needle. non -invasive blood pressure , breath and heart sounds and hb sad by pulse oxymetry were monitored.none of the older children disclosed memories of pain when asked after they regained adequate verbal contact.no complicationes were observed. antenatal maternal steroids reduce the risk of periventricular-intraventricular hemorrhage in very premature neonates treated with natural surfactants. i.apostolidou, c.papagaroufalis, g.touloumi, m.xanthou, n.kalpoyannis a' and b" neonatal icu "ag. sophia" children" s hosp. athens, greece. dept of hygiene and epidemiology, athens university, greece. obiectives: the aim of the study was to evaluate the association of periventricular-intraventricular hemorrhage (p-ivh) in surfactanl treated premature neonates with pre-and postnatal variables. methods: the population of the study was neonates admitted during the years to , with gestational age _< weeks and severe respiratory distress syndrome (rds) (mechanical ventilation and arterialalveolar oxygen tension ratio (ajapo ) < . ), who received rescue therapy of at least two doses of natural surfactants (alveofact or curosurf) and examined with ultrasound and/or autopsy for the presence of p-ivh (papile's classification). the examined factors in each neonate were the following: gestational age, birth weight, sex, multiple pregnancy, antenatal maternal steroids (complete and incomplete course of betamethasone), a/apo before the administration of the st dose of surfeclant, delivery, apgar score at min, type of surfactant, pneumothorax and patent ductus arteriosus. the statistical methods used were x and one-way analyses of variance followed by logistic regression medels, results: the incidence ot p-ivh was . %. three factors were found to have an independent relation to p-ivh (final logistic regression model): gestalional age, a/apo before surfactant administration, and antenatal administration of maternal steroids (complete and incomplete courses). for every weeks of lower gestational age the neonates had an almost doubled associated risk of p-ivh (or: . , % c : . , . ). for every . on average decrease of a/apo before surfactant administration the risk of p-ivh in the neonates was . times higher ( % ci: . , . ). the neonates whose mothers received antenatally steroids had only one tenth of the risk of p-ivh of the neonates whose mothers had not (or: . , % ci: . , . ). conclusions: our results suggest that the antenatal administration of maternal steroids, even less than hours before delivery, reduce the risk of pqvh in very premature neonates treated with natural surfactants, whereas the small gestational age and the lung immaturity still remain the main risk factors tor the development of p-ivh. we analysed retrospectively the management of ( boys, girls) accidental ingestions of foreign bodies in children (mean age : . years, range : months- years). no child had ingested more than foreign object. the majority of the ingested foreign bodies were : coins (n : ), toy parts (n : ), jewellery (n : ), batteries (n : ), "sharp" materials such as needles and pins (n : ), "large" amounts of food (n : ). impaction of food occurs more frequently in children after oesophageal reconstruction in cases of oesophageal atresia. although according to literature "coca-cola" is reported to be effective, this was not seen in our experience. / patients had minor transient symptoms at the moment of ingestion, such as retrosternal pain. only children experienced severe manifestations (cyanosis, dysphagia). in these children, endoscopy revealed oesophageal and gastric erosions. children were seen at the emergency ward within a few hours after the accident ( mean : hours, range min. - hours). chest and/or abdominal x-ray was performed as first-line investigation ( / objects were radio-opaque), and revealed an (unexpected) oeeophageal impaction in children. in / the foreign body was in the stomach. batteries, sharp objects and objects trapped in the oesophagus were removed, either by endoscopy or by magnet-extraction whenever possible. the outcome of the patients was excellent. no complications were observed. extraction is recommended in symptomatic patients, and whenever the foreign body is trapped in the oesophagus, or if the foreign object is "sharp" or a battery. objectives: two strategies were used for management of malignant diphtheria in children aged from . to years. methods: protocol n consisted of intravenous administration of diphtheria antitoxic serum, prednisolone ( mg/kg bw/day), plasmapheresis and supportive care. protocol n included the use of antitoxic serum against the background of high-dose dexasone ( - mg/kg bw/day), hemocarioperfusion and a preventive use (before the clinical manifestation of myocardial damage) of inotropic medications, inhibitors of angiotensin-converting enzyme and pentoxyphylline. each of protocols included the monitoring of serum toxin (diphtherin) levels. results: the group of patients treated according to the protocol n consisted of children with malignant diphtheria, of them with severe malignant diphtheria (grade and ). all patients exhibited the circulation of toxin during at least three days after the start of treatment. all patients with severe grade of disease demonstrated heavy cardiovascular disturbances associated with malignant diphtheria. of the children in the group died seven. the children of the second group were treated according to the protocol n . out of total of patients of this group. patients had severe malignant diphtheria. in all children a significant reduction in serum toxin level was revealed after hemocarboperfusion. in all but one case the satisfactory control of cardiovascular function on was achieved. of children admitted to the trial survived, one child with malignant diphtheria of grade and congenital filbroelastosys of the left ventriculum died. the severity of neurological complications was similar in each of groups. conclusions: the use of hemocarboperfusion, high-dose dexasone and early prevention of heart failure as a adjunct to the standart treatment has been shown to be of benefit in the management of malignant diphtheria. t. schaible, i. reiss, j. m er, l. gortner med. university of lqbeck, children's hospital, kahlhorststr. - , l~beck, germany surfactant therapy seems a promising approach for the treatment of the biochemical and biophysical abnormalities of the pulmonary surfactant system in severe ards. patients and methods: over a months period non-neonatal pediatric ards patients (age - months) in a "pre-ecmo"-situation (oi over h) were treated with bovine surfactant (alveofact| the underlying conditions-of ards were pneumonia ( ), sepsis ( ), immunosuppression ( ), near drowning ( ), neurogenous ards ( ). a total of - mg/kg b.w. was applied in several fractions. before surfactant therapy, we first tried different ventilation (best peep-finding, inversed i/e-ratio, hfo-ventilation) while monitoring the pulmonary mechanics. for hemodynamic stabilisation both norepinephrine and epoprostenol were used to optimize pulmonary perfusion for max. hrs. if there was no improvement of the oi by at least , further treatment with surfactant was initiated. in addition to surfactant all patients received a treatment with dexamethasone of mg/kg in doses. patients with no benefit (oi remained unchanged or increased within the max. - hrs) were taken on ecmo. results: nine patients improved within hours after surfactant therapy: the oi decreased from a level of (mean, range - ) before our treatment to a level of (mean, range - ) thereafter. in patients we were able to continue the positive effects of our treatment and they could be weaned of the respirator within - days. the other patients got worse despite respiratory improvement, they suffered of multiorgan failure of more than organ systems. the last patient did not benefit from surfactant, he had to be put on ecmo, but died because of a complication (hemopericard)after days. the autopsy of the ecmo-patient showed a pulmonary fibrosis, but the other death were not due to pulmonary failure. conclusion: a different sequential ards treatment integrating surfactant therapy can reduce the number of patients requiring ecmo. but ecmo as a therapeutic tool should be available in centers involved in ards treatment. l.blindl, t.p.le, h.weinzheimer, centre for paediatrics, university of bonn, germany selective reduction of elevated pulmonary vascular resistance by inhaled prostacycliu (pgi) has been reported in adults with acute lung injury, neonates with persistent pulmonary hypertension and in one infant with idiopathic pulmonary hypertension. we report on the effect of aerosolized prostacyclin in two children with secondary pulmonary hypertension. patient : in a boy with down's syndrome an avsd had been surgically corrected at month of age. at , yr of age a catheter examination revealed a pulmonary vascular resistance of % of systemic vascular resistance in room air and at an fin of . . prostacyclin ( . mcg/ml) was administered with a jet nebulizer at an fin of . . pvr declined to . systemic vascular resistance and returned to baseline after stopping pgi-inhalation. subsequent intravenous infusion ( ng/kg rain) had to be stopped after minutes because of systemic arterial hypotension. patient : a month old male infant with bronchopulmonary dysplasia developed suprasystemic right ventricular pressure inspire of therapy with oxygen and nifedipin. while he was spontaneously breathing % oxygen via face mask pao was mmhg, arterial ph was . . systolic arterial pressure was mmhg, a rv-ra gradient of mmhg was measured by cw-doppler. while fio was maintained aerosolized prostacyclin was administered over minutes. rv-ra gradient was mmhg, systemic blood pressure mmhg, pao mmhg. two hours later nitric oxide ( ppm) was inhaled at an fio of ( , . rv-ra gradient declined from to mmhg, systemic systolic blood pressure remained stable at mlnhg. discussion: sporadic experience shows that aerosolized prostacyclin selectively reduces elevated pulmonary vascular resistance in some patients. in patient the poor response to inhaled pgi compared to inhaled nitric oxide may be explained by the fact that the action of pgi is not independent from endothelial function, limiting it's effect in severe vascular disease. during the last two years ( - ), infants weighing less than gr. admitted to our referral unit. thirty four of them ( %) survived, ( % of infants weighing - g and % of infants weighing - gr survived) for the years - - the survival of these infants was % and for the years - - , % (p< . ). we analyzed the perinatal and neonatal factors influencing the outcome of these infants. the comparison among neonatal survivors ( ) to neonatal deaths ( ) shows: gestational age: . w ( ) to . w ( ) (s). birth weight: . g ( ) to . ( ) (s). apgar score: , ( ) to . ( ) (ns). presentation and mode of delivery: breech presentation is associated with higher incidence of neonatal deaths. i.v.h. (at the age of weeks): no one of the survival infants had evidence of i.v.h. respiratory problems: intubation, at the admittance of the infants . ",,( ) to % ( ) (s) use of surfactant: % ( ) to % ( ). bpd observed in % of the babies and only one was dependent on oxygen at home. antenatal betamethasone was given in % of the mothers. in conclusion: ) a great improvement in the survival rate observed in these infants the last years in our unit. ) factors with positive effect are increasing gestational age and birth weight, the absence of i.v.h. and the use of surfactant. the breech presentation and the severe respiratory problems increase the incidence of death. animal experiments demonstrated, that brain temperature determines the amount of neuronal damage caused by hypoxia and that mild hypothermia may have a protective effect. until now there is no method described and evaluated to measure brain temperature in neonatal intensive care units. we non-invasively measured brain temperature analogues, nasopharyngeal (tnasoph) and zero-heat-flux temperature (zht) at the temple whereby under zero heat flux surface temperature represents deep head and thus brain temperature. the aim of our study was to investigate the practicability of the method, the relationship of the two brain temperature analogues to rectal temperature (trect) and their dependence on insulation, thermal environment, body activity and time course. we investigated healthy preterms less then weeks postnatal age (gestational age +_ . wks; x + sd, weight +_ g) in an incubator. tnasoph was measured by a thermistor within a feeding tube, advanced to the nasopharynx, zht temple by a thermistor and a heat flux transducers both covered by an insulating pad, and trect thermal environment was characterised by operant temperature (tair . . + twall . ). body activity was video taped. measurements were performed during the following interventions: i/ insulation increased by turning the temple with sensors onto the mattress ( rain). ii) insulation increased by a cap ( min), iii) min after its removal, iiii) increased operant temperature by . + . ~ ( min). results: seven children with ea had a gasless abdomen, the endoscopic procedure excluded ( ) or diagnosticated an upper pouch fistula ( ). in patients who suspected "h" fistula ( ) broncoscopy has strong advocated method to make diagnosis and established cervical approach. from july newborns with ea and lower pouch tef received a selective transtracheal incannulation. we were not able to proceed just in case with congenital subglottie stenosis. in these patients we provided gastric drainage by radiopaque and flexible - french catheter. the knowledge of the precise anatomic position of tef consent to adjust the tip of the endotracheal tube in order to achieve best ventilation. the presence of the catheter through the fistula helps the surgeon to identify, it quickly. no complications were correlated to the procedure and no babies had early pneumonia. alimentary continuity was achieved in all patients ( primary anastomosis, resections of tef, oesophagocoloplasty and died with gastrooesofagostomy). the late mortality . % ( ) was only directly related to the severity of associated malformations. conclusion: the advantages of this technical approach are unquestionable for the anaesthesiologist and the surgeon. in our experienc e the procedure improves perioperative management of babies and appears to be safe. relation between cytokines, prethrombotic markers and endotelial injury markers in children with septic shock objectives: to establish the relationship between cytokines (tnf, il- , il- ) prethrombotic markers (d.d., pcam) and endothelial injury markers (tm, uwf) in pediatric patients with sepsis and bacteriemia without shock, and patients with septic shock. design and methods: prospective study, children ( months- years) were admitted in our picu in with the following diagnosis: bacteriemia ( ) sepsis ( ) and septic shock ( ) according to jacob's r f criteria. measurements: il- , il- , tnf, tm, vnf, d.d. pcam and routine laboratory data on admision, , , hours and on discharge. the prism (pediatric risk of mortality score) was also recorded. results and conclusions: two patients in the septic shock group died. significant differences were found between non-shock and septic shock patients in relation to tm, dd, pcam, il- , il- and tne high levels of tnf and il- are closely associated with the severity of septic shock with purpura in children. low levels of pcam on admission were associated with severe shock. who underwent open hea~nt surgery, hypervotaemia with or without oliguria was the most frequent reason to start pd ( %). in patients pd lasted less then one week and there were no complications; in patients it lasted - days (one child had a peritonitis). instillation of dialysis fluid into the peritoneal cavity was associated with a significant increase in central venous pressure. there were no significant changes in cardiac output or arterial oxygeu saturation. in all patients pd dhnjnished fluid overload or improved the metabolic status. patients ( %) survived the postoperative course and all had complete reintegration of renal function. conclusion: pd is a useful method to treat the fluid overload and acute renal failure in paediatric patients following open heart surgery with file effects of little importance on the cardiovascular fimction. obieetives: with the marketing of computerised systems for lung function testing in newborns, there has been an increasing interest in clinical approaches. percentile curves of pulmonary parameters permit an appropriate and clinically useful interpretation. however, the manual evaluation of the results using different curves is an impractical technique. therefoi'e a computer programme was developed. methods: the percentiles ( %, %, ~ %, %) of the most important pulmonary parameters were determined non-parametrically in weight-classes. for the calculation we have taken results of our own as well as other laboratories using a meta-analysis of reference studies. in all, individual data of - healthy newborns ageing between - days were collated. using these percentiles, for every parameter in relation to the body-weight the cumulative distribution was calculated approximately using piecewise linear and exponential functions. as shown in the figure the results of computing are represented numerically as well as graphically and can be included in the patient report. conelusions: clinic~d experiences with the programme have shown that representation of all measured parameters on standardised % scales allows an easy interpretation at first sight and improves the detection of pathologic patterns in the parameters. ")supported by bmft, fp "risikoneugeborene" prism (pediatric risk of mortality) score is a well known, already validated scoring system that quantifies severity of illness based on routinely clinical and laboratory variables measuring physiological instability. once computed the score by summing up the weights corresponding to the most abnormal value recorded during the first hours, the overall risk of mortality can be predicted by using the coefficients estimated by a logistic regression where prism score is the main independent variable. (pollack mm et al, -pediatric risk of mortality (prism) score. crit. care med. ; : - . to assess the applicability and validity of prism in the italian setting we launched out a prospective data collection in a sample of pediatric icus. measures of calibration (goodness of fit statistics) and discrimination (receiver operating characteristics and area under the roc curve) are planned to be adopted in the cohort of patients recruited during year period. as the validation study started on july , data collection is still on going and validation analyses will be carried out on july . up to now centers recruited cases. at present, characteristics of the sample recruited are the following: most of the patients were male ( %); the mean age is years with % of patiens having less than days; more than half were medical cases ( %) admitted from emergency room or from hospital floor ( %); % cases were admitted with an organ failure while % to be intensively monitored. icu-mortality was l %. the paper will present final results of calibration and discrimination analyses that will be carried out in the whole sample and across subgroups known to differ in terms of clinical relevance and prognosis. if calibration and discrimination assessment will produce not satisfactoty findings, a customization of the current coefficients will be made allowing a formal comparision of previous and new parameters. jf riera-faneao, m wells, j lipman. baragwanath intensive care unit, university of the witwatarsrand, south africa. [background the prism score is designed to assess the likelihood of death in ipaediatdc icu patients, using only acute physiological disturbances, age and [operative status to predict mortality. there is no evaluation of chronic health status, [including malnutrition. this may significantly affect its ability to accurately predict outcome in a population where malnutdtion is common. aim to determine the influence of nutritional insufficiency, as indicated by a low weight-for-age on outcome prediction by prism. patients & methods we analysed prism, weight and demographic data co ected prospectively from consecutive paediatdc icu admissions over a year pedod. a proportional weight (pwt) was calculated as a percentage from the th centile of the who weight-for-age growth charts. the pwt was compared for survivors and nonsurvivors, and mortality compared for pwt categodes nho wellcome classification). multivariate statistical techniques were used to identity associations with non-survival and to develop a modified logistic regression equation including a measure of i nutdtional status. receiver operating characteristic (roc) analysis was performed including and excluding patients with low pwt for the odginal and modified equations. results non-survivors had a lower weight than survivors ( . kg and . kg medians p = ) a lower pwt ( % and % medians p = . " . the incidence of malnutdtion , in our icu population was %. the mortality of manoudshed patients was' significantly increased (p = . ), with a good correlation with the degree of malnutrition. the accuracy of prism was significantly improved when malnourished patients were excluded from the analysis (roc value increased from . to . ). ! logistic regression and discriminant analysis identified a significant association between prism, pwt and outcome; age and operative status were not significantly related to mortality. the use of a modified equation including the raw prism score, pwt category and age can significantly improve the discriminatory power (az dm/elopmental sample . , az validation sample . ). the modified formula is: legit = - . + . *prism score - . *age + . *weight category, where the probability of mortality is exp(iog/t)/ + exp(iogio. discussion although we can improve the prediction of mortality by a modified or recelibrated formula, this still does not compare with the reference prism population. the need for validation of the score itself, in the association with outcome of the acute physiological variables themselves, is thus apparent. we conclude that while the odginal prism formula can be improved significantly, a modification of the basic variables in this and other third wodd populations may be essential. a high incidence of malnutrition is an independent risk factor of mortality, and an important cause of the poor discriminatory performance of prism. in order to improve the accuracy of prism, nutritional status should be taken into account. objectives: to assess the value of inhaled no to differentiate between pulmonary vascular constriction or fixed anatomical obstruction. methods: we assessed the response to ppm inhaled no in patients( m, f, median age . months, range day to years) with signs of increased pulmonary vascular resistance, there were pre and postoperative patients. patients were divided into responders(+) or non-responders(-). a positive response was defined as a % reduction in pulmonary arterial pressure and pulmonary vascular resistance(pvr) or in the presence of a left to right shunt, a fall in pvr accompanied by increasing pulmonary blood flow. left atrioventricular valve atresia + mustard pat: pulmonary atresia vsd: ventricular septal defect asd: atrial septal defect pda: patent ductus arteriosus tapvc: total anomalous pulmonary venous connection the responders( / ) were characterised by left to right shunts or pulmonary venous hypertension( / ). patient# was weaned from ecmo with inhaled no. patient# , without congenital heart disease, underwent a lung biopsy which confirmed reversible pulmonary vascular changes. patient# had a pulmonary hypertensive crisis which responded to no. all non-responders( / ) had evidence of anatomic obstruction to pulmonary blood flow (# , , )or a low pvr(# ) on subsequent cardiac catheterisation. in patient # , lung biopsy confirmed severe obliterative vascular disease. conclusions: inhaled no appears to be an effective pulmonary vasodilator. a failed response may be evidence of either irreversible pulmonary vascular disease or a residual anatomical obstruction which may be surgically remediable in the postoperative cardiac patient. therefore, inhalation of no may be a useful diagnostic test to differentiate between fixed anatomical obstruction and reversible vasoconstriction. results: during these years, the incidence of sdra was . % of the total of admissions. the most common etiology was meningococcic septic shock. since , there is a decrease of its incidence. (from % to %) and an increase of pneumonia and immtmodeficiencies. mean age of our patients was , years ( % males, % females), total mortality by sdra was % and there is an increase up to % since mean time of stay of the dead was , days and , days those who survived. although during the late years we offer in the picu a better attendance quality to the patients with sdra and the mean stay is longer, both for those who die and for those who survive, mortality of patients with sdra have increased. the incidence of sdra secondary to the septic shock of a meningococcic etiology have decreased. on the contrary, the sdra secondary to infections by opportunistic germs in patients with congenital inmmunodeficiencies or acquired immuodeficiencies have a tendency to increase. in our series, this change of aetiology is the responsible for the increase in mortality. hospital infantil unlversitario "virgen de roclo". sevilla. espalqa aims:to assess the incidence, etiology, clinical course, sequelae and mortality of the patients admitted to a paedfiatic intensive care unit with the diagnosis of severe traumatism. material and method: cases of severe traumatism in children admitted to our icu in the period from january to june were reviewed. age of patient ranged from months to years, % were males. in our series, % of cases suffered traumatism due to a traffic collision and % had a fall from a considerable height. only in one case was traumatism due to violence to the child. we assessed the first assistance received in % of cases: where was it performed, interval of time since the accident, and steps taken. these data were also studied in relation to the latter evolution. results: % of our patients suffered cranioencephalic traumadsm (ct); in % it was an isolated picture and in % of cases was associated to other lesions. there was participation of thoracic and/or abdominal organs in % of cases. % of cases presented important maxillofacial involvement. only one case presented serious cervical medullar lesion. mortality in our series was . %. in . % important sequelae remained. all of these patients presented tepas on admission equal or lower than . % of those with traumatises had slight sequelae. . % of the total evolve towards healing. a polytraumatized child is a patient that benefits considerably of it admission in a paedriatic !cu. the rapidity in receiving first aid and its quality are essential to avoid sequelae and to make mortality decrease. after unilateral lungtransplantation % of the patients develop a lung failure with decrease of perfusion and increase of pulmonary blood pressure in the transplantated lung. the improvement of perfusion is an importent task in the postoperative period. case report: a year old girl with idiopathic pulmonary fibrosis received a left sided single lung transplantation. during the early postoperative period occured a higtter demand of oxygen and an increasment of the pulmonary vascular resistence in the left lung. the pulmonary ventilation and perfusion scintigraphy indicated in comparison with the right lung a reduced perfusion of only % in spite of a ventilation of % of the transplanted lung. to improve the perfusion of the transplant we administrated per inhalation prostacyclin in a maximal dose of ng/kg/min. the arterial blood pressure decreased but the perfusion continued nearly at the same level. during the following administration of ppm no in the respiratory air we achieved a significant reduction of the respiration pressure f~m to nun h and of the pulmonary arterial pressure. the perfusion in the transplanted lung increased to ca/of the total pulmonary perfusion. after days of administration with no we were able to withdraw the axtifical respiration without any following complications. conclusions: the perfusion of transplanted lungs is a major proble_r~ in the postoperative period. this case demonstrated the advantage of no towards the inhalativ application of prostacyclin. no showed a significant improvement of perfusion in the transplanted lung of a year old girl. results: a total of children with ards were treated with bovine surfactant (alveofact| cases were evalable. the median age was . years (range weeks to , years). in six cases ards was associated with pneumonia, in two cases with lung hemorrhage; in one case isolated ards followed hemihepatectomy. the first surfactant application was performed with a median latency of clays (range - days) after first symptoms of ards witha median doseof mg/ kg (range - mg/kg). in patients doses of surfactant were applied. during the hour before therapy, the median pao / fio -ratio was - . within min. after application of exogenous surfactant the pao / fio -ratio increased to with successive decrease over a period of hours to . accordingly, an increase in pao and oxygen saturation and (less significant) a decrease in ventilation parameters could be observed. analysis of broncho-alveolar lavage before surfactant application in children receiving repeated doses revealed in most examined cases either clear surfactant deficiency or pathological function. of treated patients survived ( of the , respectively). of the surfactant doses were applied in the surviving patients.conclusions: the application of exogenous surfactant in children with ards caused a significant increase in oxygenation, which declined over a period of - hours. the effect often could repeatedly reproduced, in one case after applications. the increase in oxygenation often allowed the reduction of fio and/or the inspiratory pressure. no side effects were observed after exogenous surfactant application.in many cases the application of surfactant wag too late after first symptoms of disease (median latency days). ards mostly due to pneumonia seemed to respond to surfactant therapy less well or not at all. permanent junctional reciprocating tachycardia (pjrt) is the most common incesant supraventricular tachycardia (svt) in children. it is usually drug resistant and its onset in early life has been associated with dilated eardiomyopathy. we report our clinical experience with patients detected antenatally and another diagnosed at months of age. method.diagnosis: negative p waves were detected in leads ii,iii and f, p'r > rp" and there was not warm-up at tachycardia onset.clinical records, ekg,x-rays, echo and holter were reviewed. ep studies were undertaken only with therapeutic purposes. results. in a year period patients under y of age fullfilled diagnostic criteria; were detected prenatally ( - weeks) and one was diagnosed at age mo. the fetuses had intermitent svt during gestation. all of them had pjrt in the first month of life at rates between and bpm. they were admitted to the icu but did not develop signs of heart failure. they were controlled with digoxine (d); d and quinidine; d and propafenone in to days. one was in sinus rhytm until age y; he then showed persistent pjrt over % of the day on repeated holters and underwent successful radiofrecuency catheter ablation (rfca).the other two patients showed initially a lowering of tachycardia rate followed by sinus rhytm for over % of the day (follow-up ran and y). the mo. old infant was admitted to the icu in severe cardiac failure. echocardiogram showed marked systolic dysfunction (shortening fraction %) treatment with digoxine, amiodarone and propafenone were unsuccessful despite lowering heart rate to ; rfca was performed at m. of age with restoration of sinus rhytm and rapid recovery of contractility. all patients were given atp at admission with transient ( to see) recovery of sinus rhytm. ff,s clinical course of pjrt is variable. atp is useful only as a diagnostic tool. initial treatment with digoxine + amiodarone or propafenone is adviced. rfca is a very useful therapeutic modality and can also be performed in young infants twelve patients ( %) died. these were meningitis, head injury, sub-arachnoid bleeds, status epileptieus, leukaemie, drowning, and multiple trauma. calculated from the a admission day p edialric risk of mortality score (prism), the probability of death (p) ranged from - %. of the deaths, i were predicted by prism analysis except for the leukaemie patient (p i%) who died from haematological complications following chemotherapy. two children predicted to die (p % & %) survived. the median length of stay was days (range - days). patlents( %) received ventilatn~ support and patienta( %) were transferred to specialist units ( neurosciences, liver, cardiac, bums). this data supports the view that many paediatric patients are being adequately treated in a dgh icu. meningitis and other neurological illness caused the majority of deaths and respiratory problems caused most admissions. most deaths ( of ) occurred within a few hours of admission. ectopic junctional tachycardia (ejt) is one of the most dangerous arrhythmias in the postoperative setting of congenital heart defects since it does not respond to antiarrhythmics or defibrilation. the object of this presentation is to report on two patients who presented f_jt in the early postoperative period and developed intense congestive heart failure which could be controlled after treatment with moderate topical hypothermia. two patients, m and y, diagnosed of atdoventficular septal defect and tetralogy of fallot developed intense heart failure in the early postoperative period. taehyeardia rate was and bpm. medical drug therapy included weaning from vasoactive drugs, iv digitalization and iv amiodarone treatment. there was not response. they were both surfaced cooled by placing plastic bags filled with cold water over the patient's chest and abdomen. temperature was monitored to obtain a central temperature of ~ there was a gradual decrease in heart rate in the following hours ( - bpm) paralel to the degree of surface cooling and clinical course estabilized.both recovered normal sinus rhytm in to hours. there were not significant arrhytmias after the procedure and postop, was uneventful. conclusions. moderate hypothermia is a very useful manuever for the treatment of drug resistant ejt. since it lacks side effects of other antiarrthymics we beleave it should be the treatment of choice for the treatment of ejt in the postoperative patient. present understanding of the pathogenesis of sepsis, based on the theory of systemic inflammatory reaction, has risen new interest in the more invasive methods of treatment, like plasmapheresis, leucapheresis and exchange transfusion (et). obiectives: evaluate the effect of et in the treatment of neonatal sepsis. material and methods: from september to december , a prospective study was carried out, where the severest cases of bacteriologically proven neonatal sepsis (n= ) were treated with et. in total newborns were treated for culture positive sepsis in the intensive care unit during this study period. diagnosis of sepsis was based on the clinical criteria of suspected neonatal sepsis, used by mc harris et al., laboratory data and positive blood culture. newborns with severe congenital malformations were excluded. et was carried out with fresh (less than hours old) adsol-conserved erythrocytes, from which buffy coat had been removed, and same donors plasma, using a slow continuous two-site technique. the mean volume of et was . ml/kg. the effect of et was assessed as a change in the score for acute neonatal physiology (snap), general treatment results were compared with a historical control group of newborns, treated for culture-positive sepsis in the same icu during the first eight months in . students ttest and chi-square test were used in statistical analysis of the data. results: with the use of el a significant decrease in mortality was achieved: death of cases during the study period, compared to deaths among the controls (p< . ). no baby, receiving et, died. the incidence of severe complications did not differ in the two groups. the snap-score showed quick improvement by the first post-transfusion day (p<o. ) and the effect persisted during the five following days. conclusions: we conclude, that the use of et in the treatment of critical cases may help to lower the mortality of neonatal sepsis. it provides a quick improvement in the clinical condition of septic neonates. the granulocyte-colony stimulating factor (g-csf) is largely employed in granulocytopenic patients. experimental studies have' demonstrated the effectiveness and safety of the therapeutic use, nevertheless the human employ is reported almost exclusively in neoplastic patients submitted to chemotherapy and in patients with fungal or pseudomona~ spp infections. the authors report the data concerning three non granulocytopenic children: in the first, o girl years old, affected by pseudomomm aerug/n~a pyeionephritis, the antibiotic therapy was not tolerated in consequence of renal and hepatic failure. the second patient, an infant months old, has been treated with salbactam-ampiciilin, ceftriaxone and chioramphenicol because of haemepldlw iafluem~ meningitis; a late neurological aggravation required the antibiotic therapy recommencement the last, a years old insulin dependent diabetic boy, was affected by cared/do spp systemic infection; the antifungnl therapy w~ not practicable in consequence of renal and hepatic involvement in all the g-csf was administred subcutaneously at the'dose of $ u for days. a significant increase of granulocytes was ever noted already after the second administration until hours after the last dose. clinical signs, fever and biochemical values are promptly influenced positively and all patients are restored to health. no side affects were noted. the granulocyte colony stimulating factor, at indicated doses, can prove of great help in critical patients, in who the antibiotic or antifangal therapies can result toxye or cannot be tolerated. the ~reptococcas p~, among the gram pmltlve~ represents the main causative organism of bacterial meningitis in children, with the majority of deaths occurring within hours of admission, the third generation cepohlosporim were indicated as antibiotic of first choice, and some literature reports have demonstrated no significant dlffereuces in dinical course of patients treated with ce~rlaxoae and of those treated with ampieibin and chlornmphenicol. the authors report the ease of on infant, male, months old, submitted to a neurosurgical interventiol after days the infant became febrile and lethargic and a bacterial meningitis by ~trepmcecctz ~ was diagnosed, in spite of he was given the eoftriaxone therapy.. an amelioration was found only when a systemic treatment with vaucomyein was added. after days an intrathecal administration of vancomyein m~day was started: the norbmlization of the spinal fluid profile was uoted two days later and the infant receve~d progressively. the follow-up after eight months doem't evidentiate motosensorini sequelae-the individuation' of ~cscc~ pmmmsm/ae strains heta-loctam antibiotics resistant requires alternative therapeutic regimens: the k~terity quead vitam and quoad valetudinem of these infections justifies an intrathecal therapy, especially failing o prompt answer to the systemic treatment objectives: to evaluate the incidence of the burnout (bo) of the staff in a picu in a university hospital. the bo is a syndrome charactedzed by many factors like emotional stress, lack of personality and reduced work ability. this syndrome represents a kind of abnormal response in the working habitat, above all, where psychological and personal characters are mostly involved. the symptoms of bo are represented by demoralisation, demotivation, incapability, boredom, isolation up to organic disturbances, like migraine, insomnia, dizziness and gastrointestinal disturbances. the major incidence of this syndrome was found in the hospital staff, especially among the nurses, working in an atmospher of high emotional dsk, just like in an intensive care unit. methods: from january ' till april ' , all the staff of the picu of the a. gemelli hospital of rome, underwent a test to evaluate the bo. the test used was taken from the book "bumout: from tedium to personal growth", by pines and aronson. twenty seven people were studied ( females, males)i out of which doctors, residents and nurses. it was considered sign!ficant as mild bo, a score between - and as severe, the score of bo >. . results: subjects ( %) resulted positive for bo, out of which were females ( %) and were males ( %). the subjects with mild bo were / : was a doctor, residents and nurses. the subjects with severe bo were / , out of which resident and nurses. conclusion: the results obtained show that bo is a condition well represented in the staff of our picu. the category most at dsk seem to be the nurses ( subjects), as well as residents ( subjects), as in literature, which shows a major incidence of the syndrome in younger subjects and having a limited partecipation of functional decision. the results obtained obliged us to start a programme of serial controls so that the subjects most exposed can have a necessary psychological support to react adequately to this condition. the term systemic inflammatory response syndrome (sirs) was adopted by the consensus conference to denote a type of systemic response to severe infection or otherinsults in critically ill patients. when sirs occurs from infection it is called sepsis. sepsis occurs more frequently in persons with perexisting illness or severe trauma. there has been tremendous advances in prophylaxis, diagnosis, and treatment of sepsis. a comprehensive model of the disease progression from sirs to mods should be developed giving priority to severity of illness scoring system and other predictive methods. some recommendations for future clinical trials include: trials should not start with humans. before proceeding to human trials, animal studies should indicate an acceptable risk/benefit ratio. appropriate patient populations must be defined and treatment protocols should be standardized. full and rapid reporting of all results should be mandatory and a central repository of published and unpublished study results could be helpful. accrual at each center should be of sufficient size, and should include the number of patients accrued, mortality rates, and patient characteristics. pivotal trial should be preceded by sufficient pilot or phase ii studies. correct drug dosage and usage should be delineated in pilot studies. large, multicenter, trials should be used to enhance the unversality of trial results. analyses should be planned a priori. definitions for the target population should be explicit, reproducible, and include illness severity scores. outcomes should be relevant reproducible and include both measures of benefit and harm. mods and its reversal should be considered as an endpoint. quality of life should also be considered as an endpoint. the estimators of overall treatment effects should be controlled for base-line prognostic factors and subgroup anaiysis should only be used for hypothesis generation and not to modify the conclusoin of the trial. economic analysis should be included as part of clinical design. evaluatin of source control should be a critical component of any study. standardized clinical mediator assays should be pursued. placebo patients in clinical trials should be studied for a better understanding of the pathogenesis and epidemiology of sirs, evidence based medicine should be used to evaluate the validity of clinical. introduction: use of inhaled nitric oxide (no) as a modulator for optimizing ventilation-perfusion or lowering pulmonary artery pressure is becoming increasingly common. no is a free radical but little toxicological research has been published. clearance of nebulized mtc-dtpa is known to be, a sensitive indicator for early function impaimaent of the alveolocapillary barrier. we investigated whether exposure to no increased clearance of ~tc-dtpa from the lung. methods: three groups of white sealand rabbits (bw . kg) were anesthetized, tracheotomized and paralyzed. groups were ventilated for six hours at pressure regulated volume control, set to deliver ml/kg with a frequency of /rain, i/e ratio = : and peep = cm hzo using a modified servo ventilator (siemens, solna, sweden) with computerized no delivery system. gas mixture per group was either / or / [no (ppm) / fioz]. after six hours of ventilation in these groups and immediately after anesthesia in group (control), ~tc-dtpa was nebulized into the inspiratory line of the breathing circuit and administered as a fine aerosol. gamma counting was measured for minutes, monoexponential curves were fitted to the data and the clearance half-time (t was calculated. the t~/ mean • sd of the different groups were: t~a (mean -sd) h"e,i witl~ arf : di.ff:erent kinds, aged .q-ore mon't.hes to [ gears o : (bodi weight .~rom ., to kg), is presen .... "ed ( i,,~u::trl:e i:ibstraclive d:lse~se... ~ .ards'- ; :~,;,,arf o~ ::entral genes:i s .- , ,~ :inc lud ing men ingeenceph it :is- ~ reye ' s ~yrtdro~e-..#~,bri~:ln pes~.re~nimatior~ disease.." ). int:lrl~]. pa-. "iiulle'i,~s ariel regymes o+ l;mv,l;i"t"v were cle'l'.ermllled by ba- 'i~ier was. about . tuber,, dopamin tiara-:. t.io; was ~.".,,'.r:~r~led. cmv,cppv d~.!"~tion raniled -~rom f to dayns.,~ < .-:in , "t -irl lo;and> davs'-in 'l~atierr~{s i'i"ai s:ltiol~ o ; patterers to imv, simv modee was per.r:)rmed, ~herl pif:' decrease.d to - ml~ar, fi ~ecreased to , . lind less with a = /,,. i:lesq.lts:{ in pat:i.ents e{ group :l, who were tre,~d.ed w&th f'f'v, teoph :i. : . l:i.r~ (is- .mg/kg/day), g lucecdr t icostei~oids ( .... :~;mg/kg/day), when r exceeded in , -.];, times normal va i tea the e aqes/,'!:l"oln ~j,, ite :i.~;::.!;, ~ml"lrj), it was possible 't'(' ce 'e~ e aad]t:..~rom ! . '.' i', to !..'; , - , mml-lg in ~}.. :~.[~ houi,!; ~d'l(:i to ru:}l",g'd!~l:i. e i::h,:~e,'~c['el';i.stil obieetives : this chapter will describe what is knovca of the psychlogical responses of infant and children to hospiuiisation and attendant procedures. the factors which may modify these responses will he discussed and important considemtiorts will be outlined for optimal anaesthetic management and postoperative period of infants and children which will minimised the rise of emotional upset. methods : in this paper the autors will discttssed the probl of: . health children (asa i, ii) facing single uncomplicated surgical elective procedures . various abnormal situations including neurotic children, children facing repeted operations, chronically ill, buaaes and tsaumatically impired ones . unfortunate young patient facing and often expoclting fatal outcome from le "ul'ukaemia, tumors, cystic fibroses or otheq" disease. : management of each child must vary greatly, ifi general the phases of emotional conditioning include home and preadmissiun preparation, admitiun preoperated and operative care and postoperative period. the authors would be happy if the child passes all stages without any trauma which could be prolonged in the future life. introduction ino is used to selectively reduce pulmonary vascular resistan(~e. we applied ino in the postoperative intensive care of patients with pulmonary hypertension and the risk of right ventricular failure after surgical correction of a congenital cardiac defect. methods - ppm no were added to the ventilatory gas mixture using a specially designed equipment (messer-griesheim, germany/austria). indications for application included pulmonary artery pressure > % systemic pressure, critically depressed right, ventricular function or an oxygenation index > . assessment of n oefficiacy consisted of on-off-on measurements according to the clinical stability of the patient including hemodynamic parameters, pulmonary gas exchange, continuous monitoring of ventitatory function and transesophageal echocardiography of the right heart. results in situations ( patients, age days- , years), ino was applied - h postoperatively. oxygenation was improved in situations from _+ to + mmhg pc ; pulmonary pressure was reduced in situations from -* % to _+ % of systemic pressure. in situations, no reduction of pulmonary pressure was present, but measurement of cardiac output or echocardiographic analysis indicated an improvement of right ventricular function (right ventricular stroke volume + -* %, cardiac output + -* %). in situations (immediately postoperativ with suprasystemic pulmonary artery pressures [n= ], multi-organ-failure [n= ]), no response to ino could be determined. conclusions for a special group of patients, the selective reduction of pulmonary vascular resistance by ino has become an important part of postoperative therapy. using this selective afterload reduction, postoperatively depressed right ventricular function can be improved. this effect of ino seems to be the most important one in the postoperative period. thus, ino appears justified to be appfleo when impaired right ventdcular function could be improved even when pulmonary artery pressure is not raised or remains unchanged. obiectives : premature infant are exposed to danger of apaea due to anaesthesia during their tirst months of life. it is yet unknown whether prematurity is corelated to any other kind of reslgratory disorder due to anaesthesia within the tirst year of life. methods : we theretbre researched retrospectively for respiratory disorders in all infants under months of life belonging to asa group . they all had been anaesthetised in . in our clinic for the following surgical reasons: ingvinal haemia, umbilical haemia, hydrocelae testis and phymosis. results : in cases we tbund: lafingospasm during induction in anaesthesia ( , %), bronchospasm during induction in anaesthesia ( , %), impaired intubation ( , ~ postanaesthetic laringospasm ( , %), supposed aspiration ( , %),postanaesthetic inspiratory stridor ( , %), postinductional inngoedema ( , %), death after months in consequative of infection pneumonie ( , %), none of these disorders was correlated the prematurity, infants suffered of post anaesthetic apnea, of them had premature medical history. concludions : prematurity does not enhance the risk of respiratory disorders due to anaesthesia within the first year of life, except the danger of postanaesthetic almea needs spetial cosideration. it could be demonstrated that aepgi lowers pulmonary vascular resistance and indirectly improves cardiac function. this effect seemed to be selective, and was comparable to ino in the doses we have examined. therefore, aepgi could represent a clinically useful alternate to inc. however, further research is necessary to work up the benefits of either therapeutic strategy. objectives: heat and moisture exchange filtem (hme) are used as artificial noses for intubated patients to prevent tracheo-bronchial or pulmonary damage resulting from dry and cold inspired gases. furthermore they are used for the prevention of bacterial contamination of the anesthetic apparatus by the patient's exspired air. so they are considered as a time-and money-saving device in anesthesia. filters are mounted directly on the tracheal tube, where they collect a large fraction of the heat and moisture of the exspired air, adding this to the subsequent inspired breath. the effective performance depends on the water-and bacteria-retention capacity of the filter. this study evaluates the efficiency of four different filters under clinical conditions. methods: four different types of filters ( dar hygrobac, gibeck humidvent, medisize hygrevent and pall bb ) were investigated dudng mechanical ventilation over a pedod of hours. minipigs with hemorrhagic shock were intubated and ventilated for days in an animal intensive care unit (icu). after hours of mechanical ventilation the filter was randomly replaced maintaining the individual ventilatory conditions. the weight of the filter was determined before use and after removal after hours. the airway pressure was monitored online to record changes during use. tracheal secretions and both sides of the filter were microbiolologically tested to see whether bacteria of the animal's respiratory system could be found on the patient's side of the filter or if they even would have penetrated the barrier. results and discussion: over a pedod of hours of types of filters showed an increase in weight of + % and airway pressure. bactedal celonisation ccured in nearly all fillers ( of ) on the patient's side, whereas only three of four types of filters showed identical bacterial colonisation on both sides. the only filter that did not show bacterial penetration, increase in weight or airway pressure was the pall-hme, a condensation humidifier without hygroscopic salts for moisture retention. with respect to our data one should use a condensation humidifier if airway conditions should remain stable dudng mechanical ventilation and desinfection of the anesthetic apparatus should be avoided after each patient. aim: to assess the clinical uses of, and experiences with, the hayek oscillator. this is a non-invasive device capable ef delivering not only continuous negative pressure (cnp) but also external oscillatory ventilation around a negative baseline (eov-nb) using an external cuirass. this type of ventilation avoids the need for intubation and intermittent positive pressure ventilation (ippv) and facilitates weaning in ventilator dependent patients. patients and methods: patients in respiratory failure, age range weeks to years in a total of patient episodes were treated using either cnp or eov-nb mode. duration of treatment varied from hours to days. indications for use ef the device were: ) to facilitate weaning from ippv ) prevent reintubation of patients following unsuccessful extubation, and ) avoid intubation and ippv altogether using the hayek oscillator as the on[y means of respiratory support. results: there was an increase in pao :fio ratio after cnp and eov-nb (p < . , and p= . respectively, wilcoxon signed rank test). patients who were in respiratory failure with hypercapnia showed a statistically significant reduction in paco both with eov-nb and cnp (p= . and p= . respectively) but the magnitude of change was individually greater in the patients who were treated with eov-nb. all patients, however, showed a fall in respiratory rate (p< . ) after the application of the cuirass in cnp mode. there was no physiological deterioration related to the application of external extrathoracic negative pressure in either cnp or eov-nb modes. conclusion: the improvement in pao :fio , the fall in paco and respiratory rate were indicators of an improvement in ventilation. the proposed mechanisms include improvement in frc, recruitment of additional alveolar units, and improvement in secretion clearance resulting in reduction in the work of breathing. meek to ~ month of the lifo,the bemodyuanicfacls were defined uitb the help of tetropolar reography method!. the excretion of !he catbocholauines fcfi] mith the urine gas detertend by taylor ll,laoorsy ~ iacg/dayl. hsaltl in the hypercuagulation stage of bic we deflorteeed the acliuutiun of the tbrubio and plasiin syaet~ mitb the increase of the inhihitnrs, in this case we registered in full uahe dot this process coabined uitb the dayl~ excreliou with lho urine epinopbr ne e], nor~pinopbr no tel and dophanine io], lbat shod the inlensificatiou of the s~nthosis prnoe-s~es and the release of ea in blood fron hissue deport the actffat on of the svnpathadrenui systen ]sfisl assisted to furl the b?perd~nanical rosins of the eircuidion and increase the ,icrocirculatinn, the klinicai sings of the insufissieutly of the circulalion have not defined,that has been associated the conpensatury character uf the ehan~es of ~ and heludy~enic status, t~e uun~u|p-lion ceugulupatby bus been donoustraled in the hypocougulatien stage ~bat man xauifosted b the exhaust of lhe confulalion nod oessel-platel heuostasis, the consuxptton of cnnpononts tbronbln ,plnstin, kallek~eiu-kinln s~slots and the forniration eat in fell canoe clot uas accoqaued bs docrea,e of fl,nfl,o, the products of the xotabolisx of c~ and the activation of xonoaninoxydasu. the decrease of the extoll'on g and the exhaust deport co indicahd about t!e ]ou fund/anal reserve of ~fl~. it was one of the lain reason of ~bo heiod~uanic disbroed iheat insnfissient]~] and the uicrncireulaflion lintestinal codeme with the low effectife periferal flow] and nul[iplay organ failure,the distrued deport of sos mitb throubocytupenin no; be one of the nechanisn the dislrood of uessej-plalol heioshasis, the correlation bolueeo changes of boiostosis c~ and circulation ore reguired aduinistration nedidns, thai reslore the love s of c~ in the blood, prevent uulliplay organ failure and hetorrnge in children with sepsis, ~b~ectives: multi-measured correlative analysis of the most number of non-invasive indices of the cardiorespiratory system function was made to determine the structure of their interrelation and the ways of their adequate and effective correction. hethods: spiremetry, capno~raphy, oxygenography, indirect fick method at recurrent respiration, plethysmography, integral rheography -in all indices were used. the received data were processed on a computer by a standard package of statistical bmdp programs. results: women with ~h-gestosis (i group) and somatically healthy pregnant women (ii group) were studied. cluster analysis has shown that the rate of the mean correlation connection between ventilation indices was % in the ist group and % in the iind group; gaseous metabolism - % and %, respectively; central hemodynamics was ~ in both groups. conclusion: cluster interpretation allowed to suggest that an increase of the rate of the mean correlation connection between the indices was characteristic of effective adaptation as the system was multi-component and well-regulated. on the contrary, the increase of the rate of strong correlation connection between the indices reveals the rigidity of the system and the tensity of adaptation mschaniams, i.e. the proximity to decompensation. it follows from this that in cases of eph-gestgsis, the reliability of regulating ventilation and gaseous metabolism decreases. seve/e hypoxemia in non intubated patients represents a major contraindicafion to fiberoptic bronehoscopy (fob) and bronehoalveolar levage (bal), but these procedures are often required for a correct diagnosis of the causative agent of pneumonia. aim of this investigation was to veaify the safety and efficacy of bronehoseopic procedures during pressure support ventilation administered through facial mask (fm-psv). five intensive care patients, all immunoeompromised, ( males and females; mean age . • were enrolled in the study. all patients presented criteria for pneumonia with pao /fio ratio ~ and were responders to fm-psv. fob and bal were performed afte~ topical anesthesia with fm-psv ( ps = em h ; peep = emh ; trigger = -lemh ) continuously admires" tered ( ' before fob fio = . ; during fob, fio = and for ' alter fob, fio = . ). pao /fio ratio as well as saturation (sat) did not show signifteative changes during the procodure (fig.l) . no complication was observed and hemodynamic conditions were stable for all patients. cmv, pnenmoeystiis ( ), legionella and mycobaetermm tuberculosis were identified from bal allowmg a prompt and targeted therapy. we concluded that mask psv can represent an excellea~ technique to pexform fob and bal in severely hypoxemic patients without deterioration of gas exchanges and avoiding endotraoheal intubation. intensive care unit, hospital general of albacete, albacet~ spain. objective: to analyze the current incidence and epidemiology of total parenteral nutrition (tpn) among critically ill patients placed on mechanical ventilation. design: prospective observational study. setting: medical intensive care unit in a tertiary hospital. patients: a total of consecutive l'ritically ill patients with non-coronary related disease needing mechanical ventilation admitted in our icu during a months period. measurements: data of sex, age, diagnosis, and outcome were recorded. severity of illness and therapeutic effort in the first hours were measured using acute physiology score and chronic health evaluation (apache ii) and therapeutic intervention scoring system (ties). r~ults: mechanically ventilated patients, male and female, were studied. only ten patients needed tpn and their main diagnoses were: five cases of multiple organ failure secondary to pneumonia ( ), ards ( ) and septic shock ( ); two eases of acute panereatitis; and one mesenteric throngmsis, one status epilepticas, and one ,prolonged cholinergic crisis b~ suicidal organophnsphate insecticide subcutaneous injection. no statistically significant differences between both tpn and non-tpn groups were found: objectives: evaluate the efficacy of prone position in ards and determine its importance in the therapeutic algorithm. methods: consecutive patients with severe ards (murray-score > , ; pao / fit < mmhg; male, female, mean age years) were conventionally ventilated (pcv, peep - mbar, i:e=i:i, ppeak < mbar). if after hours pulmonary function did not improve patients were placed in prone position. change from prone to supine position was done every hours. beside ultimate survival, parameters investigated were aado , pao /fio , and venous admixture (qs/qt). results: during the first hours in prone position of patients showed a significant decrease in qs/qt ( . % vs. . %) and aado ( vs. mmhg), and an increase in pao /fio ( vs. mmttg). changes were most pronounced in patients with high qs/qt, and in patients with an onset of ards less than hours before first application of prone position. after an average of position changes ( to ) of patients could be weaned from the ventilator. patient could leave tile hospital. i the later course letality was primarily determined by additional organ failures and by the severity of the underlying disease. negative side effects were minor, including slight cardio-vascular depression and increase in p~co , and never posed a limitation to continuation of prone position. especially in patients with septic shock skin lesions in exposed areas could not always be prevented, prone position could easily be combined with all ventilation modes and with all intensive care interventions. also immediately after major surgery and in patients with open packing prone position was possible. conclusions: in this investigation prone position proved to be an efficient and safe method in the treatment of severe ards. patients with a pronounced ventilation/ perfusion mismatch and patients in the early stages of ards appear to profit most from prone position. though the immediate effect on oxygenation is striking, still more the % of all patients die from multi organ failure and underlying diseases. a proposed therapeutic algorithm for ards is as follows: if under conservative ventilation (pcv, peep < mbar, ppeak < mbar) pulmonary function does not improve within - hours prone position should be applied. when after - position changes no lasting effect can be achieved further ventilation modes (e.g. pc-irv, aprv, no, etc.) should be used in addition to prone position. standard intensive care principles, such as fluid restriction and optimization of circulation, apply also to patients in prone position. objectives: nitric oxide reacts with superoxide to form peroxynitrite, an extremely reactive and toxic species. we quantified the presence nitrotyrosine, the stable product of the interaction ' of peroxynitrite with tyrosine residues in the lungs of pediatric patients that died with respiratory distress syndrome (rds). methods: paraffin embedded lung sections, obtained at autopsy, were incubated with a polyclonal antibody raised against nitretyrosine, followed by a secondary fluorescent antibody. alveolar structure-associated fluorescence was quantified using existing methods. results: tissue sections from patients who died with rds exhibited significant specific immunostaining which was uniformly distributed across the blood-gas barrier. in contrast only background levels of fluorescence were seen in the lungs of patients who died from non-pulmonary causes. intense staining was also seen in the lungs of rats that breathed % for h, a condition known to result in rds-type illness; no immunostaining was observed in air-breathing rats. conclusions: significant levels of peroxynitrite may be formed in the lungs of patients with acute lung injury. peroxynitrite may be contributing to the pathology of rds by damaging key components of the alveolar epithelium including the pulmonary surfactant system. mechanical ventilation time was prolonged ,g • days in patients with ardsvs , _+ l, days in control . mean staylcuwas lg _+ ,g days in the ards group vs , • , days in control group postoperative mortality rate was % in ards patients vs , % in those without respiratory failure. -ards incidence in liver transplantation is low ( , % in our sene) but it causes high mortality ( %) page, gas ventilation of the perfluorocarbon-f'dled lung, supports gas exchange and circulation in small animals (< kg) with lung disease. we hypothesized that large animals could be supported by page without adverse effects on bemodynamics. we first elucidated the determinants of gas exchange in normal sheep, and applied them to a model of adult respkatory distress syndrome (ards). methods: using the ventilator settings determined to be optimal in our pilot study (fio of . , peep of cm h , imv of bpm, it of %, and tv of ml/kg), sheep weighing . ~ . ) kg had lung injury induced by instilling ml/kg of . n hc into the trachea. ten minutes after injury, sheep with pao < ton" were randomized to continue gas ventilation (control, n= ) or to institute page (n= ). page was instituted by instilling . l of unoxygenated pefflubron into the trachea and resuming gas ventilation at the previous settings. abg's were drawn at baseline, minutes after injury, minutes after injury, and then every minutes for hours. objectives: inhaled nitric oxide (no) can improve oxygenation and decrease mean pulmonary artery pressure (papm) in hypoxemic patients with ards. in severe hypoxemic copd patients, it is not known whether inhaled no can exert a similar effect on hemodynamics and gas exchange. therefore, we investigated die response of inhaled no in hypoxemic copd patients and the results compared with those obtained in a group of ards patients. methods: ten copd patients (age _+ y;fev~ . _+ . l) and ards patients (age _+ ; lis . _+ . ) mechanically ventilated were studied. hemodynamic parameters were measured using a swan ganz catheter. arterial and mixed venous blood gas determinations, sao , svo , hb and methb were measured (abl ,osm ). mean intratracheal concentrations of no and no were continuously monitored using a chemiluminescence analyzer (nox ) . during the study the ventilatory pattern and fioz were kept constant. the protocol was for ards group: basalt, no loppm, basal~; copd group: basalz, no lo ppm, no ppm, no ppm and basal . after a steady state of rain hemodynamic and gas exchange measurements were performed. a positive noresponse was defined as a % increment in pao . results: papm was similar in both groups and decreased significantly after no (ards, basal . _+ . mmhg, no . + . mmhg, p < . ) (copd, basal . _+ . mmhg, no- . _+ . nrmhg, p< . ). all other hemodynamic variables remained unchanged after no. basal oxygenation was higher in copd group (paojfio _+ mmhg) vs ards group (paojfio _+ mmhg)(p< . ). after no- , pao increased ( _+ mmhg to _+ mmhg, p< . ) and qs/qt decreased ( + % to _+ %, p< . ) only in ards group. in both groups, significant correlations between basal papm and inhaled no-induced decrease in papm were found. inhaled no-induced increase in pao /fio was not correlated with basal paoflfio . no responders were / ( %) in ards group and / ( %) in copd group (p< . ). conclusions. in hypoxemic ards and copd patients, inhaled no decreased mean pulmonary artery pressure. however, oxygenation only ameliorated in ards group because die number of responders to inhaled no were higher in ards group and this effect seems not to be related to the basal hypoxemia. these results might be explained by the v/q abnormalities present in copd patients. grant fis / . objectives: it has been recently reported that expired con slope as a function of time is modulated by total respiratory system resistance (rrs) in critically ill patients (chest ; : - ) . in this study, we analyze the relative contribution of disease (dis), endotracheal tube resistance (rtube), airway resistance (rmin), additional resistance (~rrs), autopeep (peepi) and dylmmic/static elastance (ed/es) to the co elimination in different clinical conditions. methods: we have studied adult patients ( controls, acute respiratory failure, severe ards and copd) mechalfically ventilated (servo and c, siemens) without peep. we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. objectives: alveolar ejection volume (van) can be defined as the fraction of tidal volume (vt) with minimal dead space (vd) contamination. according to the classical paradigm: limvd_~ [vco /vt] =facoz, vco vs vt relationship tends asyntotically to a constant slope when approaches end-tidal volume. we have defined van as the volume that defines this relationship until a limit of % variation. methods: six subjects with normal respiratory mechanics were studied during anesthesia for minor surgery. two subjects, otherwise normals but having high values of total resistance and dynamic compliance, were also studied. capnograms were recorded in steady-state at levels of vt ( . , . and . l) and four levels of peep ( , , and cmh objectives: patients with ards presented lung abnormalities which originate an increase in airway resistance (rmin), in additional resistance (~rrs) and in static elastance (ers). application of peep further increases ~rrs. capnographic indexes reflect lung ventilation]per fusion inhomogeneities. in these conditions, the effects of peep on lung mechanics could be better understood by simultaneous measurement of capnographic indexes. methods: we studied groups of subjects. n: normal subjects scheduled for minor surgery; arf: critically ill patients with mild acute respiratory failure; ards: patients with early ards (< h). we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. respiratory system mechanics was assessed by constant end-inspiratory and end-expiratory occlusions technique. at equal tidal volmne ( . l) a peep level of , , and cmh was applied in all patients. we calculated ers (cmh /l), rmin, c~rrs (cmh /l/s) and autopeep. capnographic indexes were alveolar ejection volume (vae)/vt ratio and expired co slope beyond vae (sipco in contrast to synthetic surfactant natural suffactants (alveofact| are able to inhibit pmn-activation. after incubation of activated neutrophils with surfactant, l-selectin expression is decreased. these effects depends on which preparation is used. we conclude, that natural surfactant (aveofact| can perhaps influence early recruitment (,,rolling") of pmn in patients with respiratory failure like ards. with ards hormann cb, baum m, putensen c, knapp r, lingnau w, putz g . clinic for anesthesia and general lntensiv care medicine, university of lnnsbruck, anichstrabe , innsbruck objectives: in thoracic ct scans of patients with severe ards atelectasis and pleural effusion can be found in the dependent lung regions. by rotating these patients from left lateral position to right lateral position a redistribution of the ct densities, a recruitment of atelectasis and therefore an improvement of gasexchange is possible within a few days ( , ). the objective of this study was to find out the mechanism of alveolar recruitment during lateral positioning by ct scanning in left and right lateral position. methodes: after approvel by the local institutional reviewboard we investigated ventilated patients with severe ards (entry criterias: murray score > , ) in the ct scann of the university hospital. after a stabilisation period of minutes in supine position a thoracic ct scan slice cm above diaphragm was taken. then two different positions of the patients were studied in a randomized order: a) degree of left lateral position, b) degree of right lateral position. each lateral position was held for minutes. at the end of each of these periods a thoracic ct scan slice cm above diaphragm was taken. quantitative analysis of ct scan data was based on the frequency distribution of the ct numbers. to quantify the alveolar recruitment during lateral positioning by means of ct scan we defined compartments within the lungs: a) normaly inflated lung, b) poorly inflated lung, c) noninflated lung ( = atelectases) ( ). results: independant of the side of lateral positioning (l) in the non-dependent upper lung a significant increase of the normaly inflated compartment (s: %; l: %) as well as a significant decrease of the noninflated compartment (s: %, l: %) was observed in comparison to supine position (s). in the dependant lower lung the normaly inflated compartment decreased significantly (s: %, l: %) whereas the noninflated compartment increased significantly (s: %, l: %). throughout the whole studyperiode we did not observe any significant change regarding gasexchange and hemodynamic parameters. conclusions: in lateral position the non-dependent upper lung is decompressed. therefore a significant recruitment of atelectases is observed in the upper lung within minutes. on the other hand the dependent lung is compressed by the weight of the upper lung and the mediastinum. a great amount of the alveoli of the dependant lung collapse in this short time intervall. therefore the net effect of recruitment of one positioning maneuver is very small. when positioning patients one should be aware, that the patient is kept in each lateral position long enough to clean up the atelectases in the non-dependant lung and short enough to compress less lung tissue in the dependant lung. objective: to analyze effects of low-dose no inhalation ia patients with severe aeut~ respiratory distress syndrome (ards) over five days. methods: we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who required no inhalation with a dose of ppm for at least days. entry criteria for no injaalafioa were murray score >i . aud pat/fie < nun hg with peep >~ em i~o for at least hours. all patients were sedated, intubated and mechanicauy vantil~ed with volume assist-control ventilation, and had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) to measure cardiac output (by thermodilufion) and relevant intravaseular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and endotraeheal tube and flow was adjusted to obtain ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endouacheal tube by the chemiluminiscence method (nox , see-seres, france). metahemoglobinemia levels were mesured daily. no inhalation was manteined if paojfio ~ improved at least % and was stopped when the change in pao /fio ~ was below % or when the patient presented a paojf > mm hg a~er minutes without no inhalation. every day we made an on-off test to determine if no inhalation improved pao /fio ~. statistics: analysis of vmiance. data: mean + standard deviation. results: the mean age was . +_ . years and mean lung injury score was . • . . mortality was % ( / ), metahemoglobinemia . • . %, and no concentrations zero. paojf~o always improved significantly al~er ppm no inhalation (see :~ conclusions: reintubation in salf-extubated patients strongly depends on the type of meehamcal venfilatory support: the probability of needing a reintabation ff ese occurs during fult vontilatory support is higher than ff ese occurs during weaning. these data suggest that some patients may remain under weaning from mechanical ventilation for unnecessarily prolonged periods of time. objective: the aim of this study was to evaluate the acute effects on gas exehonge and hemodynamics due to positional changes from supine (sp) to prone (pp) in patients with severe acute respiratory distress syndrome (ards). methods: nine intubated, sedated, paralyzed and mechanically ventilated patients with severe ards were prospectively studied. all had a murray score > . , and a pao /f~o < with peep ~ cm h for at least h. all patients had indwelling arterial catheters in the pulmonary artery as well as in the radial or femoral artery in order to measure cardiac output (by thermodilution) mad relevont pressures, and to withdraw blood samples. arterial blood gases and hemodynamie parameters were measured first in sp, and then in pp after minutes of stabilization. vontilatoly parameters remaing unchanged during all the study. statistical analysis was done by the non parametric wdeoxon test. data are expressed as mean ~= sd. results: there were men and women with a mean age of . years ( - ) and mortality was % ( / ). main results are shown below: objective: to describe and compare a new method for obtaining p-v loops (p-vcv) by using a two-way collins valve (twv) with thosu obtained by the supersyringe method (p-vss). methodology: we prospectively studied patients who had an aeute lung injury and were intubated, sedated and paralyzed, and mechanieany ventilated. we performed the p-vev loops and p-vss loops in random order, and the static inflation pressure was limited to emh with both methods. pressure (p) was measured at the airway opening by means of a differential p transducer, and volume was obtained from flow (measured with a pneumotacograph) integration. the p-vse method has already been described (h~trf a,et al.bepr ; : - ) . the p-vev method consists in the following: the inlet of a twv is connected to the ventilator's y-piece, and both outlets are couneeted to the endotraeheal tube by means of an additional y-piece; one of this outlets has a one-way rudolph valve in order to allow inspiration but not expiration during the inflation maneuver. changing the twv tap position allows basal ventilation or progressiveinflation of the respiratory system. this maneuver is as follows: during an end-expiratory occlusion, the ventilatory settings are adjusted to deliver a ml v r with a respiratory rate of /min and i/e ratio : ; at the same time the twv tap is ehonged in order to divert flow through the one-way valve. inflation then begins alter releasing the expiratory oonlusion. pressure and flow signals were digitized and acquired by a computer for subsequent data analysis. we analyzed the following parameters: inflation compllonee ( objective: to analyze the variables which eventually may differentiate ards patients who do and do not respond to low doses of inhaled no. we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who were treated with no ( ppm). the onta'y criteria for no inhalation were murray score >/ . and paojfo z < mm fig and peep >/ cm i~o for at least hours. all patients were sedated, intubated and mechanically ventilated with volume assist-control ventilation. tidal volume was between and ml&g, with constant inspiratory flow, respiratory rate was - /rain, and i/e ratio between : to : . all patients had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) in order to measure cardiac output (by thermodiintion) and relevant intravascular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and ondotracheal tube, and flow was adjusted to obi~a ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endotracheal tube by the chemilumiinscenee method (nox , see-seres, france). metahemogtobinemia levels were measured daily. we considered a response to no inhalation when an improvement in paoz/fo above % was observed after the inhalation of ppm no (group r) . when the cha~age in paojfi z was below % it was considered a lack of response (group non-r small airways functional abnormalities have been recognized as a common feature of lung pathology. however peripheral airways contribute relatively little (~ %) resistance to flow and there disturbances can not be adequately estimated by conventional measurements of respiratory mechanics. the purpose of the study was to evaluate the relationship between raw and small airways conductance following weaning from ventilator methods. patients (age: - years; males) with no serious complications al~er mitral or multiple valves replacements and with more than hrs on mechanical ventilation have been enrolled in this study. the modified flow interrupter technique (ptg "gould" with fleish head # ; differential pressure transducer pm- -tc "statham" w amplifier "kistler ") and flow-volume recording of forced expiration (fleish head # ) have been applied before surgery and following operation on mechanical ventilation (my), after extubation (t:xtijb), on ( nay) and ( day) days. airways specific conductance (sg aw) has been calculated as a mean of - consequent measurements in each patient at each stage. the sac was estimated by max expiratory flow at and % of vc on - f-v curves (mef .~ , mef ) all the data were statistically analyzed with t-test introduction : noninvasive ventilation (niv) reduces the need for endotracheal intubation, the length of stay in icu and the mortality rate in acute exacerbation of copd. however, some patients failed to be ventilated with niv. .objectives...; to further delineate patients who failed to be ventilated with niv and to obtain predicted factors of failure. patients : a cohort of patients ( • years) presenting with acute exacerbation of copd (fevi: • ml, paco : • , ph: . • . ) and nonmvasively ventilated (pressure support through a full-face mask) between april and may twenty-seven ( %) were successfully ventilated with niv (discharged alive without the need for endotracheal intubation) while ( %) failed, requiring endotracheal intubation. .methods : patients successfully ventilated and those who failed were compared according to respiratory and nonrespiratory variables univariate analysis (wilcoxon rank-sum test and fisher-exact test) was performed to select variables included in a multivariate analysis by stepwise logistic regression. results : underlying disease assessed by the simplified acute physiologic score ( • vs • , p = . ), creatinine serum concentration ( • vs • gm/l, p = . ), blood urea nitrogen (bun : • vs mm/l, p = . ), age ( • vs • , p = . ) were higher and encephalopathy ( vs %, p = . ) more frequent in patients who failed. multivariate analysis showed that encephalopathic patients (or (odd ratio) = , p = . ) older than years (or = , p = . ) and presenting with bun >_ mmyl (or = , p = . ) failed to be ventilated with niv. variables related to the respiratory" status (i.e. paco , pao , fev ) were unable to predict tile failure of niv. conclusion : copd patients older than years, presenting with acute exacerbation, encephalopathy and bun > ram/l, should be carefully monitored because of high probability of failure with niv. methods:from february to december we studied pa_ timnts, males and females(mean age +/- ); of the se had emphysema,lo chronic bronchitis, dilatative car diomyopatia,with tracheostomy and emphysema.mean pac at admission in icu was +/- mmhg,while when weaningbegan, +/- .mean autopeep was cmh ( - ).all patients were ventilated in crpv as long as four hours to calculate st tic and dynamic cmpliance and autopeep.then the ventila tion was continued with psv+cpap(peep cmh objectives: analysis of the incidence of neurogenic pulmonary edema (npe) in a population of headtrauma patients with acute respiratory failure (arf). npe can occur after a central nervous system insult. differential diagnosis: cardiogenic pulmonary edema and other forms of non eardiogenic pulmonary edema. true incidence and pathophysiohigy remain poorly defined, however the role of catecholamines seems undeniable. early onset npe (within h after trauma) is characterised by hypoxemia, transient pulmonary hypertension and bilateral central fluffy infiltrates on chestx-ray. characteristics of cardiogenic edema or pneumonia are absent. late onset npe, (beyond hours after trauma), is more insidious. the clinical and radiographic picture has to clear within to hours. ( ) methods: all headtrauma patients admitted from january to december , in a nearotrauma icu setting were retrospectively analyzed for arf with as sole criterinm a pao -fio ratio < . results: neurotrauma patients were admitted during . patients ( %) presented with severe head injury (gcs< ), patients ( . %) with moderate (gcs - ) and patients ( . %) with minor head injury (gcs - ). overall mortulity was . % early (within h. after trauma) and delayed onset respiratory incidents were distinguished, counting for ( . %), respectively patients ( . %), patients ( . %) had early and late respiratory complications. early respiratory insufficiency was caused in patients ( . %) by aspiration, in patients ( . %) by lung contusion, in patient ( . %) by fat embolism and in patients ( %) by npe. in the late onset group patients ( . %) presented with pneumonia, ( . %) with fat embolism and ( . %) with npe. the npe group, patients, presented as follows: patients ( . %) developed early npe, and ( . %) delayed onset npe. patients ( %) died within the first days after admission, showing high mortality. gcs was less than in patients ( . %), indicating severity of head injuries. conclusions: high incidence of arf with various etiology ( , ~ was found in this population. in about % of all admitted hcadtrauma patients ( , % of arf) npe was causing attetial hypoxemia. occurrence of npe seems to be related to the severity of the brain injury and thus to outcome. these data call for extreme vigilance in respect of the insidious occurrence of npe. were included if recovering from respiratory failure and if in the opinion of the primary physician were ready for extubation. patients were excluded if undergoing compassionate withdrawal of support or had tracheostomies. the attending physicians were blinded to the measurements. included patients were placed on pressure support (ps) of em h with demand-flow continuous positive airway pressure (cpap) cm h . after a minimum of minutes on the above sehiogs: gastric intramucosai pc'o , abg, and a p . were measured. the padents were then disconnected from the ventilator for a period of one minute and the patients" respiratory rate and minute ventilation were measured using a wrights respirometer to calculate the frequency to tidal volume ratio (f/vt). patients were then extubated. extubafion failure was defined as the inability to maintain spontaneous ventilation for hours for any reason. results: twenty patients met criteria and were studied over one month period in october . six of the twenty patients ( %) failed weaning. the mean and standard deviation is outlined in failure . +/- . . +/- . . +/- . . +/- . comparison between roc areas shows phi and p . to each show a statistically significant difference from an area of . (p<o. ). the area at which the test has no discriminative value. this is not the case for either the integrative index or the f/vt ratio. the differences between areas for each curve is not statistically significant. the area's for each roc curve is shown in table #' . results. of the newborns referred to us for ecmo-therapy developed barotrauma, of the required ecmo and one of the three other patients who did not recieve ecmo-therapy died. to determine the correlation between the risk factor barotrauma and the severity of the pulmonary situation, we determined the oxygenation index of each patient referred to us for ecmo-therapy . the table demonstrates , d- giessen, frg. inhalation of nitric oxide (no) and aerosulizatiun of prostaglandin (pg) i: have been suggested to achieve selective pulmonary vasodilation and improvement of arterial oxygenation in patients with acute respiratory distress syndrome (ards). we directly compared these two modes of transbronchial vasodilator therapy in ards patients mechanically ventilated for - h (mean murray lung injury score [ ] . + . ). patients were randomized to receive either first no and then pgi (n= ), or vice versa (n= ), with an intermediate baseline period. each drug was titrated individually to find the lowest effective dose for maximum improvement of arterial oxygenation. gas exchange variables, including data from the multiple inert gas elimination technique (miget), and hemodymmaics under application of no/pgi were compared to pro-and past-challenge values. no (mean dose . + . ppm) increased the mean oxygenation index (pao /fio ) from + to + mmi-ig (p < . ) and reduced the shunt-flow from . + . to . : . % (p < . ). aernselized pgi (mean dose . + . " ng/kg rain) augmented pao /fio from + to + mmhg (p < . ), and decreased shunt from . + . to . + . % (p < . ). the miget analysis showed predominant redistribution of blood-flow from shunt areas to regions with normal ventilation-perfusion ratios in response to both agents. in patients, both no and pgi caused an increase in pao /fio by at least rnmhg. two further patients displayed a corresponding improvement of arterial oxygenation in response to either no or pgiz. the mean pulmonary artery pressure decreased from . : . to . : . mmhg in response to no, and from . : . to . : . mmhg (p < . ) in response to pgi . cardiac output, systemic arterial pressure, and right and left heart filling pressures were not affected by either agent. we r that individually titrated doses of inhaled no and aerosolized pgi~ effect selective pulmonary vasodilation and redistribute blood-flow from shunt-areas to weu-ventilated regions with nearly identical efficacy profiles. obieetives: the use of extraeorporeal bypass systems for oxygenation and co -removal is performed in patients with acute respiratory distress syndrome (ards) to reduce mortality and to improve restitution of pulmonary functions. high-dose heparin -commonly used in such patients to prevent thrombotic complications -might cause incurable bleadings as a major risk. this lead to the development of heparinized bypass systems; results of animal and first clinical studies proposed that such systems might run with low-dose heparin or even without any systemic anticoagulation. methods: since , patients with severe ards were treated with extracorporeal lung assist (ela) using heparin-coated systems (type maxima, medtronic, carmeda coating) in our icu. they received a moderate systemic heparinization. standard clotting assays (act, aptt, tt, ptt, at-ill, fbg, fsp) as well as special tests (tat, r~-tg, pf , pal-l, d-dimers, protein c, cl-inhibitor) were performed. results: covalent heparin-eoating of the ela-systems combined with lowdose heparinization could not prevent major changes in coagulation: ) in mean, platelets dropped from /nl to /nl within h after onset of ela. ) tat levels were already elevated before ela start ( ug/]) and demonstrated an additional peak h after onset of ela (up to ug/[). ) in parallel, there was a transient peak of pai-i levels (from to au/ml} h after onset of ela. ) in mean, fibrinogen levels dropped from to mg/ ml within h after onset of ela. ) in mean, cl-inhibitor levels dropped significantly from % to % after onset of ela and reached the initial levels within h. ) after membrane change, there were significant changes for c -inhibitor, fibrin-d-dimers and tt. ) global clotting tests such as aptt, ptt and tt were within normal range. conclusions: patients with severe ards develop a prethrombotic state already before they get connected to the ela bypass system. after onset of ela, they experience additional involvement of procoagulant, anticoagulant, fibrinolytic, and complement systems. in parallel to laboratory findings, clinical data suggest that the use of heparin-coated systems with accompanying systemic low-dose heparinization does not avoid thrombembolic and hemorrhagic complications in tong-term ela patients. thus, at the present, higher dosed individually adjusted heparin treatment has to be recommended. thereby, standard clotting monitoring is not sufficient. objective: poor muscle performance contributes to prolonged dependence on mechanical ventilation. longitudinal data on muscle function in icu patients is scarce. we evaluated changes in inspiratory and peripheral muscle performance during prolonged intensive care in patients with acute respiratory failure. methods: patients requiring intensive care for more than one week were studied. maximum inspiratory pressure (pimax) was measured twice a week for a maximum of three weeks. handgrip power (dynamometer) and subjective fatigue (keldet score) were obtained in survivors only. one measurement was done on the date of extubation. pimax pressure was obtained by occluding the airway for seconds or at least five inspiratory breath attempts. obiectives -measurement of peep-induced changes in lung volume helps to assess respiratory mechanics in acute lung injury (ali). we evaluated the accuracy and stability of a new respiratory inductive plethysmograph (rip), in the measurement of peep induced changes in end-expiratory lung volume (eelv) and tidal volume (vt) against volume reference, pneumotachograph (pnt), methods -two hours periods of basal ventilation and stepwise increases and reductions of peep ( - - - - cm h ) were recorded in patients with all. in addition, the new rip device (respitrace plus tm) was compared to an older rip (respigraph tm, nims, fl, usa) to determine its thermal stability using cold and warm devices and a ventilated lung model. results -the difference between the new rip and pnt in the measurement of vt was - _+ mi (x _+ se) or a - . _+ . % error. increasing peep from to cm h induced a + ml change in eelv. a difference of + ml ( . % of max. eelv change) (ns) was found between rip and pnt eelv readings. during controlled ventilation with constant settings the mean change in eelv was _+ ml/ min (fig.i) . validation of calibration showed a mean error of -+ . % after rain. the new rip had a higher drift when cold (cold + ml/ min vs warm _+ ml/ min), whereas the old rip was thermally stable (cold - + ml/ rain vs warm i + ml/ min). trauma icu, hospital traumatologia y rehabilitacidn. vall d'rebron. barcelona. spain. recent data suggest that the proportion of patients with relevant discrepancies between two jugular bulb (jb) oxygen saturation (sjo ) values is higher than suspected. objectives: determine the incidence, the significance and the pro nosis value of those differences,if they exist,in severe head injured-patients. material and methods: severe head-injured patients, coma glasgow scale (gcs) , with diffuse brain injury according to marshall criteria in the first ct scan, icp recorded, with an interval from accident-double jb monitoring < than hours, were studied. data from bilateral sjo were obtained simultaneously, every hours. discrepancies were considered significant, when differences in sjo were > %. no chan es in treatment protocol (hyperventilation, man• etc) were carried out due to this study. results: men and women were studied, aged • yrs. at arrival at hospital, gcs were < in and ) in to. the incidence of high icp() mmhg) were sz at the entry. the mean therapy index level required to control lop was ~l all patients required vasopressor therapy to maintain upp over ds mmhg. in patients a s.s f swan-ganz fiberoptic catheter was used to obtain a continuous recording of sjo . in the others , sj were intermittently controhed.the mean time of monitoring were d. • days. ten patients died within this period. a total of . blood samples were analized. at arrival, sjo discrepancies were found in patients, b %. at hours, the incidence were lower, / , . %. at th day, were h/ , z and at day , when the catheters were retired, ii[ , z showed discrepancies. the ct showed new injuries in g z of patients with differences > ~ in sd values throughout treatment period. none of those were considered for neurosurgical treatment. no correlation was found between iop and sjo values and sjo differences. conclusions: the incidence of discrepancies between sjo was higher than expected in severe head-injured patients. these situation could reflect disturbances between demands. when differences are known, and those lend to change, the ct scan, nearly always, will show new injuries. platelet-activating factor (paf) is an inflamatory mediator implicated in the pathogenesis of bronchial asthma and acute respiratory distress syndrome (ards). its inhalation in healthy subjects produces transient bronchoconstriction and mild ventilation-perfusion mismatch, together with peripheral leukopenia as a result of intrapulmonary neutrophil (pmn) sequestration. likewise our group has shown in healthy subjects and asthmatic patients that aaibutamol (s) inhibits both pulmonary and systemic effects of paf, suggesting that s may inhibit paf-induced venoconstriction in pulmonary microoirculation. the aim of the present study was to investigate if s inhalation decreases pmn by lung sequestration induced by paf. we studied healthy, non-atop• nonsmoking subjects ( m/ f, + yr), which were pre-treated with s ( ,ug) or placebo, with a randomized, double-blind, crossover, design, before paf ( ,ug) inhalation. we measured the respiratory system resistance (rrs) by forced oscillation, arterial btood gases and both total white cell and pmn count every min over a min. period. simultaneously, we recorded continuously the lung dynamics of inm-neutrophil and tc m-erythrocytes activity, with a gammacamara. after placebo, paf inhalation decreased white cells (from to x /l), and pmn(from to _+ x /l), and increased aapo (from . _+ . to . + . mmhg, p<o. ) and rrs(from . . to . . cmh .s.i q ) (p < . each). the fall in total white cell count correlated with the intrapulmonary pmn retention (r = . , p < . ). by contrast, after s, paf did not induce any change in white ceil count (from to + x /i), pmn count (from to x /i), aapo (from . to . + . mmhg), and rrs (from . . to . . cmh .s.i ). compared with placebo, after s there was a lower ~lln-pmn lung activity ( . . vs . . cts/mci/pixel, p<o. ), lower intrapulmonary pmn retention ( . . vs . . %, p=o, ), and a faster washout ( . . vs . . s ~, p= , ). our results indicate that s inhibits paf-induced intrapulmonary pmn sequestration, being consistent with the hypothesis that s may offset the venoconstriction of pulmonary microcirculadon caused by this mediator. supported inpiratory muscle fatigue with failure of force generation as def'med by a tensiontime index (tti)> . - . has been shown to occur in normal volunteers and in stable copd patients with a specific imposed breathing pattern. its role, however, in hypercapnic respiratory failure is less certain. we studied failed weaning trials in copd patients in which breathing pattern, tension-time index (tti) of inspimtory muscles, dynamic peepi, dynamic lung elastance, lung resistance, and arterial paco and ph were measured at the beginning and end of a t-piece weaning trial. in addition, the change in esophageal pressure during a mueller maneuver (apes max) was measured. a weaning trail has been prospectively defined to have failed if one of the following criteria was met: a rise in pco > mmhg from baseline accompanied by a fall in ph< . ; a respiratory frequency (f) > /min; excessive accessory inspiratory muscle recruitment; and a marked increase in dyspnea. values are expressed as mean • se. weaning failure was characterized by a more rapid, shallow breathing pattern, worsened mechanics, hypercapnia and respiratory acidemia despite an unchanged tri and pes max. we conclude that in this setting hypercapnic respiratory failure is not a consequence of inspiratory muscle fatigue. rather the adopted breathing strategy and resultant hypercapnia may represent an adaptation to forestall the onset of muscle fatigue. concerning the investigated elf-par~eters, no stadstically signhqcant differences were detected between the pgi and the control group. histopathologlcal changes occured in both groups and consisted in rare focal flaaaning f tracheal epithelium with loss of cilia and slight inflammatory cell infiltration, as well as slight swelling of alveolar typo pneumoeytes. sections of generation , and from bronchial tree were free of pathological changes. conclusion: alter h inhalation of p~ji no signs of respiratory-lract tissue damage caused by the aerosol could be detected. the minor pathological findings in the trachea are most likely due to mechanical irritation by bronchoscopy, changes of the alveolar epithelium are known for long-term mechanical ventilation . objectives: the aim of this study was to evaluate of efficiacy of ganglion stetlate blockade in patients with respiratory failure. methods: two groups of patients were investigated: group i (n = ) trauma patients with acute lung injury (ali), group if (n = ) patients with asthmatic status. in all cases continuous mandatory ventilation (cmv) was used with bennett ae. in both groups bilateral ganglion stellate blockade with antero-lateral approach was performed, using . % marcain. the following parameters were analysed: pao , sao , paco~, pip and c~t~t. results: in trauma patients with aij after bilateral ganglion stellate blockade short -lived and slight improvement of pao and sao , decrease of pacoz and pir and increase of static compliance of respiratory system were found. in second group bilateral ganglion stellate blockade interrupted the asthmatic status and significant statistical improvement of parameters of oxygenation, ventilation and respiratory system mechanics were observed. conclusions: we suggest that the bilateral ganglion stellate blockade is a very useful method in treatment of patients with obstructive respiratory insufficiency. the aim of the study was to analyse whether there exists serum and urine electrolyte disorder in patients(pts.) with acute respiratory insufficiency(ari). the study included t pts. with ari (pao : , @ , kpa. paco : , i- , kpa, ph: ~: , , hco : , :~ , mmol/ , sao : , ~- , %) who were hospitally treated due to pneumonia( pts.),emboly of the pulmonary artery( pts.) and severe attack of bronchial asthma ( pts). among tham there were ( , %) males and ( , %) females, average age , ~: , years, otherwise previously healthy. electrolyte concentracions were measured at the onset of the disease in serum and urine collected during hours (sodium-na,potassium-k, chlorine-c , calcium-ca,magnesium-mgand phosphorus-p). the measured serum and urine electrolyte concentrations were compared with respective referent values (rv). by serum electrolyte analysis, the following average velues were obtained: na:l o, the object of our investigation was a group of pts with massive pneumonias, males ( . %), females ( . %),mean age yrs.thirteen ( %) of them were smokers, ( %) nonsmokers. only pt ( . %) had pre-existing chronic respiratory disease, and ( . %) were admitted for the first lime,with no previous respiratory anamnesis. diagnose was based on anamnestic data of productive cough in pts( . %),physicaly ~onchial breathing in i~s ( . %),white cell count onder x /l in pts( . %). radiographicly, bilateral massive homogeneous shadows were found in pts ( . %), onilateral in pts( . %),pleural effusion in pts ( . %). abnormal renal function was found in pts ( . %). sputum culture was positive in pts ( %): slr.pneumoniae, str.pyogenes, pse'udomonas aerug, in , , cases respectively. all patients had remarcable hypoxernia (pao range from , to , kpa) without hypercalmea. all patients needed oxygenotherapy together with antibiotics and other .symptomatic therapy. nineteen pts had anaelioration of general condition and normalization of blood gas analyses, while pts with the lowest hypoxcmia died.in conclusion, massive pneumonias are frequently followed by respiratory insufficiency which is one of the markers of pneumonia severity. as existing hypoxemia complicates the course of the disease,prolonges the recovery, makes therapy more complexe and may be cause of death , frequent blood gas measurement is recomanded. we studied the effects of bosentan (bos), an eta and etb receptor antagonist, to examine if endogenous et mediates pulmonary hypertension in anesthetized and ventilated dogs with acute lung injury due to oleic acid (oa). the gradient between pulmonary artery pressure (ppa) and occluded ppa (ppao), and gas exchange (evaluated by arterial blood gases and sf intrapulmonary shunt) were measured at controlled flow. in dogs (treatment), data were collected at baseline, during long injury (obtained rain after intravenous administration of oa . ml/kg), and again after bos ( mg/kg intravenously). in dogs (pretreatment), data were obtained at baseline, after bos and then after oa. in treated dogs, oa increased (ppa-ppao, mmhg, table, means + sem, * p < . vs base) and deteriorated gas exchange. after oa, bos did not affect pulmonary vascular tone nor gas exchange. in pretreated dogs, bos had no effect on baseline pulmonary vascular tone but prevented the increase in (ppa-ppao) after oa. the deterioration in gas exchange after oa was not influenced by bos pretreatment. objectives: the alveolar tension is measured by the application of the alveolar air equation in which the arterial pco is used or by the simplified form of this equation in which the respiratory exchange ratio is taken at the value of . . the purpose of this study was to estimate the effective alveolar tension (pao eff) during spontaneous breathing with a new bedside technique which is simple non-invasive in normal subjects and patients with chronic bronchitis-emphysema. we also compared these values with the ideal alveolar po (pao (i)), measured from the alveolar air equation in which paco was substituted by the effective alveolar pco (paco eff) and with the alveolar po measured from the simplified alveolar air equation (pa ). this study is complemantary to previous work for the estimation of paco eff. methods: the subjects breathed quietly through the equipment assembly (mouthpiece monitoring ring, fleisch transducer head) connected to a pneumotachograph and a fast response and co analyzer. the method is a computerised calculation of the effective alveolar po quite similar to that of paco eff, obtained from the simultaneously recorded at the mouth expiratory flow, and co concentration versus time curves. results: the results showed a mean difference (pao eff-pa (i)) of - . kpa in normal subjects and - , in patients. the mean of the difference (pao eff-paq ) and (pad (i]-pao z) was much greater than . in all subjects. the limits of agreement for the difference (paozeff-pa (i))were - . to . kpa in normal subjects and - . to . in patients, while those for the differences (pao eff-pad ) and (pao (i)-pad ) were very large ( > - . to > . ) in all subjects. conclusions: the effective alveolar po is very close to the ideal one in normal subjects, tn patients pao eff may excessively deviate from pa (i) due to the observed significant difference between the alveolar/tidal volume ratio for o and that for co . the alveolar po measured from the simplified alveolar air equation (pao ) differed substantially from pao eff and pad (i) in all subjects. the essential role of glucoprotein hormone erythropoietin is to control red cell production. hypoxemia, reduced blood -carrying capacity and increased affinity of hemoglobin for are the primary stimuli for erythropoietin production. both anemia and hypoxemia induce rapidly erythropoietin secretion. kidney erythropoietin rna levels correlate inversely with hematocrit and directly with plasma erythropoietin level. similarly, hypoxemia increases kidney erythropoietin rna and plasma erythropoietin. the effect of hyperoxemia (pa >lo mmhg) on erythropoietin secretion isn't very well understood. the purpose of this study was first to evaluate the erythropoietin secretion in patients with acute respiratory failure and second to determine the effect of hyperoxemia on erythropoietin secretion in patients with and without anemia. sixteen patients with acute or acute on chronic respiratory failure needed mechanical ventilation were included in this study. these patient were divided in two groups. the patient who developed anemia were included in group i and the patients without anemia in group i . erythropoietin was estimated in venous blood in three stages. the first sample was taken during hypoxemia, the second during hyperoxemia and third during normoxemia. all the patients had high erythropoietin level during the hypoxemia period (mean value • mu/ml). during hyperoxemia etythropoietin levels were reduced in both groups ( mean value . + . mu/ml in group i, . • mu/ml in group ii). in normoxemia stage, erythropoietin increased again in anemic patients, and decreased more in the patients of group i . we conclude that hyperroxemia inhibit erythropoietin secretion in spite of anemia and tow arterial oxygen content. hyperoxemia may be a factor of the insisted anemia in with oxygen treated icu patients. the purpose of this study was to determine the relationship between clinical features of acute lung injury (all) and parameters like total proteins, total and individual phospholipids, the presence of paf, and acetylhydrolase activity in bal of mechanically ventillated patients. acetylhydrolase catalyses the cleavage of acetyl-group from the second position of the glycerylether backbone of paf, leading to its inactivation. mechanically ventillated patients were divided to three groups. group i includes patients without all; group ii, comprisespatients with moderate degree all, ( . <g-i < . ); and group iii comprises patients with severe ards (all score > . ). broncoalveolar lavage (bal) was obtained after infusion of normal saline at ~ to intubated patients and cooled immediately. cells were removed after mild centrifugation ( x g, min, oc). aliquots from the supernatant were used for total protein, phospholipid and paf analysis and determination. acetylhydrolase activity was assessed after incubation of bal with h-paf labelled on the acetyl group. released label was measured by liquid scintillation counter in the supernatant after trichloroacetic acid precipitation of the non-reacted substrate. kinetic characteristics of the enzymes were also studied. total phospholipids appear reduced in bal of patients with all, while total proteins increase. these factors appear to correlate with the severity of all. paf was not present in bal samples pretreatad with equal volume of % acetic acid to denaturate acetylhydrolase. detection limit for paf under our experimental conditions: pg paf/ml bal. instead, acetylhydrolase activity was detected in amounts increasing with the total protein content. background: intubated patients without lung injury or impaired breathing control normally display an inspiratory peak flow of below l/s. the aim of our study was to investigate the inspiratory peak flow generated by patients with acute respiratory insufficiency (ari). we had to take into account that both an inspiratory pressure support (ips) and the resistance of the endotracheal tube considerably influence the flow pattern generated by the patient. patients and methods: to investigate the non-influenced flow pattern we developed a new ventilatory mode which automatically compensates for the flow-dependent resistance of the endotracheal tube (automatic tube compensation, atc). furthermore, the mode maintains a constant tracheal pressure in inspiration and expiratio n . consequently, the measured flow pattern exactly corresponds to the flow pattern generated by the patient except that the ventilator modified for this mode (evita, driiger liibeck, germany) was not able to deliver a gas flow of more than l]s. we have investigated patients with ari arising from different reasons. results: the inspiratory peak flow measured in the atc-mode was . l/s _+ . l/s. the maximal deliverable flow of l/s was obtained in of patients. the figure shows the flow pattern under atc and ips in [~s] oi:) one of these patients. conclusions: patients with ari display a highly increased inspiratory peak flow. ventilators used for spontaneous breathing should therefore be able to deliver a gas flow of more than l/s. an overproduction of no and reactive oxygen species (ros) has been demonstratred in septic shock. ros and nitric oxide (.no) are free radicals which are known to react together leading to peroxynitrite anions that can decompose to form nitrogen dioxide (no ) and hydroxyl radical (oh~ thus, no has been reported to have a dual effect on lipid peroxidation (prooxydant via the peroxinitrite or antioxidant via the chelation of ros). in the present study we have investigated in different models the in vitro and in vivo action of no on lipid peroxidation. copper-induced ldl oxidation was used as an in vitro model of lipid peroxidation. ldl ( ~g apob/ml) was incubated with cu + ( , ~tm) in presence or absence of no donor (sodium nitroprussiate or glutathione-no) from to ~m. oxidation of ldl was monitored continuously with conjugated diene formation ( nm) and hydroxy nonenal accumulation (hne). exogenous no prevents in a dose dependent maner the progress of copperinduced oxidation. ischaemia-reperfusion injury (i/r), characterized by an overproduction of ros, is used as an in vivo model. anaesthetized rats were submitted to hour renal isehaemia following by hours of reperfusion. sham operated rats (sop) were used as control. lipid peroxidation was evaluated by measuring the hne accumulated in rat kidneys in presence or absence of l-arginine or d-arginine infusion. l-arginine, but not darginine, enhances hne accumulation in i/r but not in sop (< . nmol/g tissue in sop versus . nmol/g tissue in i/r), showing that in this experimental conditions, no produced from l-arginine, enhances the toxicity of ros. this study shows that the pro-or antioxydant effects of no are different in vivo and in vitro and could be driven by environemental conditions such as ph, relative concentration of no and ros, ferryl species...these conditions are impaired in circulatory shock. methods:" the diagnostic and therapeutic approach was standardized so that data collected over a -year period were comparable. a progressive deterioration of clinical conditions and/or pulmonary gas exchanges was considered as indication for my. variables potentially predicting the need for hv were derived from clinical and arterial gas data, extrapulmonary diseases, use of drugs, chest x-ray and ecg abnormalities. results: rv, performed with external and/or internal ventilators, was necessary in patients ( %). at the hospital admission, pac was higher and ph was lower in patients requiring rv ( pneumomediastinum, pneumothorax, ateleetasis and myocardial infarction are rarely seen in bronchial asthma. these complications occur as a result of the severe asthma.the aim of our retrospective study was to analyse the complications seen in acute asthma attacks. during the years through , patients were admitted to hospital in acute asthma episode. there were ( , %) pts with complications; mean age of yrs; females ( %). clinical history, ecg and chest radiogr~hs were analysed. the mean duration of bronchial asthma was yrs (range from months to yrs), all patients were atopics. there were four ex-smokem and one smoker. the worsening of asthma symptoms begun two days before the admission (range from to days). on ecg all patients had tschycardia. rightward shift of the qrs axis and st-t changes indicative of right ventrieutur strain were found in three pts. these were the transient fmdings that improved after curing the acute asthma attack. non-q myocardial infarction oeeured in one patlent and resulted from the hypoxaemia of asthma. hyperinfl~ion was the usual finding on the chest radiograpk pneumomediastinum and subcutaneous emphysema were apparent in five pts and required no additional treatment unilateral pneumothoraccs were present in two pts and needed eontimous intrapleural drainage; one of these patienst died in eardiorespiratory insufficiency. ateleetasis of right upper lobe was present in one patient. it oceured due to inspissated secretions and needed no additional treatment all these patients, except one who died, improved on lreaanent with oxygcr~ steroids, beta-two agonists, theophylline and antibiotics. in conclusion, complications occur in acute asthma episodes as a result of the severe asthma mediastir,*l emphysema and atelectasis are not serious complications. pneumothorax and myocardial infarction are very serious life-treatening complications and always have to i:m considered in taati~ts with sev~ asthma. acute bronchial asthmatic episodes represent one of the most common respiratory mnergendes, its maximmum expression "status asthmatiens" is one entity of low incidence, still it is a risk to the physical integrity of the patient. during a total of patients with diagnosis of status asthmabcas were hospitalized. out of these palients six had a near-fatsl asthma and they were subjected to a complex examination. near-fatal asthma was defined as either respiratory arrest or acute asttuua with paco greater than , kpa and/or an altered state of consciousness. mean age was , -d: , yrs, four male and two female sex. at presentation two patients suffered from coma, others were confused. they exh'bited severe dystmoes, diffieul~ speaking, used accessory muscles of respiration, increased whee~tg while two cases had silent chest on auscultation. cyanosis indicated a very severe asthma attack in all six patients. mean respiratory rate was ~ /min and puts rate .d: bts/imn. arterial blood gases revealed a pao of , ~ , kpa, paco of , • kpa and ph of , -+- , . area-careful evaluation they received conventional therapy (immediately continuous oxygen, impelled nebulization with high doses of betatwo agonists and ipmtropium bromide, intmvanous st~oids and theophylline). in two eases signs and symptoms of deteriorating airflow and respiratory muscle fatigue determined the need for mechanical ventilation. out of six near-fatal attacks aggressive lrealanent was suscessfull in four patients and fatal in two eases. one patient admittcxl in coma died in severe hypoxae~a upon one hour and one mechanicaly ventilated died from cardiac arrhythmia. life-threatening attacks in asthmatics in our group developed gradual worsening despite neatment which r symptoms in most other patients. one patient had "brittle asthma", other long-standing acute episodes ireated with systemic steroids. conclusions: idantitiechon of fatality prone subjects may lead to fttrther muetion of seveze episodes. respiratory affest and coma upon admission, severe dyspnoca with silent chest on ausouhation, oyanusis and use of accessory muscles of respiration constitute the basic cfinieal picture. hypoxasmia must be immediately eon'ected.the patients and physicians should be able to assess the severity of asthma, a major factor in near-fatal and fatal asthma attacks. objectives :our purpose was to asses if the evolution of patients with a adult respiratory distress syndrome (ards) ,shows any relation to the pulmonary or systemic origin of the disease and whether or not there were differences in the frequency of the syndrome in both groups. methods : randomized prospective study in multidisciplinary icu. one hundred and sixteen patients with a high risk developing ards were distributed into two groups. one was named systemic origin group(so) and the other pulmonary origth group (po).ai patients only showed one cause (pulmonary or systemic) with potential risk of ards.the patient's hemodynamic and respiratory status was evaluated every hours the first day and every hours the second and third day. at the end of hours the patients were diagnosed as ards or non-ards. measurements and main results : of the total patients, were finally included in the so group and in the po group.patients in so group and po group had comparable ages (p<. ).peep in both groups was comparable (=. ) at the mmnent of admission to the study. there were no statistically significant differences for cardiac index and systemic vascular resistances. the pulmonary vascular resistances (pvr) showed significant differences at h.(p<. ) and h. (p<. ).the oxygen comsumption (vo) in patients of the so group showed statistically significant differences at h. (p<. ) with respect to initial values.fifteen cases of ards ( . %) in the so group and twenty five cases ( . %) in the po group were identified. the time of onset of ards was _+ hours in the so group and + b hours in the po group.the final outcome was very similar th both groups : mortality of % in the so group versus % in the pc group. conclusions : the pathogenesis of ards depends on whether the lesion is originated at or outside the lung. the po group showed a sborter thne of onset of ards, a faster and more severe increase of pulmonary shunt and a higher percentage of patients developing ards compared with patients of the so group.the so group showed a higher and faster increase in puhnonary resitances tbat po group and a decrease th oxygen comsumption earlier and more severe than in the po group. these data thus seem to show that there could be two mechanisms involved in the genesis of ards depending on the cause. the fact that the ards genesis is shorter in the cases of pulmonary etiology with faster impairment of pulmonary shunt, and a slower increase in pulmonary resistances in this pulmonary group, would indicate that the underlying mechanisms responsible for the hypoxemia are different to those which thitiate the increase in pulmonary resistances. finally, the exclusive inapairinent of oxygen consumption, which appears earlier than the onset of ards in the systemic origth group, could show the generalized character of the process in this group. perfusion of prostacyclin (pgi ) to treat pulmonary hypertension in adult respiratory distress syndrome (ards) worse pulmonary gas exchange due to a marked impairement of ventilation/perfusion mismatch. recently has been shown that if prostacyclin is given by aerosol instead of intravenous the net effect is an improvement of arterial oxigenation due to a redistribution of blood flow to well ventilated areas. objectives: to asses the effects of inhaled proatacyclin on pulmonary haemodynamics and gas exchange in patients with severe ards. methods : two patients with severe ards (murray score > ) recived inhaled pgi at - ng.kg.min " using an ultrasonic nebulizer. haemodynamic measurements, arterial and mixed venous blood gas analysis were performed before and after rain of pgi inhalation. results: short-terro p~i inhalation improved pulmonary g-~ e-'~hange in both patients. arterial oxygen partial pressure (pao ) increased from to mmhg in patient and from to in patient , the ratio pao to the fraction of inspired oxygen increased from to (patient ) and from to (patient ). venous admixture decreased from % to % and from % to % in patient and respectively. mean pulmonary artery pressure decreased slightly from to mmhg in patient and from to mmhg in patient . no effects on systemic haemodynamics were observed in any patient. conclusions: pgi inhalation improves gas exchange and produces selective pulmonary vaaodilation, thus can be an alternative therapy for the treatment of pulmonary hypertension and hypexemia in patients with severe respiratory falllure. methods: we treated ards-patients (age yr ( - ) mean, range) during - . the lowest pao /fio -ratio was ( - ), the worst murray score . ( . - . ), icu-stay ( - ) days and hospital mortality %. the costs of intensive care were calculated according to intensivity of patient care as assessed by tiss-scoring (therapeutic intervention scoring system). the more intensive the care, the higher are the costs. costs per year of life saved (=life-year" in us $) were compaired by other medical treatments ( - ). it is assumed that the mean expected length of remaining life in ards-survivors after intensive care is years. treatment life-year ($) ' bone marrow transplantation (acute leukemia) lowering cholesterol using iovastatin treating hypertension using nifedipine heart transplantation intensive care of ards-patients conclusions: intensive care of patients with severe ards is highly more cost-effective as compared with many other routinely used medical treatment strategies, the usually good recovery and the reasonable quality of life in survivors justifies investments to care of these patients ( ). there is a close correlation between these two methods of measuring evlw. however there is an underestimation of . % in this kind of pulmonary edema ( oleie acid induced ) with the double dilution method. although the size of the sample is small, in normal lungs there appear not to be this underestimation. the effect of peep on evlw has been studied with contradictory results, probably as a consequence oft differences in methods of measuring evlw, variations in the type and severity of lung injury, and different timings of peep application. objective= ) to analyse the effect of different levels of peep ( , and omh ) on evlw during hpe; ) to establish whether increases in intrathoracic pressure due to high peep levels can obstruct lymphatic drainage. material and methodet hpe was provoked in groups of dogs by inflating a foley catheter in left auricular to a pressure of - r~uhg. peep levels of , i or m~hg were applied. resultst objective: to assess the effect on extravascular lung water (evlw) of the application of peep and the reduction of vt in an oleic acid pulmonary edema model in pigs, using three ventila~ary strategies. material and methods: twelve adolescent pigs (weighing over kg) were randomly divided in three gmups immediately alter infusing via a central vein . ml/kg of oleic acid to produce a permeability pulmonary edema. the ventilatory parameters for each group were as follows: group i (n= ) : vt: - ml/kg; zeep. group :(n= ) : vt: - ml/kg; peep: cm h . group :(n= ) : vt: - ml/kg; peep: emil . (resulting in permissive hypereapnla) after a four-hour period of ventilation the animals were killed and the lungs excised to calculate gravimetrically the extravascular lung water using a standardized procedure ( hemoglobin content method ). ill evlw (ml/kg) group obiective: in the postoperative period, maintenance of adeguate arterial oxygen tension is a major problem in morbidly obese patients probably because of a large reduction in functional residual capacity (frc). the aim of this study was to evaluate the effects of peep on respiratory mechamcs and gas exchange in this kind of patients. methods: in nine postoperative mechanically ventilated morbidly obese patients (bmi> kg/m ) we partitioned the total respiratory system mechanics into its lung ( ) and chest wall (w) components using the airway occlusion technique associated with the esophageal balloon, during constant flow inflation (jap ; : ) . at three different levels of peep ( , , cmh ) we measured: compliance (cst), airway (rim) and "additional" (dr) resistance, frc and gas exchange. obiectives. to describe the use of prone position in our icu we analyzed the clinical records of all patients admitted in - , selecting adult patients with arf defined as: intubation and pao /fio < mmhg plus an fio > . or peep> cm i . results. patients met the arf criteria: of them ( . %) underwent prone positioning (p+). prone position use began in the early phase of arf ( . • days from the beginning, range - , median ). out of p+ pts were treated with controlled ventilation (cppv or pcv), while were on assisted ventilation (simv+ps) and on spontaneous breathing (cpap). only pts were awake when turned prone, while pts required adjuncts of sedation to tolerate the change of position. the duration of prone positioning was variable (average lenght . • h, range . - h). only minor side effects were observed (eyelids and facial edema, chest and facial pressure bruises). we consider responders (r+) those patients presenting at least . mmhg increase in pao /fio : / patients ( . %.) were responders when first pruned. the pao /fio changes induced by prone position are reported in the figure. pao /fio increased when patients were pruned (*p< . ) and remained higher than baseline values when returning supine(*p< . ). paco remained unchanged. prone positioning was used at least twice in / ( conclusions. this retrospective analysis confirms that prone positioning improves oxtgenation in the majorib' of arf patients. altough we have no available criteria to discriminate in advance r+ from r-pts, we now routinely consider the use of prone position in the treatment of severe arf. palo a, otivei m*, galbusera c, veronesi r, sala gallini g, zanierato m, iotti g, braschi a.servizio anest. e rianim. i, *laboratorio biotecnologie e tecnologie biomediche irccs s. matteo, pavia, italy inhaled no can improve arterial oxygenation and reduce pulmonary hypertension in ards patients; little information is, however, available about the dose-response curves. methods seven ards patients (lis . +. ) submitted to mechanical ventilation randomly received inhaled no doses in increasing or decreasing sequence: . , , , , , and ppm. reference measurements were obtained before and after the entire period of no inhalation. hemodynamic parameters and blood gases were measured after min in each condition. cmv was administered under sedation and paralysis, with constant ventilation, peep (lol-_ cmh ) and fit (. +. ). the changes in vt and fit due to the no ( ppm in n ) injection in the ventilator external circuit were compensated for. results . the dose of . ppm, ineffective on papm, significantly improved oxygenation. the increase of pat and the decrease of q'va/q' and papm were nearly maximal at - ppm. no deterioration of arterial oxygenation was observed at no doses as high as ppm. co exchange was not influenced by no inhalation. systemic hemodynamic variables did not change throughout the study. these results suggest that a concentration around ppm is adequate for obtaining maximum effects on hypoxemia and pulmonary hypertension in patients with ards. low-dose inhaled nitric oxide (no) induces redistribution of pulmonary perfusion in patients with severe ards and causes improvement of oxygenation [ ] . however, addition of exogenous lowdose no in the inspiratory gas mixture might be only a replacement of missing atmospheric no ( - ppb) in hospital central-supplied medical air. [ ] we have realised nitric oxide measurements in ten healthy volunteers, ( smokers and non-smokers) breathing with a mouthpiece and occluded nostrils through a ventilator circuit, with separation of inhaled and exhaled gases by a valve. no concentration was measured with a double-chamber chemiluminometer (environnement sa, france) and with charcoal/silicate purified compressed air. there was no nitric oxide detectable in the inspirat ry limb of the ventilator. unfiltered central supply medical air contained : - ppb of no and - ppb of no , whereas central supplied oxygen was no/no free. samples were taken after equilibration periods of minutes, with increasing fit levels of . , . and . for subsequent minutes periods; paired values were recorded every s. the mean no value was . ppb (sd . ) and n o significant differences were found for different fit levels both in smokers and non-smokers. these data suggest that the no concentration of pulmonary origin in the exhaled air of' healthy volunteers is probably lower than that reported by other authors [ ] and that, previously reported, differences between smokers and non-smokers are not always striking [ ] . we suggest the use of activated charcoal/silicate filters for clinical trials in order to achieve standard conditions. [ objective: to compare efficacy and safety of two doses of salbutamol. methods: sixteen adults who had severe acute a~hma were randomly assigned to receive either rag (n= ) or rag (n= ) of nebulized sulbutamol. both groups were similar with respect to age, duration of a~hma, duration of attack before arrival at the hospital and severity of a~hma according to baseline measurements (table) . evaluation was performed , , and rain after the start of nebulization. results: compared with mg regimen, mg regimen resulted in the same improvement in peak-flow and fischl index (figure). the changes in heart rate, respiratory rate and pace did not differ significantly between both groups. the incidence of side effects, which included tremor, palpitations, cardiac arrythmlas and other symptoms, was not sj~ificanfly different in the two populations. conclusion:the results of this study suggest that nebulization of ng of salbutamol is not more effective than rag in the initial treatment of acute severe asthma in adult patients. the prognostic factors of neutropenic patients admitted to the icu remain poorly known. the aim of this study was to determine the respective weight of underlying malignancy and organ system failures on the outcome of these patients. patients and methods: the charts of neutropenic patients (wbc < /mm and/or pmn < /ram ), admitted to the icu between and , were retrospectively reviewed. the characteristics of the neoplastic disease (h~emopathy or solid tumor, tumoral evolution, duration of cancer disease and of neutropenia), the mac cabe's score, the organ system (respiratory, hemodynamic, renal, neurologic, hepatic) failures and the severity scores (saps, saps ii ,osf) were registred within the st day in the icu. when discharged from the icu, the patients were classified as alive or dead. results: fifty-seven patients ( . %) had a h~ematologic malignancy, and ( . %) a solid tumor. fifty-nine of the patients died ( . %); the mortality rate did not differ between both groups ( . and % respectively, p = . ). with univariate analysis, none of the tumoral features is linked to the prognosis; only the respiratory (p < - ) and cardiovascular (p < - ) failures, and the number of organ system failures (p < - ) are associated to the risk of death. the saps (p < - ) and saps ii scores (p < - ) were higher in patients who died. with multivariate analysis (logistic regression), only the respiratory failure is correlated to the risk of death (p = - ); neither the features of the underlying malignancy (p > . ), nor the duration of neutropenia before admission in icu (p = . ), nor the severity scores figs ii: p = . ) are linked to the outcome. conclusions: the tumoral characteristics do not modify the prognosis after admission to the icu. they should not influence the decision to admit or refuse a cancer patient in the icu. respiratory failure at icu admission has the predominent weight on the risk of death in the icu. patients with respiratory acidosis due to asthma occasionally require levels of mechanical ventilation that place them at risk for barotrauma. a few case reports have described the use of an extra-corporeal membrane oxygenator(ecmo) circuit as an alternative means of co removal. generally, this has been used for short periods of time (< h) without serious complications and with low blood flows through the extra-corporeal circuit. we report a case of refractory asthma who could not tolerate even small-volume breaths from a mechanical ventilator due to severe bilateral airleak. ecmo therapy was initiated at the referring hospital prior to helicoptor transport. high blood flows were used ( % of the patient's cardiac output), sufficient to achieve both co removal and oxygenation. satisfactory gas-exchanged was accomplished (pco = - mmhg) with nearly total lung rest for a prolonged period ( h). however, the long ecmo duration was associated with two severe complica-ti ns: ) bilateral hemothoraces due to anticoagu!ation in the extra-corporeal circuit, and ) prolonged weakness as a result of neuromuscular blockade for six days. the patient was discharged from the hospital in good condition. we present the respiratory and hemodynamic features of this case aw well as the potential complications of ecmo therapy in asthma. objectives: parameters derived from tidal expiratory flow ~e) and volume (vt) can be used to detect airflow obstruction in copd patients who might be unable to perform forced spirometry (e.g., icu). however, indices such as ave/v t and at/re are highly variable (thorax, : ; ) . methods: we investigated whether the standardized for v m effective time (teff~) of a tidal breath, which is derived by asimple mathematical procedure (teff,= j'vdt/vt ), is a more reproducible and sensitive detector of airways obstruction, we studied nine normal subjects ( male, -+ yr) and copd patients ( male, -+ yr) in the seated position, with a noseclip on. they breathed quietly, through a pneumotashograph to measure flow (v). volume was obtained by numerical integration of thellow signal. each subject had an initial - min trial run, in order to become accustomed to the apparatus and procedure. when regular breathing had been achieved, all breaths over a min time interval were recorded. the mean value of six consecutive breaths (ers criteria) for each subject was used for analysis under the condition that within session variation of tidal volume (vt) was < %. lung function tests were: in normals (mean-sd), fevl%pred = • fevl/fvc%= -+ % , and in copd patients, fev~%pred= __. and fevi/fvc%= --. %. results: values are shown as mean-..+-sd in the following a su~ve~ os literature sources p~oves that t~aditlona], i.e. medicinal medication and physiothe~apeutic methods os t~eatment often p~ove to be insufficientl~ effective both currently and in the ~emote future. the goal of this study was to investigate the efficacy os t~eatment of b~onchial asti~ma patients by means os speleo-and artificial sp~ay therapy. speleotherapy t~eatment was conducted in the conditions os mic~oclimate os salt mine in solotvino hospital. a~tis sp~ay the-~apy was conducted by means os a self-made device. ou~ method is based on the p~inci-~ le os using the majo~ facto~ of speleo-he~apy -highly dispe~sed sp~ay s sodium chloride. the obtained ~esults ~e~e analyzed in five g~adations. at the end os the speleothe~apy improvement and considerable improvement was observed in , ~ os patients; inconsiderable improvement -in , ~ os patients. having evaluated the e~s os t~eatment using a~tis sp~ay therapy the indices a~e , h and , ~ ~espectively. remote ~esults of t~eatment a~e an important index os t~eatment, the ~esult os ~hich ~e~e studied by means s a ~uestionnaive-method. patients ~ho had been t~eated by speleothe~apy mo~e f~eguently ~e-po~ted a ~elapse in disease ust afte~ the course o~ t~eatment ( , h). ho~eve~, in a ]ate~ phase the ~emission ~ould last ]on-~e~ (s months in , ~ os patients, till one yea~ in ~ ~). in , ~ os patients who passed the co~se os a~tificial sp~ay therapy a ~elapse was ~egiste~ed immediately as the co~se os t~eatment. then thei~ condition stabilized ~hile in , ~ os patients a period os ~emission lasted s ha]s a yea~. , ~ of patients dida't ~epo~t a ~elapse of the disease du~in~ one yea~. evangelismos hospital, critical care department, athens, greece method#: mechanically ventilated patients ( copd, ards, other pulmonary diseases) were studied in two phases: ) during the acute phase of respiratory failure; ) during recovery - days later. we measured mip and monitored the pattern of breathing while the patients were breathing spontaneously through the respirator (pressure support mode with - cmh ) until either the point they were unable to sustain spontaneous breathing (sb) any longer (phase ) or for two hours when they could sustain sb indefinitely (phase ). subsequently the patients were sedated, paralyzed and mechanically ventilated. then we simulated the pattern of sb at the end of the sb trial by manipulating the variables of the ventilator and assessed respiratory mechanics b y the end-inspiratory and end-expiratory occlusion technique. . during recovery, a combination of reduced inspiratory load and increased venfilatory capability makes a patient previously unable to sustain sb to breathe spontaneously. . inspiratory load is reduced during recovery, mainly because both intrinsic peep and breathing frequency are diminished. obiectives: although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (bal) fluid (balf) of patients with the adult (acute) respiratory distress syndrome (ards), the pethogenesis of ards is largely unknown. leukemia inhibitory factor (lif), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated balf of patients from different patient groups. methods: lif was measured in balf by means of a specific and sensitive elisa (detection limit pg/ml)in balf (lavage of x ml in the right middle lobe). results: lif was not detected in the balf of healthy control patients and in only one ( pg/ml) out of patients at risk for ards (after cadiopulmonary bypass surgery) who underwent bal h after the end of the extracorporeal circulation. high and detectable levels were found in the unconcentrated balf of out of patients with full-blown ards ( + , mean + sem, range - pg/ml). there was a good correlation between the level of lif in the balf and a number of markers of inflammation: neutrophils/ml (r: . , p= . ), albumin ( r: . , p= . ) and protein level (r: . , p= . ). conclusions:the biological role of lif in these balfs is not readily explained by its currently known actions and it is unkwon whether lif contributes to or is a response to local tissue damage. our results indicate that this cytokine with lots of interesting _functions is a pert of the inflammatory cytokine cascade in ards. background and obiective : we recently demonstrated that cisapride -a new prokinetic drug -enhanced enteral feeding in a heter genoas group of ventilated icu patients by significantly accelerating their gastric clearance (crit care meal, ; : - ) . it remains unknown, however, whether certain subgroups of patients might benefit more from adding cisapfide to their enteral nutrition regimen than others. patients with chronic obstructive pulmonary disease (copd) might represent such a subgroup since their illness and its specific treatment put them at risk for gastric emptying disorders. design and setting : prospective, consecutive sample study in an adult medical intensive care unit in a university hospital. patients : mechanically ventilated and hemodynamically stable copd patients. interventions : gastric emptying was evaluated by bedside scintigraphy and expressed as the time at which % of a tcg~-labelled test meal was eliminated from the stomach (t / ). baseline data (do) were recorded after enteral nutrition reached to ml daily. scintigraphic measurements were repeated days after cisapride ( ml orally, q.i.d) had been added to this regimen (d ). patients were considered cisapride responders when gastric clearance improved by more than % from baseline. results : normal values for the test meal and for scintigraphic acquisitions obtained in the supine position were found to be + min. in healthy volunteers (crit care med, ; : - ) . five patients responded to cisapride (t / : + rain vs. + min at do and d , respectively) and five did not (t / : + min vs. _+ rain at do and d , respectively). in contrast with non-responders, all five responders had clinically significant maldigestion at baseline (excessive (> ml) gastric residues, vomiting (> times/day and abdominal distension) which disappeared in of them after the administration of cisapride. conclusion : copd patients who tolerate enteral nutrition well have basal gastric emptying times which are comparable with those of healthy volunteers and are not influenced by cisapride. however, cisapride treatment provides both scintigraphic and clinical improvement in those copd patients who exhibit clinically obvious gastric emptying disorders. cernv v., dostal p., zivny p., zabka l. dept. of anesth. and critical care, charles university, faculty hospital, i-irade~ kralove , czech republic objective: the aim of the study was to evaluate the effect of early entera nutrition started within hours of injury on the incidence of multiple orgar failure (mof) in trauma patients requiring vantilatory support. methods: after institutional approval patients were enrolled in the study enteral feeding was begun within hours of injury in trauma patients (en group) admitted to icu. nasuenteric tube was placed as soon as possible after admission into the distal duodenum under endoscopy. additional parenteral nutrition was used to meet patients energy and protein requirements. the control group (pn) consisted of patients fed during this period paretuerally. severity score apache ii, trauma score, cumulative balance of nitrogen (g), incidence of mof (three and more organs) and length of ventilatury support (days) were calculated. values are expressed as mean + sd. results: tab introduction : parenteral nutrition (pn) is an important aspect in the optimal treatment of patients on gastroenterology or intensive care. the aim of this bi-center study in patients has been to assess tolerence and efficacy of a new protein-lipid mixture for pn from a simple preparation. patients and m~hods : patients were selected in two hospitals (tenon and saint-lazare, paris) and were divided into two groups : group a (gastroenterology~ l short bowel syndrome) and group b (intensive care, surgical patients). all patients likely to require pig for a period of days (group a) or days (group b) were studied. the pn regimens administered were the following : combination with g of mct/lct fat emulsion end , g of nitrogen, in liter end glucose requirements were met by imfizsion of l liter of glucose - % via a "y " connection. lipid thus provided % of the non introgen calories. total daily calorie intake was to ] kced. this study monitored, before and at the end of infusions, the sennn albumin (alb), preaiburtun (prealb), triglycendes (tg), cholesterol (cs), and the serum ammotransferases (sgot and sgpt) end alkaline phosphatase (alp) activities. statistical significances were calculated using the wilcoxon-tost. introduction: many cu patients present a catabolic illness in response to inflammation and infection, characterized by a rapid loss in skeletal-muscle mass despite optimal nutritional support. growth hormone (gh) is responsible for a rise of lipolysis, enhancing the energetic balance, and of protein synthesis. recombinant human gh (rhgh) is nowaday available for clinical use, but its cost is very high. therefore, rhgh should only be prescribed to icu patients when its efficacy can reasonably be anticipated (ie. when the patients are catabolic or stressed, but in order to avoid overprescription for unstressed patients and for those who are overly catabolic). hence, we, as others, recently demonstrated that rhgh had no favorable effect in highly stressed icu patients. objective: to detect on a clinical basis, low (ls), mild (ms) and severe stress (ss) states in icu patients and validate this clinical judgement by objective metabolic mesurements, in order to select early those icu patients potentially able to benefit from rhgh therapy. methods: consecutive icu patients were prospectively stratified as ls, ms and ss by two experienced icu senior consultants (temperature; agitation; heart rate; arterial blood pressure; presence of an infection; respiratory rate; exogenous catecholamines). anabolic (insulin, igf- , gh) and catabolic (cortisol, ghicagon) hormones, and nitrogen balance were determined for each patient within hours after admission in the icu. metabolic and clinical data were then compared. the clinical stress states determined by icu physicians correlate with an objective metabolic assessment. therefore, the patients who will more likely benefit from adjuvant rhgh therapy can be detected simply and early. a prospective study on rhgh therapy in ms icu patients is in progress. berger mm md , chiolero r md , pannatier a phd , berger l , cayeux c , voirol p , hurni m md . surgical icu, pharmacy, and cardiac surgery, chu vaudois, ch-iotl lausanne, switzerland objective. nutrition of the compromised cardiac surgical patient is challenging. numerous factors influence the gastrointestinal (gi) absorption function, among which gut perfusion, which depends largely on the systemic hemodynamic status. patients in hemodynamic failure are prone to organ failure, and may benefit from an early jejunal feeding. the study was designed to assess the absorption function after cardiac surgery in patients with adequate and altered hemodynamic status, using paracetamol as tracer of gi absorption. methods. after cardiac surgery, patients, aged _+ years (mean_+sd) were assigned to groups (anaesthesia: fentanyl gg/kg + midazolam): group (n= ): reference group, with normal hemodynamic status, easy recovery. group ('n= ): patients in low output syndrome, cardiac index < . i/m on day (d ) after surgery, requiring prolonged intensive care, mechanical ventilation + nutritional support. paracetamol g, was given intragastrically on d + d : plasma levels measured (h.p.l.c), at administration (to), t - - - - - and rain. hemodynamic status assessed with pulmonary artery catheter. healthy subjects served as controls. results. compared to healthy controls, absorption was strongly reduced on d in all patients (no difference between groups). on d , peak paracetamol level was significantly lower in group (low cardiac output): in group the area under the curve on d and d were similar. there was a large inter-patient variability, reflecting the hemodynamic status. conclusion. gi absorption was decreased on d in all patients, and reverted to normal between d and d in case of normal cardiac function, but not in case of low output syndrome. the decrease on d can be attributed to fentanyl, known to slow down the gi transit. in patients with cardiac failure, correction of altered absorption was correlated with the hemodynamic status, suggesting that gi absorption is dependent on adequate splanchnic perfusion. the aim of the work was to define specific significance and evaluate efficiency of enteral component of infusion therapy in the intensive care of gastroenterotogic patients of surgical profile with pyo-septic complecations. there were used the methods of radial diagnostics and polyelectrography; the laboratory control on oxygen-transporting function, volumetric and hemodynamic state, changes in metabolic, hormonal and immunologic status was conducted. from january, [ till november, there was carried out the randomized study of patients with general purulent peritonitis; among them persons constituted the control group and -the main one. in the main g~oup the intestinal lavage, enterosorption, enteral introduction of nutrient solutions with gradual turn to enteral nutrition by equalized mixture "ovolaet" were started from the first hours after operation. the data obtained allowed to define the specifity of the program of artificial medical nutrition in the group of examined patients, based on necessity of individual selection of media for enteral introduction depending on the stages of intestinal insufficiency syndrome. it was shown that inclusion of enteral component into the program of infusion therapy during early periods stabilized circulation in the regime of moderate hyperdynamia, considerably decreases the deficiency of circulating blood volume, normalizes the values of oxygen transport, consumption an}d extraction, provides the optimal level of mycardial adaptive possibilities without tension of its compensatory functions and pulmonary circulation overload. due to combined application of parenteral and enteral nutrition the metabolic processes are shifted towards anabolism. this is supported by decrease to normal values in the contents of blood aggresive hormones (acth,hydrocortisone) and increase in somatotrophic hormone. the complete parenteral-andenteral nutrition influences positively on restoration of cellular and tumoral immunity, activates the factors of organism nonspecific protection and recovery from immunodepression, prevents the development of immunodeficiency. impact tm vs control. s atkinson, n maynard, r grover, e sieffert, r mason, m smithies, d bihari departments of surgery and intensive care, guy's hospital, london, u.k objectives: comparison of the effect of an immunonutrient enteral feed versus a control on the outcome of a mixed intensive care unit (icu) population. methods: admissions to this multidisciplinary adu)t icu thought likely to stay more than three days and with tube access to the gi tract ~r randomised to receive either impact tm, a feed with supplemental arginine, dietary nucleotides and omega- fatty acids, or an isocaloric and isonitrogenous control feed. study end points included mortality and icu stay. approval was obtained from the hospital ethics committee. rosults: patients were entered into the trial. the two groups were well matched for age, sex, and admission apache ii with an overall mean admission risk of death of . (std. dev. -+ . ). on an intention to treat basis, there was a no significant difference in icu mortality, icu stay or standardised mortality ratio (s.m.r.) between the two groups (see table) . similarly, there were no differences after stratification for patients receiving or more litres of feed. conclusion: there is no evidence of an effect of impact@, an enteral immunonutrient feed, on pre-determined end-points (icu mortality, icu stay or standardised mortality ratio) in a mixed intensive care unit population over that of an isocaloric, isonitrogenous control feed. objeeflves: evaluate changes of blood laatate levels according to patient medical status after cvvhd initj,~ion using dialysate solution containing lactate. method: review of medioal records of consecutive patients ~eated by cvvhd (dialysate solution hmnosol lg , hospal,uk, lactate concentration retool/l). date obtained hr before and - hrs at~er cvvhd initiation were analysed. results: all data are presented as mean + sem. in one patient, pre end post filter lactate levds were measured during standard cvvhd setting (blood flow ml/mlu, dialysate solution flow i /hr), and approximate daily lactate flux into the patient was calculated to be as high as mmol/d. lactate leveh measured after cvvhd initiation increased significenfly compared to baseline levels ( . + . axtd . + . ,respectively; p< . ,paired t-test). when patiente with increased basal lactete (~- ) were compared to paliente with normal basal values (n= ), no difference in laotete increase was fmmd (p= . , manova). patiente with severe liver dysfunction ( points in mop scomlg, n= ) had higher basal laotate levels than patiente with normal or slightly abnormal liver teste ( or point in mof scoring, n=ll), rite values being . + . and . + . , respectively (p< . , student t-test). increase in blood lactate did not differ between these two groups after cvvhd was stetted (p= . , manova). in pafiente with invasive hemedynamio mo~, no oorrelation batween changes in lactate levels and eitlm" changes in oxygen ddivery (t =o.ol; p--o. ) or oxygen consumption (reversed fie, k) (r -q).o ;p-- . ) were found after cvvhd initiation. conclusion: blood lactate increases on cvvhd with dialysate soh~on rich in lactate. this increase is predominantly caused by influx of lactate into the blood via the filter end does not seem to depend on the liver fimotion and/or oxygen metabolism changes. objectives: the study was designed in order to determine the effect on plasmatic proteins, of two types of aminoacids solutions of parenteral nutrition (pn) adapted to stress, having different concentration of branched chain aminoacids (bcaa), when applying to politraumatized critical patients. methods: a prospective study was performed using a randomized double blind design of polytraumafized patients, split in two groups of ten patients each, with mean ages of _+ an -+ years. due to their condition, all patients required p.n. for at least days. both groups were subjected to isocalorie and isonitrogenous solutions ( ci/kg/ day and . g of nitrogen/ks/day), varying only in the concentration of bcaa; solution a having a % concentration and solution b %. blood samples determinations during days , , , after the beginning of treatment with p.n. were total proteins., albumin, trandferrine, protein binding retinol; prealbumine and fibronectine. the anova test (one and two way) was used to compare the values between the two groups. results: the administration of solution a, showed statistically significant increases in the determinations of the values of protein binding retino] (p < . ) and prealbumin (p < . ). no significant increases were observed in the values of total protein, albumin, transferrine and fibronectin. solution b produced statistically significant increases only in the values of total proteins (p < . ). the remaining proteins did not changed from their control values during the whole period of pn administration. comparing both groups, no statistically significant differences were observed related to the type of diet. nevertheless, differences were found in total proteins, albumin, protein binding retinoi, fibronectin (p< . ) and prealbumin (p < . ) in relation to the time course of pn therapy. only the albumin values showed significant differences (p < . ) when considering the interaction of both the type of diet and the time course of pn. conclusions: . solutions of pn adapted to stress, can maintain the control values of slow turnover proteins and improve the values of rapid turnover proteins. . no significant differences on plasma proteins were found between the two solutions having % or % concentration of branched chain aminoaeids. &determination of rapid turnover proteins does not seems useful for discriminating different solutions of bcaa during pn. obiectives; the hormonal changes in the post-traumatic situation often leads to an elevated blood glucose and a negative nitrogen balance. to reduce the elevated glucose production by aminoacids the apprication of xylitol may be an alternative energy source. in a double-blind randomized study we investigated the effects of a xylitol/glucose solution (group a: aminoacids g/i; glucose/xylito g/ g/l) on metabolism and particularly on pancreatic and liver enzymes compared to a glucose based nutrition solution regimen (group b: aminoacids g/i; glucose g/i). methods: the clinical trial was carried out after the approval by the local ethical committee on patients with severe brain injury. there was no difference in body mass index bmi (group a: . +/- . kg/m and group b: . +/- . kg/m=), age, and sex. daily individual energy expenditure was measured by indirect calorimetry (deltetrac "~). nutrition was started - hours after trauma or surgery with carbohydrates and aminoacids. fat was added h after nutrition had started. to analyze the effects on pancreatic and liver enzymes we investigated the following parameters for days: blood gtucose, serum lipase, serum amylase, asat, alat, ~gt, ap, and serum cholinesterase (che). results: due to the daily indirect calorimetric measurements energy requirements were satisfied. there was no difference in blood glucose concentration and cumulative nitrogen balance between the two groups. neither were there any significant changes in asat, alat, ap, and che for days in both groups. serum tipase steadily rose to lull in group a and . lull in group b, respectively. conclusions: there was no measurable influence of either nutrition solution on liver enzymes. the xylitol/glucose nutrition regimen does not have any advantage over the glucose based nutrition solution concerning blood glucose level or nitrogen balance. the elevation of serum lipase to a -fold level in either group needs further investigation on trauma patients. the effects of fat emulsions in lung function, particularly in lungdamaged patients, have been attributed to alterations in pulmonary vascular tone caused by eicosanoid production modificatione. as the eicosanoid production may depend on the fatty acid profiles of the intravenous fat emulsion, haemodynamic, pulmonary gas exchange and plasma levels of prostanoids were investigated in acute respiratory distress syndrome (ards) patients, during different intravenous lipid emulsions (providing different prostanoid precursors). we studied in a randomized double-blind design groups (n= each) with ards. group i (lct) received a fat emulsion with long chain triglycerids (lct- %), group ii (mct) an emulsion containing a mixture of medium and long chain triglycerids (mct/lct / - %) and group iii placebo (control), during h ( mg/kg/min each). we measured before, at the end of h infusion, and h after the end of the infusion: lipaemia, arterial and venous blood gases, pulmonary and systemic haemodynamics, and plasmatic levels (arterial and in mixed venous sample) of eicosanoids (txb=, -keto pgf~,, and ltb ). at the end of the fat emulsion, groups (i and il) to , • to , • mmol/i), the paoz/fio z remained unchanged in the three groups; no changes in intrapulmonary shunt (qs/qt) were shown; neither in the mean pulmonary artery pressure. in contrast, only in the lct group: cardiac output and oxygen consumption increased significantly ( . % and %) (p< . ). eicosanoids were increased at baseline compared to reference values (p< , ). a decrease (p<o, l in the arterio-venous difference of the vasodilatador prostanoid ( -keto pgf~=) was shown in lct group. our results indicate that fat emulsions in ards patient do not influence pulmonary gas exchange, provided that the perfusion rate were keept at mg/kg/min. the present study was designed to evaluate the metabolic changes of a carbohydrate-based diet versus a fat-based diet on oxidation rate of substrates and energy muscle metabolism in patients with an acute exacerbation of chronic obstructive lung disease. patients were mechanically ventilated with a volume-cycled respirator. after an overnight fast, patients were randomnly treated with a continuous enteral feeding over a nasogastrie tube with a carbohydrate/fat ratio of / in group i (n= ) , and a carbohydrate/fat ratio of / in group i] (n = ) during consecutive days. indirect calorimetry was set at baseline and hours later the enteral feeding was started. muscular quadriceps biopsy was performed on baseline and on day of enteral feeding. urine was collected during hours and was used to measure h urea nitrogen production. the caloric intake was set according to the measured resting energy expenditure. respiratory gas exchange rate were measured using a computerized open-circuit indirect calorimeter. quadficeps femoral muscle samples were obtained by muscular biopsy after local anesthesia. analyses of glycogen, glucose -phosphate, lactate, phosphocreatine and adenosine triphosphate (atp) and enzymes (glycogen synthase and glycogen phosphorylase) were determined. after h of nutrition patients in group i showed an increase in carbohydrate oxidation (from . % to . %, p= . ), and in group ii a decrease in protein oxidation (from % to %, p= . ). after days of enteral feeding a tendency to increase in glycogen concentration (group i, p= . ; and group ii,p= . ) was observed. while patients in group i showed a tendency (p= . ) to decrease glycogen phosphorylase, patients in group ii maintained these enzymatic levels. the increased in glycogen was correlated in group li with degradation enzyme (p = . ). in group i, the pao /fio ratio increased after days of treatment (from . to . ; p= . ), but no changes in days of mechanically ventilation, length of stay in icu, or mortality rate was evidenced between groups. it is concluded that the oxidation rate of substrates used for energy production varies according to the caloric sources administered. with nutritional therapy muscle glycogen concentration increases in both diets, with different enzymatic influence. more studies are warranted to further assess the clinical implications of the different pathophysiologic behavior of the two diets. under certain experimental and human conditions (radiation and/or thermal injury) the gi mucosa is unable to perform this protective function and could play an important role in the pathophysiology of the syndrome of multiple organ failure (smof). the objective of the present multicenter study was to know the gi mucosal permeability in critically ill patients and the relationship with their outcome. the method used to assess the integrity of the gi mucosal barrier measured mucosal permeability to various hydrophilic compounds. specifically, we measured the urinary excretion ratio (uer) of two sugars (lactulose and mannitol) that had been previously administered through a nasogastric tube. urinary excretion rate was measured in healthy humans (control) and in patients admitted to the intensive care unit (icu) at days , and . the apache ii of the patients studied was _+ . there was an increase of uer in the critically ill patients compared with controls (o. _+ . vs . _+ . ) (p< . ). in contrast, no changes in uer between days , and were observed ( . -+ . . significant changes were also established in the different groups: major and minor surgery, general and epidural anaesthesia , transfused and non transfused patients except for iron and ferritin plasma levels which didn't change significantly in patients who had received blood. a positive significant correlation was established between crp and ferritin (r= . ) for patients under general anaesthesia, but not on epidural, regardless of the type of surgery. conclusions: iron and transferrin plasma levels fell acutely in surgical patients while ferritin and crp rose. transfusion implied an acute iron load.the established correlation between cpr and ferritin in patients on general anaesthesia suggests that ferritin behave as an acute phase reactant in that setting, while epidural anaesthesia may ameliorate the inflammatory response. objectives: to analize the effect of gastrointestinal complicacions (gic) related to the enteral nutrition (en) in the real volume of diet administered to icu adult patients. a prospective multicenter study was designed (comgine study) in wich en application, gic definition and his management were defined by collaborative consensus.patients treated with en in one month pedod were included. in each case, daily volume of diet prescribed (pv) and administered (av) was recorded and the volume ratio calculated (vr=pvxl /av). patients were divided for days of en according to the presence (group ) or absence (group ) of gic (abdominal distension, increase of gastdc residuals,vomits or regurgitation, diarrhea,constipation and bronchoaspiration). differences between groups were analized by anova and mann-whitney u test with p< . for statistical significance. (vr%) group (vr%) tolerance to the enteral nutrition (en) has been related to the severity of illness in icu patients. the aim of this study was to evaluate this relationship. methods. a prospective, multicenter, study was performed (comgine study) in wich en application and related gastrointestinal complications (gic) were defined by collaborative consensus. adult icu patients treated with en in one month pedod were included. gic were classified as: ) abdominal distension (abd), ) increase of gastdc residuals (igr), ) vomits (vom), ) diet regurgitation (reg), ) diarrhea (dia) and ) constipation (con). patients were divided in two groups: group a: patients with gic dudng their evolution. group b: patients without gic. differences between groups were analized for apache ii admission score or evolutive variables ( carbon dioxide production is a major determent of work of breathing. increase in co production during nutritional support may precipitate ventilatory failure and difficulty in weaning from mechanical ventilation. in the present study, co output was calculated while passive mechanically ventilated patient were fed with different amount of calories and different proportion of protein, carbohydrate and fat. four clinical stable and mechanically ventilated patients were studied. carbon dioxide was calculated while patients were paralyzed, sedated and mechanically ventilated. six nutritional regimens were used: a) no calories, b) t gr glucose/ h, c) calories equal to rest energy expenditure in special formula with low carbohydrates and high fat (pulmocare) d) calories equal to rest energy expenditure in standard formula (nutdson) e) calories double to rest energy expenditure in standard formula (nutrison) and f) calories equal to rest energy expenditure parenterel (tpn). carbon dioxide output was low while no calories and/or only gr/ h glucose was provided, the mean values of vco output were _+_ and !-_ ml/min respectively. there was no difference in vco output between with low carbohydrates and high fat regimen and standard regimen, mean values were t . -+ and _+ respectively.the high calories regimen and tpn resulted in higher vco output, mean values _+ and • respectively. we conclude that the special with low carbohydrates and high fat regimen did not reduce vco output, in the contrary, high calories intake as well as tpn increased vco output under tested conditions. klouche k., cristol j.p., vela c., canaud b., b raud j.j. m tabolic intensive care unit and nephrology department. lapeyronie hospital. montpeuier france. predictive factors for rhabdomyolysis (rh) -induced acute renal failure (arf) were studied in a retrospective study from january to january . patients (pts) (male: , female:lo; mean age: + y.o.) were admitted with rh defined as cpk> iu/ . etiologies were: traumatic and ischaemic , infectious , toxic , excess activity . factors studied were: simplified acute physiologic score (saps: . + . ), organ systemic failure (osf: . _-!- . ), diagnosis delay (d: +_ h), clinical parameters (sepsis, dehydration), blood chemistry data (cpk, bun, creatinine, potassium, phosphorus, calcium, proteins, hematocrit) and urinary ph. severity of rh was estimated by ward score determined according to phosphorus, albumin, potassium, cpk, dehydration and sepsis. urea appearance rate (uar) and creatinine index (ci*) were determined over a hours period. arf was observed in pts. in non-arf and arf groups respectively, saps ( . _+ . vs . + . ), deshydratation ( vs ), sepsis ( vs ), phosphorus ( . + . vs . -+ . ), calcium ( . + . vs . _+ . ), ward score ( _+ . vs . + . ) were significantly different. however, no significance was observed in uar ( -+ vs -+ ) and ci ( _+ vs _+ ). patients required hemodialysis (hd) ( : sessions) and remained dialysis free. only osf ( . _+ . vs . -+ . ), ward score ( . _-/- . vs . _+ . ) and ci ( +_ vs -+ ) appeared significantly higher in pts requiring hd. pts died from associated disease. all patients suffering from arf recovered a normal renal function. we confwmed that an elevated ward score (over ) is a good predictive index of arf. in addition we found that ci is a severity factor for arf requiring hd. thus, patients suffering for rh with elevated ward score and ci, have a fair chance of dialysis and should be treated more intensively. * ci (expressed in mg/kg) = (car + feces creatinine) / weight. where car: creatinine appearance rate; feces cr~t..= mean plasmatic creatinine x . . tr~er k., cetin t.e., tugtekin i., georgieff m., ensinger h. universit~tsklinik flir an~sthesiologie, uim, germany introduction: endogenous as well as exogenous adrenergic agonists have a profound effect on carbohydrate metabolism in human critical illness. in this study the effects of noradrenaline (nor) and dobutamine (dob) on carbohydrate metabolism during a hr infusion were investigated. methods: after approval by the local ethic committee healthy volunteers were studied. hepatic glucose production (hgp [mg/kg/min]), using , -d glucose as stable isotope tracer, as well as plasma concentrations of glucose (glc [mmol/i]) and lactate (lac [mmol/i]) were measured prior and during infusion of nor ( . pg/kg/min) and dob ( pg/kg/min). blood samples were drawn before and during the agonist infusion. results: no major changes in insulin and gtucagon plasma concentrations could be found during the study period. ::i:::: :iiiii~ ~ i ::i: ~:: : :: i:ii. mean-+sd are shown. # p< . , anova for repeated measurments. conclusions: the effect of nor on hgp and glc were smaller as compared to adrenaline (i) with a similar time course. in contrast to the effects of adrenaline and nor, dob had a different effect on carbohydrate metabolism: a decrease in hcp and glc, which is uncommon for a / -adrenoceptor agonist. since hgp is an energy consuming process that might deteriorate hepatic oxygen balance in critical illness, the differential effects of adrenergic agonists may be of importance and need further clarification. the nutritional insufficiency often accompanies post-operative hypercaloric states, inanition, serious infections and weakening chronic illnesses. that is why the early nutritional support, sufficient and appropriate for each individual base, is a fundamental component of intensive care unit as an indispensable factor for recovery. per this reason, our unit, developed a software for the implementation and nutritional control of t~e assisted patients. this software is incorporated is an expert system called ~i~su, designed and developed by the computational division of our unit. this system arrives to inferred diagnoses such as : respiratory, hepatic, renal(with and without dialysis) dysfunctions, pancreatitis, ards, decrease of consciousness, diabetes. according to these data objectives: to compare the effect of short term enteral feeding versus parenteral nutrition, when a isonitrogenous and isocaloric feeding solution is administered by either mute. methods: in a prospective controlled clinical trial patients were studied; all exhibited moderate degree of malnutrition, normal liver and kidneys, and a functi ning gastrointestinal tract. the patients were randomized to receive a free amino acid and small peptide diet ( patients) or an isonitrogenous isocaloric parenteral support (tpn) ( patients) (total energy: kcal, nitrogen: . g, carbohydrates: g, fat: g, n/non protein calories: / ) at least for days. results: there were no significant changes in anthropometric parameters within either group. nitrogen equilibrium was aqhieved by day in the tpn group and by day in the enteral group ( . % of the enterally fed patients and % of the tpn patients maintained in positive balance the day of the study). there were no significant changes in serum albumin within either group. serum level of transferrin reached a significant increase in both groups (p= . ). thyroxine-binding prealbnmin rose significantly in both groups as well (p= . and . respectively). statistically significant rises in lymphocyte counts (p= . and . respectively), in levels of c (p= . and . ) respectively), iga (p= . ), igg (p= . and . respectively) and igm (p= . ) occurred in either treatment group. there was a high incidence of negative skin tests at the start of the study in the enteral group ( . %) and the tpn group ( %). by the end of the study the incidence of negative responsiveness was . % and . % respectively. despite maintenance of similar glucose levels in both groups, tpn led to significantly higher serum insulin levels. the serum insulin increased almost linearly over the study period and eventually prevented fat mobilization and lipolysis, so that free fatty acid levels had fallen significantly. a significant elevation of the liver enzymes over the study period occurred in . % of the tpn group, but not in the enterany fed patients. conclusions: the present findings provide no evidence that enteral diets containing free amino acids and small peptides, as their nitrogen sources, are in any way inferior to isonitrogenous isoealoric regimes parenterally given. aim: the aim of this study is to describe and explore the expectations of the functions of the critical care nurse to enable the formulation of guidelines for the scope of practice for the critical care nurse with a south african context, methods: phase i was to determine the expectations of the critical care nurse, the nursing service managers and the doctors with regard to the functions of the critical care nurse. a focus group interview was held with a group of experts in the field of critical care. the results were used to compile a questionnaire. this questionnaire was sent to the critical care nurses, the nursing service managers and the doctors in south africa for completion. from these results the functions of the critical care nurse were determined. phase ii was to formulate guidelines for the scope of practice for the critical care nurse within a south african context. through usage of the date (phase i) the scope of practice was formulated. guidelines were formulated for the practise, education and research regarding the limitations of the professional-ethical authoration and the implementation of the scope of practice for the critical care nurse. objectives : high output gastric aspirates arc occasionally observed during fasting in critically ill paticnts, preventing any attempt of feeding via the enteral route. although these patients are often said to suffer from "gastroparesia", the motor correlates of this condition arc lurgcly unknown. in this stud?', wc recorded the gastrointestinal motility of critically ill patients with abundant (> ml/ hours) fasting gastric aspirates. methods : antral ( sites separated each other from . cm), duodenal ( site) and jejunal ( site) contractions were recorded simultaneously by ~eans of a multihimen tube assembly positioned trader fluoroscopic control (perfused catheter technique). tracings from prolonged recordings were obtained on a multichannel recorder ( a recorder, hewlett-packard) then anal) ,ed visually, with a special attention for the following abnormalities which are characteristic of intcstinal pseudoobstmctiou: l) absence or aberrant propagation of the migrating motor complex (mmc), ) presence of bursts (> min) of nonpropagated phasic pressure and ) presence of sustained (> min) uncnardinate pressure activity. patients with a volume of gastric aspirates of • (sd) [median ml/ hrs were investigated for - [median minutes. results : only one patient had no detectable motor abnormality. mmcs were either absent (n= ) or migrated abnormally (retrograde propagation : n= ; retrograde and stationnary : n= ) in pts. bursts of nonpropagated phasic pressure activity were present in the duodenum in pts and sustained uncoordinate pressure activity was found in pts. additional abnormalities included episodes of prominent pyloric activity. (n=l) and sustained antral pressure activity (n= }. conclusion : critically ill patients with large volume of gastric aspirates have manometric evidence of intestinal pseudoobstruction. prokinetic therapy in these patients should thus focus not only on enhancing gastric motility, but also on restoring a normal propagative contractile activity in the intestine. this prospective, open-label, randomized placebo-controlled study included patients with hypokalemia in whom rapid potassium replacement ( meq kci in h) was performed: patients received mg sulfate ( g in hours) and patients received a corresponding saline infusion. measurements were made at time , + , + and + hours results: k levels increased more in mg treated patients than in the patients who received saline infusion at time and h (p < . -students-newman-keuls). (table ). introduction. dual lumen uaso-gastrojcjunal tubes are a major ads'ance in nutritional therapy of mechanically ventilated critically ill patients since the " authorizc jejunal feeding with concurrent gastric decompression, there,, reducing the risk for aspiration. unfortunately, placcmem of these tubes in the jejunum regularly dictates to resort to endoscopy in order to facilitate pyloric intubation. recently, the remarkable gastrokinetic properties of the well known macrolide antibiotic er}lhromycin have been demonstrated in gastroparetic critically ill patients . aim. in the presem stu~,, we evaluated the feasibility of placing dual lumen naso-gastrojcjunal feeding tubes at the bedside without endoscopy, using edthromycin to help iranspy'loric migration of the tube under fluoroscopic control. methnd each patient admitted in our icu during a months period and requiring artificial ventilation and enteral nutrition for a period of at least days was included in the study.. after inserting the tube (stayput| sandoz, usa) in the gastric anmnn, e.rythromycin ( rag) was aduunistored intravenously, to help fluoroscopic positioning of the tube into the jejunum. the total duration of the procedure (from nasal intabatiun to jejunal placement), as well as the duration of ftuoroscopy were recorded in each patient. results. patients (male/female : / : mean age : . + . years; mean apacbell score : .t • . ) wore enrolled into the study.the procedure was performed within the dab,s following institution of mechanical ventilation. jejunal access was obtained in all patients without resort to enduscopy in , • . min.(total duration of the procedure). mean duration of fluoroscopy was . + . rain. conclusion. we conclude that placement of dual lmnen naso-gastrojejunal tubes can be obtained in mechanically ventilated critically ill patients without resort to endoscopy., provided that e rythromycin is used as gastrokinetic agent to help pyloric intubation. the following ad and dis parameters were considered in all patients: -mid arm circumference, triceps skinfold thickness, serum transferrin, albumine and lymphoeites and urinary creatinine/height index. patients whose results were bellow % of normal values in or more of the above criteria were considered undernourished (und).statistical analysis was performed using % analysis.statistical significance was established at p<o.o . results: a total of patients( female, male) -with a mortality rate (~) of , % -were studied, aged -+ years and a median ]enght of stay of days. -nourished (nou) at ad and at dis - ; ~ %; -nou at ad and und at dis - ; ) , % ; -und at ad and und at dis - ; ~ . %; -und at ad and nou at dis - ; ~ , %. we observed a p< . when we compared groups and (p= . ), and groups and (p= . ). variation in nutritional status and longht of stay: -nou at ad and nou at dis = > median lenght of stay days; und at ad and und at dis = > median lengbt of stay days; nutritional status and age at admission: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) nutritional status and age at discharge: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) we observed a p<o. when we compared groups and (p=o. ) and groups and (p = . ) conclusion: such study permits to conclude that most of our patients ( . %), staying in icu for more than days, were und, namely the elder. we observed that this kind ef patient had a longer median length of stay in icu, associated with higher mortality rate. in conclusion, the nutritional management is an essential element in suportive care of critical)y ill patients. ohiectives: sirs is associated with hypercataholisnl and resistance to nutritional support, despite raised circu&ting levels of growth hormone and insulin. serum igf- levels however are low; thercti~re rhigf-i administration might produce nsefnl anabolic effects. the pharmacokinetics of exogenously administration rhlge-i in such patients are likely to differ from that seen in the less seriously ill due to changes in circulating blood volume, increased capillary permeability, poor nutritional stares, and alterations in binding proteins. the ol jective of this study was to determine the clearance, apparent vohnne (if distribution (vd), time to peak concentration (tmax) and elimination half-like (tia) of a single subctkaneous il~ieetion of rhlgf-i in patients with sirs on the intensive care unit (icu). methods: icu patients with sirs were entered into the study, which had been approved by the ethics comjnittee. in each patient baseline hlood samples for circulating gf-i were obtained over a hour period, prior to il!iection of p.g/kg of rhlgf- subcutaneously. a further l samples were taken fi'om each subject over the next hours. circulating ige-i was measured in serum at each time point by radioimmtme assay, and the area under the curve tbllowing administration of rhlgf-i was derived tbr individual patients fixm~ baseline a~!justed igf-i levels. clearance values were caietdated by dividing the administered dose of rh[ge-[ by the total area under the etnve. vd and tv were calculated by regression analysis of the terminal part nf the log sertnn concentration time profiles. results: results are expressed as median (range). age ( - ) years, apache ii score ( - ), and length of icu stay ( - ) days. baseiine circulating igf- levels were low ( < - ) ng/ml reaching a peak of only ( < - ) ng/ml. of the patients had basal levels predmnhaantly below the inwel-limit of detection of the assay, and showed no appreciable rise in serum igf-[ levels tbllowing rhigf-i injection. parmacokinetic variables could not therefi)re be determined in these two patients. following rhlgf-i injection in the remaining patients tmax was at ( - ) hours, clearance was ( - ) ml/min, vd was . ( . - . ) l/kg, and tia . ( . - . ) honrs. conchlsions: there was marked patient wu-iability in response to rhlgf-i administration. vd was similar to that seen in poshq~erative maior surgery patients ( . vs . l/kg), but clearance was greater ( vs ml/min), tmax earlier ( vs hours) and t~a shorter ( . vs i . homts). if riaigp-i is to be administered to dtically ill patients the dose should he nlodified m the light of these findings. baekgronnd: acute bacterial endoearditis continues to be a condition with high morbidity and mortality. the majority of patients are treated with high dose antibiotics, but a patient group requires surgical treatment. methods and results: from january to march , patients underwent surgery for acute bacterial endocarditis: had native valve endocarditis and had prosthetic valve endocarditis. there were men and women. streptococcus viridans was the predominant infecting agent in native ~alve endocarditis and staphylococcus epidermidis in prosthetic valve endocarditis. progressive congestive failure, uncontrolled sepsis and peripheral emboli were the most common indication for surgery. although the mitral valve is more commonly involved in acute bacterial endocarditis, the aortic valve most often requires surgical inlervetion. the postoperative bleeding in the no-aprotinin group was + cc and in the aprotinin was :t: (p < , ). the mortality in icu was , %, the staphyloccocical endoearditis mortality was , % and the no-staphyloccocical endocarditis mortality was , % (p< , ). conclusions: the early surgery is indicated if endocarditis has no response with medical treatment. the mortality of staphyloceocical endoearditis involving left valves was higher than caused by other infecting agents. aprotinin treatment improved prosta#andin metabolism and preserved pletelet function during open heart surgery and could be useful in this type of interventions. urgent surgery had a high mortality ( %). selective digestive decontamination (sdd) has increasingly become the subject of critical discussion sine~ the development of multiresistant organisms has become an issue. moreover, a selection of gram-positive pathogens must also be taken into account when using the sdd regimen, which is primarily directed at the gramnegative bacterial specumn, with the methicillin-resistant staphylococcus aureus strains (mrsa) being of particular importance. the objective of our study was to determine the extent to which colonization with mrsa strains is promoted by sdd. method: patients (ventilation period > days) were randomized and allocated to the sdd group (n= ) or the control group (n= ). in their general intensive care theraw, there were no differences between the groups. the sdd regimen consisted of the four times daily administration of rag polymi~ mg tobramycin and mg amphotericin b in the nesc, mnoth and stomach. systemic prophylactic ~dmini~/rution of antibiotics was not part of the sdd regimen. smears were taken from the nose and the rectum twice wceldy and from the pharynx and trachea once wceldy, and tested for mrsa. further samples were taken as clinically reqnircr results: smears were examined in the sdd group. mrsa strains were detected in samples ( . %) from patients, and in patients they were detected for a period of up to weeks. the positive smears were districted as follows: tracheal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal ( . %). severe mrsa-induced infections were observed in patients (infection rate . % of the colonized sdd patients). smears were examined in the control group. ivlrsa swains were r in samples ( . %) from patients, but only repeatedly over a period of up to days in patients. the po~tive snmars were distributed as follows: traclmal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal / ( . %). there were no mrsa infections in the control group. conclusion: the data collected support the view that the use of sdd promotes a selection and persistence of mrsa strains. longer-term colonization with mrsa and sovere systemic inf~ons were only found in the sdd group. although the clinical and epidemiological impact of resistance develol~ng when sdd is applied ~maine unclear, this question should be given close scrutiny. tazobactam/piperacillin (taz/p p) is a new broad spectrum antibiotic, in which the acylaminopenicillin piperaeillin is protected by the betatactamase inhibitor tazobactam from hydrolization by bacterial enzymes. taz/pip has shown to possess a high antibacterial activity against almost all clinically relevant bacteria and is a registered drug in germany. obiectives: purpose of this investigation was to evaluate, whether faz/pip . g is suited for efficient antibacterial monotherapy of severe infections and what influence dosage frequency reveals on clinical efficacy. methods: hospitalized patients have been documented in this multicenter trial during a year period. as this investigation should reflect the usual clinical treatment, the only criteria for enrolment were the typical signs of infection as e.g. temperature > ~ leucocytosis or an isolated pathogen. exclusion criteria did not exist and the patients were treated in accordance to the severeness of infection, underlying diseases, risk factors etc. with taz/pip . g t.i.d, or b.i.d. results: patients suffered in most cases from infections of the lower respiratory tract (n= ), followed by intraabdominal (n= ) and skin and soft tissue infections (n= ). % of the lrtis wvre nosocomial acquired and in % the treatment was conducted as monotherapy. in % the lrti was treated with taz/pip b.i.d, and in % t.i.d. pseudomonas spp. (n= ) and staph..aureus (n= ) were the most isolated pathogens pretrcatment. the clinical response rates (cured/improved) after treatment with taz/pip . g b.i.d, and t.i.d, were % and % respectively. results for intraabdominal-and skin and soft tissue infections will be presented. conclusions: in hospitalized patients with severe infections successful treatment with taz/pip in monotherapy is possible. in this population a reduction of the dosage frequency to . g b.i.d, revealed equivalent clinical response rates. objectives. retrospective evaluation of cases of severe generalized tetanus (sgt), treated in our icu the last years. we review cases of sgt ( m, f), mean age . years. in eases the entry site of c.tetanus was a skin laceration, in case it proved to be the external genitalia, while in the rest no portal of entry could be determined. in the first cases incubation period was short ( - days) and so was the period of onset ( - days). all patients needed mechanical ventilation (range - days), initally through an orotracheal tube,and later through a tracheostomy, performed • days after admission. clinical manifestations of sgt included muscle rigidity and i generalized spasms, persisting for up to weeks in the most severe cases. significant autonomic nervous system dysfunction was present in cases occurring - days after the admission and following the time course of generalized spasm. besides general supportive measures, specific treatment included passive +active immunization, penicillin g, magnesium sulphate and sedation in a variety of regimens. neuromuscular blockade was required in cases. nosocomial infections occurred in eases, with sepsis and mof in one. average stay in the icu was - days. one patient died with severe septic complications and one was discharged with severe disability due to anoxaemie ancephalopathy, after a cardiac arrest on admission. ~ disinfectant in suspension test, without presence of organic load, disinfectants showed efficacy on lm. in the carrier test, in the presence of organic load, out of examined disinfectants did not exposed efficacy on lm. the results of examinations clearly showed that evaluation of disinfectant's efficacy partly depend on the used test method. antun basi , intensive care unit, kb firule split spin~ideva ! jugoslavia bacteremia and sepsis are frequent complications encouuntered in severe icu patients.microorganism identification with hemoculture presents the basis for adequate and successful antibiotic treatment.in many patients damage and vulnerability of the peripheral veins presents an obstacle for obtaining the blood culture from the central venous (cv) catheter sample could be also used. material and methods blood cultures were perfomed in lo patients on blood samples simultaneously obtained from the peripheral vein and cv catheter three times in a -hour period.criteria for the suspected bacteremia were body temperature above c and leucocytosis above ioooo leucocytes/dl. the site for venipuncture and the cv catheter stopcock port were cleansed with povidon iodine.after the initial ml of blood were discarded,lo ml were used for the blood culture.standard laboratory technique for blood cultures was used. results and discussion in ( %) patients hemocultures was negative at both sites,whereas in the remaining ( %) they were positive.for twentyone ( ~ of the positive patients the same results were obtained at both sites (peripheral vein and cv catheter),whereas in ( . %) patients the blood culture were positive only for the cv catheter samples.the cv catheters were in place for less than days in patients and for more than days in patients.from patients with positive blood culture from the cv catheter,one patient had the catheter for three days,whereas the other had the catheter from - o days. we neither found significant differences in hemodynamic dates : objectives: , to count and evaluate bacteria isolated from endotracheal (et) suctiori samples (with and without saline). . to establish the exogenous source(s) of pathogens isolated from carer's hands and the equipment involved in sampling in order to reduce the incidence of contamination and infection. method~: this prospective study included consecutive ventilated patients ( male and female, _ + yr; apache ii score -+ ) over a period of months. et aspirated samples with and without saline were taken daily from day of intubation until pathogen~ were presented in counts of _> per ml. at the same time, samples from both carer's hands were taken before and after et suction and a swab from the ventilator tube. results: the overall length of intubation varied between to days. bacterial transfer between staff and patients was noted in % of patients until day of intubation. there was no significant correlation between severity score and appearance of colonization. the incidence of pneumonia in studied patients was % with an overall mortality rate of %. acinetobacter anitratas (no ), staphylococcus aureus (no. ), klebsiella pna~moniae (no. ) and pscudomonas aeruginosa (no. ) isolates predominated in all our specimens. we noticed increased resistance to most antibiotics with the exception of imipenem for gram (-) bacteria and vancornycin for gram (+) bacteria. conclusions: i. tracheobronchial colonization appears directly in the maiority of intubated patients. . there is a close relationship between the microflora of personnel, patients and equipment. . bacteria transfer was noted both to and from patients. . strict hand disinfection policy remains an important measure for the proper care of mechanically ventilated patients to reduce respiratory infections. nnseeomial pneumonia is the most common nnsocomiai infection in the icu-settiag, reported in up to % of patients admitted to the icu following surgery. it is associated with significant mortality that ranges from ~ to %. enteric gram-negative bacilli have been implicated in % to % of ventilntor-associated pneumonias and pseudomonas aeruginosa accounts for % to % of these pneumonias. importantly, epidemics of/ - actamnse-pruducing enterobacter spp or klebsiella spp that are resistant to extended spectrum cephalosporins or penicillins, pose serious obstacles to effective antibiotic choices. carbapenems provide in ~tro activity against a wide range of enterobacteriaceaeand other gramnegative aerobic bacteria, except steaotrophomonns maltophilia. in vitro meropcnem is more active against pseudomonas spp than imipanem (especially p. aeruginosa and p. cepacia), imipenem and meropenem are effective against more than % of strains responsible for nnsocomial infections. all major pathogens associated with lrti are usually covered by the carbapenems, exceptions are pathogens involved in so-called atypical pneuomouia like mycoplasma, chlamydia and legionella. carbapenems are highly stable in the presence of most chromsomal and plasmid-mediated blactumases and usually offer a postantibiotie effect lasting for three hours against most of the enterubacteriaceae. reeent studies comparing imipenem/cilastatin with other ~-lactams and fluoroquinolones in severe lrti in icu patients resulted in favourable clinical cure rates and good tolerance, but development of resistance in p. aeruginosa and ;. aureus during treatment were of some concern. meropenem offers the advantage of greater stability against enzymatic degradation, so no concomitant administration of an enzyme inhibitor is necessary, and meropenem appears to be associated with a lower risk of seizures, particularly when used at high doses. results from studies with meropenem in lrti, especially in critically ill patients with acute exacerbations of chronic bronchitis, demonstrated excellent cure rates and better gastrointestinal tolerance of this new carbapenem. both earbapenems are effective candidates for use as empiric monotherapy in nosucominl infections of critically ill patients. qbl~ctives a favourable effect of iv immunoglobulins in septic surgical patients has been reported, but not sufficiently validated. we conducted this study on trauma patients to: i) investigate the effect of ivig on septic complications and il) quantify this effect by means of serum bactericidai activity (sba) assessment and iii) to explore the effect of temperature increase (from to ~ c) on the sba methods: twenty trauma patierits matched on admission for age, sex, inju~ severity score and glasgow coma scale, were allocated to receive either wig (ivig group; i patients) or equal volumes of human albumin % (control group; patients). wig (sandoglobulin) was administered in a total dose of g/kg divided in a four time regimen on days , , and post-admission. three blood collections were performe& before the first dose (day ) and hours after the third and the fourth dose (days and respectively). complement, lgg fractions, the sba at ~ and at o c and clinical parameters were recorded. results-similar lgg and igg] serum levels were found in groups ivig and control on day ( +_ vs • ns and + vs + , ns), whereas they were significantly higher (p< ) in the v g group on days ( _+_ vs + , p< ) and ( _+ vs +i , p< . ). the various complement-fractions increased in both groups without inter-group differences the mean (• sbas ( ~ c) at rain in ivig group vs control group were: - _+ vs - • ns for day , _+ vs - _+ p< for day and _+ vs - + p< for day . the mean (+sd) sbas ( ~ c) at rain presented a significant improvement over those of ~ c but for the control group remained negative a~d were respectively as following: -~ • vs - + , ns for day , +_ vs - _+ , p< . for day and _+ vs - _+ , p< . for day . the increase of temperature induced a -fold improvement of sba in iv g group and -fold ofcontrol-~oup positive blood cultures, and the product of the infectious episodes number multiplied by days of occurence, were significantly lower (p< ) in the ivig group than in the control ( vs , and vs , respectively). conclusions: our study shows a significantly favourable effect of ivig administration on septic complications and on sba of trauma patients. the increase of temperature results in a significant improvement of sba of patients that received ivig, which theoretically means a farther prevention of infection in the febrile state. pharmaceutical microbiology, university of bonn, meckanheimer aune , d- bonn, germany infectious diseases in intensive care patients are common in comparison to patients on other wards and out-patients. the main difference is that intensive care patients are much more sensitive even to less virulent bacteria. thus, the spectrum of infecting organisms is different. strains often regarded as pathogens with low virulence cause serious infections in these patients. strains such as serratia, however, have intrinsic resistance to most commonly used agents such as rd generation eephalosporins. furthermore, the common pathogens like staphylococci, psoudomonas aeruginosu, enterocneei and gram-negative bacteria, enterobacteriaeceae as well as the non-fermenters are less sensitive if isolated from intensive care patients. it is difficult to generalize on intensive care units as different patient groups are in different icus aud there are great changes from one hospital to another and from one country to another. if we take s. aurens strains from one study from the'overall resistance in intensive care units towards oftoxacin was %, whereas in other hospital wards the percentage of resistance was . %, in out-patients, however, only .$ %. the same trend was true for entercnecus faecnlis, coagulase-negntive staphylococci, and other bacteria as well as other drugs. one most striking difference was found with klebsialla pneumoniae and gantamycin resistance, which was $ times higher in intensive care units as compared with outpatients, whereas in the same species no difference was to be seen with the resistance towards carbapenems. however, differences between countries seem to be even more striking, as example gantamycin resistance and staph. anrens is given. the extreme difference is more than fold. thus, it is evident that there is a general trend towards higher resistance in intensive care units, but no generalizatiouis possible. therefore, surveillance studies in intensive care units are needed and the antibiotic policy has to be adapted to the specific needs of the unit. in the icu setting the most potent antimicrobial agents are required to address problem organisms including those resistant to penicillins, cephalosporins and aminoglycosides. carbapanems would appear to present a useful option in this setting. objectives of this study was the evaluation of systemic candid• in postoperative cardiac surgery patients (pts) with prolonged icu stay. methods: out of postoperative adults pts of mean age . + . years old, with a mean icu stay of . _+ . days, following an open heart surgery from july to april , pts ( %) remained in icu for more than days because of severe perioperative complications. patients were included in the protocol if they had clinical signs of infection or sepsis, and fungi isolated in blood culture or in culture from at least three different sites. the patients who developed systemic candidiasis received iv fluconazole ( mg/day) ( patients) or amphotericin-b for at least four weeks, and then they were closely monitored. results: out of postoperative pts with prolonged jcu stay, pts ( . %) developed systemic candid• usually after the th postoperative day. they were males and females of mean age +_ . years old. this group of pts had prolonged bypass and aortic cross-clamp time compared to control group ( min vs , and vs min). all these pts received inotropes per• (mean value= . ). during their icu stay, pts developed sepsis of bacterial origin, while the other two severe infection, and received antibiotic regimens for prolonged period. the patients were submitted to mechanical ventilation for a median period of days. the median icu and hospital stay was and days respectively. all pts have been improved and finally negative cultures were obtained. conclusions: . a significant percentage of patients who remained in the postoperative icu for more than days developed systemic candidiasis. . all patients who developed systemic candidiasis had received antibiotics because of sepsis or severe infection, for prolonged period. . fluconazole seems to be a very good alternative to amphotericin-b. . fluconazole is a safe antifungal agent with few side effects. botulism is the most severe and an odd food poisoning. although it is more commonly related to preserved meat derivatives, preserved fish and vegetables are also responsible for a number of cases. obiectives: to evaluate four familiar outbreaks of botulism . methods: we study the patients that were admitted in our hospital because of botulism from may to february . results: the thirteen pacients involved had a previous history of home preserved beans ingestion. after a -hours incubation period, gastrointestinal symptoms (abdominal pain, vomits, constipation) appeared and lead them to hospital consultation in the th to th day after ingestion. two patients died (acute respiratory failure before admission), seven were admitted in icu, two in ward and two of them were discharged from emergency room. clinical symptoms and the previous history of the ingestion established the diagnosis, that was emg confirmed. in all cases, symptoms were consistent with b-toxin botulism. b-toxin was isolated in serum and food proceeding from the third outbreak, and the serum was negative in the other ones. neurological symptoms were predominant: midriasis ( %), dry mouth ( %), dysfagia ( %), asthenia ( %), palpebral ptosis ( %), accomodation paralisis ( %) and urinary retention ( %). muscle weakness lead to acute respiratory failure in three patients (one of them required mechanical ventilation). four patiens developed infections (respiratory, urinary and phlebitis). both died patients and one another presented severe hypertension. all admitted patients were treated with polivalent anti-toxin. the two patients who underwent a more severe muscle weakness received also guanidine hydrochloride, with no answer in one case and provoquing a cholinergic crisis in the other one. icu length of stay was days. at hospital discharge, patients continued symptomatic, mainly with dry mouth, disfagia and impaired vision. conclusions: although botulism is a serious illness, the pronostic seems favorable if treatment and support measures are avaible. usually neurological symptoms we predominant and at discharge some of them could still persist. the arrow "hands-off" (aho) thermodilution catheter (tc) is completely shielded during balloon testing, preparation, and the insertion procedure. in order to assess the value of the aho thermodilution catheter in the prevention of systemic infections associated with pulmonary artery catheterization (siapa), we conducted a randomized prospective study over an -month period. methods : the patients (pts) were randomly assigned to two groups : group i for a standard tc customarily used in the department, versus group for the aho thermodilution catheter. the diagnosis of siapa was determined on the basis of a positive culture of tc and bacteremia with the same organism, with out any other nearby focus, in association with regression or disappearance of the clinical signs of infection after removal of the thermodilution catheter. results ( objectives: the mortality rate (mr) of tb requiring mechanical ventilation (mv) is high ( - %). the aim of the study was to evaluate mr, associated factors, and prognostic significance of mv and hemodynamic disorders from tb in icu in patients with tb. methods: clinical parameters on admission, and complications in icu were related by univariate analysis to icu, hospital, and month outcome. patients required mv; were immunocompromised (ic) including hiv. tb was pleuropulmonary in , disseminated in and meningeal in . results: mr was % in icu, % in hospital and % at month. / ( %) < . mortality was associated with a high saps score, initial shock, mv and nosocomial septicemia. the mr dramatically increased when ards occurred during illness, despite the lack of correlation between mr and initial po /fio ratio or initial murray score. the site of infection did not influence the mr. surprisingly, the mean therapy delay was shorter for non survivors. mr was not related to ic status, nor hivstatus, but was only related to previous steroid therapy. conclusion: mr of tb requiring icu is high ( % at month). need for mv increased mortality ( % vs %). general severity and respiratory dysfunction seem to be major prognostic factors in icu rather than tb per se or than therapy delay. in spite of the improvement in the prognosis of pneumococcal meningitis (pm) with third generation cephalosporins (tgc), this infection still presents a great mortality which could be increased with the appearance of antibiotic resistant streptococcus pneumoniae. objectives: to asses intensive care mortality and morbidity of pm and to define patients (pts) at risk of complicated evolution. patients and methods: a retrospective evaluation of pm cases (all diagnosed by csf culture) admitted in our icu from january tit march . in all pts we analized: demographic data, underlying disease, apache ii score, clinical symtomps, treatment, complications and outcome. statistical analysis was done using bmdp sofware package. results:a total f pts were studied, males; mean age , _+ ( - ); apache ii score , + , ; glasgow coma scale (gcs) at admission , _+ , ; ( %) pts suffer from cronic pathology; ( %) pts diabetes mellitus (dm), ( , %) pts had had a previous cranial traumatism. in cases the source of infection was otic and also in ( %) episodes of pm there were bacteriemia. in out of ( %) pts that ct was performed no radiologic abnormalities were shown, of them presented cerebral oedema and pts a cerebral abscess. twenty-eight percent presented seixures, % hemiparesia, , % respiratory failure, , % shock, i % renal failure, , % multiple organ failure (mof). as for treatment refers , % pts recieved only penicillin, , % pts only tcg, , % pts tcg followed by penicillin and , % pts tcg+vancomycin. seventy-five percelat of pts recieved corticosteroids and , % vasoaetive drugs. the mean icu stay was , : days ( - ). twelve ( , %) pts died, two of them presented pm relapse (resistant streptococcus pneumoniae) and another two pts developed neurological sequelae. factors associated statistically with bad prognosis were dm, the use of vasoactive drugs, shock, mof, the apache ii score at admission, the gcs at the and hours from admission in the icu but not the gcs at admission. didn't resulted statistiealy signifcative age, previous eronie pathology, seizures, baeteriemia, renal failure and coagulation disorders. conclusions: mortality was high and associated to apache ii score at admission, to gcs at and hours after admission, shock, vasoaetive drugs and mof. objectives:the aim of the study was to analyse some of significant immunologycai changes in surgical patients,requiring intensive health care,and to determinate the possibility for evaluation,dynamical examination and importance of immunologycal problems for treatment. methodes:the study concerns a number of patients with expanded surgical intervention or serious postoperative complications.the results has been carried out with fiowcytometryc analyses of lymphocytic suhpopulations and routins methods for investigation of humeral immunity.the"panel" for evaluation of (} immunologycal parameters has been offered:t-calls total/cd +/;t-helper/cd +/;t-supressor/cd +/ th/ts ratio;b-cells/cd +/;naturai kilier/nk/cells;skin test for cellular immune function;phagocytic and oxidative activity;serum levels of immunogiobulins-g ,a,m;protease inhibitors;c-reactive protein.all patients have been studied during suffering and after surgical procedures dynamicaly. results:there have been estimated significant changes in immunologycal parameters especially:decrease of t-cells: cd +mean= . %/ . %- . %/and cd +mean= . %/ % - . %/;inverted th/ts ratio ,mean=o. / . - , /;reduced or negative skin teste;reduced phagocytic and oxidative activity before septic complications. conclusions:dynamical examination of immunologycal parameters shows,that the prolonged t-total,t-helper lymphocytopenia with functional deficience of ceils-mediated immunity correlates with the stage of clinical condition of the patients and has prognostic importance.it's clear,that immunologycal monitoring gives a possibility for immunecorrection. patients (pts) with the human tmunodeficiency virus (hiv) infection have a decreased immune response and are particularly susceptible to infectious endocarditis (ie). the aim of our study was to analyze the prevalence of ie, its clinical and therapeutic implications in a hiv population we prospectively studied pts, . % ( / -group ie+) with ie during the clinical course of this disease. we analyzed the following parameters: age, gender, race, type of hiv, cdc classification, number of t and t type cell population and its ratio, therapeutic with azt, type and number of opportunist infections (inf, mycobacteriosis (mb), neoplasm's (nee) the echocardiographic parameters were lv internal diastolic and systolic diameters, lv percentage of fractional shortening, interventricular and posterior wall thickness, the degree of valvular regurgitations and the presence of pericardial effusion. el was located at the mv in . %, tv in . %, av in % and pv in . ~ and was multiple in . %. hiv el+ pts had larger lv diameters and more frequent significant valvular regurgitations ( % tr, pe %, mortality %). these two groups differed significantly in the following clinical parameters: the typical symptoms were watery diarrhea, high fever, tachycardia,luekocytopenia and oligouria within th postoperative days. the patients with mrsa enterocolitis had positive mrsa culture from the many materials except feces.mesa strains frequently had coagulase type ,enterotoxin a and toxic shock syndrome toxin- .eight of patients had postoperative organ failure.most of the mrsa strains in japan were similar in coagulase type to our hospital and our department.all of mesa strains were susceptible to vancomycin and arbekacin,tbough most of them showed resistant to many other antibiotics.we have employed guidelines for therapies such as oral or enteral administration of vancomycin and correction of the hemodynamics for dehydration and circulatory failure due to diarrhea from .futhermore we have placed colonized or infected patients in private room,worn gown and mask,and carefully washed our hands from . these countermeasures for prevention of nosocomial infections after significantly reduced the incidence of mrsa enterocolitis. conclusions:earlier diagnosis and treatment, and distric prophylactic measureres against mrsa infections are very important. -- cdo ivda leptespiresls affects all the organs with widespread hemorrhage that is more prominent in skin, mucosa, skeletat muscles, liver and kidneys. lung involvement is usually mild and less common. suli, it is very uncommon acute respiratory failure to be the pr sontirlg symptom. a case with leptosplrosl..,s which was presenting with acute respiratory failure is described. a year-old man admitted to icu becauso of fever, myaigla, aevere c~, hemopty~s. his blood gases showed: pao : mmhg with fio : . , pco : mmhg, ph: . , hco : mecl chest x-ray film demonstrated diffuse bilateral alveolar pattern occupying beth lung / ). trarmamlnase, bllllrubln, ~ and esr were elevated, wbc was . mm , platelet: . ram , hematesrlt: %, hemoglobin: .sgrldl=. there was no clinical or ecttlographlc evidence of left heart failure.patient fulfilled the criteria for diagnosis ards he was found to have an ~lutinatlon tlter for leptoq~lral antigens(indirect he~lutlnatlon atomy, ilia} very high ( / , negative<ill ) and iglm antibodies also very high (elisa, a= . , negative< . ) strongly suggesting leptospirosls. treatment with tetracycline and non-tnvaslve mechanical ventilation by nasal mask were started. pre~jre support mode and cpap was usod. the following days the clinical picture,the oxygenation and the chest x-ray of the patients were improved, and patient dl~herged from the icu. the control of leptosplremlc phase as well as his good cooperation during nipsv contributed to rapid recovery and excellent outcome in hiv infections, pneumonias (pnm), mainly due to pne~ mocystis carinii (pc) have an outstanding place in pu ! monary complications. the aim of this work was to compare two group> of patients admitted with pnm in our icu during the same period ( - ): group a, patients hiv+, and group b, patients hiv-. apache ii was identical in the groups (p=ns). group a required more often mechanical ventilation (p= ,o ), had a higher p(a-a)o (p= , ) and metabolic acidosis was more frequent (p= , ). regarding laboratorial parameters group a had a lower no. of linfocytes (p= , ), a higher ldh (p= , ) and a more marked hypoalbuminemia (p=o, ). mortality was higer in group a ( , %) than in group b ( , %), (p= , ). analysing the a group patients, we found no significant differences between alive and deceased patients, with exception for albuminemia, which was lower in the deceased patients (p= , ). in conclusion, the hiv+ patient's pnm have a more agres sive behavior when compared with community acquired hiv-patient's pnm. the prognosis was not influenced by the apache ii. perhaps other parameters such as p(a-a)o , metabolic acidosis, linfocytes, ldh and albumin shoud be more evaluated as possible predictive indices. some prognostic factors, usually accepted as predictive in the analysis of hiv+ patients do not seem to be worth in the late stages of aids, mainly when they reqquire intensive care. intensive care unit, onassis cardiac surgery center, athens, greece. objectives of this study was the comparison of two different antibiotic regimens as prophylaxis in cardiac surgery patients. methods: in a prospective randomised comparative study, two different forms of antibiotic regimens were investigated : a single dose of cefuroxime (zinacef, gr) (group a) given during the induction of anaesthesia, versus a four days combination of amoxiculine (amoxil, gr tid) plus netilmicin (netromycin, mg bid) (group b). a total of patients (pts) ( males and females, of mean age . + . years old) were included in the study over a period of one year; in group a and in the group b. patients were checked for the occurrence of infection during the first postoperative month. results: the total rate of infection in cardiac surgery pts was . %; . % in group a and . % in group b (p=ns). pts ( . %) developed infection following cabg, pts ( . %) following valve replacement and pts ( . %) after other cardiac surgery. they were males ( . %) and females ( . %). endocarditis has occurred . % in group a and . % in group b. severe wound infection was recorded in . % in group a and in . % in group b. one case of sepsis ( . %) in group a and in group b ( . %). respiratory infection occurred in pts of group a ( . %) and in pts of group b ( . %). two cases of urinary tract infection was in group a and one in group b. catheterrelated infection was occurred in ( . %) in group a and ( . %) pts in group b. pts ( . %) had fever of unclear aetiology in group b. conclusions: there was no statistically significant difference regarding the rate of infection in both groups. a single dose administration of cefuroxime is accordingly just as effective as a four days regimen of amoxicilline plus netiimicin. legionella pneumophila is a common bacteria of the environment, and it is an agent responsible for severe community acquired pneumonia (cap). we analyzed the patients with lpp admitted in our icu during the last years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . they represented . % of cap. seven patients were males and female, with mean age . + . years. tiss was . + . and apache ii . + . . all, but patient, were under mechanical yen tilation (mv) during a mean period of . • (min-l, max- ) days. two pneumonias occurred beyond the season, while patients had an epidemiological history. only patient had no risk factor. in all the others tobacco smoking and alcohol abuse was quite frequent. diagnosis was based on serologic test and culture or direct fluorescent antibody staining of bronchial secretions. seven patients had a multisystemic disease with hepatic dysfunction in , renal failure in (due to rhabdomy~ lysis in ). one patient had a prosthetic valve endocarditis and another developped ards. nosocomial septicaemie occurred in patients. mortality rate was %. deceased patients had initially higher apache ii, (a-a) , and lower natriemia. comparing lpp with the other cap (n= ), both submitted to mv, mortality rate was similar ( , % versus . %). in conclusion lpp can occur all over the year. there was a high incidence of severe complications and outcome was similar to the other cap when requiring mv. prospective specimen brash (psb) with culture > cfu cfu/ml. broncho-alv~lat lavage (bal) ~= c'fu/rnl or positive blood culture. were excluded for rapture of treatment ; were analysed (shift with oral antibiotic : ; prohibited antibiotics associations : ; resistant germ : ). clinical data : age , • , ; saps • , ; mac cabe i : , % -ii : , % -iii : , . , % of the patients were intubated and under mechanical ventilation. the pneumoaiae were : primitive in ( , %), copd ( , %), aspiration pneumonia ( , %). germs were isolated (psb , bal , blood culture ) : s. pneumoniac ( , %), h. influeazae ( , %), sttep~:occns ( , %), saar ns ( , %), enterobaetdrindr ( , %), mosexella catarrhalis ( , %), othem . / ( , %) were sensitive to freatment. the ltentment was mg/kg/d of ampiclllin and mg/kg/d of sulbactam in continuous iv adminisu'ation during at least days. clinical eff~ienev : success ( %), failures ( %) with superinfeetion , worsening or relapse , dead , side effects . there was no difference between etiologies : primiti~;e~ , %, copd , %, aspiration pneamoniae , %. the bacteriological effieieacy was evaluated only for patients with eradication ( , %), eradication but super~ection ( , %) : with pseadomoaas a&ogiuosa , eater~ac~ ; beeteriological failure ( , %). in conclusion, the aasor ampicillin -sulbactam is effective for the i~eatment of severe acquired community pneumonise. objectives : to assess the efficacy of chlorhexidine (cl) gel or suspension applied in the nose and in the op for the prevention of the tmcheobronchial colonization. methods : thirty-seven patients expected to be intubated for > h were randomized to received topical application oga cl suspension ( %) qshrs, a cl gel ( %) q hrs or a placebo. in addition all vpts received a nasal and a op spray ( %) of either cl or placebo administrated according to the same schedule. semi-quantitative cultures of the anterior nares, the oropharynx (op) and the trachea were obtained on admission and once a day until extubation (just before the next application). the results were assessed according to the following criteria: success = no acquisition of gnb in the trachea ; failure = acquisition of gnb in the trachea. acquisition was defined by a follow-up culture positive for a gnb not present in the trachea on admission. results : success failure nosocomialpneumonia overall morality clsusp. placebo clgel placebo n= n= n= n= / / / * / / / / * / / / / / / / / / i *p = , byfisher'sexacttest conclusions : these results suggest that topical cl gel administered q hrs may prevent tracheal colonization by gnb. f. daumal*, m. daumal**, c. plot**, v. vurmmen ~ e.colpurt**, b. manonry** * hygiene hospitali&e, ** service de r enmmtion, * service des admissiens-urgeuces centre hospitalier g- ndral - saint-quentin -france obiectives: evaluate the nosocemial risk due to peripheral venous inserted short catheters, and the quality of care. patients-methods: the intensive tare unit (i.c.u.) is a beds unit. the prospective study includes all the patients comn~ in from / / to / / . the recruitemont uses an evaluation schedule of local clinical signs. the nurses aimed to create this evaluation data which includes the place of entry site, the duration of catheterization and the cause ot withdrawal. only patients staying longer than days in the i.c.u. are accounted for. the diagnosis of uosoenmial infection is assured by the physician taking care of the patient and by the hospital epidemiologist on the next signs: evident pus at the catheter entry site, positive culture of the strain, with or without the same pathogen in the blood sla'uam,the patient having no other distant source of infection. analyses were performed on epi/nfo. results: the occurrence of nosoeomjal inthrtions: i abcess and bacteremia during the first part of the study lent the medical staff to modify the protocol of insertion end survey of the device. so we analysed different periods: period ( / / to / / ) and period ( / / to / / ) for all .e peripheral catheters inserted in the i.c.u. period , % , % en infection due to peripheral venous device is a daily threat. the severity of some clinical situations requiring admission in icu proves it. the motivation of nurses for rigid adherence to established protocol, the daily survey of the entry site, the withdrawal of the peripheral catheter every hours aimed to reduce significantly the local signs of inflammation end infection of peripheral catheters inserted inside the i.c.u. objectives: to investigate the use of a new metabolic monitoring device for different ips levels by comparing oxygen consumption (vo ) to measurements of the mechanical work of breathing (web) and p . . methods: the study was approved by the institutiotml ethics committee. eight patients were investigated during weaning after prolonged mechanical ventilation ( - days) for various diagnoses when the clinical physician judged the patient to be ready fur weainag. ips was setto , , , mbar far rain periods each. all patients had a peep between - mbar.. respiratory frequency (f), tidal volume (tv), minute ventilation (ve) were read from the ventilator display ( ae, puritan bennett, carlsbad, usa). flow and airway pressure were measured at the endotracheal tube site. esophageal pressure was measured using an esophageal balloon catheter (fa. ruesch, frg). web was determined as the area subtended by the pleural-pressure-vohime curve. p . was determined by using standard occlusion technique and graphical analysis of the airway pressure tracing. vo and vco were measured using the pb metabolic monitor (puritan bennett, carlsbad, usa) connected to the pb ae ventilator. all data are given as mean• deviation for each ips level. comparison between the different ips levels was performed using anova for repeated measurements. significance was considered at p< . , compared to ips mbar. results: the values for breathing pattern, web, p . , vo and vco are given in the table for the different ips levels; significance is indicated by ~. objectives: fluidized beds are often used in the management of critically ill mechanically ventilated patients. critically ill patients are increasingly colonized with resistent pathogens [ie: p. aeruginosa, methicillinresistent s. aureus (mrsa), extended spectrum i~-iactamase producing enterobacteriaceae ] that can ultimately cause nosocomial infection. methods: we prospectively monitored bacterial colonization of mechanically ventilated patients and of the fluidized bed (clinitron) inwhich they were treated. multiple samples for quantitative bacterial cultures were taken from oropharynx, trachea, feces and bedsores. samples of ceramic beads from the bed were also taken both during and after patient stay (after bed operation in the absence of patient). re,~ults: episodes in consecutive patients (mean age: . years) were analyzed. all had bedsores and/or urinary catheters and fecal incontinence, patients had nosocomial pneumonia, had urinary tract infection [ with extended spectrum imactamase producing k/ebsie//a pneumoniae (ki~lse)], one had positive blood cultures with mrsa, and one patient had a ki~lse found in high concentrations ( - s cfu/ml) in occasions in feces. patients were heavily colonized: the , samples from ceramic beads showed no growth or became sterile without any sterilisation procedure (even in one case of presence of kf~lse) during the patient stay. conclusions: fluidized beds do not put patients at high risk of acquiring nosocomin pathogens, and cross-contamination between patients seems unlikely, even when multiple resistent organisms were initially present. the recommandation from some manufacturers to undergo extensive sterilization of fluidized beds after use does not seem warranted, at least with the bed used in this study. ant. koutsoukou, a, tahmitzi, p. kithreotis, m. koutonlidou, k. stavrakaki, kainis e, g. vlahogiorgos and e. eliopoulos icu-centre for respiratory failure -chest diseases hospital of athens. the cost-effectiveness issue is becoming vital in modern medicine and may lead to moral dilemmas since sometimes certain groups of patients may not have access to highly specialised modalifies. objective: our study compared the mean daily cost for antimicrobial medication in copd patients treated in icu versus all other patients in the context of relevant epidemiological, prognostic and outcome data. methods: age, sex apache ii score, length of icu stay (los) and in -icu fatality were retrieved from the files of all icu admissions over . mean daily cost for antimicrobial therapy per patient (dcat) was estimated. these variables were statistically compared between copd and non-copd patients. significance was assumed at p< . results: of the total admissions were fully evaluable. of them ( %) were copd patients. data (m---sd) results for statistical test are given in table i . copd patients were significantly older spent more time in the icu and presented with significantly higher apache ii scores. outcome and dcat were comparable in the two groups. objectives: the use of heat and moisture exchangers (hmes) during long term mechanical ventilation (mv) is increasing. in icu patients, they are routinely changed every day, according to the recommendations of the manufacturers, but the clinical basis for such a daily practice is lacking. we therefore prospectively assessed whether changing hmes (dar hygrobac, spa, mirandola, italy) every h only would affect their clinical and bacteriological efficiency. methods: two consecutive groups of patients requiring mv for > h were compared: group = hme replaced every day, n= episodes of mv in patients; group = hme changed every h, n= episodes in patients. tubings were not changed in the same patient during the whole length of ventilatory support. diagnosis of nosocomial pneumonia (np) was based on a positive quantitative culture (~ cfu/ml) of a protected specimen brush in patients with clinical signs of pneumonia. quantitative cultures of pharynx, trachea and y-cannector were performed every h. results: the groups were similar in terms of age, indication for and overall duration of mv ( +_ . vs +_ days, p= . ), and severity of illness (saps: --- . vs . +_ . , p= . ). the maximal values for peak airway pressure were identical in both groups ( . -+ . vs . • cmh , p= . ). obstruction of the tracheal tube was observed in only one instance in a group patient who had tracheal bleeding. circuit colonization was very rare, and of low grade in both groups. the level of patient colonization and the type of organisms were identical in both groups. more importantly, the incidence of np was the same ( / vs / , p= . ), as was duration of mv before the occurence of pneumonia ( • vs . +_ . , p= . ) and overall mortality rate ( vs , p= . ). conclusions: the clinical efficiency of this hme does not seem altered after days of use. indeed, replacing this hme every h only neither affect circuit and patient bacterial colonization nor the incidence of np. therefore, substantial savings could be obtained changing hmes every other day only. obiectives: to evaluate the usefulness of different paraclinical investigations for the diagnosis and prognosis of acute viral encephalitis in icu patients. methods: we reviewed patients (pts) admitted to our icu from july to december with the diagnosis of acute viral encephalitis. all were in coma and were initially treated as presumed herpes simplex virus (hsv) encephalitis. the causative agents were: hsv ( cases), herpes zoster varicellae ( ), measle ( ), rabies ( ), unidentified ( ). eleven pts survived and three presented neurologic sequelae. twelve pts were investigated by mri, and eleven also by spect and multi-modality eps. including brainstem auditory eps (baeps). these investigations were obtained as soon as possible following admission and were repeated during icu stay when possible. the clinical outcome was noted. results: six pts ( / ) had an abnormal mri. among them, pts made a complete recovery, in comparison with / pts with a normal mri. in one hsv infected patient, mri remained normal despite clinical deterioration and bad outcome. when repeated, mri became abnormal in cases (with poor outcome in one) and was improved in one. spect was found abnormal in / pts (among them, pts had thus a normal mr/). the correlation regarding the topography of brain lesions was poor between mri and spect. the findings of spect could not be correlated with a poor outcome. the baeps confmned in % of the pts the clinical diagnosis of brainstem involvement. changes in visual and somatosensory eps were mild in all the pts and were not helpful for the prognosis. eps were otherwise interesting for the follow-up of the coma in these sedated and ventilated pts. conclusions: the value of mri and eps for the diagnosis of acute viral encephalitis is of limited interest. spect seems to show early modifications, even in pts with a normal mri, but this test is poorly specific and does not correlate with mri changes when present. concerning the prognosis, larger studies should probably confmn that a normal mri could usually result in a good outcome. this serie illustrates also that hsv encephalitis could be demonstrated only in a small number of cases and that the prognosis of non hsv encephalitis is not easily assessed. objectives: to study the influence of gram (-) bacterial lung infections on liver function i~ mv icu pts. pts and methods: we studied pts, # ( , %), ( , %). hean age: , • years ( - ). mean stay in icu: , • days ( - ). they were divided in groups: a( pts) who did not suffer from pneumonia and b ( pts) who developed a gram(-) bacterial pneumonia. both groups were consisted of pts with same age, sex and disease distribution and same systemic failures. we measured sgot, sgpt, total bilirubin(tb), direct bilirubin (db), alk.phosphatase (al.ph.), v-gt and albumin (alb.) times: on days o, and of the pneumonia for group b and respectively for g~oup a. conclusions: ) in elderly intubated pts of an icu, kp is isolated more frequently than in icu pts< years (p<o, ). ) the frequency of isolation of kp in icu pts during - was - %, but now ( - ) kp becomes more and more rare ( - %) and is isolated especially in elderly pts. ) its sensibility to antibiotics remains always the same. ) the prognosis of np in our study was independent from age (p<o, ), sex, presence of bacteremia (p< , ) and type of invading microorganism. gram neg bacteria and renal failure (rf) from aminoglycoside toxicity are common and serious complications in critically ill patients. the aim of this prospective, pilot study was to compare the safety and adequancy of the endotrecheal (et) vs the intravenous (iv) administration of aminoglycosides. were measured in the plasma and the bronchial secretions at and hours after the iv (bolus) or the et (nebulized) administration of mg of gm in seven criticcally ill patients ( with established renal failure). safety was defined as peak and trough plasma gm levels _< than and ijg/ml respectively and adequancy as gm levels in bronchial secretions _> , ijg/ml. results: gentamicin was administered by the et and iv routes in and separate sessions respectively. a total of samples were assayed, in bronchial secretions (bs) and in serum. the et route resulted in higher gm levels in the bronchial secretions compared to the iv route ( , + , vs , _+ , pg/ml respectively, p = ns ). adequate bronchial gm levels were achieved in % of patients after et administration, compared to % after iv aaministretion. the blood levels of gm were significahtly lower after the et vs the iv route ( , + , vs , • , pg/ml respectively, p _< . ). the et administration resulted in toxic bronchia~ gm levels in % of the specimens. % of these samples were from patients with renal failure, however toxic blood levels were reached in only % of these. gentamicin seems to be a safe and adequate alternative route of treatment for the lrti. however, in patients with renal failure the et administration of the aminoglycosides should also be modified and continuously monitored. in order to evaluate the pathogenic role of anaerobes in nosocomial pneumonia (np), we investigated the systemic humoral response in patients who developed a np with anaerobic bacteria, especially prevotella species. methods: blood samples from groups of patients were tested. group i: patients with a np in which prevotella spp. was isolated from protected specimen brush (psb), group ih a control group of patients with a np without anaerobic bacteria, group ill: a control group of patients with dental stumps but without pulmonary infection, group iv: a control group of healthy voluntary people with prevotella spp. isolated from the dental plaque. an elisa was used to evaluate the total antibodies level against a mixture of four prevotella strains and a western-blot method was done to identify the antigenic proteins. results: data are expressed as means .+ sd. the antibody levels in patients of group i ( • was statistically higher (p=o.o ) than in the control groups (respectively: + , _+ , _+ ). using western-blot method, the intensity of the response was roughly superposable to levels obtained by elisa and the profiles were different according to the prevotella species. the occurence of a np with anaerobic bacteria (prevotella species) isolated from psb leads to an antibody response which seems specific of the prevotella species isolated. fever is common in the intensive care unit, but is not always related to an infection. we sought to define the epidemiology of febrile patients in a general medical/surgical icu. methods: we prospectively analysed the source of fever (t > . ~ c) in all adult patients admitted for >- hours in the icu during a two month period. these patients were studied for consecutive days. and werc classified in groups according to the evidence of infection (center for disease control criteria) after complete evaluation: documented infection: cdc criteria + isolation of pathogen (d); possible infectron: cdc criteria without isolation of pathogen (p); unlikely infection: patients who did nol meet the cdc criteria (u). results: of a total of patients studied, dec'eloped fever ( %). including (after complete evaluation) d, p and u palients. both the highest temperature in tile first day of fever and the maximal temperature were higher in d than in u ( . • versus . • and . -~ . ~ versus . - . , respectively p= . and p= . ). most common sources of infection in d were the lungs in patients ( %) and urina .ry tract in ( %). of these patients had positive blood cultures ( %). the overall mortality was % ( % in d, % in p and % in u. differences ns). antibiotics were given in % of d, % of p and % of u ( patients). in p there was a non significant lower mortality." in patients who received antibiotics ( / ( %) versus / ( %) patients, respectively). conclusions: in febrile icu patients both the highest first day" temperaturc and maximal temperature are significantly higher in infected than in non infected patients, but the differences are too small to be useful clinicall). mortality rate is not significantly influenced either by the presence of an infection or by the administration of antibiotics, obiective: retrospective study to determine the influence of candida infection on icu outcome. methods: patieet with a stay of more than days in inteaasive care were screened for candida infection. patients were treated with antifungal therapy due to either an increased antigen titre of -> : or clinical evidence of candida colonization. serological candida-antigens (ramco, pastorex) and antibody titres (hemagglutination, lgg-, igm-elisa) were examined routinely. seroconversion was defined as a threefold increase of antibody titre or a titre of : or higher. results: the median length of stay was (ranging from to ) days, the mean apache ii score on admission was (+_ . sd) points. of patients patients died ( . %). in the group treated with antifungnls ( patients) patients died ( . %). although of the patients only ( . %) developed a candida infection as defined above the mortality in the group that showed signs of infection was significantly higher ( . % vs. . %, p < . [chi-square-test]). in patients an antigen concentration-> : was measured. seroconversion was found in patients. the most common fungus was candida albicans ( . %). furtberm re, candida glabrata was found in . %. most of the patients were treated with x mg fluconazole ( patients). in patients therapy was changed to amphotericin b/flucytosine. in patients therapy was started with amphotericine b and flucytosine. in patients a threefold decrease of candida antigen titre was found. patients showed a decrease of candida antibody titre. conclusions: meticulous screening for eandida infection seems to be necessary since the number of patients with fatal outcome is significantly higher in the group with signs of fungal infections and thus requires immediate antifungal treatment. objective: early diagnosis of patients with ventilator-associated pneumonia (vap), and subsequent identification of causative microorganism, and selection of the appropriate therapy are critical important points that affect morbidity and mortality. the results of the quantitative bacterial cultures are not available for at least hours, while a two hours period, since the specimen are obtained is enough to know the gram stain results. the aim of this study is to determine the usefulness of gram stain in specimens obtained by bronchoaiveelar lavage (bal), through the bronchoscope. material and methods: we studied patients ( males and females, age + ) with suspected ventilator-associated pneumonia. the bal gram stain was considered positive when the specimen after a centrifugation at rpm for min revealed: i) more than leukocytes per optic field, ii) squamous epithelial cell less than percent and iii) one or more microorganisms per optic field on magnification. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap and patients did not. in cases the bal specimens (quantitative bacterial cultures) established the diagnosis of vap in the remaining three patients the vap diagnosis was established by other procedures (blood or pleural fluid culture, clinical outcome, autopsy). apache fl score in patients with vap was , -+ , , while in patients without vap was , + , . there was a significantly higher incidence of vap in patients who had i) coma (gcs < ) and ii) been receiving neuromuscular blockade (p< . ) . the sensitivity of the gram stain for vap diagnosis was %, the specificity , %, the positive predictive value %, and the negative predictive value , %. conclusion: our data indicate that the gram stain of bal specimens is useful for the early diagnosis of vap and the subsequent administration of the appropriate treatment. the role of anaerobes in mechanically ventilated patients with pneumonia (mvp) have been poorly investigated aim of the study : analyse the prevalence of anaerobic isolation in mvp. methods : between october and february all suspected mvp were investigated using protected specimen brush (psb) technique. brushes were rapidly transported in shaedler broth to laboratory. a special care was tooken for anaerobic isolation. results : among the psb performed for suspected mvp ( nosocomial and community-acquired pneumonia), yielded at least one micro-organism (positive psb : %). of positive psb demonstrated only aerobic bacteria and ( %) yielded with anaerobes. in out patients, anaerobes were associated with aerobic bacteria. anaerobes were mostly isolated in nosocomial pneumonia ( / positive psb). strains of anaerobes were isolated. prevotella species represent out these strains ( %) the most frequent anaerobic species were prevotella oralis ( ) p. intermedia ( ) and p. buccae ( ). comments:using adequate methods, anaerobic bacteria are frequently isolated in mvp. it could be off importance to take in account anaerobes in the choice of empirical antibiotic therapy in mvp. objectives: the majority of patients with multiple trauma are considered immunocompromised. the aim of this study was to identify risk factors of pneumonia in mechanically ventilated patients with multiple trauma or after surgery. methods: in this prospective study we studied multi-trauma patients (mean age + years, apache ii . + ), admitted to a general intensive care unit (icu). all patients were intubated and mechanically ventilated. we were considered that a patient had ventilator associated pneumonia (vap) when the specimens of bronchoalveolar lavage (bal) or protected specimen brush (psi?,), ebb'ned through the bronchoscope, had one or more microorganisms in concentrations greater than and cfu/ml respectively. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap, and patients didn't. in the bivariate analysis, the glasgow coma scale (gcs)< (x = . , p< . ), the administration of neuromuscular blockade (x = . , p< . ), the duration of mechanical ventilation to be greater than days (x = . , p< . ), the flail chest (x = . , p< . ), the parenteral nutrition (x = . , p< . ), the ards (x = . , p< . ), the abbreviated injury scale (ais) of more than for thorax (:,: = . , p< . ), the pneumothorax (x = . , p< . ) were statistically significant related to development of vap. in multivariate regression analysis, using the stepwise technique, three of the seventeen studied factors showed to have an indepantent association with the development of vap:the administration of neuromuscular blockade (f: . , p< . ), flail chest (f: . , p= . ), and gcs (< ) (f: . , p= . ). conclusions: in patients admitted to icu for multiple trauma or major surgery, the administration of neuromuscular blockade, the flail chest, and the gcs (< ), in the population under study, were the indepedent risk factors for vap. mof is a sereous complication of differem states: infection, sterile inflamation, extensive fissure injure, intoxication, ets. there is close correlation between extension of mof and death, developement of nasocomial infection. immunologic disfunction. in order to prgnose probability of risk of mof development among the patients with sepsis and septic shock, we achived an eqation, allowing to recive a coeficient, closely connected with this probabiliti. we have used retrospective analisis of cases of sepsis. diagnosis of sepsis was based according to bone's criterions of sepsis. mof was assessed as disfunction of or more systems according to bone's classification of mof. having used correlation analisis we have estimated factors which have had high correlation coeficient with the probability of development of mof. there were: apache-ii score points, evidenceof septic shock, endocrinopathy. with the help of multyple regression analisis we acheved next equation: y= , + , x~ + , x + , x , were x i-apache-ii score points, x -evidence of septic shock, x -endocrinopathy. the explanatory power of this quation was evidenced by roc of . , se (v - . introduction: the presence of liver dysfunction in the process of multiple organ failure is associated with an adverse outcome, particularly when it becomes progressive to liver failure. disturbances of liver function may occur early and their detection may be of significant importance for the further development of organ failure. routinely used liver function tests appear to be inconsistent indicators of hepatic damage. in this study, we used p_lasma disappearance rate (pdr) of indocyanin-green dye (icg) as an early estimate of liver function. methods: we serially evaluated pdr and routine liver function tests (serum bilirubin, sgot, sgpt), as well as acute phase and non-acute phase proteins (crp, transferrin) in patients during the first week after trauma or the onset of sepsis. patients: group : (n = ) multiple trauma iss > , group : (n = ): abdominal sepsis, acute necrotizing pancreatitis (anp) grade iii. patients were selected on the basis of clin cal estimates that these patients would require continued icu observation. pdr was determined by means of a fiberoptic catheter and a computerized system (cold z- , pulsion), which permits repeated bedside measurements. the initial values of pdr, serum bilirubin and transaminases were not significantly different in trauma, sepsis and anp. in trauma patients pdr improved during the first week. in patients with sepsis and anp pdr remained low and worsened with time. the decrease in pdr preceeded an increase in biochemical liver function tests in these patients. + . &-_ ( - ) discussion: routinely available blood tests of liver function are usually altered several days after injury. however, they are generally non-specific indicators and they are influenced by extrahepatic factors. pdr seems to be useful to evaluate impaired liver function early after the onset of sepsis and trauma. objectives: to study frequency of organ system failure (osf) and it's influence on outcome in granulocytopenic patients with hematological malignancies and septic shock(ss). materials and method: retrospective review of medical records of granulocytopenie(wbc< , xl ) patients with hematological malignancies and ss, who were admitted to the intensive care unit (icu). frequency of osf before and after ss was analysed. the patisnts were categorised on survival and non-survival. results: signs of osf were observed in . % of patients before ss and in all patients after ss. only patients presented with hypotension refractory to inotropic therapy. nevertheless there was a significant increase of frequency of acute respiratory failure (arf), acute renal failure (arenf) and liver injury (li) after ss occurred(showed on the figure). only frequency of organ failure before and after objectives: statusmetria allows to define the effective level of oxygen status and accordance to it means of carbon dioxide and elec-trolyte in critical care. the conception of syndrome int~ive care (sic) is exhausted itself and invariable outcomes of sic of multiergan system failure (mosf) confirms that. therefore, an alternative to sic should be advanced. methods: efficlenoy of treatment has been asscsaed in patients with mosf using value of metabolic rate and ability of an organism to cover it by oxygen and substrate supply. oxygen pulse (op) and index of efficacy of oxygen transport (ieto ) was monitored. ~lt~.lntenaive care is considered to be homeostasis-securing therapy (hst) if energostructure deficit is eliminated and necessary for recovery regeneration rate is .restored. op in patients with mosf was . mt-m " , and le,~ and ie'i~ w~ . units in sic. we managed to maintain op of . - . ml.m " and ieto of . - . units in hst. patients from with mosf survived in sic and patients from survived in hst. efficiency of hst appeared to be two times as much as efficiency of sic. cr of homeostasia-se-'uring therapy is advancing. the conception provides restoration of regeneration rate due to effective then in sic elimination of en=gostructure deficit. the conception may be a basis of new technology for treatment of mosf. helen f goode phd, nigel r webster phd. anaesthesia & intensive care, university of aberdeen, ab zd, uk. objectives: xanthine dehydmgenase is converted under conditions of ischemia, reperfusion and endothelial damage to xanthine oxidase, with superoxide anion as a co-product of its catalytic activity. multiorgan dysfunction syndrome is associated with splanchnic vasoconstriction resulting in significant and prolonged gut ischaemia. aggressive volume resuscitation with prompt restoration of blood flow results in reperfusion of the tissue and is likely to cause xanthine oxidase-mediated release of oxygen-derived radicals. this study investigates xanthine oxidase activation and oxygen-derived free radical-mediated damage in such patients. methods: fourteen consecutive patients on itu who met established criteria for septic shock and secondary organ dysfunction were studied. serum xanthine oxidase activity was measured using oxidation of a chromagen in a dual enzyme system and plasma malondialdehyde was measured using a specific spectrephctometdc assay. apache ii scores, blood pressure, svr, cardiac output and day survival were also recorded. biochemical data were compared with results from healthy subjects. results: xanthine oxidase activity was . + . units/i in patients (mean :t: sem) and . + . units/i in controls (p<o. , mann whitney u test), and was highest in the patients who survived (p< . ). malondialdehyde concentrations were elevated ( . • . prnol/i compared with . • . pmol/i in controls, p< . ). xanthine oxidase activity did not relate to apache score or any of the cardiovascular parameters recorded, and was not influenced by the degree of organ dysfunction. conclusions: patients with sepsis and secondary organ dysfunction have xanthine oxidase activation and evidence of free radical damage. the finding that activity was highest in those patients who survived suggests that reperfusion was incomplete in patients who died, with decreased tissue xanthine oxidase ~tash out' into the circulation. influence objective : evaluation of the feasibility of measuring the intragastrie partial pr~sure of carbon dioxide (pco ) using a chemilumin~nt optode and fibre~ptics originally developed for intrav~cular blood gas monitorlng(p ) methods the pco electrode w~ calibrated i~-vitro according to the m~ufaeturers instructions the sensor w~ then stripped of its outer c~ing and threaded down the pile tube of a g~ c enema e (gt) so ha he ens ng portion sat well within the balloon. the modified gt was inserted n~og~trically after induction of anesthesia in ten patients undergoing c~diopuimonary byp~s throughout results: according to the datas of integral rheography % of patients were revealed to have hypodynamic type of blood circulation (cardiac output was decreased on - % and general peripheral resistance increased on - %). it was effective to use complamin (xantinoli nicotinas) in the complex therapy of su~h patients. the dosage was - mg/kg during - days. as a result of such therapy was also the oliguric stage shortening (ac n ).in , % of the cases unsatisfactory datas of central hemodynamic,combined with high (more than cm h ) venous pressure,lung oedema.then nanipruss ( , - , mkg/kg/min) was succesfutly used in complex with routine therapy.in the patients with low cardiac output and low general peripheral resistance mesaton ( , - , mg/kg) and dopamine ( - mkg/kg/min) were effective.change for the worse in the hemodynamics datas, inspire of therapy during - days,was prognostically unfavourable. conclusions:we consider early diagnostic of hemodynamic disorders and adequate correction of them is one of the most important factors, determined the outcome and prognosis in arf patients. obiective: to evaluate the results of renal replacement therapy (rrt) in surgical icu patients with acute renal failure (arf). arf in icu patients is associated with high mortality rates. we investigated the relation between mortality and organ failure in different categories of surgical icu patients receiving renal replacement therapy (rrt) for arf. methods: the records of surgical icu patients with arf requiring rri-(haemodialysis or cavhd) were examined. five different patient categories were defined; .ruptured aneurysm of the abdominal aorta (raaa) n = .elective vascular surgery (evs) n = .abdominal sepsis n - .trauma n = .others ( e.g. malignancy, obstetric emergencies) n- seven organ systems (cns,circulatory,respiratory,hepatic,renal,digestive,haematologic) were scored for possible failure using the mof score. results: mortality was as follows: all patients % , group % , group % , group % , group % , group % . mortality increased with the number of failing organ systems; mortality for all patients with > failing organsysterns was % the only exception being the subgroup of trauma patients where mortality under these circumstances was o% conclusions: mortality in surgical icu patients receiving rrt for arf is high. no significant difference in mortality is found between raaa and evs. mortality increases with the number of failing organ systems. the subgroup trauma patients shows a lower mortality compared to the group as a whole, even with > failing organ systems. to look for the most accurate scoring system to measure the severity of the complications occuring in the early phase ( first day) of kidney transplantation and to asses their prognostic value. methods: in our retrospective study we applied the apache li and the goris scoring system for the kidney recipients who developed multiple organ failure (mof) as a consequence of their pulmonary and. cardiovascular complications following kidney transplantation. we evaluated the recipients the distribution of the women and men ( % ~ % ) was the same as in the kidney recipients. applying the apache ii system most of the patients had their score between and , and the function of , or organs were affected at the time of the onset of mof. the apache ii system gave adequeate information about the disturbance of the function of other organs beside the kidney failure even at the time of the transplantation. the scores and the number of the affected organs correlated with the condition of the patients in the goris scoring system but not as sensitively as in the apache ii scoring system. conclusions: both the goris and the apache ii scoring system can be applied to measure the severity of the multiple organ failure occuring during the early phase of kidney transplantation. however the apache ii system is more suitable to follow not only the stateof the patients at the time of the admission but also the changes occuring in their condition during the complication. v.v.erofeev, v.v.ivleva scientific research institute for general reanimatulogy russian amsci, moscow, russia objectives: the analysis of ssc and results of their treatment in patients following critical states showed the necessity of developing a combined antibacterial therapy. methods: according to the protocol patients ( - years old) with combined trauma and massive hemorrhagy following vast aml traumatic operations were examined. microflora's composition and resistence to up-to-date antibiotics was studied using the anaiyser iems reader by "labsisteme"(finland). general clinical, bacteriological, immunological indices, as weil as the duration of the treatment and recovering rate served as criteria of the combined antibacterial therapy effectiveness. results: it was proved expedient to administer antibiotics in staphylococcus infection in the following combinations: riphampizin with fluoroquinolones; i-ii degeneration, cephalosporins with aminoglycosides; cephalosporins with fluoroquinolones. in case of singling out the exciters of the euterobacteriaceae family, including the pseudomonas aereginosa, -fluoroquinolones combined with modern amynoglycosides; fluuroquinolones with ureidopenicillines; ureidopenicillines with amynoglycosides; amynoglycosides with the ii-iii generation cephalosporins; cephalosporins with fluoroquinolones. in severe ssc caused by combined infection (including anaerobes) clindamicin with modern amynoglycosides was prescribed. conclusion: the combined antibacterial therapy allows: ) to increase the effect on microbic agents and the efficacy of treatment in combined infections; ) to lessen the possibility of the exciters'resistence to antibiotics; ) to prevent the development of superinfection: ) to decrease the doses of medicine and its toxic effect. objectives: two methods of blood volume measurement in a group of critically ill patients were compared to investigate the practical possibilities of a new easy to use method based on carbon monoxide (co) uptake. methods: all patients had multi-organ failure and haemodynamic monitoring with a swan-ganz catheter. mean apache ii score was ( - ). when indicated, patients had blood volume measurements simultaneously based on the techniques of, i) dilution of ~cr labelled red cells, and ii) inhalation of carbon monoxide gas with measurement of the rise of carboxyhaemoglobin produced. the co was administered via a newly designed, ventilator driven, fully closed circle system ensuring co retention and co removal with automatic addition of oxygen to m}ttch patient uptake. a portable computer performed all necessary calculations. results: volumes obtained by co uptake were compared with the "gold standard" radiolabelling method. mean blood volume determined by the co method was ml ( - ml) compared with ml( - ml) with slcr labelled red cells (r= . ). regression analysis produced an intercept at ml. the slope of the regression line was . ( . - . , % confidence limits). discussion: the co method produces volumes in excess of the radiolabelling method. there appears to be a systematic error, and one possible explanation is co binding to substances other than haemoglobin. conclusion: the co method is easier to use than radiolabelling and of the lower cost, since cohb measurement only is required. aceuraey is sufficient for clinical use and our preliminary findings suggest this system will meet the requirements. objectives: this study was conducted to determine the role of nitric oxide (no) in the pathophysiologic alterations and multiple organ damage, and the possible effects of " " " (l-n -monomethyl-l-arglnlne nmma) on hemodynamics and mortality in rats caused by a prolonged hypovolemic insult. methods: a prolonged hemorrhagic shock ( - mmhg for rain) was induced in anesthetized rats followed by adequate resuscitation. l-nmma was administered intravenously at doses of . mg/kg or . mg/kg at the end of resuscitation. results: infusion of . mg/kg l-nmma diminished the fall in mean arterial pressure, significantly increased the cardiac index (ci) and stroke volume (sv), together with remarkable protection from multiple organ damage compared to the controls. the h survival rate was significantly improved from . % in the control group to . % in the treatment group (p< . ). in contrast, the high dose of . mg/kg l-nmma resulted in a strong blood pressure response but a marked reduction in ci and sv concomitant with an increased total peripheral resistance index within the observation period, and caused severe damage to various organs at h after treatment. in addition, marked elevation in both endotoxin and tnf levels were observed in animals subjected to shock insult. conclusions: these results suggest that no induced by hemorrhagic shock in rats is an important mediator for pathophysiologic alterations associating with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. thus, regulation of no generation and use of no inhibitors might provide new aspects in the treatment of hemorrhage related disorders, and the use of l-nmma would be either deleterious or salutary in a dose dependent manner. (hebert, chest- ) . the purpose of this study was to assess the risk factors for hepatic dysfunction in mosf. methods: patients have been hospitalized in our icu from january to may . , ( %) with mosf. among mosf pati~ts, ( %) have had hepatic dysfunction defined according to hebert (bilirubin ~ ttmop , chest ). thirty six of these patients acquired hepatic dysfunction after admission in the icu. these patients were compared with mosf patients without hepatic dysfunction selected blindly. chrorfic diseases, severity scores, eanse of admission, clinico-biologieal and hemodyunrrfic parameters, use of vesopressors, use of hepaiotoxic drugs, use of nutritional support and mortality were compared for hepatic failare and non hepatic failure groups.twenty nine patients had postmortem hepatic histologic examination, results: univaciate analysis: only parameters with p _< . are pre~nted. including these paramet~'rs in a multivariate analysis, anly c~hosis and vascular surgery remain independent risk factors for hepatic dysfunction. in particular, pao /fio , arterial lactate, do were not different between the two groups, some de~'ee of histological abnormalities was found in all liver samples, despite a normal bilirubin level in % of the cases conclusions: in our patients, conu'ary to previous studies, hypoxic and hemody~anfic parameters were not independent risk factors for hepatic dysfantion. this might be due to the inadequacy of the usual biologic definition of hepatic dysfunction as well as to the poor sensitivity of general hamodynamic parameters. critical states of various origin are complicated with the mldtiorgan farm (moi~ oceuzr~ce. due to their and functional features the lungs become the primmy damage target in various critical.states. ard that occurs in such states is associated with pulmonary edema development because of capillary permeability increase mediated by humeral and cenular responses to amag/~ factors exposure. r nmst be emphasized that mediators and effecto~rs of this respo~e affect not only puknonary capillaries, but other organs capiu~es as wellenhancing their permeability. orsans edema is a conmm~ finding at the autopsy of patients died from mof.clinical and radiolosial findings allow to have a diagnosis of pulmonmy edema before ~mi!ar lesions in other organs occm. additionally, there are some techniques that permit quantitative assessment of pulmonary edema flv.id (evlw) volume. in conclusion, we suggest that evlw changes in .dyn~rmcs in patients with mof are considered as a critical state severity measure which reflects indirectly the edema in other organs. objectives: we compared three different dialysis membranes to find out whether or not there were differences between their clearance characteristics on substances such as inuline, creatinine, urea, and phosphate to be eliminated in acute renal failure (arf). moreover, if a loss of clearance did occur we were interested in whether this was due to heparinization and a high production of the thrombine-anti-thrombine-complex (tat). methods: we carried out a randomized controlled study on consecutive critically ill patients presenting with arf, most of them in association with multi-organ failure, to be treated by continuous pump-driven arterio-venous renal replacement therapy on continuous low-dose heparinization. three different types of high-flux filter membranes (f tm [fresenius] , ct tm [baxter] , and filtra tm [hospal]) were assessed. each filter was changed intentionally after a hours" use. together the data of filters were evaluated, each at three different times (immediately after its onset [ hi, after h, and after h). the clearances of creatinine, urea, phosphate, and inuline were measured. results: there were some significant differences in clearance characteristics of inuline, creatinine, urea and phosphate between the filters (p< , ) showing the f tm membrane excelling filtra mand ct tm the more. the loss of inuline clearance ( mi/min/m ) after h, however, was insignificant for all filter types. a continuous low-dose heparinization scheme was applied without any relevant prolongation of the aptt. even lower losses were noted for the clearances of creatinine, urea, and phosphate. we found the tat-producfion increased after h (p< , ), but it did not rise any further. conclusions: as we could demonstrate in our study the clearance data of different types of filter membranes applied during continuous renal replacement therapy do show significant differences. on the other side, no relevant loss of clearance occurs during a hours" period indicating a high efficiency over time. to consider commercial aspects as well it shows that inexpensive conventional filter membranes can successfully be applied even for a longer renal replacement period, if needed. a retrospective study was performed on patients with acute renal failure (arf). we analysed survival in continuous (cd) and intermittent dialysis (hi)). mean age of the patients was years (y), patients ( % ) were < y, patients ( %) were >= y. the incidence of dialysed arf in our mixed intensive care departement is %/admission/y. statistics: fischer's exact test, mann-whitney-u test. efioloev: the contribution sepsis, cardiac failure and aminnglycosidcs was respectively %, % and %. treatment: cavh (cd) or cvvh (cd) was used in patients ( %), hemedialysis (hd) was used in patients ( %). data: mean apache scores were the same for cd and hd ( for both groups), patients treated with continuous dialysis techniques had significantly (p<o, ) more need for ventilation ( % vs %), elevated bilirubin ( % vs %) and a higher vasopresser need ( % vs %@ than patients treated with hemedialysis. there was a trend towards more sepsis ( % vs %; p= . ) mad coaguiation disorders ( % vs %; p= . ) in cd. taere were sign/ficantly more younger patients (< y) treated with cd ( % vs %, p< .os). mean apache score was significantly lower in patiants< y than as patienta>= y ( vs ; p< . ). patients< y had significantly (i}< . ) more coagulation disorders ( % vs %) and elevated bilirabin ( % vs %). there was no significant difference in vasopressur need and ventihatio~ between age groups. outcome:. hi) had a better sr compared to cd ( % vs ~ p< . ). patiants>= y had a comparable sr vs patients< y ( ") */e vs %; p----a.s.). tha global survival rate (sr) was % ( patients). conclusions : diaiysed arf has a well known lowsurvival rate ( %): hc~raedialysed patients had a better survival rate than patients treated with continuous dialysis. this can be explained by the fact that the latter were in a worse condition considering organ failure (more vantilatian, elevated bflirubin and need for vasepressurs), apache score couldn't illustrate that. patient~ y with arf have the same survival rate as patients< y: although patients >=- y have a higher apache score they have less organ faille. the avacbe score is not a good oredictor of survival in p with organ failure. departments of surgery and intensive care, guy's hospital, london, u.g-obiectives: a randomised controlled trial of a management protocol utilising the regular measurement of gastric intramucosal ph (phim) to control the administration of dopexamine. methods: patients admitted to a multidisciplinary teaching hospital intensive care unit (icu) undergoing insertion of a pulmonary artery catheter were managed according to a resuscitation protocol. randomisation was to either the protocol alone or to insertion of a nasogastric tonometer and subsequent management guided by phim. phim < . initiated volume and inotrope resuscitation and, if unsuccessful in elevating phim, dopexamine was commenced. approval was obtained from the hospital ethics committee. results: patients were considered for analysis and the two groups were well matched for age and sex. overall, there was a high hospital mortality of . %. there was no difference in icu or hospital mortality between the two groups (see table) . objectives: to compare cardiac output (co) measurements between continuous termodilution (cco) by thermal wire on pulmonary artery catheter (cco/svo vigilance. baxter critical care), and co measurement using a trans-esophageal doppler (dco) ultrasound system (odm ii, abbott laboratories), in the immediate postoperative period of cardiac surgery. methods: patients undergoing myocardial revascularization were monitored with cco by a swan-ganz catheter and an intra-esophageal dco probe, after induction of anesthesia. exclusion criteria were: aortic valve disfunction, previous valvular surgery esophageal disease, absense of sinus cardiac rhythm, and need of ventricular or intraaortic assistance. hemodynamic parameters, co by both cco and dco, svo . sao , diuresis, pha, and hemoglobin were repeatedly registered during the first hours after surgery, as the patients were kept under sedation and mechanical ventilation. results were compared using the method described by bland and altman. results: measurements of co were obtained, ranging . objectives: a decreased tissue oxygen delivery is responsible for a higher morbi-mortality rate among surgical patients; this diminished oxygen delivery/consumption rate (dojvo ) may origin the lactic acidosis observed in the gastrointestinal tract, reported in patients undergoing hypothermic cardiopulmonary extra corporeal surgery, and can be registered by tonometry as result of the gastric mucose ph. the purpose of this study is to evaluate the reliability of the intramucosal ph (phi) measurement by a nasogastric catheter as indicator of the do /vo > its co> relation to other parameters of do /vo disturbance, and with postoperative complications and clinical course. methods: patients ( male, female) undergoing cardiac surgical procedures were included ( myocardiai revascularizations, valvular substitutions, constrictive pericarditis). mean age was + years, mean weight _+ kg. a nasogastric probe (trie tonometrics) was placed after anesthesia induction; phi values were registered in the postoperative period ( ', ', ", ' and h after surgery end). the corresponding hemodynamic parameters, venous oxygen saturation (svo ), diuresis and arterial ph (pha) were also recorded. results: phi values ranged . to . (mean . ( . ); the mean values of clinical evolution were: extubation time, _+ hr.; discharge from postoperative care unit, - hr.; and hospital total postoperative time, _+ . days. complications registered were: perioperative acute myocardial infarctions, cases of respiratory insufficiency, occlusion of coronary bypass, an ease of hyperamilasemia. all patients with severe complications needing specific treatment showed either a low phi value, or a considerable descent in comparison with the initial register. statistic correlation between low phi and presence of complications was found; the low significance (p > . ) degree may be due to the low population size. conclusions: phi measurement in cardiac surgery patients is a non invasive, uncomplicated method for prediction of doz/vo disturbances, thus reflecting risk of increased major complications, and may precede changes in other usual indicators (svo , pha, cardiac output, ...). work-in-progress with a greater population size may offer more significant results. references: ( ) gutidrrez g: lancet ; : - . ( ) landow i: acta anaesthesiol scand ; : - . the haemoglobin-level (hb) is besides the arterial oxygen saturation and the cardiac index one of the relevant parameters of oxygen supply to the tissue. in contrast to otherwise healthy patients, there is no agreement on tile so-called transfusion-trigger in critically ill patients. in i?ont of this background the question arises, whether and to what extent blood transfusion in critically ill patients improves oxygen supply io tile tissue. this study was performed in critically ill/septic patients in the postoperative period alier an inlcclive/scptie revision operation of the hip or knee joint. on cardiac/seplic reasons monitoring consisted beside other measures of a pulmonary arlery catheter and of an indwelling arterial line li~r measurering/calculating standard haem~dynamic as well as systentic oxygen parameters. the indication for blood transfusion was given by hb together with the cliuical slatus of thc patienl (asa-scorc and multiple organ dysfunction (moi))). statistical analysis w~ks performed by mann-whitney-u-test. by fisher's exact-test and by wii.coxon-test: statistical significance was set with p< . . according tu the pretransfusion value of hb and of lactate (lac) palicnts ;,,'ere divided into groups as follows: a: hb< and b: >sg/dl: i: ac< . and ii: > .smm. in either group blood transfusion results in zt significant increase in hb (a: . _+ . to . + . g/dl; b: .(~ . tt, . + . g/dl; i: . -+ . to . -+ . jdl; i : . -+ . to . + . g/dl). wlailc, however, haemodynamic parameters do not difl)r significantly from each other before and alter blood transfusion, oxygen delivery (do, -ml/min x m-') increases significantly hi either group studied (a: -+ to -+ ; b: + to + ; : -+ to -+ ; i : -+ to -+ ), in contrast oxygen consumption (vo~ -ml/min x m e) does not change significantly in either group (a: i -+ to -+ ; b: -+ to -+ ; i: -+ tu -+ ; : -+ to +_ ); oxygen exlraction ratio decreases. this study in critically ill/septic patients demonstrates, that in this group of patients studied blood transfusion at a base-line-value of > . -+ . g/dl expectedly rises do~, however, it does not improve vo=; even not in septic patients with elevated lac-values. paclitaxel in a new anticancer agent, extract from the bark of the yew tree (taxus brevifolia), employed against breast and ovarian cancers resistant to chemotherapy. it promotes the polymerization of tubuline, and disrupts the normal microtubule dynamics. hematologic toxicity, hypersensitivity reactions (bronchospasm, urticaria and hypotension), and peripheral neuropathy are the main reported toxic effects. cardiac side effects are rare: atrioventricular blocks of higher degree are reported in . % of patients; congestive cardiotoxicity was discussed only in one trial in patients treated with paclitaxel and doxorubicin. we describe the history of a -years-old worn an with a breast cancer, diagnosed in , initial staging t nim , treated with mastectomy, axillary lymphadenectomy, andchemotherapy with a cumulative dose of anthracyclines of mg/m until august . the patient complained of dyspnea and severe hypotension immediately after an intravenous infusion of mg paclitaxel, given over hour for the treatment of bilateral, malignant pleural effusion. at echocardiography die left ventricular ejection fraction was reduced to %. she died days later because of a severe cardiac low output with hepatic and renal failure; an impressive hepatic cytolysis was observed. the post mortem examination confirmed the dilatation of the cardiac cavities, especially of the right ventricle, bilateral pleural fluid, and ascites. the histology was suggestive for a cardiomyopathy secondary to anthracyclines. the electron microscopy revealed a deposition of an unusual pathological pigment in the myocytes; subsarcolemmal deposition or membranous were absent. we hypothesize that paclitaxel was the cause of a major hypersensitivity reaction with shock and severe hepatic cytolysis, worsening the myocardial damage induced by anthracyclines. the possibility that a low doge of paclitaxel could directly increase anthracyclines cardiotoxicity -as decribed in the medical literature -will be discussed. objectives: activated endothelial cells release soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selectin (selam- ). sicam- , svcam- , selam- , and inflammatory cytokines were determined. methods: sicam- , svcam- , and selam- were determined by elisa. tnf-a, il- , and il- were also measured by elisa. endotoxin was measured by an endotoxin-specific endospecy test after pretreatment of new pea method. results: the sicam- and s vcam-i levels were significantly higher in the septic multiple organ failure (mof) and sepsis groups than in the non-septic mof group. the selam- level was slightly higher in the septic mof group than in the sepsis withut mof group and non-septic mof group. the increases of soluble adhesion molecules were not in agreement with changes of plasma endotoxin level. levels of soluble adhesion molecules were correlated with the levels of plasma tnf-a and il- , but the level of il- . discussion and conclusion: the slcam- and svcam- levels in septic patients closely reflected the severity of the pathophysiological conditon. it was possible that the release of sluble adhesion molecules were not stimulated by plasma endotoxin, but endotoxin in the local infectious region. tnf-c~ and il- also were suggested to be involved in the release of these soluble adhesion molecules. obiectives: cardiopulmonary bypass (cpb) surgery is associated with a systemic inflammatory response attributable to the release of various inflammatory mediators and the activation of complement or coagulofibrinolytic system. in addition, adhesion molecules, such as icam- , elam- , and vcam- , appear to be of central importance in the inflammatory process following cpb surgery. we previously reported the effects of a synthetic protease inhibitor, fut- , reduced release of inflammatory cytokines (tnf, il-lg, il- ), activation of complement (c a, c a) or coagulofibrinolytic system (tat, pic, fpa) and protected platelet function (gpib, gpiib/llla) following cpb surgery. methods: in this study, we analyzed fut- on soluble adhesion molecules following cpb surgery. patients undergoing cpb surgery were divided into two groups, group a consisted of patients who received omg of fut- in priming solution, followed by a continuous infusion at mg/kg/hr during cpb in addition to initial heparin dose of mg/kg. group b, a control group, included patients who were injected with heparin only. the plasma slcam- , selam- , and svcam- concentration was measured by elisa. results: every soluble adhesion molecules decreased during cpb in both groups, and rose after cpb. selam- and slcam- reached their peaks on hours after cpb and on pod respectively in both groups, but they remained lower in group a (selam-i: . + . vs. . • ng/ml, p< . , slcam-i: • vs. • ng/ml, p< . ), svcam- , in both groups, remained lower than preoperative levels, but did much lower in group a. conclusions: fut- reduced adhesion molecules and suggested to be the effect on postoperative organ dysfunction. in the last few :,'ears the conditions of treatment in continuous hemofiltration/hemodiafiltration were discussed controversially. a significant removal of tnf-alpha and il-i could be demonstrated in cvvhd. the aim of our study was to investigate the elimination of tnf-alpha, l- , il- , il- , s-cd- and ifn-gamma in cvvh by measurement in plasma and hemofiltrate of critically ill patients with an acute renal failure. the patients of our study were treated with a continuous veno-venous-hemofiltration (polysulfone-filter, blood flow: - ml/h, filtration rate ml/h). the samples, hemofiltrate and plasma, were taken one hour after the start of treatment. the patients suffered from septic shock ( ), the so called hepatorenal s~aldrome ( ) and a severe pancreatitis ( ). the cytokine concentrations were measured with elisa-method. in contrast to elevated concentrations in plasma for tnf-alpha ( cases), scd ( cases), il- (l case) and il- ( cases), hemofiltrates contained no activities. only il- was removed in significant amounts with even higher levels in hemofiltrate than in plasma. this phenomenon was described so far for tnf-alpha and il- and may be due to the absence of metabolic properties (possibily enz~natic) in hemofiltrate. it can be shown, that tnfalpha, il- , il- could not be eliminated in cvvh with a filtration rate to ml/h. in contrast to findings of other investigators with a higher filtration rate (> ml/h), we found no significant concentrations of tnf-alpha and il in hemofiltrate. we conclude, that for a significant removal of important cytokines higher filtration rates (> ml/h) are necessary. objectives: multiple organ dysfunction syndrome including liver and renal impairment is a fatal complication in patients with the diagnosis of sever sepsis. this study focused to the effects of removing toxic substances from inflamnatory tissue by hemodiafiltration. ~ ethods: eleven patients were admitted to the icu in emergency center and met the criteria of systemic inflammatory response syndrome in association with infection. all patients developed liver and renal dysfunction and were treated by hemodiafiltration with high flux membranes (fb-u:nipro). the hemodiafiltration were performed times using nafamostat mesilate as an anticoagulant in hours with l of substitution fluid (hf-b:fuso). the serdm levels of endotoxin, cytokines, endothelin-i (et-]), human neutrophil elastase ~ -proteinase inhibitor complex (hne-pi), fibronectin (fn), lactate, and amino acids were measured before and after the hemodiafiltration. the hemodiafiltration would be effective to renal dysfunction by reducing endothelin and beneficial to tissue metabolism represented in fisher's ratio, but might be harmful to respiratory function by activating neutropila in patients of severe sepsss. background : intermittent hd may be poorly tolerated in the early phase of arf in hemodynamically unstable patients (pts). this technic may fail to achieve steady state urea low levels in hypercatabolic pts. method : nt = consecutive pts treated with hd; n = consecutive pts treated with cvvhf. hemodynamic unstability is defined by arterial hypotension and requirement of inotropie support despite adequate filling. rate of change in urea (u), ereatinin (cr), k + , ph were computed from a linear regression .analysis of data vs time in each treatment group during the first days of application of the two technics (anova). dally worst values were recorded. results : hd-group : apach% score = _+ ; mean number of organ system failure (osf) = . -+ ; mean blood pressure (mbp) = • mmhg (first day of application of hd). cvvhf-group : apachen score : + ; osf = -+ ; mbp = + mmhg (first day of application of cwhf discussion : during the first days of application of hd/cvvhf, u and cr decreased much more rapidly in the cwhf-group. k* and ph were maintained within normal range in the two groups. initial mbp which was much lower in the cwhf-group significantly improved during the application of cvvhf while mbp remained unchanged in the hd-group. conclusion : despite higher severity of disease in cvvhf group (apachen score, osf, lower initial mbp), we obtained a better performanco with cvvhf regarding the decrease of u and cr and the improvement of mbp. in relation to the different and continuous renal replacement techniques, the continuous venovenous one is the alternative method to continuous arteriovenous for critical patients with acute renal failure (arf). we present you our experience with cvvh in patients with mof. in our intensive care unit (icu) patients with mof were treated with cvvh in the period between january in to march in . the mean (• age of our patient population was , • years, being % male and % female the whole patient population was with mof iust at the moment the technique was accomplished; % was in mechanical ventilation, % needed vasopressor support and % required both of them (mechanical ventilation and vasopressor support) apache ii score mean of the patient population was , ~: , (range - ) and ati of them were with arf oligoanudc. technique: cvvh was accomplished using a single-d~al iumen catheter, ptaced in either a temoral or subclavian vein by the stand ard seld{nger technique. pol{sultone hemofitiers were also used, and the extracerporeal circuit used standard arterial-venous blcod tubing. blood flow and hence oltrafiltration pressure, within the circuit was generated by a roller blood pump. the modulus has a roller pump, a pressure transducer connected in an arterious and venous line, such as an air-transducer which is adapted to a drip-chamber in the return way. the replacement used was a peritoneal dialysis solution. medicine , st. george's hospital medical school, london. england. hepatic sinusoidal endothelium shows a major inflammatory response in porcine sepsis that can be attenuated by the administration of dopexamine hydrochloride. dopexamine is a beta and dopaminergic receptor agonist. the specific beta adrenoceptor antagonist ici has been shown to reduce the protective effects of dopexamine. we investigated the effect of this antagonist on hepatic ultrastructure in porcine sepsis. six pigs ( - kg) divided into groups were anaesthetised and intubated. cardiac output and portal blood flow were measured using standard techniques. the groups were; placebo, (peritonitis induced); blocker, (peritonitis induced and pg/kg ici bolus infused then given hourly). caecal content was aspirated and peritonitis induced. colloid was infused to maintain pawp at - mm hg for eight hours the animals culled, hepatic tissue removed and prepared for electron microscopy. in the placebo group hepatic endothelium was swollen and the sinusoids occluded by wbc. but in the ici blocker group, much of the sinusoidal endothelium was absent and there where large extra sinusoidal spaces among the hepatocytes. an assessment of the two groups showed worse hepatic architecture in the blocker group. the b antagonist blocked any protective effect of endogenous beta adrenoceptor agonist (adrenaline) on hepatic endothelium in porcine sepsis. george's hospital medical school, london. england. dopexamine hydr chloride, a beta and dopaminergic receptor agonist reduces hepatic damage in porcine sepsis. we tested dopexamine's effect on cerebral oedema. the beta adrenoceptor antagonist ici was infused to block any protective effect of dopexamine. nine anaesthetised pigs ( - kg) were randomised into groups; placebo, (peritonitis induced); dopexamine, (peritonitis induced and ~tg/kgdar of dopexamine infused); blocker, (as in dopexamine group but in addition pg/kg ici bolus given then infused at that rate hourly). caecal peritoneum was induced and colloid infused to maintain pawp at - mmhg for eight hours when the animals were culled, cerebral tissue removed, prepared for electron microscopy and digitisation. digitisation of the area of oedema surrounding the blood vessel and expressed as a percentage of the micrograph. . _+ . , dopexamine . + . ", blocker . + . . data expressed as mean + sd. significance p< . . * dopexamine compared to placebo and blocker. in the dopexamine group the area of tissue oedema was significantly lower than either the placebo or blocker groups. there were no significant differences between the placebo or blocker groups. the antagonist completely blocked the protective effect of the drug on cerebral oedema in porcine sepsis. beta adrenoceptor stimulation is protective of cerebral oedema in porcine sepsis. objectives: the hemodynamie~ of hepatic circulation during multiple organ failure (mof) have not been suffleienly studied. we investigated liver hemodynamics in two subgroups of patients with mof, those with either liver or lungs as the main organ of involvement. methods: three groups of patients were created: i) mof-hepatic involvement (mof-hi) ( patients) with bilirubin > . mg/dl and lung injury score < . , it) mof-ards ( patients) with respective values < . and > , iii) patients with head injury with respective values < and < , served as group control. all patients were in haemodynamieally stable state with an oxygen delivery index > ml/min/m prior to measurements. two swan-ganz catheters 'were inserted, one in the hepatic veins and one in pulmonary artery and the following measurements were determined: the hepatic vein free pressure (hvfp), the hepatic vein wedge pressure (hvwp), cvp, paop and co. the gradient of hvwp-hvfp represents liver perfusion pressures. by injecting contrast media at dose of iml/lokg with the balloon inflated to achieve sinusoidai image, the hepatic blood flow (hbf) was concluded by the time in seconds of media removal after balloon deflation. results: the co, cwp and cvp were comparable to all three groups. namely, for mof-hi, mof-ards and control groups the mean (+sd) value of co was . _+ . vs . _+ . (ns) and . _+ . respectively, of the paop was . +_ . vs +: (ns) and . + . respectively and of the cvp was .+. . vs . + . (ns) and . respectively. in contrast the two mof groups were different after the cut-offinclusion criteria ie the mean (+sd) value for bilirubin was . + . vs . + . ( < . ) and . _+ . respectively and lung injury score was . objectives: oxygen delivery (do ) and oxygen consumption (vo ) are increasingly monitored parameters in the icu. there still remain controversies about an oxygen supply dependency in critical illness particularly with respect to vo determination by either indirect calorimetry (vo m) or tick calculation (vo c). the purpose of this study was to investigate the changes in vo m and vo c following do increase. methods: the relatives of critically ill patients (mean age years, mean apache ii , mean mof-score ) gave their written informed consent to participate in this institutionally approved, prospective study. do was increased by fluid loading (hydroxyethylstarch %: mean volmne ml, mean duration of infusion min) and catecholamine support (dobutamine: mean dose , ~g/kg/min). changes in vo m and v c were recorded sinmltaneously before, during and following interventions. calorimetry was obtained with the metabolic monitor integrated in the ventilator (puritan bennett, carlsbad, ca adaptive endocrine response of organism to septic shock consisting in activation of the production of adrenal hormons, renin -angiotensin -aldosterone system (raas) and other hormonal systems has an influence over microvascular changes in these states and for development of multiple organ failure (mof). in patients with peritonitis of different origins ( nonsurvivors and survivors) were followed the changes in cortisol level and raas by radioimmunological methods and many variables for evaluation of respiratory, renal, hepatic function, coagulation etc. as a signs of mof. it was observed significant increase of the level of cortisol ( +_ , nmol/ i), aldosterone ( , • , nmol/i). by factorial statistical analysis we found significantly high correlations between hormonal changes and respiratory function (for example r=- , , p < , between cortisol and pao ; r = , , p < , between cortisol and d (a-v) ; olso renin -cao r=- , , p < , , renin d ~,vl o r = , , p < , ). such significant correlations was found and for raas with respiratory, renal function, byproducts of arachidonic acid thromboxan b and p fla, soluble fibrine degradation products etc. these correlations between the degree of endocrine changes and multiple organ failure in patients with septic shock produced by peritonitis suggest that their effects upon peripheral vascular resistance and constriction of the splanchnic, splenic, renal and other organ vasculatures are not always with physiologic expediency and there are perhaps the possibilities of therapeutic influence. intredu~on : dopexamlne has previously been shown to control hyperkalaemia ia patients with acdto renal failure (arf), however effects on the subsequent course of art are undomunente~ ob_iectlv~ : to evaluate clinical progress in patients with acute renal failure (arf) in an intensive care unit (icu) with regard to biochemical control, need for -and time to -dialysis, and outcome in patients receiving dopexamine. m~ods : consecutive patients meeting standard criteria for diagnosis of arf were included in the study. full cardiovas~dar, biechemical and intervention/outcome details were recorded. dopex.~min~ was infilsed at a dose of pg/kg/min in conjunction with a regimen of inotropir support and blood volume optimization. resn]~ : following the intzoduetion of dopc',~mine ilrinr vohlmes increased slightly over the next hrs fzom + ml/ hrs to + ml/ hrs (ns). data expres,uxl as mean + sem. three patients ( %) became polyuric with urine output > ml/hr within days and did not need dialysis. in the remaining patients the time to dialysis (to correct acid-base deficits or volume overload) was . + . days. serum potassium levels were well controlled. day or immediate pre-dialysis levels were . + . mmol/l compared with pre-lreatment . + . mmol/l overall mortality in this series was / ( %). duration of acute dialysis in survivors with renal recovery was . +_ . days. patients ( %) progressed into chronic renal failure and needed continuing renal replacement therapy. no adverse cardiovascular altects were seen at this low dopoxami~ dose although its competitive inhibition to adrenergic reuptake mechanisms meant that doses of pressor agents could often be reduced. : dopcx:~minr nsed in conjunction with inotropic support and blood volume oplimitntion, can safely postpone, or even avoid, the necessity for acute haemodialysis in icu patients. no evidence of tachyphylaxis to the effect on serum potassium levels was seen over the duration of the study. hen'era m., suarez g., dagn d., varela a., ramos j., garoia jm, aragdm c, jurado l, medina a. icu. hospital regional. malaga. spain. objective: to evaluate the haemodinamic tolerance to the veno-venous continuous hemefiltration (vvchf) system in patients with systemic inflammatory response sindrome (sirs), and the possible beneficial effect of this technique on the haemodinamics in these patients. material: patient admitted to the icu, with diagnosis of sirs and monitored with a pulmonary artery catheter at the beginning of wchf. we performed a complete haemodinamic study to all these patients (cardiac output, vascular resistanoss, ph and co in arterial and mixed venous blood samples, saturation of pulmonary mixed venous blood, do and vo calculations and temperature) and determined the respiratory mechanics (compliance and pao /fie relatinship) before starting the procedure, after minutes operating with the ultraflltrate branch closed (without filtered fluid production), afler and minutes of zero fluid balance bemofiltration and after minutes of filtration with negative balanos adjusted to the patients conditions. for the statistical analisis we have performed the anova test over the mentioned variables. results: we have not detected statisticaly significant differences of the analyzed variables before the beginning after operating the pun'@ for minutes without filtered fluid production and after minutes of zero fluid balance hf. only temperature shows a meaningful decrease in time. objectives: among many organs, playing the important role in pathogenesis of multiple organ failure, the particular place is taken by the intestine. ~ethods: the study was carried out in dogs !~n"~h pi was modelled by severe operative trauma (ot). the dcm was estimated by the indices values of work time (wt), contraction frequency (cf), mean amplitude of contractions (~ac) and motility index (mi) measured by method of tensography. "sl", created on the basis of sorbit and sodium lactate ( mosm/l), was injected in the dose of .o ml/ kg into v. cephalica antebrachii after hrs of ot. the results of the present study are the evidence of "sl" stimulative action on dcm and are experimental ground for "sl" using in complex therapy of pi in clinic. with splanchnic venous blood pc p.f. laterre p. goffette, j.p. fauville, a. poncelet, p. loneux, m.s. reynaert. intensive care unit, st. luc univ. hospital, brussels, belgium. determination of gastric intramucosal ph (phi) by gastric tonometry using the henderson-hasselback equation is expected to allow the detection of splanchnic ischemia in critically ill patients. because of bicarbonate concentration and acidbase balance influences on the calculation of phi, it has been proposed to use arterio-gastric pco,_ gradient [p(gast-a)co,] to assess splanchnic perfusion. htpothesis : pcoz in the gastric mucosa is in equilibrium with intraluminal co z and with co, in the blood leaving the stomach (mesenteric and portal blood). objective: mesure pco; and ph in portal vein blood and compare its value with pco and phi obtained simultaneously by gastric tonometry. material and method : in a patient ( y.), a fiberoptic catheter (baxter r) was positionned in the portal vein after transhepatic stent shunt repermeabilisation. hemodynamic parameters, do, (vigilance n baxter), gastric co and phi (tonometrics baxter) and portal blood gas were determined at regular intervals. results : sets of data were obtained and are expressed in mean + sd. gastric pco z was , + compared to , + . mmhg for portal pco . phi was . +._ , vs . +._o, for portal ph. no correlation was found for these parameters. p (gast-a) c was . + mm hg vs + . mm hg for p (portal-a) coz (no correlation). there was a good correlation between do e and p (portal-a) co z (r = , ) [figure] but no correlation with p (gast-a) c . obiectives: desaturation is a common finding during haemodialysis (hd). pulmonary oedema might be one cause for impaired gas exchange ( ). the aim of this study was to quantitate the amount of extravascular lung water (evlw) and gasexchange in chronic renal failure patients during and after a regular hemodialysis session. methods: chronic renal failure patients without symptoms or diagnosis of cardiac or respiratory disease were studied at the start (i), at the end (ii) and two hours after (iii) a regular bicarbonate hemodialysis session. the double-indicator dilution method, with indocyanine green and the stable isotope h as tracers, was used to measure evlw ( ). arterial bloodgases and endtidal co were registered. evlw data was compared to a group of renal healthy patients ( ). dcp n evlw, ml -pao , mmhg h~o +, nmol/l control group - -- l _+ "* -+ _+ crfgroup ii -+ ~ +- ns -+ "(" iii +- t _+ ns -+ t ** p < . dcp i from dcp , t p < . dcp li or i from dcp i, :~ p < . dcp ii from dcp i the evlw at the start of dialysis was larger in the crf group than in the control group. the evlw decreased significantly to a level not different from the control group in response to the reduction in weight after hd. pao~ was normal at the start of hd and showed a nun-signficant reduction after hd. paco ( . + . kpa) and etco ( . + . kpa) were unchanged while h o+ decreased and bicarbonate increased significantly. conclusions: the elevated level of evlw at the start of hd did not impair gasexchange. the decrease in evlw did not inhibit the decrease in pao . the reduction in h + followed by a fall in alveolar vantilation is the most plausible cause for the decrease in pao in bicarbonate dialysis. . prezant lung ; : - . . wallin j appl physio ; : - . a. dona~ d. battis& l col~ r danieli, d. achill~ l viglienz;~ c. giov-anaini, p. piaropao~ oblectives: to verify if intraoperative modifications of mtramucosal gastric ph (phi) below the normal lowest value . , can be predictive for important complications, as perforation, sepsis, mof or death. methocls: we have considered patients who andenvent major abdominal surgery. all patients received the same drugs in pre-anaesthasia, the same type of anaesthesia (balanced anaesthesia) and the same treatment with h -bloekers. after the induction of anaesthesia a gastric tonometer was positioned and a catheter was positioned in the radial artery. during the operation, every minutes, the following parameters were measured at the same time: phi, arterial ph (pha), blood lactate, mean arterial pressure. in follow up we considered death and complications happened during the hospital stay, in relation to intraoperative phi falls below . . results: among the patients, had a drop of phi below . during surgery. in three of them this fall was a single episode and happened within the first hour after the begiluting of the operation. after that phi rose to nomml values until the end of the operation these patients had a normal post-operative period, without complications, the other patients had a fall of phi during the demolitive manoeuvres. two paticots of them died. the first had a lowest phi= . and the second . . the first one ~zs operated on for hepatic istiecitoma, suffered a complete del'dseenco of the surgical wound on the th day after operation and died on the th day, the second one was operated on for a hepatic carcinoma had an intraoperative haemorrhage and died ~vo hours after the end of the operation. the other patients with a fall of phi had a lowest phi= . . . . . . . respectively.the first patient,operated onfor sigmoid carcinoma, underwent on a second operation for a transmural necrosis of the colic segment on the th day; the second one, operated for carcinoma of the right colon, had a cardiac ischelnia on the th pest-operative day and a dehiscence of the surgical wound on the th day: the third one, operated on for a sigmoid carcinoma, had melena in h post~ operative da b, and finally the fonrth patient, operated on for carcinoma of the tight colon, suffered a fistula of the surgical enteral anastomosis.all these patients were discharged alive from the hospital. the other patients, who had not reductions of phi ditring the operation, had a normal pest-operative period, without complications. conclusion: phi was able to predict the arising of some complications, probably due to intraoperative ischemic events. we can say that gastric tenometry, for its low invasivi.ty, can be included among the intraoperative monitoring in patients that tmdenvent on major abdominal surgery. (ttd),t"ea~rrerj.~ of hours duraticn. all l:atients nm.'-~ms_(~lly va~ ated in eantrol wcde ard_ la':'ad a a,~m--ganz catheter, with optic fibers for contirums mmsuremmt of svo mic studies were performed, c~e before the hegir~ of hd, c~e rain after the ~, ~ne at the middle, ~ne rain before lhe erd ard one rain after the erd of hd. paired t test ~as used far slatistical eval~ti~n. results: daring i~d there was a significant'reductton (p<o.~) of: c~tr~ venc~s eres~.re ( ve)emm to . ~ ~, ) ~arn'~w capil~ ~f~e pressure (i<~p) fr~n to ~mg hg, ) i~ from to . mmg hg. ~here was also a less pmnameed bat also-slatistics/ly significant r~ucticn (p<o. ) of: i) s~o~ from to patients undergoing surgical reconstruction of the aorta due to anenrysms of its abdominal part may develop transient and sometimes sustained episodes of dysoxia despite the conventional appeoreneas of being adequately resuscitated. indirect masurement of gastric mussel ph (phi) is being widely evaluated as a minimally invasive and sensitive means of assessing the adequaey of tissue oxygenation in these circumstances. the duration end degree of gastric intramucosal acidosis are related to the risk developing injured gastrointestinal tract end its putative consequences, i.e. translceation, cytokine release, organ dysfunction end failure, sepsis end death. measurement of phi is obtained indirectly by measuring pc in the lumen of the stomach with a silicone balloon tonometer (tonometrics, inc., worcester, ma, usa) and the bicarbonate concentration in arlz,,rial blood, end substituting these two values in the henderson-hasselbalch equation. objectives: to evaluate whether perioperative phi changes are predictive of complications end outcome end how they compare to standard haemodyuamic and oxygen trensport parameters. methods: patients ( males and female) urtderwent surgical replacement of abdominal aortic anonrysm with the aortic simple or bifurcated grail. patients were operated on eleetively, had an emergency surgery for raptured enentysm. haemodynamic, arterial ph and bicarbonate concentration measurements were taken before and after induction of anaesthesia, after cross-clamping and declamping of the aorta end at admission to itu. phi calculations ware done at the sime time except before induction, as tonometers were inserted after patient had been asleep. we used pulmonary utilizing a computer billing survey as well as hospital service transfer data from a month period ( / - / ), all obstetric patients that were transferred to the med/surg icu were identified, as well as their diagnoses and procedures. twenty-eight obstetric patients were transferred to the med/surg icu, compared to , deliveries occurring during that time period for a . % rate. the following procedural indications for icu transfer occured: insertions of endotracheal tubes, arterial catheterizations, temporary tracheostumy, and venous catheter. the following medical diagnoses were found: hypertensive/eclamptic episodes, hypotensive episodes, pulmonary embolism, mitral stenosis, and coagulation deficiency. there were four episodes of respiratory failure ( %). the historical rates of respiratory failure from the medical literature seen at a university hospital ore higher than those at our community hospital despite comparable icu transfer rates for critically ill ob patients. objectives: to evaluate the usefulness of several isss used in order to predict risk of death (rd). design: prospective data collection for months in a multidisciplinary -bed icu. methods: data from consecutive patients admitted to the icu from / / to / / were studied. all the necessary informations were stored in a computer using special software for every day computation of three isss (saps, saps ii, apache ii) and of the rd predicted by saps ii, mpm , mpm and odin. data from days of hospitalisation were used for comparative evaluation of isss and rd, while sensitivity and specificity in death prediction (cut off point of rd = %) were evaluated from data collected during the day of admission (saps ii, rpm , odin) or after hrs (mpm ). agreement between rd predictions was evaluated by bland and altman analysis. results:our results were the following: objectives: a) to create and validate software specially designed for the collection of demographic data and estimation of illness severity and predicted rd and b) to provide data necessary for the evaluation of the effectiveness and the efficiency of our icu. design: prospective data collection in a multidisciplinary -bed icu. methods: prospective data on specific physiological variables, selected demographic characteristics, comorbidity and the reason for icu admission were recorded every day for consecutive patients admitted to the icu from / / to / / . data were entered into a portable computer using specially designed software allowing the calculation of usual illness severity scoring systems (isss) and the corresponding predicted rd. results: we studied men and women, with a mean age of years. we conclude that, although observed mortality was higher than predicted rd, this difference was not statistically significant. the fact that the sd of predicted rd was too large, limits the usefulness of isss predictions for a comparative evaluation of different icus. objectives :the importance of objective evaluation of patients prognosis at their admission to an emergency department is clear. the aim of this study was to appreciate the prognosis of patients with the simplified acute physiology score ii (saps ii), and correlate this score to the prognosis and orientations of patients. methods : the score which is a reduced form of saps ii was calculated from clinical variables and laboratory items for patients. sensibili}y (se), specificity (sp) and accuracy (ac) were calculated to evaluate the performances of saps i . thresholds were calculated with the youden's test (se+sp- ). results : patients were admitted in the intensive care unit (icu)and patients in medical units; patients died. the saps ii was higher in patients which died than the survivors ( , + , vs. , + , , p< , ; respectively), the best threshold was , se was de %, sp was %, the ac was / . thus for patients admitted in icu than in medical unit ( , : : , vs. , + , , p< , ; respectively); the best threshold was , se was %, the sp was %, the ac was %. conclusions : these preliminary results suggest that saps ii can be used to determine the short term prognosis and the destination of patients seen in an emergency department. design: data was collected on all admissions over a six month period. all patients had a screening hiv elisa test. confirmatory ifa tests, western blot and flow cytometry were performed on hiv positive patients. the institutional ethics committee considered the major clinical impact of the study sufficient cause to waive the patient's right to informed consent, icu staff and patients were blinded to hiv results. following discharge patients were given the option of being advised of their hiv status. setting: the study was conducted in a bedded surgical icu at a tertiary care teaching hospital. patients, participants: all patients admitted during the period in question were included. interventions: "all patients were treated according to standard icu protocols. there were no interventions. results: most patients were admitted following trauma. there were no patients with aids, hiv positive and hiv negative patients. with respect to the latter two groups, the mean age and sex distribution was similar, there was a significant difference in organ failure ( % versus %, p < . ) and septic shock ( % versus %, p , : ) but no difference in icu/hosp[tal mortality or duration of icu/hospital stay. flow cytometry changes in hiv positive patients were consistent with the quiescent phase of hiv infection. conclusion: while morbidity is higher in hiv positive patients, there is no difference in mortality. hiv status should, therefore, not be an exclusion criterion for icu admission in this patient population. , n= ) and january-march (period , n= ) were studied. interventions: a resident micu team led by a trained intensivist took over the medical care from the primary physicians when the patients were admitted to the micu. the intensivist also vetted micu admissions and decided on micu discharge. in addition, there was a resident respiratory therapist to attend to vendlatory care during office hours. after office hours, the care of the micu was delegated to the on-call team on a rotational basis among the medical departments. results: the patients in the two groups were similar with respect to age, sex, race, source of admission and apache scores. the icu and hospital mortalities decreased from . % to . % (p=ns) and . % and . % (p=ns) respectively in period . the mean icu and hospital stay was also decreased from . __+ . to . + . days (p=ns) and . __+ to . • . days (p=ns) respectively. the improved micu length of stay for survivors in period was statistically significant ( . • . days vs . • . days = . ). there was no significant differences in the vse of peritoneal dialysis ( . % vs . %) and mechanical ventilation ( . % vs . %). however, utilisation of intra-arterial lines and pulmonary artery catheters increased from % in both to . % and . % respectively in period . conclusion: the duration of critical illness was reduced in period . hence, we believe that the closed |cu which was staffed by an intensivist and had the services of a respiratory therapist was beneficial for the care of the critically ill. the intensivist, was also more likely to utilise invasive monitoring. in the absence of liver transplantation, intensive care for patients with acute hepatic decompensation arising from alcoholic liver disease (ald) is indicated only for those who are likely to benefit from conventional means of organ support. we have attempted to elucidate potential risk factors and the efficacy of organ support in relation both to hospital outcome and icu costs so as to allow the earlier identification of relatively futile intensive care in this group of patients. methods: over a period of one year, ald patients ( males; females; median age years, median apache ii score ; hospital mortality %)with severe complications ( [ %] with bleeding oesophageal varices, [ %] with hepatorenel failure, [ %] with respiratory failure, [ %] with septic shock, and [ %] others) were studied in our liver icu. organ system failure, daily therapeutic interventions and icu costs were assessed using a patient management system (riyadh intensive care program). results: whilst survivors had a significantly lower admission apache ii score compared with non survivors (medians and , p< . ), or more organ systems in failure in the first hours of icu admission was associated with a % ( ) mortality. mortality was also related to child's grading and the numbers of organs supported. of the patients who received more than one form of organ support only one survived. organs supported mortality a (n= ) % none / ; % b (n= ) . % one / ; % c (n= ) . % two or more / ; % the icu costs for the patients were only s but s ( %, patient days) was utilised by the patients who died, giving an effective cost per survivor (ecps) of s . although the cost of treating the patients with or more organ systems in failure on the day of admission was s ( % of the budget) the ecps was s . conclusion patients with ald who have or more organ systems in failure early in their icu course have a poor prognosis and in the absence of liver transplantation, traditional strategies of organ support are ineffective. this begs the question whether such costly care is appropriate as although the ecps in this sub group is comparable with other patient groups with multiple organ failure, their outcome is considerably worse. objectives: to evaluate the economic impact to the healthcare sector of using dopexamine hydrochloride infusions to deliberately increase perioperative oxygen delivery in high-risk patients. methods: effectiveness data were obtained from a controlled clinical trial in which surgical patients were randomly assigned to either a control group (n = to receive best standard optimal fluid resuscitation perioperatively, or a protocol group (n = ) to receive, in addition, an infusion of dopexamine hydrochloride to increase the perioperative oxygen delivery index to greater than ml/min per square metre. resources consumed by patients during treatment were recorded prospectively and costs of resources at / prices were obtained retrospectively. cost-effectiveness ratios were estimated by dividing the total cost for each treatment group by the total number of patients in each group and by the clinical outcome of mortality days postoperatively. results: in the protocol group, there was a % reduction in mortality days postoperatively (p = . ), a significant reduction in the number of complications (p = . ) and a reduction in length of stay in the icu and surgical ward. the average cost per protocol patient to achieve a . % survival rate days postoperatively was s , , resulting in an average cost of s , per surviving protocol patient. the average cost of a control patient was s , to achieve a . % survival rate days postoperatively, resulting in an average cost of s , per surviving control patient. the use of dopexamine to deliberately increase oxygen delivery perioperatively generated a cost saving to the nhs of s , per patient together with a % reduction in mortality at days postoperatively. hence, the cost per surviving protocol patient was s . less than the cost of a surviving control patient. conclusion: the additional cost of dopexamine in protocol patients was offset by a lower incidence of complications and a shorter stay in the icu and on the surgical ward. hence, increasing oxygen delivery perioperatively in high-risk surgical patients saves both money and lives. objective: although king's college criteria are widely used, indication and timing for liver transplantation in acute liver failure is still far from certain. long-latency sensory evoked potentials -a proven measure of metabolic brain dysfunction (grimm et al. lancet ; : - ; madl et al. lancet ; : - ) -are markedly affected in patients with acute liver failure. serial sensory evoked potential recording should provide very useful information for the management of patients with acute liver failure. methods: recordings of standard bilateral sensory evoked potentials were performed in patients with acute liver failure. findings were focused on cortical n peak -a stable negative deflection occuring • ms after median nerve stimulation in healthy subjects, which can be recorded by skull electrodes over the sensory cortex. results: nine patients recovered spontaneously, patients were referred to emergency liver transplantation, and patients died. in all patients who recovered spontaneously, n peak was detectable between and ms. all patients who were referred to liver transplantation and of patients who died, developed a loss of a prior detectable n peak during the course of acute liver failure. objective: to determine high risk arid low risk patient groups in a medical intensive care unit regarding short term and long term outcome. methods: data on all admissions of the year were collected prospectively. according to their mode of admission patients were classified as admissions by the physician staffed ambulance service (as), admissions through the emergency department (ed)i referrals from non-intensive care wards (ni), and secondary referrals from other hospitals (oth). outcome was assessed in terms of in-unit mortality, in-hospital mortality, and long time mortality. patient groups were compared using the \ -test. life table analysis were per{ormed by kaplan-meier method comparing patient groups by log-rank test. the software spss for windows . . was used for statistical calculations. results: in-unit mortality: / patients ( . %) --oth . % > as . %> ni . % > ed . %; p = . . in-hospital mortality: / patients ( . %) --oth . % > ni . % > as . % > ed . %; p = , . mean survival time in days after discharge: as < ni < oth < ed ; p = . . conclusions: despite an excess in-unit mortality of secondary referrals from other hospitals the iongtime course of this special patient group is not different to others. solsuam, j, marrugat*, g, mirs, j, nolla, a, vazqu~z-sanchez, l alvamz, ~ioio s xndioina i~siw. ir~itate l(~icipal da l~sti~isn l~di~*, ~ospits dal objective: to study the influence of modifiable variables (complications derived from therapeutic activities) on the prognosis of ~atients admitted to the icu indapemently on thn severity of illnsss. patients am methods: between january asd ]lay data from , patients over years of aqe who retained in the icu for mare than hours ~ere pr~pectively regiatered. a cohort st~ly with follo~-~ nf patients durin~ ~eir stey in the hospital was deni~.el in all patients, reasons for a~issien, principal diagnosis sad severity of illn~s moasared by the saps scare vare recorded. fastens affecting patients' outcome that my be proventsd or modified included technical :omplisafioss, heapital-acqnired infections and in~pro~riate therapeutic decisions. a logistic regression model was used to assess the relative risk (l~} for in-heapital mortality adjusted for each variable. results: ic~ mortality ~s . % and in-hospitul mortality . %. patients who died showed a higher spas score then survivors ( , ~ i ,i). after adjusting hy severity of illness, co~;licetices that statistically increased the risk of in-hospital death were septic shock secomery to hoapitul-acqdired infection ( ~ . ; % el, . to . ), pmo~othor~x related to mocasnical ventilation (@ . ; % cl, . to . ) and delay in the insertion of a fln~-quidod catheter (ii~ . ; % ic, i.i to . ). col~lusien: registration of complicaticas derived from therapeutic activities is a valuable tool far quality central in the icu. g, ~i~ , j.l mle~ma, j, ~amqat*, j..~lla, a, vazquez-saltemz, f, alvamz , servioia de nndicina l~siu. i~stitutu ~icipal de ln~sti~acidn ~ i:a*, hospital dsl objective: to dstsr~ine the incidence of self-extebatien and its effect on ~ortality. patients and ]~etheds: betveen january and april , all i~tiente in whom selfextubatien w~s registered were inclnded in a prospective study. patients were divided into @nee who needed r~intabatinn within hoers and those who did not. in all patients, dsmoqraphie and ciinical data were recorded as well as icii mortality, in-hoapital mrtality and severity of illness according to saps score. eta were analyzed usi~ the cbj-square test for cathgorical verinbls, the analysis of varianc~ (anva) for aontinuc~ ~ria~les and a leqi tic regression anal~is to estimate the relative risk (iiii) for mortality as result of celt-nxtt~ation after adjusting for severity of illness. results: a total of intnmtsd patients amre stndied. self-extu~atien occurred in ( . %) patients and . % required reintuhot~pn. when a co,arise was made between patients who did not required reint@atinn and patien~.s who did, statistically significant differences in eqe ( . v_s . years, p = .~ ), ~verity of illness ( . ~ . spas score, p = . ), dia~isstia category ( s. % v_s . % of patients with res~iratury conditiono, p = , } and mean length of stay ( , ~ , days~ p = . ) were fo~m, a~ter ad~sti~ for severity, patients with self-ext@atinn who did not reqnired reintalatien showed a . iir for mortality ( % ci, .i to . ) as co~arod with patients in when self-ext@ation did mot occur. conclnsien: self-~extamtice that does not require reint@ation is associated with a isamr in-hospital natality probably dt~ to a prolonged period of weaming. patients' admissions to ices am often delayed doe to the shortage of beds available. @ile amaltieq icu admission, these patients are treated in observation nits of @e emergency services which bare ,either tile structure nor the trained ~reomenl that are available in leb~. objective: to daterdno the effect on the patient's proqusis of a delay in tile admission to the icu when criteria for icij admission are fulfilled. ~terials and methods: between jme am l?ece~ber all patients who fulfilled criteria to be almittod to the ic who for waste~r reason retained in tile observation unit for more than hours were included in a prospective stedy. in all patients, des~raphic end clinical dabs amre recorded as well as severity of illness aencrdi~j to saps score. a cesucontrol dasi~ was eend with a total ss~ln of , patients who suffered no delay is admission to icii over a period of years. data wen analyzed using the chl.-squ~re test (to aeons the association hetwenn in-patienty mortality end categorical vari~lns) and a maltipln logistic reqression model to sstimta odds ratio for) for in-hospital mortality as result of delay in icy admission as compared with early ad~issi| after adjusting for severity of illness end use of assisted mchenical ventilation. ~ &ults: a total of patients remained in the observation nit for more than hours with a del w in igd admission of . _+ . hoers. assisted mechanical ventilation was requited in % of patients and only monitericatien in %. itsse patients were cspared with ntients from the tet~l sample ratchod by age, sp~ score and rennoss of admission. in-hospital mortality for cases warn % as compared with . % for controls (p = s). after adjamtilg fen spas, age and mobamioal ventihtien, no statistically significant differences between both ~renpa were foam, altho~b there was a tendency towards a higher mortality amen@ patients with delay in icu admission (or = . ; % ci, , to , ). conclnnien: ~se findings suggest that prognosis of critically-ill patients is no worse as a result of admission to the loll being deln~d for borers. all data appropriate for the calculation of the apache ii score (aps) together wi'th other specific cardiac details relevant to these .patients were collected daily, verified and enter~ into a computer database. results: patients were studied. six patients died and five of thee underwent cardiac surgery. the mean aps was for survivors and t for non-survivors (p < . ). the mortality ratio was . and the major markers of mortality were apache ![ score, presence of chronic ill health, mean duration of ventiiation, mean length of icu stay and need for emergen~ surgery. sixteen percent ( ) of icu bed days were occupied by % of patients (non-sarvivors) which resulted in cancellation of cardiac sot#cat sessions in momhs. conclusions: this study concludes that apache t could be used as an audit tool in a cardiac surgical icu and demonstrates the severe compromis~don of cardiac surgical throughput by a few non-survivors, organ to determine the number of organ failure free days (offd) in a cohort of survivors and non-survivors with sepsis syndrome followed over a day period. ) to determine sample size requirements for clinical trials utilizing a increase in the number of organ failure free days as the primary outcome as opposed to mortality. methods: beginning december through to april , patients who met inclusion criteria of the "cardiopulmonary effects of ibuprofen in sepsis syndrome" and who did not have hiv/aids. brain death or moribund state were prospectively identified. presence or absence of failure of organ systems (pulmonary, cvs, renal, hepatic, gi, hematologic, & cns) was recorded daily until death or until days. a score of one was assigned to each organ system free of organ failure in patients still alive, ie, maximum daily off score= , maximum day off scorn= , sample size estimations were performed for variable detectable differences in off scores (delta). alpha was set at . (two-sided), with n/group = [(z a +z b ) o conclusions: a clinically relevant increase in off days may be detected with as small a sample size as to patients per group. this represents a significantly smaller sample size than needed to detect a change in mortality from % to % ( % relative risk reduction) where the n/group= . scoring patients in this manner prevents a lethal inte~entien from providing an improved organ failure score. in addition, an intervention that prolongs survival must also provide greater organ failure free days in order to be counted by this scoring method. survival as an outcome provides no information about the quality of that survival. off days provides a measurement of burden of illness. interventions which lessens this burden may be just as valuable as those that decrease mortality by providing a measure of the quality of survival and by decreasing costs of care. they may also prove to be an accurate surrogate marker of mortality. the advantage of this approach is that the event rote is much higher and sample size requirements are subsequently smaller. this would mean that clinical trials can be completed faster and at lower cost. outcomes such as mortality could then be assessed at a later date utilizing recta-analysis. we suggest that the use of off days is a valid outcome measure that may be utilized in clihieal trials of sepsis syndrome. the icu is perceived by many as being a stressful environment for both patients and staff. stress has been defined in three ways: a stimulus producing a particular response; the physiological and psychological response to a stimulus; an interaction butwom an individual and their environment. stress is currently thought to be a dynamic system of stimulus and. response which takes into account the individual's perception of the stimulus and their ability to respond effectively. stress may, therefore, be positive and allow personal development but an individual unable to respond effectively to a stimulus will experience negative effects or strain. critical illness is an intense stimulus to which the body needs to respond effectively. physiological responses are vital and most of intensive care involves supporting these. alternatively, blocking them, for instance with atom(date, increases mortality. psyehological responses are also vital but often poorly appreciated because of communication problems. many of the problems patients experience in an icu are evidence of psychological strain. this can be exhibited in various ways, for instance, anxiety, depression, passivity and confusion. dealing with critically ill patients is perceived as stressful. we recently studied occupational stress in our icu. most aspects of intensive care were not generally perceived as stressful indicating a self-selectien of icu staff. the most stressful aspects of icu work for nursing staff were the structure of the organization and career opportunities. medical and nursing staff had different stressors and different coping strategies. support for occupational stress, therefore, should focus on the individual and concentrate on information and communication. atmosphere, and especially at intensive care units, we face up to daily decision making. in most cases these are taken on the basis of personal opinion and the processing of a very limited amount of information. rising need to optimize the results of medical attendance becomes necessary to set structured system of d@cision making in which ethical basis have a sp@dial significance in view of next considerations: -we live into a pluralist society in which the importance of values is different. -most persons consider health as the first value only in the event of illness. -medical resources available are limited, whereas medical, attendance demand from population increases in a way many people consider it unlimited. in consequence, it becomes necessary to set up priorities in patients treatment. ehtical basis that rule decision making are essentially these ones: i. beneficence: to provide the patient that is being treated the highest profit. . non maleficence: it is our first duty to avoid hurting or damaging the patient."primum non nocere" . autonomy: in every particular medical attendance, the patient has ability to decide by himself. . justice: as equity: to provide the same treatment for those who have the same pathology, ignoring another factors such as age, sex or race. severe application of these principles can cause difficulty, which resolution requires a systematization of decision making. ( - ) . the lenght of stay between survivors and non survivors didn "t show statistical significance (p = . ). the mean aiii score when considering all admissions was , ( - ) . the initial score between survivors and non survivors showed ststistical difference ( . vs . ) respectively (p < . ). univariate logistic regresion analysis demostrated a % increment in death probability for every points augmentation in the aiii score with a sensitlbity of . % and specificity of . %, the roc curve showed that the best cut off point for death prediction was points with a sensitivity of . % and specificity of . %. if a patient is classified as high risk (> ) the bayesian analysis showed a . probability of death and for one class(fed as low risk (< ) a death probability < %. conclusions: the first day aiii score in this population showed to be a good discriminator between survivors and non survivors, and the risk of death augments as the aiii does. in this population an aiii score > points is asociated with a greater risk of death. using the aiii score in conjuntion with the clinical judgement will help clinicians reducing uncertainty in the every day decision making and better predict outcome, the results from this study should been taken with caution because the data were obtained from a small sample. objective: the quality of life has been considered a "uniquely personal perception" resulting from a mixture of health related factors and social circumstances [t. m. gill, jama , : ] . the aim of this study was to evaluate two measures of pqol in intensive care unit (icu) admitted patients. patients and methods: during icu stay and six-months after hospital discharge, co-operative icu admitted patients were directly interviewed about their pqol. we administered ftrstly the uniscale (pqolu) [sage et al crit. care med. , : - ] and then a step verbal scale (pqolv): best, good, fair, poor, worst. of the studied patients, at the first interview, were able to use both scales, but ( . %) understood only the verbal one. at the second interview, patients were not able to answer, used both scales and only pqolv. statistical analysis was performed using wilcoxon signed ranks, spearman rank correlation, student's t and chi square tests. results: of all cardiac surgery pts, pts ( . %) died in icu. they were males ( . %) and females ( . %). their mean age was (+ ) years and mean ef was . (+ . ). nineteen pts ( %) had low (< . ) preoperative ef. mortality was . % in the coronary artery bypass grafting (cabg) group (n= ) and . % in the valve replacement (vr) group (n= ). in the cabg +vr group, mortality was . % (n= ), and . % in the remaining pts (n= ). cardiogenic shock was the sole cause of death in pts ( %), septic shock in pts, whereas sepsis in combination with ards in pts, sepsis and stroke in two pts. in addition, pts died from cerebrovascular accidents, one from ards and one from pulmonary embolism. the pts who died in the icu had a significantly longer bypass and aortic cross clamp time and received more blood transfusions (p< . ) than a matched control group that survived to icu discharge. the duration of mechanical ventilation and length of icu stay were greater in the pts who died in the icu than in the control group. conclusions: . although cardiogenic shock is the main cause of death ( %)in cardiac surgery pts, sepsis and cerebrovascular accident are relatively frequent causes. . patients who died in the icu had longer bypass and aortic cross clamp time and received more transfusions, compared with the control group. . although renal or hepatic failure contributed to death in some pts, they were not the primary cause of death in any patient. objectives: evaluate the acute and follow-up outcome of patients (pts) treated with primary ptca (without prior thrombolysis) in acute myocardial infarction (ami) after and up to hours after onset of typical thoracic pain ("late" primary-ptca). methods and patients characteristics: from / to / consecutive pts with ami were treated by primary ptca in the wuppertal heart center pts ( , %) were admitted to our hospital > hours and < hours after symptom onset with ongoing chest pain and typical ecg-changes.mean age was years ( - ). pts were male, four female. % had an anterior wall myocardial infarction, % suffered an inferior/postero-lateral wall myocardial infarction.two pts were in cardiogenic shock at admission. singlevessel-disease was documented in . %, multi-vessel-disease in . %. average time of onset of pain to recanalisation was min ( - ). angiography revealed timi-flow in . % of the pts, timi-flow i in . %, timi-flow ii in . %. average follow-up (fu) period was months ( - months). timi iii lv-ef ~ -day major late re-late flow p.i.* aeute/fu mortality bleeds infarction mortality . % %/ % . % . % . % % early mortality occured in the two pts, who were in cardiogenic shock at admission no pt required emergency coronary artery bypass grafting.restenosis > % was seen in % of the pts. conclusions: "late" primary ptca achieves a favourable high recanalisation rate of about % (timi ill-flow) in our study group. additionally, there seems to be a trend for lv-ef improvement in follow-up. early high mortality is influenced by the patients admitted in cardiogenic shock. there might be a trend for increased major bleeding complications. objective: to assess the validity of saps ii (new simplified acute physiology score), comparing it with the previous version, (saps), in a sample of patients recruited by giviti, a network of icu's representative of the italian icu system methods: measures of calibration (goodness-of-fit statistics) and discrimination (receiver operating characteristics curve and area under the curve) were adopted in the whole sample and across subgroups differing in relevant prognostic characteristics. of the patients recruited during one month period, a total of patients were included in this study. for the purpose of the comparison of the two scores, patients with less than years, or having cardiac surgery or staying in the icu less than hours were excluded. vital status at icu discharge in the whole sample and at hospital discharge in half cases wher adopted as outcome measure. re$ ~: saps ii fits the data equally well compared to the older version (goodness-of-fit p= . and in the new and old versions, respectively) but its performance is somewhat better in terms of capability to distinguish patients who live from patients who die (areas under the curve . and . , respectively). furthermore, saps ii is better in terms of uniformity of fit across relevant subgroups, although substantial over prediction of mortality was observed in trauma patients and in patients admitted without organ failure to be intensively monitored. saps ii performed very wet] also in the subsample where hospital mortality was the dependent variable.satisfactory measures of calibration (goodness-of-fit p-- . ) and discrimination (receiver operating characteristics area= . ) were observed. c nr saps ii, a multipurpose scoring system developed in an international study, retains its validity in this independent sample of patients recruited in a large network of italian icus. although it has shown a good performance when adopted to predict icu and hospital mortality in the entire sample, further investigations are warranted. the observed over prediction of mortality in a few subgroups indeed call for a through assessment of the impact of confounders and biases on model performance when saps ii is adopted in samples that do not reflect the "average" icu patient. objectives: ) assess the effectiveness in a group of intensive care units by means of a quality performance index (qpi); ) assess the efficiency by means of a resource use index (rui); ) evaluate the performance of individual icus with respect to both indices (clinical and economical) while controlling for severity of illness. critical from ucis in catalonia patients alearic islands have been included in the study. inhospital mortality and weighted hospital lenght-of-stay (los) have been considered the outcome variables. severity of illness has been measured with the mpm ii at admission. in each icu, expected mortality has been obtained adding the probabilities of dying for its patients. expected los has been estimated adjusting a second order polynomial to the severity of illness. performance indices have been obtained by dividing the observed by the expected outcomes. re~ult~: the overall qpi was . and it ranged from . to . in the icus. the overall rui was and it ranged l~ont . to . . there was not a trade-offpattern between clinical performance and resource use. objectives: teaching hospitals often provide [cu care across a variety of specialized services. overall, this approach appears to result in the best risk adjusted survival rates, but at the highest cost (critical care medicine ; : - ): recently, there has been increasing focus on markers of overall hospital performance. however, in large teaching institutions, such markers may fail to detect intra-institntional variation at a large tertiary care medical center. methods: first intensive care unit (icu) day, acute physiology and chronic health evaluation iii (apache iii) and active therapeutic intervention scoring system (tiss) data were collected on random admissions to specialty icus with beds (range - ) between february i and december l, . post-operative solid organ transplant recipients were excluded. units included general medical, general surgical, and trauma, neurosurgery, cardio-thoracic surgery, and coronary care units. data were analyzed for risk adjusted outcomes: icu and hospital mortality and length ef stay (los); risk of requiring active cu treatment; and icu readmissinn using apache iii risk prediction models. results: the study icus cared for a diverse group of patients. mean apache iii scores ranged from . - . ; predicted risk of hospital death ranged from . - . %. standardized mortality ratios ranged from . to . with icus performing significantly better and performing worse than predicted (p< , ). los ratios and icu readmission rates ranged from . to . (ns) and . to . % respectively. patients predicted at low risk of requiring active icu treatment ranged from , to . % conclusions: there was wide variation in the mean level of patient severity between icus. after controlling for this severity, outcomes also varied widely. no clear pattern of overall institutional performance was evident. these data suggest that efforts to assess performance, improve quality, and maximize efficiency must be focused within individual units. programmatic evaluation of outcome allows for focused review of the processes of care contributing to good outcome (best practices) and where to focus ongoing quality improvement and cost reduction activities. background and method : we compared icu mortality in different age groups presenting with the same severity of disease. we assessed severity of illness by the physiological day -apache~ (physio-aa) score (thus excluding the age related points). for each of the following physio-a n score intervals ( - ; - ; - ; - ; > ) , we compared tcu mortality within age intervals (< ; - ; - ; - ; - ; > years - , - , - ) . in these groups mortality may be twice higher in the > years patients than in the _< years. mortality does not vary with age in low (physio a n = - ) and high (physio a n = > ) risk groups. in the low risk group, mortality is low in all the age intervals because of the begninity of illness. in the high risk group, extreme severity of disease probably blunts the impact of age and leads to high mortality rates in all age intervals. introduction: to access the actual social/clinical outcome of the patients who undenvent intensive care therapy oct) is rather difficult, quality of lilr is not easih.' defined and ohserver subjectivity is a prime factor in the evaluation. mortality ratio after discharge must be established and its causes understood. obieetives: the propose of this stud)-is to look into the mortality ratio that occurred on a series of patients that undorwent ict at our unit from of the ~iew point of severity of the original illness and the diagnostic groups. material and methods: during the period of one )-ear ( ), patients were treated at the unit, of them died, and ~ere not matched in our series because os incumpletc records. thirteen patients died in hospital after their reference to other departments, twelve patients were lost after discharge. thus. at the end. only patients were evaluated on the fu. the, were classified into the follov ng three groups: acute medical, elective surge d and acute and emergency postoperative. the patients were seen at , and months after discharge. the, were evaluated in accordance to their abili~, to being self supported in their daily life and capecity to fully return and hold to their pre~ ous jobs. apache scores were evaluated for each of the three groups and correlated to the icu dead, hospital dead, and mortality after hospital discharge, spss package was used for statistical analysis. remlts/conclasions: data shows that / patients died after discharge from the hospital, of ~itch nine died in the first three months. seventy-eight per cent of the patients were fully self supported in their daily life and % showed some kind of handicap. fosty-nine per cent of the patients wore on retirement either due to age or some form of chronic disease, when admilled to our unit. thirty-two peg cent had not been able to return to work, because the" were incapacitated on discharge. only % had return to their fully jobs but the period of the stu~, is not enough for all of them to be fully physically recovered. preliminmy statistical analysis shows us significant differences among groups. the aim of the present study is to compare the prognostic performance of five general severity indices ou coronary patienta and to find out if a proper ntatistical hundling of these indices could provide better results in these patients. methods: saps ii, mpm ii (mpm ii i mpmp ii ), apach ii end gaprik were evaluated o~ patients with acute myocardial infurction admitted to intensive care units from catulunye. calibration and discrimination were calculated for each index. calibration was calculated by th bosmer-lemeshow test. discrimination was evaluated by the area under the relative operating characteristic (roc)curve. if a model did not show a good performance it was customized using multiple logistic regression. finally, tworeduced models were developed, one fro~ the mpm series (mpm ii cor) and one from the group apache-saps (sapsiicor).their performances were again evaluated. results: discrimination was high enough for all models. neverthelees, oelibration of apache ii, saps ii and mpm was not satisfactory. thus,mpm ii , saps ii and gaprik were customized for coronary patients using the logits of both models, and obtaining good calibrations. mpm ii , and apache-saps were adapted and reduced to (mpm ii cor) end to variables (sapsiicor), respectively . both models showed better oalibrutions end discriminations than the original models. conolusion| models developed for multidisciplinary patients show a good discrimination when applied on aoronar i patients, but some needed customization in order to improve calibration. the number of variables of the principal model can be reduced (even to or variables) without loosing prognostic accuracy. objective: to compare the ability of two methods to predict outcome for intensive care patients. methods: we included consecutive intensive therapy unit (itu) admissions with an itu stay> hrs in a month prospective study (exclusion criteria: burn injury and age < yrs). data were couectsd applying the criteria described by the developers [ , ] . the definition of coma (mpm ii) was modified and the best assessment within in's, rather than the admission score, was used. statistical analysis included classification tables and receiver operaung characteristics (roc) curves to assess discriminative power, and lemeshaw-hosmer statistics and calibration curves to test accuracy of prediction. results~ average abe was yrs (ranse: - ) with a male:female ratio of . : . the actual hospital mortality was . %, mean predicted death rates were . % (mpmz ii) and . % (ap hi). non-survivors had siguitlcanfly higher predicted risks than survivors applying both methods (p< . l, t-test). the total correct classification rates (tccr) for apache iii were bett~r for all decision criteria applied (tccr, decision criterion %: apache ]/i . %, mpm ii . %). the area under the roc curve was . (ap iii) and . (mpm ii) confirming the better discrimination of apache ill. accuracy of risk prediction was similar for both models (ap nl ~ - , mpm b ;( - , lemeslmw-hosmer). showing some fluctuation, calibration curves lay close to the ideal line for predicted risks -< % with increasing deviation for higher risk groups (s. figure) . apache iii underestimated the risks of hospital death for almost all risk groups (curve above diagonal), whereas considerable overestimation for predicted risks > % ceenred with mpm~ii. objective: to assess the goodness-of-fit of the apache iii model for british itu patients. methods: we prospectively studied a cohort of adult patients consecutively admitted to a medical-surgical itu over a period of months. patients with burn injury, age < yrs and itu stay < hrs were excluded. using a eomputerlsed database, we routinely recorded hrs apache ill scores. predicted risks of hospital death were computed by critical audit ltd, london. accuracy of risk prediefion was assessed by hosmer-lemeshaw chi square (;( ) statistics and calibration curves [ ]. discrimination was tested employing classification tables and receiver operating characteristics curves (roc). restths: the mean age of the male and female patients was yrs (range: - yrs). of these patients, % were medical admissions, % were admired after emergency and % after elective surgery. the observed hospital mortality was . %, the overall mean predicted death rate was . %. mean predicted risks were siguifieanfiy greater for nonsurvivors ( . %o) than for survivors ( . %, p< . l, t-test). apache iii showed good calibration (z -~ , lemeshaw-hosmer). however, the calibration curve lay above the diagonal for almost all risk groups reflecting the tendency to underestimate actual mortality (s. figure) . the best total correct classification rate (tccr) was . % (decision criterion: %). the area under the roc curve was . % confirming the good discriminative ability of the model. objectives: the aim of this study is to point out the discrepancies between needs and actual treatment of less severely ili patients admitted in italian intensive cam units (icus) requiring only intensive monitoring, and verify the substantial likelihood of data comparing those collected from a national short term study with a regional long ternl use. ~: less severely ill patients ("observed patients") were only monitored; they did not require intubation, even if for a short period (less than houm) or major cardioeiranlatory supports, and were neurologically normal. epidemiologieal national data were obtained from giviti group (gruppo italiano valutazione interventi in terapia intensiva); this cohort study, collected patients, in two months in summer in all over italy. regional data were echieved in a three years entlection ( -i ) in lombardia' icus from archidia group (arehivio diagnostieo), including patients. mortality, severity score, diagnostic category and some typical intensive procedures were analysed and compared in both studies. patients' disgunstie categories were defined as surgical, medical and trauma, according to the main diagnosis and the presence/absence of surgical procedures. rr observed patients account for . % and % of all icu's patients respectively in national and regional data. very tow mortality rate was found in national data ( . %) and extremely low mortality in regional data ( . %). in both studies mortality, s.a.p.s. and length of stay were much lowor in "observed patients" than in general icu's population (mortality: . % and . %; .a.p.s. score: . and ; iength of stay: % and ). homologous distribution of patients in the two studies was noted for what concern their diagnostic category, aside from a slight prevalence of tranmatised patients in the giviti study. in the two groups the surgical patients were respectively % vs. %, medical patients were % vs. % and traumatised were % vs. %. % of "observed patients" in national study and % in the regional did not received any intensive procedure. only a minority of these patients availed haemodynamie eonu'ol with swan-ganz or renal haemofiltration. conclusions: these results underline that about one fourth patients admitted in italian icus benefit an oversized slructure i, relation to the real needs of their pathology. in hot more than % did non received any advanced treatment and mortality and s.a.p.s. score were substantially lower respect to general population. the results obtained from these two studies are similar, suggesting an uniform distribution of the case mix in italy, even if a different recruitment period and a different gengraphieal distribution were used. some discrepancies in the two studies were found in the diagnostic categories moreover regarding the tranmatised patients ( % vs. %); this can be explained from the seasonal (summer) characteristic of the national study. mutuality, yet very low, is different in the two groups, but these data do not allow any definite explanation. finally these epidemiologieal survey suggest need of further studies settling more strict criteria of admission in icu. this study aims to evaluate patients outcome, quality of care and effectivity of therapy in our intensive care unit. the main goal was to indentify factors that the most influence that outcome. during . the authors collected data of patients outcome and predictor variables. overall mortality rate was , %. the most common causes of death were infection. the diagnosis of sistemic inflammatory response syndrome (sirs) and multiple organ dysfunction syndrome (muds) significantly correlate with death ( %). average length of stay was . days ~. % patients died in the first ten hosiptal days and only % after days. age was directly correlated with death % of dead were older then sixty years. an analysis of physiological variables showed that serum levels of gl~cose ( %) and natrium ( %) were in optimal physiological values. serum proteins ( %) and haemoglobin ( %) levels were inversely related to death. multivariate showed that alveolo-arterio difference in content was the most informative of all mortality predictors (mean value , mmhg in % patients io>mrnhg). factor that most influence the patients outcome was infection (sepsis) and muds. use of predictive indicators of outcome in critically ill patients may help to assess treatment regimens and to compare patient groups. acute physiology and chronic health evaluation (apache if) score (crit. care had. ; : - ) and the sepsis score of elebute and stoner (br. h surg. ; : - ) have been used, objectives: to compare sepsis score and apache ii score in predicting outcome of critically ill patients. methods: overall survival during the past years for patients in our icu was calculated = % (prior probability). the outcome of patients who were admitted to our icu for > hours was observed. apache ii score on admission, patient predicted risk of death (apache ii risk) and the sepsis score on the first day of antibiotic course were prospectively recorded. discriminant function analysis of the scores in relation to outcome was performed. results: apache ii and sepsis scores in the survivors were significantly lower than in those who died ( . i . v~s . • . and . • v's . • . respectively p < . ). correct prediction of outcome by each score is shown in discussion and conclusions: although both scores have been previously evaluated in predicting outcome of icu patients, studies of the sepsis score were conducted in small numbers of patients or involved additional measurements not routinely available. this study demonstrates that the sepsis score alone or in combination with apache ii score is more effective than apache ii score in predicting outcome. objective to test the hypothesis that resuscitation titrated against gastric intramucosal ph (phi) improves survival in critically ill patients as suggested by gutierrez et al~. method emergency admissions to the intensive care unit were randomized into control and intervention groups. in the control group phi was measured at , and h while in the intervention group phi measurements were made hourly for h. both groups were managed according to the same guidelines to achieve the following targets: mean arterial pressure > mmhg, systolic arterial pressure > mmhg, urine output > . /ml/kg, haemoglobin > g/dl, blood glucose < mmol/ , arterial oxygen saturation > % and correction of uncompensated respiratory acidosis. if the phi was < . after achieving these targets, or after maximal therapy to achieve the targets, patients in the intervention group were given fluid to ensure an adequate cardiac preload and then dobutamine at then mcg/kg/h, titrated against phi. this additional therapy was continued until h after entry into the study. in each year patients were subdivided in two series with random selection, so that the st series contained abeat / and the nd / of the patients. the st series of all the years constituted the devdoping data set and the nd series the validation data set. with data of the st series ( patients), we created the predictive model, using stepwise logistic regression (bmdp, usa). each patient has been evaluated in die st, th, th and th day, calculating for each lime the apache ii score (for a total of records), independent variables were, besides time and apache ii of the time ( michaloudia g,, melissaki a., alexias g., gogafi c., kolotoura a., krimpeni g., pamouktaoglou f, filias n. objectives: to determine the medical staff's attitude towards various ethical issues methods : between january and february , anonymous questionnaires were sent to intensive care units, all over greece. results : questionnaires ( , %) were replied and returned back. of them , % were answered by male and , % by female. the doctors replied in the following rate : , % aged up to , % aged between and , % aged over . questions were answered and were divided into main topics, as following: . admission criteria: limited bed availability was the main cause for refusing admission in , % of icu's. , % evaluated each case's viability and only , % used some prognostic score system. , % of icu's accepted all cases and a significant percentage ( %) gave in to pressure coming from their colleagues ( , % female and , % male). . informing the patient/relatives: only , % was willing to tell the whole truth, while , % had given selective information.. in the case of iatrogenic incident, , % withheld it, because either they feared legal implications ( , %), or lost of trust ( , %). doctors are asking consent from the patient and/or his family, in order to include him/her in research protocols, in a rate of , %, while only , % found informed consent necessary for the proposed treatment procedure. . withdrawal of therapy/dnr orders/organ donation: , % were willing to withdraw complex treatment in patients with short life expectancy, except of administi'ating intravenous fluids, feeding and analgesics. in , % such a decis~n was unanimous, while the percentage of those carrying it out was , % ( , % female, , % male). in case of brain stem death , % ( , % female, , % male) withdrew any life support. , % would like therapy withdrawal to be legally established, while only , % would perform euthanasia, if there was substantial legal cover. for these cases, relatives' consent was considered to be necessary from a percentage of only , %. , % considered organ donation to be a necessary proposal, while , % refused to ask the patients' relatives for an organ donation, either because they didn't have the psychological strength for it ( , %), or because they doubted the procedures' objectivity ( , %). note: in greece, icu beds are less than % from the total number of hospital beds available. only a percentage of - % of these admissions comes from the same hospital, with a potentially direct evaluation. usually an icu doctor has to be informed through the telephone. finally, employment conditions in greece are such that any changes of the medical and nursing staffare limited. conclusions: the mathematical model we found has been validated also in the second series and the discrimination capability increases with time. using this model we can evaluate the probability of survive at every, time. its application at different times permits a better evaluation of haemodinamically instable patient trend. introduction: the feasibility to assess pulmonary capillary pressure (pcap) offers the opportunity to determine the longitudinal distribution of pulmonary vascular resistance (pvr). the purpose of this study was to measure pcap and to calculate pvr to determine whether relevant shifts in the distribution of pvr could be expected after routine cardiac surgery. methods: the study population consisted of consecutively admitted patients after cardiac surgery. surgical procedures included coronary artery bypass graft (cabg) (n= ) and mitral valve replacement (mvr) (n=t ). pcap was estimated by analysis of the pressure decay tracing after pulmonary artery occlusion. after estimation of pcap precapillary (ra) and postcapillary resistance (rv) was calculated. a complete set of hemodynamic variables was obtained at hour and at hours after operation. results: there were no significant hemodynamic changes during the first hours after surgery. the mvr group maintained pulmonary hypertension and higher levels of pcap. ra/rv, reflecting the longitudinal distribution of resistances, remained unchanged. however, rv predominated ra during the postoperative period in both groups. objectives: evaluation of the influence of long-term continuous i.v. administration of the ace-inhibitor enalaprilat on regulators of circulatory homeostasis. methods: t trauma and sepsis patients randomly received either . mg/h (group i, n= ) or . mg/h (group , n= ) of enalaprilat i.v. or saline solution (control, n= ) as placebo for days. plasma levels of endothelin- (et), atrial natriuretic peptide (anp), renin, vasopressin, angiotensin-ii, and catecholamines were measured before injection of enalaprilat (='baseline' values) and during the next days. results: except for et, plasma levels of all vasoactive substances exceeded normal range at baseline. angiotensin-ii significantly decreased during enalaprilat infusion ( . mg/h: from . • to . • pg/ml; . mg/h: . • to . • whereas it remained significantly elevated in the untreated control patients. vasopressin increased only in the control group (p< . ) and decreased after . mg/h of enalaprilat. et remained almostunchanged in group , whereas et increased significantly in the control patients (from . • to .t• on the th day). catecholamine plasma levels (epinephrine, norepinephrine) markedly increased in the control group (p< . ), but they did not change significantly throughout the study period in both enalaprilat groups. conclusions: continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat beneficially influenced systemic and local vasoactive regulators of the circulation, which are normally increased in the critically ill. thus patients at risk of (micro-) circulatory abnormalities may profit from enalaprilat infusion. objectives: to determine the time taken for hemodynamic and gas exchange variables to a reach stady-state after a change from supine to trendelenburg position (trp). methods: we prospectively studied adult patients with severe sepsis or septic shock requiring hemodynamic monitoring. usual cardiorespiratory parameters were measured at baseline, min after the patient was placed in a trp and again min after the return to a supine position. a fiberoptic pulmonary artery catheter (svo~ oximetrix, abbott) allowing continuous svo monitoring wa~used. during the protocol we also continuously measured sao~ by pulse oximetry and vco~ and vo by monitoring partial concentration of o and co ir~ inspiratory and expiratory gases (deltatrac metabolic monitor, datex). therefore, we were able to monitor cardiac output variations by dividing vo~ with arteriovenous difference according to the fick equation (co-fick). results: no significant difference in hemodynamic status was observed min after the patients were placed in trp. despite the fact that no significant change was observed in co and vo~ estimated by thermodilution, co-fick had a tendency to dedrease continuously in trp and then to return to its initial value when patients regained supine position. respiratory gas analysis showed a small but persistent continuous increase in vco without a similar trend in vo values. conclusions: we conclude that no significant hemodynamic effect was detected in our patients after min in trp. evaluation of vo from respiratory gases analysis after a change in body's position should be interpreted with caution, since the patient may not yet have reached a stady-state after rain. since vo did not change, vco~ increase was probably due to position related changes in-pulmonary gas exchange and not to a change in patient's metabolic status. objectives: to determine whether changes in svo and/or other hemodynamic parameters during weaning trials could be used to predict successful weaning. methods: we prospectively studied adult patients with a history or clinical evidence of cardiovascular dysfunction, who were unable to tolerate spontaneous breathing (sb) for hours. for all these patients right heart catheterisation was considered necessary in order to detect hemodynamic alterations during weaning. a fiberoptic pulmonary artery catheter (svo ximetrix, abbott) allowing continuous svo monitoring was sod. hemodynamic status was evaluated ~t baseline and after one hour of spontaneous breathing through a t-piece. patients were assigned to one of two groups depending on whether they tolerated sb for hours. data were analysed by analysis of variance and unpaired student's t-test we also used multiple linear regression analysis to determine which hemodynamic variables were correlated with the magnitude of svo~ change and multiple discriminant analysis to determine if asy of the above variables were associated with toleration of sb for hours and/or successful weaning (s-w). (j physiol ; ." - ) . we tested the hypothesis that the ventilatory stimulation by dead space (vd) loading and % co inhalation is accompanied by a proportionate cardiovascular change. methods: six healthy subjects, mean age, year, performed three incremental exercise tests in a randomized order: ) inspiring air without vd (air control, ac); ) inspiring air with vd of ml (avd); ) inspiring % co ; % oxygen, balance nitrogen. the ventilatory responses were examined at matched heart rate (hr) equivalent to % peak hr. results: ventilation (vi) was significantly greater (p< . ) during the avd and co tests than during the ac test at the same work rates. end-tidal co (petco ) and estimated arterial co (paco ) were significantly greater (p< . ) at w and w. oxygen saturation was significantly lower (p< . ) during the avd test than during the ac and % co exerdse. at matched hrequivalent to % peak hr, vi was significantly greater (p< . ) during the avd and % co tests than during the ac exerdse ( l, l, and /). conclusion: we conclude that the increase in xri and petco due to vd loading and % co inhalation is not associated with an acceleration in hr. sup.ported by mrc (canada). objeetlve: the production of large amounts of oxygen radicals from the onset of ~en may be responsible, st least in part, for peroxidative damage to myocardial tissue. the aim of this study was to evaluate the time dependence of plasma tbars in patients with am] receiving thrombolytie therapy (tt). patients and m~hods: filiy eight patients admitted in icu ( men and women; mean age . - . years) rec~ving systemic tt for possible am] were ~died. all patients received recorabinant haman tissue-type plasminogen activator (r-tpa). the mean time fi'om the onset of symptoms and the be~nning of tt was . - . hours. peripheral veao~s blood samples were obtained fi'om each patient before and serially after tt ( , , and hours). tbars levels woe determined by using a spectrophotometrie technique. rq~r fusion was identified by the timing of ereatine phosphate kkmse (cpk) peak (< hours). table i list the variation of plasma eoneenlrations of tbars (mean -sd) in groups (a,b, and c) as a function of time from the beginning of tr. co,arisen oftbe time cuncentzatiens reveal a difference p<o. between group ami (a and b) versus group c. the between-groups (a-c) comparison showed significant differences (p<~). ) at , and hours fi-om de begin~g of'it. comparison ofthe , and hours eonocnlratiens did not reveafl any difference becween n~ (group b) and angor (group c). condmien: we have observed a maintenance of high level of tbars in reperfused patients enly. these results suggest that the increase of tbars levels may be due to phospholipid derangament of reperfused myocytes. objective: to detemline if tbars levels may be an early index reflecting peroxidative damage in ami patients. patients and methods: by using a spectrophotometric teclmiqtm, based on a modificatien oftbe buege and aust method, tbars levels ware determined in healthy subjects (group i) , patients with several risk factors of ischaemic cardiopathy (group if) and icu patients with possible aim ( were confirmed ami (group ma) and were angor (group iiib)). peripheral blood was obtained at the time of the icu admission in the group i . electrecardiographic data and eehocardiographic wall motion were used to identify ami location (anterior, inferoposterinr and indeterminate). statistical analysis was made with a standard statistical package (rsigma, horus hardware). , h , s, , h statistically significative increase of ' ix~e/ea.ee x~* tbars levels (p< . ) only in pstients with con/tuned ami (group ilia) . no differences were found between the rest of the groups. the figure shows the relationship between the tbars values and the time from the onset of the aim's symptoms. conclusion: we have found that in am/patients the tbars levels can be used as an early index reflecting peroxidative damage occurring to ischemie tissues. perioperative risk in patients with ischemic heart disease. the protective role of diltiazem. lg. hatziantoniou, p. tassiopoulos, c. fakiolas, ! g. foussas~ m. lycourinas perioperatlve morbidity and mortality are mainly of cardiac origin, particularly among elderly patients (pts) ~ith ischemic heart disease. we performed a randomized trial, in order to investigate the possible protective activity of diltiazem (d). methods: pts (aged zo• with a history of coronary insufficiency were subjected to major urological operations. they were randomized to two groups: group i ( pts) -p:ithout d and group ii ( pts) -d ~as administered . mg/kg iv bolus hours prior to anesthesia and . mg/kg/h upon the end of operation and for at least hours post-operatively. iv was substituted by oval administration of x mg starting the next day and for the rest of hospital stay. all pts underwent daily clinical, electrocardiographic and laboratory (ck-mb) control. results: are shown in the following interactions between the heart-lung unit and a cardiac assist device are the crucial issues for successful outcome of patients under mechanical circulatory support. several factors have been indicated and we can diffrentiate between anatomical and hemodynamic interactions. especially right heart failure and pulmonary hypertension have been proven to limit left ventricutar assist device (lvad) performance. in order to study the effects of right heart failure (rhf) and pulmonary hypertension (pht) on mechanical circulatory support, we designed an experimental study in dogs and combined in six groups left heart failure (lhf) and rhf and pht, respectively. in the control group we induced lhf with subsequent occlusions of lad and cx followed by reperfusion: in the next group we supported with an lvad during minutes starting minutes after cx occlusion (group if). in the next group we added right ventricular ischemia by occluding the rca simultaneously to the cx (group iii). these both groups we repeated only with pre-existing acute pht induced by the injection of o fm glass beads (groups vi and v). a last group was similar to group v (lhf and rhf and pht), but instead of a lvad, we used bvad support. in i and v no animal survived the second perfusion period ( hours). in ii and iii (no pht), all dogs survived in stable conditions. in iv (lvf, pht), % survived, the remainder died of incomplete recovery. in vi with bvad, only % survived. in iii and v, during occlusion of the rca, the right ventricle stopped contracting and right atrial pressure and mean pulmonary pressure equalized. this lead to a significant drop in inflow on the left heart side, which still provided sufficient lvad performance in case of absent pht (iii) and lead to death due to "low lvad output" syndrome in v. this "low lvad output" snydrome could be partly overcome by bvad support. we conclude that heart-lung interactions play a major role in lvad performance. by optimizing the perioperative management, they all can be overcome, except the occurrence of alveolar leakage syndrome. obiectives : we propose a new approach of transmural pulmtmary artery occlusion pressure (paoptm), in presence ef peep, from the folluwing hypothesis : if respiratory swings of paop are compared to those of alveolar pressure (apalv = plateau pressure -total peep), an index of transmission of airway pressures to pulmonary vessels is obtained (i t = apaop/apalv). the value of the product of it by peep can be substracted from end-expiratery paop (paopee) to obtain a calculated paoptm (paoptrnc). thus paoftmc = paopee -(apaop/apalv x peep). methods : we tested this hypothesis in patients by comparing paopee, paoptmc, and paopnadir obtained within the first seconds after disconnection from the ventilator, value of reference of paoptm in absence of intrinsic peep (peepi). at zeep, peepi was absent in patients (group a) but present in others (group b). patients were studied under the peep level chosen by the attending physician-(gr a : +_ ; gr b : _+ cmh ). results : l. gr a : paopee ( _+ mmhg) differed (p < - ) from paopnadir ( • mmhg) and paoptmc ( _+ mrahg). gr b : paopee, paopnadir, paoptmc differed between themselves ( " - , + , + mmhg respectively). . good correlatkm (r - (i. ) and agreement between paopnadir and paoptm were found in gr a, while there was no agreement in gr b (bland and altman analysis). . lung compliance (v t/bpah,) correlated well with i t in both groups (r - . ), suggesting that our hypt)thesis was strtmg even in patients with peepi. conclusions : paoptm under peep ventilation can be obtained, even in patients with peepi, from parameters easily measured at the bedside. introduction: cardiopulmonary bypass (cpb) may cause ischemia in several organ systems like the heart, brain and kidneys. reactive oxygen species (ros) are formed by subsequent reperfusion and stimulation of neutrophils by cpb. ros are harmful to biological systems e.g. cellular membranes, enzymes~ dna. many natural antioxidant systems protect against the effect of ros. in patients undergoing cabg we evaluated the production of ros by total plasma antioxidant status (tas) and lipid peroxidation measured by lipofuscin flip). methods: tas (randox, uk) and concentrations ofllp (tsuchida et al.) were measured in consecutive patients undergoing cabg. all the patients had a normal serum creatinine clearance (> ml/min). serum samples were obtained a) before operation, b) after removal of the aortic crossclamp, c) at admission to the icu, d) hours after operation, e) hours after operation. results: tas was significantly decreased after removal of the aortic crosselamp ( b, c and d lower than a), followed by a subsequent significant increase of lip ( c and d higher than b). the levels of tas and lip returned to baseline hours after operation. methods: patients with preoperative lvef< % undergoing coronary artery bypass grafting were studied. after surgery, a f femoral artery catheter was inserted and connoted to a fiberoptic monitoring system (cold z- t; pulsion medizintechnik, germany); this allows, with a double-indicator dilution technique, the calculation of cardiac index (ci,l/min/m ), intrathoracic bood volume (itbv,ml/m ), pulmonary blood volume (pbv,ml/m ) and extravascular lung water (evlw,ml/kg). with a f pulmonary artery catheter, wedge (w,nunhg) and central venous pressure (cvp,mmhg) were measured, while extraction ratio (o exr,%) and oxygen delivery (do ,ml/min/m ) was calculed. peak inspiratory pressure (pawp,cmh ) and mean airway pressure (mawp,cmh ) were measured with a varflex flow transducer (bicore,sensormedics,us). the patients were studied after minutes (to) of volume controlled standard ratio ventilation (vc), and after minutes (ti) of stabilisation period of pcirv ( % inspiratory time, % pause). vt,ve and total peep were held constant in every mode of ventilation. +_ . " *'p < , versus to conclusions: these data show that pcirv : is a safe ventilatory support also in cardiac patients with impaired ventricular function, and monitoring of itbv is more reliable to measure and optimise circulatory volume status, than w and cvp. c.ledeki-,g.rldisis,s.karotzai,c.micheilidis,m.agioutantb, g.beltapaulos. objeolivee:to evaluate the influence of lvswl on the well known correlation of sr and svo . paw eight patients ( melee end females) were included in this study regerdlen of the icu ~h"niseion couse. all paints were ,'~theta~ with e fiboroptir pulmonary artery catheter connected with an oxymetfir (r)~ so /co abbot computer.for any pulmonary artery catheter insertion, two pain= of sr and svo were obtained, one dudng inserlion and one during taking the catheter out. for any pair obtained, we eleo collected the deta concemig with the pedient's hemodynamir and oxygenation end we calculated the lvswi. were significantly (p<o. ) higher in group i. conclusion: breathing room air, the less hypoxemic patients had a rather satidactory do and tissue oxygenation (pro ) because they had properly adapted their ci. the absence of this mechanism (right heart impairement ?) in the hypoxemic patients, in spite of higher blood ne and e, was responsible for the poor do and pro . objectives: acute massive pulmonary embolism (pe) increases pulmonary artery pressure (pap) and dght ventdcular aftedoad, which may lead to dght ventdcular failure. inhaled nitdc oxide (no) selectively dilates pulmonary vessels. thus, inhaled no may be of potential therapeutic value in the management of the acute phase of pe. methods: following institutional approval, ten piglets (body weight + kg) were anaesthetised (midazolam/piritramide) and ventilated using a modified servo ventilator (siemens elema, sweden; fio . ). the following variables were obtained: systolic pap (spap), mean pap (mpap), diastolic pap (dpap), mean artedal pressure (map), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), cardiac output (co), and artedal (pao ) and mixed venous (pvo ) oxygen saturation. pulmonary vascular resistance (pvr) was calculated. to induce pe, pm microspheres (sephadex g coarse, pharmacia biotech, freiburg, germany) were injected in an amount sufficient to increase mpap to mmhg initially. rain after embolisation when haemodynamics were in a steady state (control ), inhaled no was administered. further measurements were taken min after ppm no (no ), min after ppm no (no ), and min after discontinuation of no administration (control ). the administration of inhaled no resulted in a significant decrease in spap, mpap, and pvr. the cessation of no inhalation led to a complete return to pretreatment control values (table) . co, map, cvp, pcwp, pao?, and pv~ remained unchan no administration. objectivss:evsluate the yield of recombinant tissue plasminogen activater(rt-pa, actiiyse ~ oehringer ingelheim) as a thrombolytic agent ie pulmonary embolism ie .kr~auma patients. methods: in five patients with diagnosed pulmonary embolism(blood gases, chest x-ray, echocardiography, perlesion lung scans) were given rag of actij.yse as ~ hrs infusion, followed by heparin~single j. ihjaction snd iefusion ie doses - j./kg/day).the effectiveness of rt-pg thrembo].ytic sctier~ was svaluated im . . hrs(blood gases) amd on the third dayafter t~eat-,ment(~chocardiography and lung scan). results: three hrs after actilyse was given we observed significant clinical imprevemeet,confirmed by elevation of pao and sao in dlood.echocardiegr~m on the third day showed regression of pulmonary hypertension and lung scans showed % improvement in total lung perfusien. except slight bleeding from the site of injection nc~ more thromboiytic complicatioos were observed. conclusiens: actilyse used in five hrauma patients with pulmonary embol.ism was a very effsctive and safe thrombolytic agerlt, inducing rapid and evident clinical improvement. intermittent positive pressure ventilation ( ppv) by increasing pleural pressure, decreases the pressure gradients for systemic venous return and left ventricular (lv) ejection. we have previously shown that when inspiration is synchronized with systole using synchfjv in patients with severe cardiomyopathy, that cardiac output (co) was increased relative to both ippv and non-synchronized hfjv ( ). however, it is not known if similar effects could be realized in ventilatordependent patients with lesser degrees of lv dysfunction and fluid overload. we thus compared synci-ifjv to ippv in stable patients following coronary artery bypas grafting. methods: normothermic who were stable (< % variance/h.) were studied following admission to the sicu. heart rate (hr), mean arterial (pa), pulmonary artery occlusion pressure(ppao), co by continuous thermodilutiun (vigilance, baxter, usa), mixed venous saturation (svoz) and arterial blood gases (abg) were measured after rain. of each step. ippv was simv adjusted for a rate, tidal volume and fit to insure both normal abg and a peak airway pressure < cm h,o. syncfifjv was delivered by a hfjv ventilator (acutronic) during systole with ventilator parameters adjusted to optimize abg. protocol: patients received three ippv runs (ippvi. , ) with synchfjv runs interposed (hfjvz ). statistics: anova for repeat measures and paired t-test were used to compareruns and demonstrate variability. results:no significant difference in any of the measured hemodynamic variables were seen among the ippv and synchfjv runs (table) . post hoc separation of patients by preoperative ejection fraction (ef; ef > % ; n= and < %; n= ) did not alter these results. back~ound: in man, vascular endothelium-bound ace is expressed in concentrations greater than x that in serum and is believed to be the site of synthesis of circulating angioteusin il it is unclear whether ace inlubitors interact similarly with ace in different vascular beds. coronary vessels possess all the components of the renin-angiotensin system, including ace which may be involved in normalcardiac homeostasis, as well as in the pathogenesis of various cardiomyopathies. obiecfive: to develop a method for assaying the interaction of ace inkibitors with coronary endothelium-bunnd ace in man, methods: ace a~aty was meas~ed in five patients undergoing cabg surgery, from the transeuronary hydrolysis of the synthetic ace substrate h-bpap. trace mnou~ of ~fi-bpap ( gci) were injec~d as a bolus in the root of the aorta and simultaneously blood was withdrawn from a coronary sinus catheter into a syringe containing protease inhibitors which prevented the convession of umeaet~ ai-i-bpap by blood ace. the sample was later centrifuged to separate cells from plasma and the radioactivities due to formed product (~rl-bphe) and total sh were astimated in a [b-counter. two additional such determinations of ace activity were perform~ the second in the presence of . pg/kg e (coinjected with ~-i-bpap) and the third ten minutes after e. results: all subjects were hemodynamically stable throughout the course of the there were no noticeable hemodynamic effects of e. control transcorunary metabolism of~-bpap averaged g -a: %, in agreement with previously reported data. in the presence of e, % metabolism of ~-bpap was reduced to • reflecting a • inhibition of normal ace activity. ten minutes after e, ~ri-bfap metabolism had partially recovered to :l: %, representing a -a: % inhibition of control ace activity. from this data, the dissociation constant of e for coronary ace in vivo was estimated as . x " sec "l. conclusions: we have demonstrated the feasibility of repeated, reproducible measures of coronary endothelium-bound ace activity and of its inhibition by e. this procedure is safe and can be used to study the role of ace in normal cardiac function and in card pathologies. objectives. primary pulmonary hypertension (pph) is a progressive fatal disease of unlmown origin, with median life expectancy of less than three years after diagnosis. the responsiveness of pulmonary hypertension to a variety of vasodilator agents led to the speculation that, concomitant with vascular renmdelling processes, persistent vasoconstriction is an important feature of the disease. long term use of ca-channel blockers and intravenous pgiz may improve mortality in certain populations of pph patients, but both of these treatments lack selectivity for tire lung vasculature. the aim of this study was to test the efficacy of aerosolised prostacyclin and its stable analogue, [loprost for selective pulmonary vasodilatation in pph. methods: in three patients with pph, we compared aerosolisation of prostaglandin iz (pgi ) and iloprost to a battery of vasodilatory agents (diltiazem, nifedipin, inhaled nitric oxide, intravenous pgiz). results: nebulisation of pgi and iloprost tumed out to be most favourable for achieving effective and selective pulmonary vasodilatation. pulmonary vascular resistance decreased from + to -+ dyn*s*cm (p< . ) and pulmonary artery pressure from . + . to + . mmhg (p < . ), cardiac output increased from . + . to . _+ . i/rain (p < . ), mixed venous oxygen saturation from . _+ . to . + . % (p < . ) and arterial oxygen saturation from . + . to . _+ . % (mean _+ sem of trials in patients). -month iloprost nebulisation in one patient ( gg/day in six aerosol doses) demonstrated sustained efficacy of the vasodilator r~men. conclusion: aerosolation of pgi or its stable analogue may offer as new strategy for selective pulmonary vasodilatation in pph. endothelial adhesion molecules may play an important role in the pathogenesis of myocardial cell damage, and may contribute to the progression of heart failure. we measured the plasma soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selecfin (selam- ) levels in patients with acute myocardial infarction admitted within hours after onset. peripheral venous plasma-samples were collected at the time of admission, , , , , and hours after onset. plasma soluble adhesion molecule concentrations were determined by elisa. patients were divided into groups as follows: group ; killip's class (k) and without thrombolytie therapy, group ; k and with thrombolytic therapy and group ; k and . both plasma sicam- and svcam- concentrations in group and were elevated rapidly and significantly and maintained at a high level during the first days. plasma selam- level did not change in any of the groups. these results suggest that the adhesion molecules icam- and vcam- may play a role in the pathogenesis of myocardial reperfusion injury and may indicate its severity in myocardial infarction. objectives: nitric oxide (no) is known to exert cytotoxic and negative inotropic effects on cardiomyocytes. no synthase activity has been reported to be increased in infarcted area in animal model of myocardial infarction. these findings suggest that no may be an important regulator for myocardial damage and cardiac function after myocardial infarction. we measured plasma no no -(nox) levels and estimated serial changes in acute phase of myocardial infarction. methods: subjects were patients admitted within hours after onset. venous blood samples were collected at -hour intervals on the first day, -bour intervals on the nd day and -hour intervals on the rd day and th days after onset. plasma nox concentrations were determined by griess method. results: the time course of the plasma nox levels (mea~+sem) displayed a tendency to gradually increase and to make a biphasic pattern with two peaks about hours and - days after onset (basal level; . _+ . , first peak; . !-_ . , second peak; . + . ram/l). plasma nox concentration was not influenced by the thrombolytic therapy, and nox values at the time of hours after onset were significantly correlated with maximal plasma creatine kinase level (r= . , p< . ). the levels of plasma nox in the early stage of myocardial infarction (from admission to the th day after onset) did not correlate significantly with the hemodynamic parameters (left ventricular ejection fraction, pulmonary capillary wedge pressure). conclusion: the early and late increase in no production after myocardial infarction may be implicated in the deterioration of myocardial contractility and induction of myocardial damage in the early phase of myocardial infarction. range - ) fullfilling the high risk criteria of shoemaker (colectomy , gastrectomy , pancreaticoduodenectomy , others ). patients were admitted to the icu preoperatively. arterial and pulmonary artery catheters were inserted and hemodynamics and oxygen transport were measured at admission and after stabilization to predetermined physiological end points. patients were considered stable when ci > . l/min/m , pcwp > mmhg, hb > g/l, sat >. . objectives: evaluate the acute effects of , mg ipratropium bromide and , mg fenoterol (ibf) inhaled dose on pulmonary function in nonsmocers (nb:m) and smocers (s) with sever (new york heart association class ii-iii), stabile congestive heart failure(chf) and healthy subjects. methods: pulmonary function tests were performed < h postprandial. the tests consisted el arterial blood gas aspiration followed by routine spirometry and pletismography, and single-breath gas analysis. after performance of these maneuvers, the patients was administred puffs-ipratropium bromide ( , rag) and fenoterol ( , rag). for , h, spirometry was repeated. results: in resting, pulmonary abnormalities observer in the s group were more severe then abnormalities observere in the nsm group. after treatment with ibf the improvement in pulmonary function was even more marked in patients who had smoked. the mean changes by forced expiratory volume in second(eevt) was , % (p< , t) improvement and , % (p< ,ob), forced expiratory flow betwen % and % of the forced vital capacity (fef . ) was , % (p< , ) and , % (p< , ) and maxamal voluntary ventilation (mw) was , % (p< , ) and , % (p<o, ) improvement. the mean changes in normal subjects were mild (fev increased by , %,fef - by , % and mvv by , %). we observed no adverse heamodinamie conseevence and no arrthytmogenicity. conclusion." in patients with chf the airway response to ibf is highly significant. further study is needed to determine whether therapy with ibf will load to improvement quality of life in patients with chf with dearly documented venti/atory defects. compared with unilateral ima grafts, usage of bilateral ima grafts in cabg patients causes greater thoracic trauma and further reduces blood supply to the sternum and intercostal muscles. these effects may be associated with increased postoperative respiratory complications obiectives: to study the effects of bilateral ima grafts on postoperative respiratory morbidity in cabg patients. methods: two groups of patients undergoing cabg were prospectively studied: group (n= ) received both imas as grafts and group (n= ) received only the left ima. the two groups were matched for age, smoking habits, total number of grafts and preoperative ejection fraction. pao /fio ratio was measured in all patients in the icu, at , , minutes on mechanical ventilation (mv), at , , minutes after extubation (ex) and on postoperative day (pod) . in addition, radiografic scores of atelectasis and pleural effusion were assessed postoperatively. results: group had significantly longer bypass ( _+ vs + . p< , ) and aortic cross clamp time ( +- vs + , p= , ). pao /fi ratio was significantly higher in group only at minutes after extubation (table) . there was no difference in the incidence or severity of atelectasis or pleural effusion between the two groups. the duration of mv was longer in group ( +_ vs _+ , p= , ), but the length of icu stay and hospitalization were similar. there was one case of pneumothorax in group and one case of pulmonary infection in each group. after extubation m[n min min min* rain min pod ' _+ _+ + -+ - -+ _+ _+ _+ _+ -+ _+ _+ -+ mean_+sd, *p=o, o conclusions: compared with unilateral ima grafts, the usage of bilateral ima grafts in cabg patients is not associated with increased postoperative respiratory morbidity. the diagnosis of rv ischaemia is difficult in the critical care setting. the purpose of this study was to determine the ability of rv endomyocardial and interstitial ph electrodes to detect rv ischaemia in an animal model of rv infarction produced by fight coronary artery ligation. we hypothesized that changes in transmural and interstitial ph would accompany the induced tissue hypoperfusion. rv interstitial (phint) and transmural endomyocardial ph (phendo) were measured in adult anaesthetized pigs before and serially after coronary ligation. phendo and phint fell progressively and significantly following coronary occlusion. this was accompanied by ischaemic ekg changes. the absolute and relative rates of change were greater for phendo compared to phint, particularly after minutes of ischaemia, ph was unchanged in control experiments when the electrode was placed within the fight atrial or ventricular chambers, as well as when coronary ligation was not performed. these data suggest that rv myocardial ph measurements reflect coronary ligation induced rv ischaemia, ph recorded from an electrode placed against the rv endomyocardial wall via a central vein was as useful as an interstitial measurement that required a thoracotomy. this newly described technique may be helpful in clinical settings where differentiation between ischaemic and nonisehaemic causes of rv dysfunction is important. centre. depts of cardiac surgery and anesthesiology, university of bari, italy. lung injury secondary to cardiopulmonary bypass (cpb) is well recognized. nevertheless, mechanical respiratory changes after cpb have been poorly investigated. aim of the study was to evaluate the effects of cpb on respiratory mechanics. elastance of the lung (est l), chest wall (est cw), and total respiratory system (est rs) were measured in patients without previous pulmonary disease undergoing elective cardiac surgery. there were males and females; no pleurotomy was done. cpb was carried out with membrane oxygenator. mean cpb and cross clamping times were _. and • min. flow (pneumothacograph), airway opening and esophageal pressures (pressure transducers and esophageal balloon) were measured on patients sedated and paralysed. measurements were obtained before sternotomy, at the end of cpb after chest closure, four and seven hours later. est rs, est l and est cw, were measured by occluding the airways and the end of a tidal breath. before end cpb- h after h after stemotomy closed chest cpb cpb estrs (cmh /l) . + . . - . " . _+ . * . - . * est cw " . _+ . . • . + . . -+ . est l " . -- . . - . " . -_ . " . _+ . " x + sd. * p < . : anova vs "before sternotomy". our data show that cpb induces increase in est l, whereas est cw remains unchanged despite sternotomy. impairment in est l after cpb evolves within the first hours and stabilizes hours later. during the clinical course of human imunodeficiency virus infection (hiv), patients (lots) can develop congestive and dilated cardiomyopathy syndrome (dcm). the aim of our study was to analyze the prevalence of dcm among an hiv population, its clinical and echocardiographic changes under a long term follow-up and therapy with an ace-inhibitor agent (captopril). we prospectively studied pts, % ( / ) developed dcm during the follow-up study. among this group % ( / pts) were in class i and ii and % ( / pts) in class iii and iv of the nyha classification. we divided this population in a acei+ ( pts) and acei-( pts), according to the administration of captopril. we analyzed the following parameters: age, gender, race, ivda, type of hiv, cdc classification, number of t and t type cell population and its t /t ratio, therapeutic with acei, type and number of opportunist infections, mycobacteriosis and neoplasm's. we analyzed several echocardiographic parameters, which included the initial (i), final (f) and variation (a) of the lv internal diastolic (lvdd/mm) and systolic (lvsdimm) diameters, lv % of fractional shortening (lv%fs/%), ivs and posterior wall thickness and lv mass (lvm/g). the two groups differed significantly in the following parameters: left ventricular functional indices of patients (pts) with iscjhemic dilated cardiomyopathy (idcm) have a critical value in terms of clinical prognosis of this disease. three-dimensional echocardiography ( -de) is a recently developed method that gives a better evaluation of lv morphology and function. the purpose of our prospective study was to assess the clinical applicability of this new -de method in a population with ischemic dcm diagnosis and calculate its lv indices of global and regional function. we studied a group of idcm pts, mean age _+ yrs, % male gender, using a combined -de tee approach. all pts were in class ill/iv of the nyha classification. first, ekg gated images were acquired through a mechanical pullback of the tee probe, and each set of data was transferred to a conventional ibm-pc system using a dedicated -de software. computer processing and analysis of the tee images led to a -de reconstruction matrix and off-line calculation of several lv global and regional indices. in all idcm lots the lv cavity was clearly reconstructed and end-systole and diastole in several orthogonat projections, out in multiple planes and its function quantitated using -de derived indices. mean values of -de lvesv= -+ ml, lvedv= _+ ml, lvstv= _+ ml and lvef= -+ % were obtained. for all these -de parameters, good correlations were observed with -de lv measurements obtained through biplane tee analysis of the lv cavity (r>. ; p<. ) as well as regional analysis of sequential -de cut planes. conclusion: in our group of patients with the diagnosis of ischemic dilated cardiomyopathy, this new -de method could be applied. our results show that this method allows a better assessment of the lv morphology and spatial geometry, with the calculation of global and regional indices with critical clinical and prognostic value in this particular cardiovascular pathology. simultaneous left atrial (la) and left ventricle (lv) inflow analysis assessed by pulsed doppler tee illustrate the loading conditions and reflect the hemodynamics of the left heart. we performed a prospective tee pulsed doppler study with recordings of the transmitral lv filling and pulmonary venous (pv) flow drainage in a group of patients with dilated cardiomyopathy (dcm). a group of dcm patients, mean age _+ yrs, % male were studied. this population was divided according to tee severe lv dysfunction (group slvd+ % pts; group slvd- % pts) in each pt we measured the peak velocities (vel/m/sec) and time velocity integrals (vti/m) of the transmitral early (e) and late (a) filing waves, the vel and vti of the pv systolic (s), diastolic (d) and atrial contraction (c) reversal flows. -de tee evaluation of the lved, lves, lvst volumes and lvef were obtained. we calculated other parameters, such as e/a, s/d and a/c ratios and the sum of c+a vel, that refelect la systolic function and lv compliance. + -_ . simultaneous and quantitative analytical approach of the pulmonary venous and transmitral flows and ventricular volumes improve the non invasive assessment and understanding of left ventricular diastolic function and cardiac performance in dilated cardiomyopathy patients. objectives : to assess the hemodynamic effects of fluid loading (fl) in acute circulatory failure (acf) due to acute massive pulmonary embolism. methods : hemodynamic measurements (fast-response thermistor pulmonary artery catheter) were performed at baseline (baseline) and after a rapid fluid loading with (fl ) and (fl ) ml of dextl'an (rhemacrodex| in patients free of previous cardiopulmonary disease ( • yrs) with acf (ci < . l/rain/m ) due to angiographicalty proven mpe (miller score > ) . results : are expressed as mean _+ sem and compared by anova. a significant negative correlation (r = . ) was observed between baseline rvedv[ and the effects of fl on ci. such correlation was not observed between baseline rap and the fl induced increased in ci. conclusion : fusibmificantly increases ci in acf due to mpe. however, the simultaneous decrease of arterial content due to hemodilution, limits the benefits expected from improved ci on peripheral oxygenation. obiective: to examine the hemodynamic effects of external positive endexpiratory pressure (peep) on right ventricular (rv) function in acute respiratory failure (arf) patients. methods: incremental levels of peep ( - - - cmh ) were applied and rv hemodynamics were studied by a swan-ganz catheter with a fast response thermistor for right ventrieular ejection fraction (rvef) measurement in mechanically ventilated arf patients (lis = . ~- . sd). according to the response to peep , two groups of patients were defined: group a ( pts.) with unchanged or increased rv end diastolic volume index (rvedvi) and group b (h pts) with decreased rvedvi. results: in the whole sample cardiac index (ci) and stroke index (sj) decreased at all levels of peep, while rvedvi , rv end systolic volume index (rvesvi) and rvef remained anchange d. at zeep the hemodynamic parameters of the two groups did not differ. in group a, ci decreased at peep , rvef decreased at peep (~ . %)~ rvesvi increased only at peep (+ . %) and rvedv[ reded unchanged. in group b, ci and rvedvi started to decrease at peep , 'rvesvi decreased only at peep (- . %), anf rvef was unchanged. individual behaviors of the hemodynamic parameters at the levels& peep were studied. rvedvi and ci were significantly correlated in out of:l patients in group b, and in no patient of group a. on the contrary, mpap and rvesvi were significantly correlated in out of patients in group a, and in no patient of group b. the slope of the relationship between rvedvi and rv stroke work index (rvswi) expresses rv myocardial performance. this relationship was significant (no change in rv contractitity)in patients of group b and in patients of group a. in some patients of group a, increments of peep shifted the rvswi/rvedvi ratio rightward inthe plot (rv function decrease). conclusions: in arf patients peep causes more often a preload decrease with unclmnged rv conctraetility. on the contrary, the finding of increased rv volumes during the application of peep is related to a decrease in rv myocardial performance. thus, these data suggest that application of peep might be considered as a stress test to assess rv function. right introduction: after heart transplant (ht), the right ventricle can be subject to an acute pressure overload, especially in cases where there is a preexisting severe pulmonary hypertension. this provokes right ventricular failure and, occasionally, circulatory collapse in intensive care unit. desire the advances that have been made in systems for preserving the donor heart and in post-surgical management, we have failed in our attempts to totally avoid this problem. the right ventricular function, although it usually remains within tolerable limits in these patients during the post surgery period, represents a factor which limits the results achievable in clinical transplant programmes. objectives: to determine the maximum tolerance of the right ventricle (mxtrv) when faced with acute pressure overload. to study the function of both ventricles of the healthy heart (donor) when faced with different degrees of pulmonary hypertension. to detect possible interactions between the ventricles in the absence of the pericardium to approximate the experimental model to the clinical model of ht. materials and methods: the pulmonary artery is progressively constrained in an experimental model until biventricniar failure is detected. this experiment is performed in two diffferent situations: with and without pericardial integrity. results: when pericardial integrity is maintained the mxtrv faced with a pressure overload is . + . nun hg. when this pressure is exceeded there is a circulatory collapse with a sharp fall in the cardiac output and in the aortic pressure. however, when pericardectomy is performed (model similar to ht), only • . nun hg is tolerated (p < . ). conclusions: with the pericardium open, as in heart transplant, the maximum pressure that the right ventricle can support is significantly less than with the pericardium closed. the pericardium has a positive effect in protecting the systolic ventricular interaction. it is, therefore, advisable to close the pericardium after heart transplant. jb prrez-bernal, a ordrfiez, a. heroandez, jm borrego, map camacho, c cruz, mac s~nchez, j monterrubio, c garcia, e. gonz~lez. hospital uulversitario " virgen del rocio ". sevilla. espaiqa. introduction: nowadays cardiomyoplasty isused incases of cardiac insufficiency as an alternative to cardiac transplant. after surgery the patients show a noteable improvement with the aid of this "biological circulatory assistance". some researchers suspect that the improvement could also be due to the formation of new blood vessels from the muscle that wraps the heart, nourishing the ischemic myocardium. objectives: our cardiovascular research group has proposed as an objective, the detection of any possible myocardial neovascularization through the muscle used for cardiomyoplasty. in the case that there are new blood vessels to the diseased myocardium through the wide dorsal muscle in which it is wrapped and which aids it mechanically, it would be possible to confirm the worldng hypothesis that cardiomyoplasty not only improves the cardiocirculatory funcfinn mechanically but also by facilitating a better blood flow to the ischemic myocardium. materials and methods: the cardiomyoplasty technique is described using an experimental model of myocardial ischemia. the vascular cast is achieved by injecting methacrylate simulataneously into both the coronary tree and the wide dorsal muscle, in five experiments the connections between the coronary vascular system and the vascular structure of the wide dorsal muscle are demonstrated, conclusions: we have demonstrated that cardiomyoplasty, as well as improving ventricular function, favours the revascularization of the myocardium. cardiomyoplasty could be indicated for cases of ischemic cardiopathy in patients in whom it is not possible to perform direct revacularization using conventional methods. a the therapeutic cardiological manouevres necessary in cases of ischeima reperfusion have increased considerably: fibrinolysis, transluminal angioplasty, coronary revascnlarization surgery and cardiac transplant. the appearance of a specific pathology ht acute reperfusion has been related to free oxygen radicals (for) generated by oxidative damage. objectives: to evaluate the appearance of for during a conti-olled process of ischemia-reperfusion in an experimental biological model and compare it with that in clinical cases. materials and methods: transitory cardiac ischemia was performed in five rabbits by reversible surgical ligation of the descending anterior coronary artery. after minutes coronary reperfusion was performed. blood samples were taken in the basal situation, at the end of ischemia and at , and minutes after the start of reperfusion. malondialdehyde (mda) was measured to evaluate the degree of lipid peroxidation (oxidative damage to the membrane). in ten patients undergoing conventional cardiac surgery the production of for was measured after aortic clamping. results: we observed that after minutes of reperfusion there was a highly significant increase (p < . ) in the mda values (mean = . /zmols/l). these returned to basal levels after and minutes of reperfusion. conclusions: an "explosion" of oxygen free radicals was detected very quicldy, just a few minutes after post-ischemia reperfusion. thus, if antioxidant agents are to be used to reduce the toxic effects of the for, these will ordy have a therapeutic effect if they are administered in the early phases of reperfusion. introduction: aortic connterpulsation is a ventricular assistance widely used in intensive care units in patients with cardiogenic shock as a provisional ventricular assistance. paraaortic or external aortic counterpnlsation is been investigated as a definitive veutricular assistance in those cases of terminal congestive heart failure and when heart transplantation is counterindicated. aims: to assess the haemodynamic effects of an aortomyoplasty in a biological model of congestive heart failure. material and method: as specimens, we used "large white" pigs. mean weight was kg. after the administration of conventional anaesthesia, dissection of the ladssimns dorsi muscle was performed on the samples at the laboratory of experimental surgery of our hospital. then we performed a thoracotomy at the level of the fourth intercostal space to reach the thoracic aorta. the aorta is dissecated centimetres from the exit of the subclavia and it is wrapped by the dissecated muscle. a cardiomyostimulator is provided in order to allow the synchronization between the diastole and the muscle contraction. the model of heart failure was provoked using verapamil plus propanolol i.v.. results: a significant increase of the aortic diastolic pressures and a significant decrease of the left ventricle telediastolic pressures were observed. this improvement in the parameters (dpti/tti) implies an increase of the coronary perfusion in a model of heart failure. conclusions: using the external aortic counterpulsation, the aortomyoplasty improves the coronary perfnsion and the heart efficiency in patients with heart failure in whom no conventional therapeutic action is possible. the permanent character of the paraaortic counterpulsation is it main advantage. the appearance of specific pathologies as a resuk of myocardial reperfasion has been related to the oxidative damage secondary to the release of oxygen derived free radicals (ofr). during the myocardial ischemia induced during heart surgery with extraeorporeal circulation, severalsubproducts of the oxygen are produced that shall cause toxic effects after the reperfusion which could be counteracted by the physiological antioxidant systems and/or provided by the medication. aims: to asses the ofr during heart surgery. to check whether an antioxidant treatment administered in the preoperative period make decrease the levels of ofr before and after the myocardial reperfusion and to verify whether its administration have any beneficial effect on the intra and extraoperative management. material and method: the study comprehends patients studied as two groups of individuals each (a and b). all patients underwent conventional heart surgery of valvniar substitmion or myocardial revaseularization. group a patients were administered rag/ hours of vitamin e (tocopherol acetate) hours prior to the intervention as antioxidant treatment. group b patient were not administered vitamin e. we assessed the quantity of malondialdehido (mda) to assess the degree of lipidic peroxidation or oxidative damage of the membrane during the myocardial ischemia and nm after the reperfusion. conclusion: patients who underwent heart surgery and were treated with tecopherol acetate in the preoperative period presented levels of rlo significantly lower than those who were not administered the drug, both during the intraoperative period and after myocardial reperfusion. we detected in these patients a need for antiarrhythmicals and pharmacoiogical support with catecholaminas, although not significant, both in the introaperative period and the immediate postoperative period. recommendations for the treatment of pulmonary embolism (pe) in the presence of right atrial thrombus (at) are conflicting. because of a significantly higher mortality rate due to fulminam or recurrent pe, there is a necessity to treat patients (pts) with mobile type a thrombi compared to pts with adherent type b thrombi. therapeutic strategies include anticoagulation, thrombolysis (t) or surgical thrombembolectomy. combination thrombolysis (cot), predominantly used for the treatment of acute myocardial infarction proved to prevent reocclusion of the infarct related artery at a comparable rate of hemorrhagia. benefit has been related to the alteration of hemostatic proteins by non-fibrinspecific thrombolytic s. administration of cot in pe has been performed sporadically. in the present case, a -year old male with no history of prior cardiovascular disease developed acute dyspnea which was related to pe in the presence of deep vein thrombosis of the left femoral vein. therapeutic anticoagulation was installed for a couple of days until there were several bouts of deterioration. biplane transesophageal echocardiography (tee) was performed and revealed a large, wormlike, hypermobile thrombus within the right atrium. computer tomography (ct) of the chest detected a saddle embolus in the bifurcation of the pulmonary tmnk almost occluding the entire left pulmonary artery (pa) and parts of the right pat consisted of mg frontloaded rt-pa and the subsequent continuous administration of urokinase in a dosis of . u/hr for hrs followed by therapeutic anticoagulation. symptoms, blood gases and ecg improved steadily during infusion, no adverse effects, i.e. minor or major hemorragia were registered. follow-up ct promptly after termination of t showed almost complete resolution of the saddle embelus, whereas tee showed complete dissolution of the at. ' finally, the patient was switched to oral anticoagulants and had an uneventful clinical course until he was discharged. conclusion: in the present case, cot was effective for the treatment of a complicated pe without any adverse effect. introduction: nowadays we can assist hearts with problems of insufficiency by techniques other than transplant. many researchers believe that the best way of assisting insufficient heart muscle is with another muscle from the patient. this technique of ventficular assistance is known as cardiomyoplasty. we describe the surgical technique of cardiomyoplasty using a biological model. the transformed skeletal muscle is transferred to the thoracic cavity where it wraps the heart and assists it. the choice and preparation of this muscle is currently under investigation. our group has focussed on the development of protocols for electrical stimulation to transform a skeletal muscle into a muscle which resists fatigue and which is functionally similar to the myocardium. we detect the optimum time at which this muscle has been transformed, by studying the transmembrane action potentials using intracellular electrodes. when the action potential of the trained muscle behaves like cardiac muscle we consider it ready for cardiomyoplasty. conclusions: cardiomyoplasty is an alternative surgical technique to cardiac transplant, which has a great future in the treatment of patients with advanced cardiac insufficiency. we describe methodology which, by intracellular techniques, allows selection of the optimum moment of transformation of a skeletal muscle trained to perform,like cardiac muscle, without suffering fatigue. purulent pericarditis is a rare disease. its treatment associate systemic antibiotics and drainage of the pericardium. we report a ease of purulent constrictive pericarditis in which intraperieardial fibrinolysis was use. a years old patient admitted in our icu for a constrictive pericarditis as a complication of a purulent pericarditis diagnosed seventeen days before. he had also an aehalasia and the o'esogastric endoscopy had found an oesophageal neoplasm. a fistula was not seen, indeed pericardial of flora was the same that oropharyngeal. hemodynamie and echographic study had confirmed a constrictive pericarditis. because of the poor state of the patient an intraperieardial fibrinolysis was prescribed ( . ui of streptokinase on days , , , ). fluid drainage was improved and cardiac output was also improved (day : . .min "i, day : . l.min'l). no change ofhemostasis was noted. a pericardeetomy and an oesophagectomy were performed after days of evolution. eighteen months latter the patient was still alive. intraperieardial fibrinolysis seems an interesting therapeutic way if rapidly prescribed in the purulent pericarditis course. the decrease in the systolic pressure following a mechanical breath, termed ddown (delta down), has been shown to be a sensitive indicator of preload ( , ) . however, the clinical use of this method necessitates the introduction of a short apnea. we have therefore developed a respiratory systolic variation test (rsvt) which obviates the need for apnea. the test is based on the delivery of successive breaths of increasing magnitude ( , , , and ml/kg). a line of best fit is drawn between the minimal systolic values (one after each breath) and the downslope calculated as the decrease in blond pressure for each increase in airway pressure ( mmhg / cmh ). in mechanically ventilated patients the rsvt was performed during controlled mechanical ventilation under sedation. the test was repeated after the administration of ml/kg of plasma expander. the initial mean downslope of the rsvt was -. + . mmhg/cmh . following volume loading the downslope decreased to -. + . (ns). at the same time, cardiac output (co) increased by . + . l/min (p<. ), end-diastolic area (determined by tee) increased from . + . to . + . cm (ns), and paop increased from + to + mmhg ( p < . ). the preinfusion downslope value of the rsvt correlated significantly with the increase in the co (r = . ) and the eda (r = . ). methods: an expert system has been constructed running on a multimedia computer with the two objectives in mind, viz training of inexperienced staff, and protocol guidance with treatment regimes for all staff. the system is based on experience gained from two previous systems, the one for dealing with acid-base and electrolyte problems in icu patients; the second for stabilisation of patients with heart rate and blood pressure abnormalities. the training section takes the form of a stage-by-stage account of the insertion of the pac and displays of correct waveforms, coupled with indications of possible incorrect placements, and guidance when failing to achieve the perfect positioning. the treatment protocol section extends an existing protocol for correcting abnormalities in heart-rate and blood-pressure, and now takes account of all the indices as measured by the pac. the system will suggest treatment to correct such things as abnormal wedge pressures concomitant with parameter values throughout the rest of the cardiovascular system. the type of patient eg post-operative cardiothoracic or i. c. u. trauma, will be taken into account when recognising abnormal parameter values and when prescribing treatment. results: a working system which will be improved by the finetuning being carried out. the results and lessons learnt will be presented at the conference. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion ~ . g/kg/ rain with a map --< mmhg. cardiovascular support was limited to na + dobutamine (db). c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t - ); and at the end of treatment (t - ) with c . conclusions: c does not appear to increase mpap or worsen pulmonary gas exchange in patients with septic shock, when given by infusion for up to h. c is a novel vasoactive agent for the treatment of septic shock which will now he evaluated in a randomised, placebo-controlled safety and efficacy study. objectives : to compare cardiac output (q) data obtained for thermal indicators in pulmonary artery (qtpa) and aorta (qtao) and for the stable isotope hzo in aorta (q v~ o) with indocyanine green (icg) in aorta (qicg) as reference. methods : an indicator solution of ice cold h ( . ml), h ( . ml) and icg ( mg) was injected as bolus via the injection port of a swan-ganz catheter. qlco and qzmo was measured using a dual optical system (penn lab instruments, philadephia, pa, usa). qtpa and qtao was measured using a in contrast to the recoveries of thermal indicator in pa and h in aorta the :~covery of thermal indicator in aorta was significantly increased in group ii (n= boluses) over group i (n= boluses) ( . <- . vs. . +- . , p= . ). conclusions: the "overrecovery" of thermal indicator in aorta is in agreement with " biscks deconvolution study (i) and results in erroneous values for q. the most pausible explanation is the distortion of the thermal curve caused by the slow response time of the thermal detection instrument as shown by ganz ( ) objectives: to compare data obtained with the double indicator dilution method using indocyanine green (icg) and the stable isotope h for the estimation of extravascular lung water (evlw hzo) to gravimetriu lungwater data (evlwg~). methods: an indicator solution oflcg ( rag) and h ( . ml) was injected as bolus via the injection port of a swan-ganz catheter. dilution curves for icg and zh was registered in aorta with a dual optical system (penn lab instruments, philadephia, pa, usa). cardiac output and mean tranist time was measured for both tracers (qico, tlco, q n o, t o) ( ). data analysis: evlwg~av was reference for evlwzhzo calculated as q hzo times the difference in mean transit time between t nzo and rico (atm n). as reference for atzn o evlwg~,v was divided by q~cg to obtain atg~,. a reference distribution volume for h was calculated as the sum of central blood volume and evlwg=v. boluses were administrated in a group (i) of anaesthetized pulmonary healthy sheep while q was altered. another boluses were administrated in a group (ii) of anaesthetized sheep with stable oleic acid induced pulmonary oedema. evlwg~v measurement was performed postmortem. results: for boluses h parameters were not significantly different from their respective reference parameter: at vao . +_ . s vs. atg~, . + . s, evlwzh o -+ ml vs. evlwg~,~ + ml. in group i the ratio between hzo parameters and respective reference parameters (n= ) were independent of qlco from . to . l/min. obiectives: to assess the thermo dye method using indocyanine green (icg) and thermal indicator for the estimation of lung water (evlwt). methods: ice cold indicator solution of icg ( mg) in water ( ml the aim of the study was to assess left and right ventricular function in the early postoperative period after orthotopic heart transplantation to elaborate therapeutic approaches of heart function abnormalities correction. mathefial and methods. haemodynamic monitoring data of twenty one patients ( men, women ) age from to were studied. cardiac output, pulmonary artery, right atrium and pulmonary wedged pressure were measured with swan-gans catheter. central haemodynamic indices were calculated with the help of computer-based monitoring system. relations of ventricular stroke work index to it's end-diastolic pressure were used for ventficular function assessment. results. in most cases right ventricular disfunction was the main problem. isolated fight ventficular failure with high pulmonary vascular resistance (pvr) was observed in % ( pts), without high pvr-in % opts) and with left ventricular failure-in % ( pts). one of the most important reasons for fight ventricular failure was the time of heart ischemia more than min, which is of great importance in the ease of distance harvesting. the most effective treatment for cardiac failure was combination of dobutamine with i oprotherenol, atrial pacing and vasodilatators in case of right ventfieular disfunction. all cases with isolated right ventricular failure were treated sucsessfully. biventricular heart failure was a sighn of bad prognosis and the reason of death in cases. conclusion. right ventfieular disfunetion is the main problem during transplanted heart adaptation in the early postoperative period. optimal therapeutic management of cardiac disfunction includes infusion of dobutamine in combination with isoprotherenol, atrial pacing and vasodilatators. cardiology-department of clinical centre-kragujevac institution for occupational health "zastava"-kragujevac, sr yugoslavia the aim of the investigate is analisis five years survives patients with a.i.m.in dependence of locality and risk-factors. we ana~sed- ~-pat~e~ts ( males and woman), average , years. for statistic evaluation we used life-table slstem in oder to estimate prognostic determinants. patients with respkatory muscle paralysis may benefit from respiratory assistance by abdomino-diaphragmatie pneumatic belt. we used a non invasive technique, m-mode sonography, to assess the effect of this device on diaphragmatic excursion. we measured the amplitude of right diaphragm motion in seven patients with duehenne muscular dysl~ophy in supine position with various thoracic posture ( ~ ~ ~ without and during pneumatic belt respiratory assistance. without respiratory assistance, the thoracic posture had no significant consequence on the amplitude of diapttragm motion, either in quiet or deep breathing. the pneumatic belt increased the diaphragm motion amplitude from . +__ . mm to . +_ . ram (p = . ) at ~ tilt angle, and from . + . mm to . + . mm (p = . ) at " tilt angle. the tidal volume increased from + to + rut a * tilt angle, and from + to + ml at * tilt angle (p = . ). two patients could not bear the horizontal position ( ' tilt). in the five other patients, the pneumatic belt increased but not significantly the amplitude of diaphragm motion ( . + . mm to . + . ram). after an overnight respiratory assistance, pao increased from . +_. . to + . mmhg ( = . ), sao increased from . + . % to . +_. % (p = . ), and paco decreased from + . to . +_. mmhg (p = . ) according to the ventilatory pattern result, m-mode sonography allows to measure non invasively the improvement of diaphragm kinetics obtained by pneumatic belt respiratory assistance, and may be helpful for its adjustment. objective: to study the effect of flow triggering (flow sensitivity and l/min) vs pressure triggering (-lcmh ) on inspiratory effort during pressure support ventilation (psv) and assited/controlled mode (a/c) in stable copd patients non-invasively ventilated with a full face mask. methods: the patients were studied during randomized min. runs using a bird st ventilator at zero peep (zeep). trigger values for pressure (-lcmh ) and flow ( l/rain) were the lowest allowed by this ventilator. the transdiaphragmatic pressure time product per breath (ptpdi), dynamic intrinsic peep (peepi,dyn), maximal airway pressure drop during inspiration (apaw) andl ventilatory variables (ti,te,ttot,rr,vt and minute ventilation) were measured. results: no major problems due to airleaks or to auto-triggeriffg phenomena were observed in the patients, so that all of them were able to perform all the protocol runs. minute ventilation and respiratory pattern were not different using the two triggering systems. the ptpdi was significantly higher during both psv ( . + . cmh: x sec) and a/c ( . + . ) with pressure triggering, as respect to psv ( . + . , p< . ) and a/c ( . + . , p< . ) with flow triggering ( l!m). no differences were observed between and l/min flow triggers. apaw was also significantly larger during pressure triggering; peepi,dyn was reduced during flow triggering being . + . cmh (psv flow trigger) vs . + . (psv pressure trigger) and . +_ . (a/c flow trigger) vs'f~ +l (atc pressure trigger). conclusions: in stable copd patients non-invasively ventilated, flow triggering reduces the respiratory effort during both psv and aic mode as compared to pressure triggering. this may be partly due to a decrease in peepi,dyn using a flow-by system. objective. cardiac output is higher during alternating ventilation (av) (i.e. differential ventilation of the lungs with a phase shift of half a ventilatory cycle) than during synchronous ventilation (sv) of both lungs . we verified the hypothesis that the higher cardiac output depended on a lower central venous pressure and intrathoracic pressure, due to a lower mean lung volume, which we attributed to part of the expansion of the inflated lung at the expense of the expiring, opposite lung . we studied this interaction between the lungs during one-sided inflation, which we called cross-talk. method. in anaesthetized and paralyzed piglets we applied short periods ( s) of one-sided ventilation ( breaths per rain, bpm), while the other lung was open to the ambient air. the air flow into the non-ventilated lung during expiration of the ventilated lung was integrated to volume. we studied -to-r and r-to-i cross-talk at ventilatory rates of , and bpm. the amount of cross-talk was the volume displacement in the non-ventilated lung. results. during bpm the r-to-i crosstalk was _+ . % (mean +__ sd) of the tidal volume to the right lung and the -to-r crosstalk _ . % of the left tidal volume. both values increased at bpm to _ . % (p < . ) and _ . % (p < . ) respectively. the values at bpm were in between., conclusion. we concluded that the lower mean lung volume and lower thoracic expansion during av compared to sv depends on partial expansion of the inflated lung into the non-inflated lung, resulting in a lower mean intrathoracic pressure as the main reason for the higher cardiac output during av. obiective: natural surfactant given for rds in premature infants leads to a rapid improvement in oxygenation, but lung compliance did not improve in most studies. however, acute effects on lung mechanics during and immediately after surfactant administration have not been studied before. methods: a total of administrations of bovine surfactant in recommended doses was given via a small catheter into the distal endotracheal tube either as a bolus (n = ) or as a slow infusion (n = ) in infants with established rds. static compliance (c), resistance (r) and time constant (tc = cxr) of the lung were measured every minutes with a lung function cart (sensormedics ) without interrupting ventilation. infants receiving synthetic surfactant were studied as controls. results: after surfactant as a bolus or during infusion c first decreased but then increased, whereas r increased immediately with great fluctuations but did not return to baseline. this pattern was more pronounced in infusion than in bolus administration. change of c and r varied greatly in the individual case, maximum c was > %, maximum r > % of baseline value. retreatment was followed by an increase in r in all patients, but c increased only in the one who was responder. patients receiving synthetic surfactant had no change of c or r and were non-responders. ob~i ctives= acute lung injury (ali} sometimes induces severe hypoxernla which may be refractory to conventional modes of mechanical ventilation (mv). the elm of this study was to observe some cardio-pulmonary effects of an alternative method of ventilatory management of severe ali. five patients with severe ali (murray scores > ) requiring mv were studied. protocol inclusion was considered when a control-mode of mv (with a pzo~=l. and a peep level < cme=o} was not able to get either a p.ojf=o= ratio > or a s.o= > %. patients were sedated, paralyzed, and a ventilator (serve c) was used for pressuz'e-control ventilation (pcv). fio= was maintained at . and peep removed. continuous gas flow ( • ml/kg] was humidified and jet delivered through a tube ( ram id, ml capacity, . ml/cm h=o compllancel ended in a nozzle ( . mm is) attached to the endotracheal tube connector. a thermodilution flcw-dlrected catheter was inserted in pulmonary artery. following variables were recorded minutes before and after protocol started: tidal volume (vt), minute ventilation (vz), intratracheal pressures (p~w), wedge pulmonary artery pressure (wp), central venous pressure (cvp), mean arterial pressure (map), cardiac index (ci), arterial and mixed venous oxyhemoglobin saturation (sao=, svoa) , oxygen delivery (do~) , oxygen consumption (vo ) , intrapulmonary shunting (q./qt) , and oxygen extraction ratio (ero). this observation suggests that hfpv could allow to ventilate at lower fin and improve blood oxygenation during the acute phase after inhalation injury reducing toxicity risk related to high fin . further studies are necessary to confima these results and evaluate the possible implications on mortality alter smoke inhalation and for other icu pts. objectives: to design a system for volume controlled high frequency ventilation (hfv) and to estimate the dependence of the tidal volume (vt) on frequency (f) in normocapnic ventilation in rats at frequencies - hz. methods: a new system for volume controlled hfv was devised consisting of the generator of the constant flow during inspirium and the constant pressure during expirium. the ventilator allows ventilation at frequencies - hz with the relative inspiratory time (ti) . - . . the airway pressure was measured at the proximal port of tracheostomic cannula , at the same site inspiratory and expiratory flow was measured using modified lilly-type of pressure-differential flow sensor. non-linearity of flow sensor was compensated on line by derived equation based on calibration at static and dynamic conditions. flow and pressure data were evaluated on line using original software. value of the positive end expiratory pressure (peep) was serve-regulated by analogous feed-back. in animal experiments white wistar rats ( - g) narcotized with ketamine/xylazine with cannulated carotid and femoral arteries were kept at the rectal temperature ~ the arterial pressure was monitored. after traeheotomy the metal cannula ( mm [.d.) was inserted, animals were curarized and ventilated at the following condition: peep = . kpa, ti = . . the dead space of ventilator including canula was . ml. the initial frequency was hz and rain after each change of the ventitatory regimen the blood gases analysis was performed. the frequency was changed according to the following schedule : hz--> hz--> hz--> hz--> hz--> hz--~ hz--> hz. vt for each frequency was regulated to maintain normocapnie ventilation with arterial pco = + mm hg. the arterial po was always above mm hg. results: for normocapnie ventilation in rats the following tidal volumes vt [ ml/kg] were found : vt = . --+ . ml/kg for ft = hz, vt = . + . mukg for fz = hz, vt = . +_ . ml/kg forf = hz, vm = . + . ml/kg forf = hz andvmt= . + . mukg for fs = hz (presented as mean values _+ s.d., n = ). the regression analysis using the mean values resulted in the equation for normocapnic vt in rats in our experiments : vtn = . * f-e. . conclusions: the described system allowing ventilation in a wide frequency range - hz with accurate measurements of airway pressures and vt might be useful for optimisation of artificial ventilation in new-barns with different lung pathologies. supported by grants iga mz cr nr - and gacr nr . s intensive care unit. university. hospital of south manchester, uk. methods: measurements were conducted on ventilated patients (puritan bennett ac with metabolic monitor pb set to measure end tidal co ). all measurements were repeated with the patient stabilised at cm. cm and cm peep. inclusion criteria were: ) haemedynamic stab(l( .ty for hr; ) pulmonad" anon" flotation catheter in situ: ) volume control ventilation with plateau of . s: ) fio ~ > . to maintain pao~. > kpa with em peep: ) qs/ot > %; ) pao /fio ratio < . measured variab!es included: r minute volume: plateau ainvay pressure: applied and intrinsic peep: fractional end tidal co ; arterial and mixed venous blood gases and hacmod).ttamic variables. results: statistical analysis was performed using repeated measures anova. significant decreases in cardiac index (ch p< . ), compliance (p<t). ) and o,'gcn deliver, index (do , p< . ) occurred with increasing peep (table ) . no other variable showed any significant change. methods : all consecutive patients orally intubated in the micu between january to april were studied. etts were positioned according to the reference marks mentioned above (measurements from upper incisors). the position of the ett tip in relation to the carina was measured on the chest radiograph done with the patient's head in neutral position. results : a total of men and women were studied (n= ). the mean distance of ett tip to carina was . cm. using the reference markings, cases ( . %) had the ett tip < cm from the carina and cases ( . %) > cm. one case resulted in an endobronchial intubation. the mean height of all patients were cm ( - ) for males and cm ( - ) for females. of the patients with ett tip < cm from carina, the mean height was cm and cm respectively. ~ onclusion : adopting the above quoted reference marks did not result in ideal positioning of the ett in a significant proportion of cases ( . %). we postulate that [s because our asian population is generally shorter than those in previous studies. objectives: to measure the changes of pulmonary mechanics before and after tracheostomy in patients with prolonged mechanical ventilation and to determine factors that predict the outcome of liberation from mechanical ventilation. design: prospective. setting: respiratory intensive care unit (ricu) in a tertiary hospital. patients: twenty patients with chronic lung disease requiring long-term mechanical ventilation. tracheostomy is indicated for further care. intervention: tracheostomy. measurements and results: pulmonary mechanics including respiratory rate (rr), tidal volume (vt), peak inspiratory pressure (pip), intrinsic positive end ex~ piratory pressure (peepi), lung compliance (cld), mean airway resistance (rawm), work of breathing (wob), pressure time product (ptp) by bicore cp- pulmonary monitor were recorded hours before and after tracheotomy. ventilator setting parameters remained the same during surgical intervention and were also recorded for comparison. generally, the mechanics including pir wob, raw~x and ptp showed improvment after tracheostomy. but only pip was significantly reduced (pre . _+ . to post . _+ . , p < . ). changes of wobp showed significant correlation with pre-operation rr, minute volume (mv), wobp, and peep(. changes of raw m were also significantly correlated with pre-operation peep, vt, and raw m. the patients were divided into two groups according to their outcome after two week follow-up. group included eight patients who were completely weaned from ventilator; group included twelve patients who still remained ventilator-dependent or were mortality. there was no difference in age, duration of mechanical ventilation, pro, post or changes of several lung mechanics between the groups of patients. pre-tracheostomy peep i and cld showed significant difference between these two groups ( . _+ . vs . + . in peepi; . _+ . vs . _+ . in cld, p < . ). pre-tracheostomy ventilator setting in mode of assist/control also showed significant higher percentage in group ( % % in group vs . % in group ). conclusion: in prolonged mechanical ventilation patients with chronic lung disease, tracheostomy will significantly improve pip and slightly reduce wobp, raw m and ptr patients who used pressure support mode before tracheostomy had better underlying lung conditions (lower lung compliance and auto-peep) will have better chance to wean from mechanical ventilation. forty-eight infants with congenital diaphragmatic hernia presenting within the first hours of life, who underwent surgical rapair,were analysed prospectively in order to produce a reliable inde x of severity of disease that would reliably predict eventual outcome. there were survivors and deaths in this series (mortality %).using arterialpco values measured hours after surgical repairand correlating them with an index of mechanical ventilation,we have been able to clearly define two groups of diaphragmatic hernia based on their response to hyperventilation. the first group, with co retention and severe preductal shunting,was unresponsive to hyperventilation with high rates and pressures the mortality was %. the second group responded well to hyperventilation and demonstrated reversable ductal shunting only. survival in this group was %. arterial co accurately reflects the degree of lung development in this disease and separates those patients with severe pulmonary hypoplasia where the outcome is invariably fatal, from those with a well developed contralateral lung where there is excellent potential for survival. respiratory failure unit, dpt medicine, univ. thessaloniki, thessaloniki, greece the variability of arterial blood gases (po , pc ) and the ph (abg) was examined in stable icu patients, few hours before a successful weaning from the ventilator. all patients were lightly sedated and the ventgatory conti~ons were pressure support (ps) for and ps plus intermitted mantatory ventilation in ii. [n each patient, speciments of abg were measured at min intervals during a - study period. at the same time with abg the arterial blood pressure (bp), the heart rate (cf), the tidal volume (tv) and the respiratory rate (n r were measured. for all the patients, the mean coefficient of variation (c) was . percent for po , . percent for pco and . percent for hco . the average sd for ph was . , the corresponding c for systolic bp, diastolic bp, cf, tv, rf were . , . , . , . , . percent. we conclude that the spontaneous variability of arterial blood gases in icu patients is not substantial ~hen they have stable the heamodynamic and the ventilatory parameters. deptx?fa'aaesthesioiogy and reanimation, rhe sechenov medical academy, moscow, russia objective: ~he prevention and treatment of hypoxia in the critical patiems. methods: i~fusions of perphtoran -a blood substitute with gas-transporting fimclion based on perphtorhydrocarbon -in patients with acute hypovolemia, microcirculatory distnrbance~ tissue gas exchange and metabolism; pulmonary iavage in ; iongterm extrapulmonary oxigenation with tleoroearboa oxygenator in combination whb ~trafiltra!ion, hemosorption and hemodialysis -in patients. results: pe~htoran increases blood volume, co,sv, decreases svr, improves capillary blood flow, increases the blood oxygen capacity, tissue oxygen tension, del, vo by improving the rheologic properties of blood and plasma, normalizes ext., prevents and eliminates fat embolisation and ards. decreases the need for blood transfusions and infusions of plasma expanders by . - . limes. alveolar venti!ation-perfusion ratio remains unchanged with its increased effective utilization. there was no surfactant destruction during lavage. extrapulmonary oxygenation of small volumes of venous blood eliminates venous destruction and then arterial hypoxia and increases pulmonary oxygenation. the use of lluorocarbon cxygenators during hemosorption and hcmodialysis provides the atraumatic and iongterm oxygenation of arterial blood and increases elimination of co which prevents the development of hypoxic complications. conclusions: perphtoran and fluorocarb~n oxygenators are effective in the correction of hypoxia in the criticat patients. objeqtives: to determine if there are differences in oxygen consumption (vo ) during weaning from mechanical ventilation (during total ventilatory support and spontaneous ventilation with cpap), and to compare different predictive parameters of weaning in predicting success of weaning. methods; prospective study in critically ill patients treated with mechanical ventilation for at least h, who fulfilled at least of standard weaning criteria (vt> ml/kg; respiratory frecuency (f) < ; pimax > cm h ; pao /fio > ). baseline measurements: t, vt, p . , pimax, f/vt, p . *(f/vt), p . /pimax. study protocol: measurement of vo , vco (medgraphics), vt, f, ve, and arterial blood gases during total ventilatory support (cmv), and after and minutes of spontaneous ventilation with cpap cm h . the weaning trial was stopped, failure to wean diagnosed, and mv resumed it a patient presented significant tachypnea, tachycardia, bradycardia, cardiac rythm disturbances, hypertension, hypotension, hypoxemia or hypercapnia. results: four patients did not complete the weaning trial, were extubatad, and of them had to be reintubated before h, being considered also weaning failures. during cmv, vo /kg was . + . ml/kg/min, and . _+ . mlo- /kg/min after ' on cpap cm h (p < , ). of patients ( %) with standard criteria were extubated, while only of ( %) with criteria (p< , ). next objectives: compare the extent and distribution of lung injury in dogs preinjured with oleic acid (oa) and ventilated with high tpp and adequate peep in the prone and supine position. methods: lung injury was induced with oa ( . - . ml/kg) in anesthetized, paralyzed, and intubated dogs (n= ) during volume controlled ventilation: rate= /min, peep= cmh , ti/ttot= . , fio = . , vt= ml/kg. animals were rotated during the oa infusion and the following minute stabilization period to assure uniform injury. in the supine position, peep was set - cmh above the lower inflection point (as determined by the pressure-volume curve), and vt was set to obtain a tpp of cmh : animals were ventilated in either the prone (n= ) or supine (n= ) position for four hours. pulmonary artery occlusion pressure was maintained constant ( - mmhg) with saline infusion. at the end of the protocol the lungs were removed and divided by template into dependent (d) and nondependent (nd) sections for wet weight/dry weight (v~n/dw) and grading of nstologic lung injury (hli; scale - ). oseillatron | is a pneumatic device that generates high frequency, oscillation by means of a reciprocating system in the form of a membrane. it generates sinusoidai wave form at ( to ( cycles/rain. the system does not deliver gas but must be adapted to the proximal respiratory, circuit of a conventional ventilator, resulting in ci-ifo. it was developed to enhance intrapnlmona~ diffusion during mechanical ventilation and to mobilise endebronchial secretions. methods. we measured arterial blood gases and haemedynamics during a first period of conventional ventilation (cppv) followed by. two rain periods of chfo (sequences : ( and ) c/rain : group l, n = l: and c/rain : group , n = ). measurements were made at the end of each period. cardiac output was measured using thermedilution method: flu and peep were kept unchanged throughout the study. intrinsic peep was also evaluated by, means of an occlusive valve. results. pa is not significantly modified during chfo at or c/rain. paco is slightly decreased at c/rain (p = .( ). however, intrinsic peep remains unchanged. there is no sequential effect (gr. l vs gr. ). there is no more effect of chfo for patieets who are at a flu higher than . (n = ). no changes in haemodynurmcs are observed except a slight increase in central venous pressure (cvp) during ci-ifo (p < .ol). obiectives: to examine the effects of inspiratory muscles unloading on neuromuscular output at controlled levels of chemical stimuli. methods: the ventilatory response to co was examined in ten normal subjects using rebreathing method. ventilation ~) and respiratory muscle pressure output (pmus) at the same end-tidal partial pressure of co (petco~) were compared with and without combined flow and volumeproportional pressure assist in two protocols (a and b). protocol a (n = ): two levels of assist were studied; flow assist (fa) of cmh /i/sec and volume assist (va) of cmh /i (assist ), and fa of cmh /i/sec and va of cmh /i (assist ). all conditions were applied randomly. v~, tidal volume (vt) and breathing frequency (f) were measured breath by breath and plotted as a function of petco~. protocol b: in subjects, in addition to above measurements, esophageal (pes) and gastric (pg) pressures were measured and the time courses of transdiaphragmatic pressure (pdi) and pmus were calculated. one level of assist (assist ) was studied in this protocol. results: in both protocols inspiratory muscle unloading did not change the f response to c%. compared to control, with assist v t response was displaced upwards; at petco of mmhg v t was increased significantly by . + . i and . + . i in protocol a with assist end , respectively, and by . _+ . i in protocol b with assist (p< . ). ~/~ responses showed similar changes as vtresponses. in both protocols the slope of v~ response (s did not change significantly with unloading. at low petco~ ( mmhg), pdi and pmus waveforms did not differ with and without assist. with unloading, at high petco ( mmhg), pdi and pmus at the end of neural inspiration decreased by . -+ . % and . + . %, respectively, from control values. neither change was significant (p> . ). by theoretical analysis we estimated the expected changes in vt and ~/~ when the levels of assist used in both protocols were applied in the absence of : any change in neural output response to co z. the predicted response was similar to that observed, indicating that the small difference in pdi and pmus between control and unloading runs was due to intrinsic properties of respiratory muscles end respiratory system. conclusions: these results suggest that when chemical stimulus is controlled, respiratory motor output is not downregulated with unloading. the determinants of the response of the respiratory output to inspiratory flow rates (v~) were examined in awake normal subjects. subjects were connected to a volume-cycle ventilator in the assist/control mode and v~ was increased in steps from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. in six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (protocol a) and in subjects the effects of airway anesthesia (upper and lower airways, protocol b) on the response of respiratory output to varying v~ were studied. in protocol b, in order to calculate muscle pressure during inspiration (pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. independent of conditions studied breathing frequency increased . significantly and end-tidal concentration of c% decreased as v~ increased. the response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas and airway anesthesia. with and without airway anesthesia (protocol ) neural inspiratory and expiratory time and neural duty cycle, estimated from pmus waveform, decreased significantly as v~ increased. at all conditions studied the rate of change in airway pressure prior to triggering the ventilator tended to increase as v~ increased. the changes in timing and drive were nearly complete within the first two breaths after transition with no evidence of adaptation during a given ~/~ period. we conclude that v~ exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate and airway anesthesia. the response most likely is neu~'al in origin, mediated through receptors not accessible to anesthesia such as those located in chest wall or below the airway mucosa. it has been shown, in mechanically ventilated awake normal humans, that increasing inspiratory flow rate (~/~) exerts an excitatory effect on respiratory output. it is not known if this effect persists during sleep. to test this seven normal adults were studied during wakefulness and nrem sleep. subjects were connected through a nose-mask to a volume-cycled ventilator in the assist/control mode and ~/t was increased in steps ( - breaths each) from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. forty-one trials during nrem sleep and during wakefulness were analyzed. both during sleep and wakefulness minute ventilation increased and total breath duration (ttot) decreased significantly in a graded and reversible manner as ~' increased. these changes were complete in the first breath after v{ transition. the response was significantly less during sleep than during wakefulness (p< . ); at i/min ttot, expressed as % of that at i/rain, was . +_ . % during sleep and . +_ . % during wakefulness. during wakefulness, at i/min, the rate of change in airway pressure prior to triggering the ventilator, an index of respiratory drive, was % of that at i/min (p< . ). the corresponding value during sleep, was % (p> . ). in four sleeping subjects the increase in v~ was sustained for . - min. there was no evidence for adaptation of the response; tro t, averaged over the last three breaths, did not differ from that obtained when vj was sustained for only - breaths. we conclude that ) vt exerts an excitatory effect on respiratory output, mediated by a reflex neural mechanism and ) the gain of this reflex is attenuated by sleep. chest radiographs is a common complementary technique for patients in critical care units, with a low cost and easily available. however, it has certain well-known limits in diagnosis, the most important derived from the low quality of some pictures. in this paper we make a general review of some new technical approaches developed for improving the quality of the images, and so incrensing the diagnostic value of conventional radiology. we begin deaeng with the correct positioning of the patient, trough the filtering techniques, the synchronization of radiology and ventilation, and we make reference to the new computerized systems for digital image processing. conclusions: the portable radiographic system is a device that probably with maintain for many years in critical care units as a basic non-invasive diagnostic tool. but we need an increase in the efficiency of it, applying means as simple as a correct positioning of the patient, or the use of fitlers or synchronizers. thus we should improve the general standards of portable radiography. "are circular circuits safe? quantifying undelivered tidal volume in pediatrics patients". objectives: to evaluate the overall influence of internal compliance of circular circuits on delivered tidad volume (vt). methods: we studied prospectively asa i pediatrics patients ( to yr. old) scheduled for elective general surgery. mechanical ventilation was supplied by an ohmeda excel (circular circuit). the internal compliance of the circuit (cc)-anesthesia machine plus external circuit-was determined by the supersyringe method: corrugated dar tubes of mm. id and . m. long (children < kg), and a corrugated dar set of mm. id and . m. long (children > kg) were respectively used for ccl an cc values of . and . ml/cm h . a vtof mlg/kg and respiratory frequency was adjusted for an end-tidal co (etpco ) between mmhg. tidal volumes (measured by spirometry) and airway pressure (paw) data were recorded every ten minutes. volumes and thorax-lung compliances were calculated as follows: (vt delivered = vtadjusted-vol compressible, being vol. compressible = co x ppeak (aw). apparent compliance (ca) = vt adjusted/pplateau(aw), and true compliance (ct) = =vt delivered/pplatean(aw)). comparative statistics were separately designed between calculated compliance data and tidal volumes on a paired sample ~test basis. results: calculated values for volumes and thorax-lung compliances were: conclusions: due to the elevated internal compliance of the circular circuit there is a remarkable dilference between adjusted and delivered vt: mean undelivered vt was . % and reached as high as . %. teere is also a significative error in calculating true thorax-lung compliance: its overestimation can be as high as . %. circular circuits are considered safe and cost-saving for anesthetical practice. nevertheless we conclude that anesthetists should bearin mind vt losses when using circular circuits, due to compressible volume. tracheal stenosis is one of the most serious complications of patients submitted to prolonged endotracheal intubation, in which the decrease in inner diameter of upper airway makes it very difficult to achieve a correct ventilation. objectives: compare the results of applying high frequency jet ventilation (hfjv) to some of these patients with conventional controlled ventilation (cmv). methods: we used a prototype of high frequency jet ventilator (santiago- ) developed in our university, and we developed a tracheal tube in wich we modified the distal tip (conic tip). we applied this system to two patients which were initially ventilated in the operating room with usuai controlled mecanical ventilation (cmv) following the standards of our department, and then intubated with the special endotracheal tube and ventilated with hfjv. results: we could verify a proper ventilation of both patients with cmv and hfjv. during hfjv, the airway pressures were lower than those recorded during cmv. a lower airway pressure prevents lesions due to high pressures. conclusions: hfjv is a good method of ventilation for patients with significative stenosis of the trachea, not only during surgical procedures, but also during ventilation for long periods in critically patients. the ventilatory setting is pressure support mode. the pressure level and fit were kept constant during h/d. arterial blood gas, wbc count, and mean bp was checked according to the schedule: '(immediately before h/d), ', ', ', ', ', '. respiratory drive (represented by poa), tidal volume(ti) and minute ventilation(ve) were continuously recorded by pulmonary mechanics monitor (bicore cp- ). the mean value of the breaths minutes before blood sampling were used to represent the ventilatory status of that period. anova test is used for comparison between groups. for poa, hierarchical cluster method is applied to divide the cases into two groups of similar change. conclusions: our data suggest that pl is very useful, non invasive and low-expensive emergenc e support for arf, expecially in the elderly with severe chronic pulmonary disease and relative controindications to eti. pl seems to be an effective alternative when it is not immediatly possible to perform etl. the multiple inert gas elimination technique (miget) can be used to assess the effects of any given mode of mechanical ventilation on the pulmonary and systemic factors determining arterial po and pco> however, a potential problem in mechanically ventilated patients is that the l mixing box (mb- l) placed in series in the expiratory side of the circuit of the ventilator to sample mixed expired gas may provoke substantial discrepancies between the tidal votume set in the ventilator and the effective tidal volume delivered to the patient, due to the increase in the compression volume (vc) of the circuit. the effects of the mb- l on the v c were compared with those produced by a new l mixing box (mb- l) specifically designed to produce adequate gas mixing and to prevent loss of the two most soluble gases (ether and acetone) used in the miget. at any given peak cycling pressure (p~ak, cm h~o), the v c (ml) provoked by the mb- l was substantially higher (vc= . *ppeak) than that provoked by the new mb- l (vc= . *ppeak). at a ppeak = cm h ~ the v c were ml (mb- l) and m{ (mb- l), respectively (p< . ). in a group of subjects ( m/ f, _+ years), for each of six the gases used in the miget, the regression line between the mixed expired partial pressures simultaneously obtained from mb- l and mb- l fell on the identity line. it is concluded that the new mb- l allows adequate assessment of the effect of different modalities of mechanical ventilatory support on pulmonary gas exchange, with less potential for gas compression and thus hypoventilation. objectives evaluate the influence of different pressure support ventilation (psv) levels on cardiovascular and respiratory funcion in icu polytrauma patients. metbed&we studied polytrauma icu patients , who were in weaning process , after long term mechanical ventilation for acute respiratory failure . mean age ( - ) yrs . they all were connected to servo ventilators siemens c , and all were in stable condition , without sedation , inotropes or diuretics. the hemodynamic studies were done with continuous svo , swan ganz catheter (oximetrix, abbott). they all were in spontanuous mode (spent) with cm h cpap for at least one hour. we turned them to psv with inspiratory assistance (psv cm h ) and after rain we applied psv cm h , and after min psv cm h . hemodynamlo and respiratory measurements were done before and after the application of insiratory assistance. the results were statistically analyzed with anova. resets . respiratory variables . no significant changes in minute volume (ve). tidal volume (vt) and mean airway pressure (mpaw) increased statistically significant (p< . ) . respiratory rate (rr) decreased significantly (p< . ) . blood gase showed no difference . cardiovascular variables. cardiac output (co) decreased ns , heart rate (hr) had no change , central venous pressure (cvp) , mean pulmonary artery pressure (mpap) , pulmonary capillary wedge pressure (pcwp) , increased ns , oxygen delivery (do ) decreased ns, oxygen consumption (vo ) decreased ns. conclusions. psv is a very useful respiratory mode helping patients to be weaned from long term mechanical ventilation . it has beneficial effects on respiratory function and oxygen consumption without affecting seriously the hemodynamic parameters, possibly due to a decrease of the work of breathing. a. michalopoulos, a. anthi, k. rellos, j. kriaras, s. geroulanos intensive care unit, onassis cardiac center, athens. objectives of this study was to examine the effect of different levels of peep on postoperative svo and pvo values in a group of patients, following open heart surgery. methods: upon transfer to icu, patients ( males and females) of mean age _-+ years, were randomly assigned to receive (n= ), (n= ), or cm of peep (n= ). there were no statistically significant differences in demographic data or preoperative respiratory status among the three groups. all patients were ventilated on the assist control mode with a tidal volume of ml/kg. the fraction of inspired oxygen (fio ) was adjusted to keep a pao around mmhg. mixed venous po and svo were measured at min, and hours after application of mechanical ventilation in the icu, just before extubation (be), half hour after extubation (ae), and at hours post-extubation. differences at each study time were analysed by anova. results: mean svo and pvo values among the three groups, for all study intervals, are presented in the table. conclusion: we found no differences (p=ns) in tissue oxygenation (expressed by svo and pvo ) among the three groups, at any study interval, in the early postoperative course of patients following open heart surgery. intrinsic peep (peepi), and high elastance and resistance increase inspiratory work load in copd. cpap reduces work of breathing by counterbalancing peepi. pav provides flow (fa) and volume (va) assistance proportionally to patient resistance and elastance and inspiratory effort. we studied the effects of partitioned support (cpap-fa-va) on breathing pattern and inspiratory effort in five copd patients on pav compared to spontaneous ventilation (sv) and full support (fs: cpap+fa+va). flow, volume, minute ventilation (ve) respiratory rate (rr), inspiratory swing in esophageal pressure (apes), and its integral per breath (pti/b) and per minute (pti/m) were measured. objectives: to evaluate airway pressure fluctuation (apf) during spontaneous breathing in a high compliance cpap system. methods: the cpap system consisted of two l weighted balloons in a wedge shaped holder. ventilating gas flowed from one balloon through a low resistance one way valve into a tracheal tube (ett) provided with a pycor co sensor to monitor rebreathing. the ett was connected to a piston drive mechanical lung. expired gas flowed through a low resistance valve into a second weighted balloon, from where it was exhausted through a peep valve connected in parallel with the second weighted balloon. we evaluated system performance at v r from to ml, at rr from to bpm, while closely monitoring cpap airway pressure swings. at v v of and ml the rr was limited to bpm. for comparison we explored aps of a one l balloon cpap system, the cpap mode of the puritan bennett , and siemens ventilators, when connected to a healthy adult volunteer breathing through an ett. results: the compliance (cpl.) of one l balloon system was linear over a range from . to . l, with a cpl. of . l/em h .the cpl. of the l balloon ( . l/em h ) was linear between a volume of and . l. apf of the weighted balloon system was under em h at all v r (except at a v r of ml aps was . em h ), while the apf in the l balloon was up to em h . apf witli human volunteers with the two commercially available ventilators in the cpap mode was about cm h ; while under identical conditions apf in the l balloon system was . emhzo; and in the two l balloon system was below lcm h . conelusions: cpap using the two balloon system exhibits lower airway pressure fluctuations than a single balloon system; and is substantially lower than found in the two commercially available ventilators when used in the cpap mode. objective: to perform independent lung ventilation (ilv) with individual tidal volume (vt) set at a value generating a plateau airway pressure (pplat) < crnh~o and to evaluate the usefulness of the continuous monitoring of endtidal co (etco ) as a guide to titrate individual lung vt during ilv and for the weaning from ilv. methods: in seven patients, ilv was performed with ttvo ventilators set with the same fio: and respiratory rate. each lung was ventilated with a vt that developed a pplat < cmh~o. this setting led to a lower vt on pathological lung (pl). vt was increased in pl following etco~ and paco -etco variations. ilv was discontinuated when etco~., vt and statical compliance (cst) were similar in both lungs. results: one hour after starting ilv (ti), pl mean vt was significantly lower than in normal lungs (nl) ( + ml vs + ml, p< ) two individual behaviours were observed on tl in pl: four patients presented low etco: (range - mmhg)and normal pacoz (range - mmhg), while three patients had normal etco (range - mmhg) with high pac (range - mmhg). one hour before stopping ilv (t ), vt, etc and paco were the same in each lung. the pao /fio: ratio improved in all patients from the beginning ofllv cst of pl was + % of the normal lungs' cst on ti and improved to . + % ofnl's cst on t (p< . vs conclusions: setting vt of pl to a value not overcoming a pplat threshold does not impair oxygenation and is helpful in avoiding barotraumatism. measurements of differential etco and of the differential paco -etco gradient can be used to titrate vt allocation during ilv and as a guide for the weaning from ilv. total respiratory resistance in mechanically ventilated patients exceeds values obtained in normal subjects, due to the added and highly flow dependent resistance of the endotracheal tube (rett). this can adversely effect the efficacy of pressure regulated modes of assisted ventilation, such as pressure support (psv) and proportional assist ventilation (pav). recent work demonstrates that the influence of rett during psv can be overcome by using tracheal (ptr) rather than airway opening (pao) pressure to regulate the pressure applied (intensive care med :$ , ) . the purpose of this study was to see if this approach would also be effective during pav. flow, volume, pao, ptr, and transdiaphragmatic pressure (pdi) were measured in intubated patients in which either pao or ptt were used to regulate the pressure applied during pav where volume assistance was varied from to % of respiratory elastance. representative results (mean + se) are shown below. compared to spontaneous breathing (pav %), pav increased tidal volume (vt) while reducing respiratory rate (rr) so that minute ventilation ('~e) also rose. this was associated with a reduction in inspiratory effort, as reflected by a decrease in the pressure-time integral ( [ p) of pes and pdi both per minute and per liter ~re. the effects on breathing pattern were similar for pao and ptr regulated pav. in contrast, the reduction in inspiratory effort was always greater for ptr regulated pav. in conclusion, the volume assistance provided by pav is more effective when ptr rather than pao is used to regulate the pressure applied. pav methods: retrospective data analysis of adult patients with normal pulmonary function before operation and uneventful course following coronary artery bypass graft surgery over an month period. we compared assist/controlled mandatory ventilation (s-cmv, patients), synchronized intermittent mandatory ventilation with inspiratory pressure support (s-imv/psv, patients) and biphasic positive airway pressure ventilation (bipap, patients). results: patients ventilated with bipap had a significantly shorter mean duration of intubation ( . h, p< . ) than patients treated with s-imv/-psv ( . h) and s-cmv ( . hi. with s-cmv . % of the patients required single or multiple doses of midazolam but only . % in the s-imv-/psv group and . % in the btpap group. the mean total amount of midazolam of these patients was significantly higher in the s-cmv group ( . mg) than in the s-imv/psv group ( . mg, p< . ) and in the bipap group ( . mg, p< . ). the consumption of pethidine and piritramide did not differ between s-cmv and s-imv/psv but was significantly lower during bipap (p< . ). after extubation the paco patients was highest in the s-cmv group. conclusion: ventilatory support with bipap reduces the consumption of analgesics and sedatives and duration of intubation. unrestricted spontaneous breathing as well as fully ventilatory support allow adequate adaptation to the patients requirements. bipap seems to be an alternative to s-cmv and sqmv/psv ventilation not only in patients with severe ards but also in short term ventilated patients. _objectitives: after end-inspiratory airway occlusion we examined the ensuing gradual decrease in tracheal pressure (ptr) with the following equations proposed by bates et al. and hildebrandt: pv = p'v e'~cccl~ +pst, rs (bates) [ ] where p'tr is tracheal pressure immediately after occlusion, to= is occlusion time, "r is viscoelastic time constant of respiratory system, and p t is static elastic recoil pressure of respiratory system. p~(t) = h -h log t (hildebrandt) [ ] where h~ and h are parameters depending on lung volume, and initial time is s for analytical reasons. materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecuronium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pressure was measured in the trachea. flow was measured with a pneumotachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a frequency of hz and processed on a pc. the influence of the cardiac artifacts during the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean (+ sd) coefficient of correlation using eq. was , -+ . , and using eq. was . + . . the values ofz~ (eq. ), however, decreased with increasing the tidal volume (vt) according to the following equation: "~ = . - . v t, similary, the values of h~ and h increased with increasing v t according to the following functions: h~ = . + v i and h = . + . v t. conclusions: the behaviour of "% of eq. suggests that the linear viscoelastic model is not sufficient to further describe the mechanical properties of the respiratory system over the vt range ( - ml/kg) in ventilated patients. infect this model predicts that "c is constant and independent of tidal volume. on the other hand the plastoelastic model is not sufficient to further describe the mechanical properties of the respiratory system. in fact "r obtained by fitting an exponential for data of eq. , is determined by the time of endinspiratory airway occlusion. obiectives: according to the viscoelastic model, the viscoelastic pressure of the respiratory system pv=rs during lung inflation with constant flow e~ is t/ r wh t lsms ira tlmeand r given by:pv~c.~ = d~( -'e-~ )[ ] ere " ' p" tory " and "r are resistance and time constant of viscoelastic unit. in the past, the viscoaletic constants were determinated by performing a series of occlusions at different lung volumes, or a sedes of occlusions at a fixed lung volume achieved with various inflation flows. in the present study we have developed a new method for determining "c and r which requires a single constant flow inflation. our method is based on determination of pv~r, during a single breath constant flow inflation, and of z during the ensuing end-inspiratory airway occiusion. dudng the occlusion the tracheal pressure p~, declines according the following function: ptr = p'lr e " too= " z + e~t.r= [ ] where p'~r is tracheal pressure immediately after occlusion, toc c is occlusion time, p,i.rs is static elastic recoil pressure of respiratory system, and ~ is viscoelastic time constant. we first determinated "~ by analyzing the time-course of ptr according to eq and next determining r according to eq. , using the expedmental values of p,i=~, ~ and ti, as well as "~ obtained with eq. . materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecurenium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pres-sure was measured in the trachea. flow was measured with a pneumniachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a fi'equency of hz and processed on a pc. the influence of the cardiac artifacts dudng the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean coefficient of correlation with eq. was . . with v t of ml/kg, the mean values (+ sd) of ': and r of the subjects amounted to . • . s and . • . cmh i "~ s. with the traditional multi breath method the corresponding values were . + . s and . _+ . cmh i " s, respectively. with the t-test the difference between new and traditional "~ was statistically significant, between new and traditional r was not significant. conclusions: with the single breath method it is possible to compute ': and r . the mean values of r with v t of nd/kg, however, was slighuy different than those obtained with the traditional multi breath method. the application of modem principles of respiratory care and mechanical ventilation in icus has resulted in increased survival of critically ill individuals with neuromuscular, skeletal and irrevers~le pulmonary diseases. in these chronically ill individunts mechanical ventilation, long term therapy (ltot) and continuous home care is considered a chronic life supporltng technique that can not be withdrawn after their discharge from an icu. the aim of this study was to present the results of a rehabilitation programme and home care that runs in our ward. twenw three patients were referred to our clinic f~om icus during - . a specific rehabilitation programme designed according to individual's needs was performed. patients that benefitted from this programme were grouped into the following disorders. ) post tb respiratow failure ( %) ) neuromuscular diseases, ( %) } undiagnosed sas { %) ) cope) ( %) ( patients had a overlap syndrom). the programme consists of : ) assessment and mechanical support ff needed of the respiratonj system with non invasive methods (nasal or via tracheostomy). ) group and individual respiratory therapy ) mobilization ) nutritional support ) educational classes for the members of the family. three from the patients passed away (during the year), are under nippv during night with or without supply, pts recieve ltot. conclusion: the development of a programme for chronically ill individuals in especially designed wards in hospitals and the overall care at home is considered necessary at least in hospitals with icus. a rehabilitation programme and home care permits the fast but safe discharge of these patients from units of acute medicine that the cost of treatment is high and besides permits beds that are invaluable. we considered that the rehabilitation prod'amine and home care in our ward is the first performed in greek chronically ill pts and even though there is no special administxative support we think that the results are quite saltsfactory. objective: we postulated that the product of the respiratory frequency (f) and the ratio of inspiratory pressure (ip) to maximal inspiratory pressure (mip) would predict the weaning outcome in deeompensated copd patients better than either variable alone or other indices previously proposed. methods: in decompensated copd patients with difficult weaning, we measured, daily, respiratory mechanics data both during mechanical ventilation and after ten minutes of spontaneous breathing. then we calculated weaning indices reported in literature and some new integrated indices. according to the results of the discriminant analysis, we considered the integrative index crop (acronym of compliance, rate, oxygenation and pressure), the rapid shallow breathing index f/vt, the load/capacity ratio ip/mip, and the following new index: f x ip/mip. we used receiver-operatingcharacteristic (roc) analysis by calculating the area under the curve considered as the overall probability of correct classification. results: main results are reported in the following objective: to evaluate the reliability of some indices of endurance in predicting the weaning outcome of decompensated copd patients. methods: in decompensated copd patients with difficult weaning from mechanical ventilation (mv) we measured, daily, blood gas analysis, ventilatory and airway pressure pattern during mv, breathing pattern (frequency (f) and tidal, volume (v~)), inspiratory pressure (ip), and maximal ip (mip) during spontaneous breathing (sb). thereafter we calculated the following weaning indices: crop (compliance * mip * (pao /pao ) / f), flvt, ip/mip. data obtained the day at which the patient was considered ready for a trial of sb on clinical grounds but weaning failed (wf) and those obtained the day of the successful weaning (ws) were compared statistically through the wilcoxon rank-sum pair analysis. in order to quantify the predictive accuracy for each index with respect to successful weaning we calculated sensitivity, specificity, and diagnostic accuracy according with the standard formulas. methods : five patients ( + yrs) suffering from ards (lung injury score > . ) for hours or less entered into the study. irv (volume controlled, decelerating flow, % inspiratory pause, lie = / ) was compared to conventional ventilation (cv) (volume controlled, constant flow, no inspiratory pause, iie= / ). these two modes were applied for hours in a randomized order, with the same levels of total peep (peept = peep + peepi), tidal volume ( . • . ml/kg), respiratory rate ( • "bpm) mad fit ( • %). measurements (respiratory mechanics, hemodynamics, arterial and mixed venous blood gases) were performed after , , and hours of application of each mode. rvsuils : are expressed as mean + sem and compared by anova. backeround and methods: periodic breathing (pb) is characterized by repetitive cyclic variation in minute ventilation. pb is considewxl to be provoked by an instability in the respiratory control. inintubated, spontaneously breathing patients conventional modes of pressure support ventilation, i.e., triggered inspiratory pressure support ps), do not allow patients to breathe with theirinherent breathing pattern. therefore, pb, if existing, will appear mainiy after extubation. since our new mode of pressure support ventilation" automatic tube compensation" (atc) continuonsly corrects for the flow-dependent tube resistance during insnmdon and expiration ("electronic" extubatim), it pemaits patients to maintain their own inherent breathing pattern. then, ff necessary, tracheal pressure can be additionally supported by volume-proportioead and/or by flow-proportional pressure support (proportional assist ventilation, pav). (~as~: we report the case of a -year-old male patient who was intubated due to acute respiratory insufficiency after acute myocardial infarction with left ventricular dysfunction. during ips of mbar the patient showed a regular breathing pattem which became periodic during atc. in addition, proportional assist ventilation of mbar/l increased periodic breathing in such a way that the typical cheyne-stokes breathing pattem occurred (see figure) . baqkground: the hering-breuer reflex (hbr) is characterized by an inhibition of inspiration during lung inflation. this response has been recognized as an important vagally mediated mechanism for regulating the rate and depth of respiration in newborn mammals. in adult man the hbr is considered to be active only at lung volumes well above functional residual capacity, i.e., at tidal volumes above ml. assessment of the hbr requires specialized methods such as single breath or multiple occlusion technique. methods; in the presence of desynchronization between ventilator and patient, which frequently occurs during triggered inspiratory pressure support ventilation (ips)(see figure) , prolongation of the interval between inspiratory efforts (indicated by negative deflection of the esophageal pressure) due to lung inflation exposes an active hbr. we examined the occurrence of hbr in intubated critically ill patients. strength of hbr was assessed by the formula: prolongation [%] = ((inspiratory interval of interest -preceding inspiratory interval)/preceding inspiratory interval) * ( . rr of patients examined showed moderate to severe desynchronization. in of these patients a (re)activation of the hbr was found. the strength of hbr amounted to + %. there was a significant correlation between tidal volume and strength of hbr. in contrast to previous reports, an active hbr was shown during lung inflation well below ml. b pck~round: triggered inspiratory pressure support ventilation (ips) is commonly used to support inspiration in intubated spontaneously breathing patients. despite its usefulness ips shows some disadvantages which can be deleterious in crificauy ill patients: -additional work of breathing to be performed by the patient due to the flow-dependent tube resistance -desynchronization between patient and ventilator due to inherent triggering failures of the ips mode suppression of the patient's inherent breathing pattern -inability to predict successful extubation in difficult-to-wean patients methods: based on the known flow-dependent tube resistance our new mode "automatic tube compensation" (atc) compensates for the pressure drop across the endotracheal tube ("electronic" extubation). then, if necessary, tracheal pressure can be supported by volume-proportional pressure support (vpps) and/or by flow-proportional pressure support (fpps). results: hitherto, we have examined patients after open-heart surgery and patients with acute respiratory insufficiency (ari) or ards using atc with/without vpps/fpps. preliminary results suggest that the new mode avoids additional work of breathing due to accurate compensation of the pressure drop across the endotracheal tube during in-/expiration prevents desynchronization between patient and ventilator allows patients to breathe with their inherent breathing pattern accurately predicts the outcome of extubation even in difficult-to-wean patients due to "electronic" extubation conclusions: the new mode atc with/without vpps/fpps allows to support ventilation in a more physiologic manner and overcomes the disadvantages of conventional modes of pressure support in intubated patients. backgound: cheyne-stokes respiration (cs) is characterized by regula]; recurring periods of hyperpnea and apnea. in normal subjects, cs may occur after hyperventilation, after arrival in high altitude, or during sleep. it has also been observed in patients with prolonged circulation time due to congestive heart failure, as well as in some neurological patients. there is no report about the influence of sedative drugs on periodic breathing (pb) and cs. methods: in intubated patients conventional modes of pressure support do not allow patients to breathe with their inherent breathing pattem. therefore, periodic breathing and cs are rarely seen. since our new mode of pressure support ventilation "automatic tube compensation" (atc) continuously corrects for the flow-dependent tube resistance during inspiration and expiration ("electronic" extubation) it permits patients to maintain their own inherent breathing pattem even if pathological, e.g., periodic. results: using this new mode of pressure support ventilation, periodic breathing was unmasked in of intubated patients, of which showed cs. in of these patients the occurrence of cs was linked to impaired left ventricular function with increased circulation time. normal left ventricular and neurologic function was found in the remaining patients. in of these patients cs disappeared after intravenous administration of the benzo-diazepine antagonist flumazenil (figure). consequently, in this patient cs was induced by benzodiazepine sedation. objecti',~s: in contrast to conventional rhodes for pressure supported spontaneous breathing, our newly developed ventilatow mode ,,automatic tube compensation" (atc) completely compensates for the flow-depandant pressure drop tlpm-r across endotracheal ttlbe (ett). in the atc mode, the ventilator supplies a flow v' in order to maintain a constant tracheal pressure p~,,~. to this end, pk,,= has to be oontinuousiy determined. since continued measurement of p,,~ by introducing a catheter via the ett is not reliable, we opted for its continuous calculation socordng to the following equation: p~ = p,,, -aperr, pw being the continuously measured airway pressure. this also requires the continual measurement .of flow v' to calculata apm-r using the non-fineer approximation: aport = kvv' + k .w. the constant tube coefficients k~ and k are mathematically determined by mesns of a least-squares-fit procadum based on laboratory investigations. tracheal secretions, however, reduca the omss-saction of the ett. consequently, ~ values of ki end k are changed rendering the p~,ch calculations inaccurate. therefore, k and ~ have to be pedodcally updated to ensure an a~urete monitoring of pn,~ and a complete tube compensation under atc at any time. background: one of the first steps in weaning patients from controlled mechanical ventilation is to stop muscle relaxation and to reduce sedation. it can take several hours, however, until the patient is able to trigger the ventilator and to breathe spontaneously. during this period, many patients display a sudden increase in peak airway pressure of up to %. patients and methods: to investigate the reason for this potentially dangerous effect, we continuously measured lung and chest wall mechanics in post-operatively ventilated patients. lung mechanics (airway resistance and lung compliance) was measured using the esophageal balloon technique as described in [ ] . chest wall mechanics (tissue resistance and chest wall compliance) was calculated from lung mechanics and total respiratory system mechanics as described in [ ] . results: we found a decrease of chest wall compliance (cw) to be the main reason for episodes of sudden airway pressure increase while lung compliance (cl) remained unchanged. the decrease of c w can be inter- gil cano a, san pedro jm ~, sandar d, herntndez . , carrizosa f, , herrero a. emergency and intensive care department, hospital of jerez, spain objective: ) to determine the incidence of hypoteasion (h) associated with emergency intabatian of mechanical ventilation, and ) to establish its relauonship with respiratory mechanics (rm) and arterial blood gases. mechanical ventilation performed in the emergency room, in a prospective eans~eative manner, were evaluated. data collected included patient demographics, diagnoses, blood pressure and arterial blood gas levels before and at~er intabatian, and p_m, including calculated pulmonary end-inspiratory volume above functional residual capacity (veic) and calculated dynamic hypetinflatien (dhc). all patients received midazolen and awaanrinm to facilitate tracheal intubatien and rm measurement. hypotension was defined as a decrease in systolic pressure higher than mmhg or an absolute decrease in systolic blood pressure below to mhg within hour of intabatian. patients were excluded because met at least one of the following exclusion criteria: preexisting shock or h ( ), cardiac arrest ( ) . there weren't any association between peepi or other airway pressures (paw) and h, but calculated pulmonary volitmes had tendency to be larger in patients with h (p < . ). high paco before lrasheal intubatian ( . - mmhg) with a quickly decrease alter starting mechanical ventilation was a usual finding (p < . ) in patients who developed h. paw. ) thexe was a good relatienship between h and high arterial paco before traqueal intahatian and its fast "washing" with mechanical ventilation. ) because cao patients had the highest incidence of h, controned mechanicel hypoventilatien driven by paco changes and pulmonary volumes monitoring instead paw, should be attempted in these patients to avoid this cemplication after tracheal intubatiert. introduction: the endotracheal tube (ett) and demand valve devices cause an added work of breathing (wobadd), which is the work necessary to overcome the resistive load of the ett and the breathing circuit ( ). application of ips has been shown to partly compensate this added work ( ). since tbe amount of wobadd is flow dependent, a fixed ips is not adequate to completly compensate the wobadd ( ). therefore, atc has been developed as a new form of assisted spontaneous breathing ( ), which provides a flow-dependent pressure support. thereby, it theoretically should compensate all the wobadd due to the tube. the purpose of this study was to evaluate the reduction of wobadd with ips and atc for different ett. methods: a mechanical lung model (ls , dr*alger, liibeck, frg) was used to generate a constant spontaneous breathing pattern. the ls was connected to an artificial trachea (at, cm long, mm id). the at was intubated with three different tubes of . , . , . mm id and connected to an evita ventilator modified to provide atc as an option (dfager, liibeck, frg). flow and airway pressure were measured between the y-piece and the ett for four different modes of ventilation: cpap, ips of and cm i and atc all with a peep of cm h . the tracheal pressure (ptrach) was measured in the at. total wobadd was calculated as the area subtended by the ptrach-volume curve below peep. results: the results for total wobadd in nd/ are shown in the figure for the three different ett: breath/mln, s=success, f=failur% *~p<. , **-p< , ns = non significant, f versus s neveltheless, in / patients, invasive ventilation was necessary in mean . _+ hours after beginning of fmpsv. there was no significant difference between the two groups (success, failure) in following parameters : sex, age, previous histoly, medical treatment, saps & , clinical signs (rr, spo , heart rate, blood pressure, glasgow score...), radiological and echocardiographic findings and standard biological parameters. only two parameters were related with failure : .a low value of pac on admission until the patients were intubated. . an increased level of cpk in relation with an acute myocardial infarction ( / cases in the failure group, vs / cases in the success group, x~(with continuity correction) : p<. ). conclusion : fmpsv is a noninvasive, safe, rapidly effective method of treatment in acpe, which may avoid tracheal intubation. further studies are necessary to precise if association of arf and low paco (< mmhg) and/er acute myocardial infarction represents an indication of immediate invasive ventilation. introduction: since the added work of breathing (wobadd) imposed by the endotracheal tube (ets and the breathing circuit is regarded as an important contribution to the total work of breathing, considerable effort has been tmdettaken to compensate for this added work. ips has been fotmd to decrease the wobadd imposed by different ventilators ( , ). because of the flow dependent pressure drop across the etf the tracheal pressure (ptr) should be measured to estimate the total imposed wobadd (wobtut) ( , ). the aim of this study was to assess the circuit imposed work (wobcirc) and wobtot (including ett) for different demand valve ventilators during cpap and/ps. methods: a mechanical lung model (ls , driiger, lfibeck, frg) generated a constant spontaneuus breathing pattern. the ls was connected to an artificial trachea (at), intubated with an . nun et]', end connected to one of four ventilators (servo c and servo , siemens,-elema, sweden; evita , driiges, liibeck, frg; pb ae, puritan bennett, carlsbad, usa). three different modes of ventilator settings were tested (cpap, ips and mbar; trigger set at maximal sensitivity, peep always mbar). flow and airway pressure (paw) were measured between the y-piece and the etr; tracheal pressure (ptr) was measured in the at. wobtot was calculated as the area under the ptr-volume curve below peep, wobcirc was calculated as the area under the paw-volume curve below peep. results: in the foti g., patroniti n., cereda m., sparacino me., giacemini m., pesenti a. inst.of anesth.and intensive care-univ.of milan -sgh monza i aim of the study was to assess cpl,rs measurement obtained by the airway occlusion method during psv. we therefore studied paralyzed cppv ventilated ali patients (lung injury score = . • that were weaned to psv. we performed end inspiratory and end expiratory airway occlusions using the hold function of the ventilator (siemens serve c), first during cppv and then within the th psv hour. airway pressure and flow signals were recorded (cpi bicore) for subsequent analysis. an airway pressure plateau was defined as a flow tracing in which airway pressure was stable for at least . sec. end inspiratory (pel,rsi) and end expiratory (pel,rse) recoil pressures were then measured as the mean airway pressure during plateaus. cpl,rs was computed as tv/ (pel,rsi-pel,rse i) cpl,rs can be adequately estimated during psv using the airway occlusion method; ) during psv inspiratory plateaus are longer than the expiratory ones; ) the length of plateaus is negatively affected by the respiratory drive. foti g., de marchi l., *tagliabue m., gilardi p., giacomini m., sparacino me., pesenti a. inst.of anesth.and intensive care,-univ.of milan *dept.of radiology-sgh monza i we retrospectively compared ct scan and gas exchange findings between a group of patients successfully weaned from vcv to psv (group s = ii patients) and a group who failed the weaning (group f = patients). we selected ali patients (lis= . • in vcv mode who had available a chest ct scan performed within days from the weaning trial. a psv trial was began as soon as the patient reached hemodynamic stability and a pao > mmhg, irrespective of fie (peep < cmh ). maximum psv level was < (pel,rs-peep) measured during vcv, where pel,rs was the respiratory system elastic recoil pressure at end inspiration. psv ventilation was considered successful if a respiratory rate < bpm, an increase in fie lower than . compared to vcv, a pace increase < % of vcv value and hemodynamic stability were maintained during the next hours of psv. if any of these conditions was not met the trial was declared a failure. interdisciplinary critical care unit, regional hospital lugano-ch *surgical critical care unit, university hospital, geneva-ch objective: to assess the degree of correlation of cardiac output measured by thoracic electrical bioimpedance and thermodilution in mechanically ventilated patients with different levels of positive end-expiratory pressure (peep). methods: prospective study with ventilated patients, after head injury and with postoperative sepsis, with normal cardiac output: simultaneous determination of cardiac output by thermodilution and thoracic electrical bioimpedance performed with different levels of peep ( - - cm h ). results: cardiac output measured by thermodilution during sequential increment of peep did not vary: . + . for peep , . + . for peep and . + . l/rain for peep . simultaneously the bioimpedance device recorded a significant increase in cardiac output from . + . for peep to . + . l/mi for peep . (p < , ). conclusion: cardiac output measured by bioimpedance cannot replace the invasive thermodilution methods of cardiac measurement output during mechanical ventilation with peep. we also isolated a subset (h) of patients who had been hypercapnic (paco > mmhg) for at least days (range to days) before the end of cv. the psv trial was started as soon as pao was > mmhg, irrespective of fie and with peep < cmh and the psv level had to be < (pplateau-peep) as measured during cv. pace , pha, base excess (be) were collected before discontinuation of cv and on the ist day of psv: ) . ) weaning is more difficult in pts with head injury(p<o, ) and iss> (p<o,ol), in elderly(p<o, ) and in pts who need fi > , (p<o, ) and peep>io cm h (p<o, ). ) pts with iss> need longer duration of mv (p<o,ol). ) the mortality rate is higher in pts with iss> (p<o,o ), with head injury (p<o,ol) and in elderly (p<o, ). ) paradoxally, compliance was found to be higher in pts> years than in pts< years (p<o, ). s. crotti, p.pelosi, d.mascheroni, m.cerisara, a.lissoni, l.gattinoni. istituto di anestesia e rianimazione -irccs, milano, italia. obiectives. we investigated by ct scan the effects of extrinsic peep (peepe) on lung inflation, tidal volume distribution and regional compliance in sedated, paralyzed chronic obstructive pulmonary disease (copd) patients with dynamic hyperinflation (peep• methods. two ct section (end expiration, end inspiration) were obtained at lung base level in patients (individual analysis for each of the eight lungs) at peepe levels: peepe = cmh (zeep) and peepe amounting to %, % and % of the peep• at zeep ( . • cmh ). tidal volume was kept constant ( • . ml/kg). each lung section was divided into zones equally spaced along the vertical axis: upper (the most ventral), middle and lower (the most dorsal) zone. for each zone we computed: gas volume at end expiration (gase) and at end inspiration (gas• tidal volume (dgas=gasi-gase) and compliance (cpl=dgas/dp;.dp=plateau pressureactual peep• we also computed the lung inflation as the entire ct section gas volume at end expiration (total gase). results. at each peep level both gase and gas• were higher in the upper than in the lower zone ( we cone!ude that in copd patients with dynamic hyperinflation only the application of peepe higher than peepi produces a further increase of lung inflation, decreasing cpl of the upper zone (the more expanded one) probably by stretching phenomena, and causing dgas redistribution from the non dependent to the dependent lung zones. i. ravagnan, p. vicardi, f. valenza, d. tubiolo. p. pelosi l. gattinoni. st . anestesia e rianimazione, universita' di milano, ospedale maggiore -irccs, italy objectives: to investigate the effects of peep and ps on respiratory. pattern and inspiratory effort during ps ventilation in patients with acute lung injury or acute exacerbation of chronic lung disease. methods: pts with acute (a) (paco = • mmhg, pao /pao = . • and pts with chronic (c)(paco = • mmhg, pao /pao = . : . ) lung disease were studied in ps ventilation during the weaning phase. measuring airway pressure, esophageal pressure and gas flow we computed respiratory rate (ril bpm), tidal volume (tv, ml) and pressure time product (ptp, cmh *s/min), which is an index of oxygen muscle consumption. measurements were collected, after rain of stabilization, at and cmh ps and at two different peep levels ( and cndd conclusions: during psv: ) breathing pattern and ptp are different between a and c; ) in both groups peep does not modify breathing pattern; ) peep reduces ptp in c but not in a; ) ps modifies breathing pattern and reduces ptp in c but not in a. to test the performance of a new heat and moisture exchanger (hme): twistair, baxter. this is a hydrophobic-hydrophilic hme without hygroscopic salts. method: we evaluated the hme performance with a previously described method (i); it consists of a "lung simulator" connected to a mechanical ventilator and a flow divider, with a dry and a wet thermal probe inserted into inspiratory and expiratory limbs. on average ps level changes were associate( with opposed changes in both p . and rr. changes in p . were remarkable, homogeneous and highly significant (p<. ), while changes in rr were less pronounced, inhomogeneous and less significant (p<. ). it seems therefore that p . is a better index than rr for estimating a change in load for the respiratory muscles. recently, the lsf method has been described as an interesitng alternative to conventional tecniques used to measure total respiratory mechanics, providing, over these latter, advantages such as no need for hold maneuvers and no need for particular flow patterns. data on the reliability of the lsf method, however, are still few. methods. sets of measurements were obtained in each of ards patients, paralyzed and ventilated in cmv with constant inspiratory flow and an end-inspiratory pause equal to % of ttot. the lsf method provided data for total compliance (ctotlsf) and total resistance (rtotlsf) by multiple linear regression analysis of airway pressure, flow and volume change, applied over the entire breath. the lsf measurements were automatic and continuous, and each value used for analysis was the average of consecutive cycles. conventional measurements of dynamic.compliance (cdyn), quasistatic compliance (cqs), minimum inspiratory resistance (rmin) and maximum inspiratory resistance (rmax) were obtained by the constant flow, end-inspiratory occlusion method, each value being the average of measuremts. ctotlsf was compared with cdyn and cqs, while rtotlsf was compared with rmin and rmax. results. ctotlsf showed a high correlation both with cdyn (cdyn=. .ctotlsf+l. , r =. ), and with cqs (cqs =. .ctotlsf + . , r =. ). the average difference between ctotlsf and cqs, yet, was much lower (+. + . ml/cmh ) than the one between ctotlsf and cdyn (+ . + . ml/cmh ). rtotlsf correlated much better with rmax (rmax=. *rtotlso+. , r =. ) than with rmin (rmin =. .rtotlsf +. . , r =. ). the average difference between rtotlsf and rmin was + . + . cmh / /s, while the one between rtotlsf and rmax was +. + . , confirming the better agreement between rtotlsf and rrnax. conclusion.the agreement between rtotlsf and rmax suggests that rtotlsf takes into account both the airway and the tissue components of resistance, unlike rmin which only expresses airway resistance. the agreement between ctotlsf and cqs indicates that ctotlsf expresses the pure elastic components of the respiratory system. in the paralyzed patient, the expiratory time constant (rce) of the unit represented by total respiratory system and ventilator can be calculated from the slope of the expiratory flow-volume curve. recently it has been suggested that an estimate of this slope is provided by the ve/v'epeak ratio, ve being the exaled tidal volume and v'epeak the peak expiratory flow.the reliability of this method is still little known. methods. sets of measurements were obtained in mechanically ventilated ards patients during paralysis and cmv. measurements of ventilator expiratory resistance (rext) and of total respiratory mechanics were performed in order to calculate these reference measurements for ve/v'epeak: rcdyn=(rmin+rext)ocdyn, rcstat=(rmax+rext)ocqs, rclsf=(rlsf+rext)~ cdyn (dynamic compliance), cqs (quasistatic compliance), rmin (minimum inspiratory resistance), rmax (maximum inspiratory resistance) were obtained by the constant flow, end-inspiratory occlusion method. clsf and rlsf respectively corresponded to measurements of total respiratory system compliance and resistance by the least squares fitting method. ve/v'epeak showed a high correlation with all reference measurements, rcdyn (ve/v'epeak= . orcdyn-. , r =. ), rcstat (ve/v'epeak = . rcstat -. , r = . ), and especially rclsf (see fig the static pressure volume curve of the respiratory system (p/vst) provides valuable information, but the extensive data analysis prevents its use in clinical routine. dynamic p/vcurves are simpler to record. the objective of this study was to develop an automated method to obtain quasi-static p/v-curves (p/vqs) during low flow inflation as well as to measure resistance. preliminary tests were done in normal subjects and subjects with varying degree of lung disease. methods: a computer/ventilator interface (cvl) was constructed for control of a servo ventilator c during an automatic sequence: a) a normal breath, b) a prolonged expiration at zero peep, c) a low flow inflation of a predetermined volume, d) analysis of ventilator pressure and flow. pressure was corrected for tube resistance. airway resistance was calculated from a) and used to derive p/vqs from c). as reference, p/vst was obtained by the occlusion method. results: in non-obstructive diseases the method performed well at volume and pressure controlled ventilation. static and quasistatic compliance were virtually identical. p/vqs clearly reflected the lower inflection point and, when present, the upper inflection point (uip). in some patients uip was more evident in p/vqs, especially at an increased inflation flow rate. in obstructive diseases, the method for subtraction of resistive pressure was inadequate. conclusions: the system for automated computer controlled studies of lung mechanics based on a standard ventilator provides comprehensive information. differences between p/vst and p/vqs imply that the latter reflects also other factors than p/vst that contribute to impedance at hyperdistension. the clinical significance of the two curves remains to be shown. obiective: to evaluate the effect of combined high frequency jet ventilation (chfjv) in patients with severe respiratory insufficiency (sri). methods: in a retrospective study of the period - we analyzed patients suffering from sri who were refractory to conventional mechanical ventilation and were treated with combined high-frequency jet ventilation (chfjv). refractory to conventional mechanical ventilation was defined as a pao /fio < , despite maximal ventilator settings: peep > cm hz , fit > . . a total of patients matched these criteria, males and females with a median age of ( - ) years. seventeen suffered from severe trauma. chfjv was started following a median period of ( - ) days of conventional mechanical ventilation. prior to chfjv ventilation parameters expressed as median were the following: fit . , pao /fio , peep cm h peak airway pressure (pap) cm h . chfjv consisted of high frequency jet ventilation with a frequency of to breaths/minute, driving pressure of . to . arm, and inspiration time of to percent, superimposed on the whole cycle of conventional mechanical ventilation with a frequency of l to breaths/minute and tidal volumes of to ml. results: following two days of chfjv of patients showed an improvement of ventilatory parameters; peep could be reduced to < cm h in patients, the pap was decreased with > cm h:o in patients, fio could be reduced to < . in patients and finally the median pao /fio ratio changed from to . during chfjv patients died, of respiratory failure and due to multiple organ failure, died within two days of chfjv. the median duration of chfjv in survivors and nonsurvivors was days in both groups. conclusions: our data show that with chfjv in the majority of patients with sri who are refractory to conventional mechanical ventilatior" the ventilatory parameters can be improved. backeround and obiectives: although ventilation with peep above the inflection point (pinf) has been shown to reduce lung injury by recruiting previously closed alveolar regions, it carries the risk of hyperinflating the lungs. in the present study we set out to develop a new strategy to recruit the lung during ventilation with small vt, while maintaining peep levels as low as possible. we hypothesized that if the lung was recruited with a sustained inflation (si) to total lung capacity, recruitment would be maintained as long as the peep level was higher than the critical closing pressure of the lung, as observed on the deflation limb of the pv curve (ajrccm ; ( ) :a ). the purpose of this study was to examine the hypothesis that a strategy using si and a peep<pinf would induce less lung injury during small tidal ventilation than ventilation at the same low peep level without using a recmitment strategy in a model of respiratory distress syndrome. methods: we used a randomized protocol with groups to ventilate nonperfused, lavaged rat lungs with small vt ( to ml/kg) for hours and studied the effect on compliance and lung injury. group : peep>ping group : peep<pin f with an si, inflation to on h over sec, to recruit volume; group : peep<pinf without si; group : control group, lungs were inflated at peep<pin f, but not ventilated. results: in group and group static compliance did not change after ventilation (table) . in group static compliance fell significantly. group showed significant changes in the pv curve, which were less severe than in group . results from morphological examination are pending but preliminary results showed less lung injury in group , compared to group . conclusions: small tidal ventilation following a recruitment manoeuvre in a model of respiratory distress syndrome allows ventilation on the deflation limb of the pv curve at a peep below pinf. this strategy ( ) minimizes lung injury as well as, or better than using peep above pint" and ( ) ensures a lower peep to minimize the detrimental consequences of high lung volume ventilation. i~peep>pin~ _objectives-this report is presenting the results of the clinical study for using eeg examination as a method of the evaluation of patients ability for weaning. methods: the study inclljqles eeg examinations with fourier spectral analysis' of patients ~vith respiratory insufficiency and prolonged control mechanical ventilation (cmv). all patients have had a-rhythm of eeg before weaning. we have followed respiratory rate, tidal volume, respiratory pa{tern, end-tidal co and blood gases during weaning. results: patients had invariable eeg activity or short -waves period (till one hour). the weaning of this patients was fast arid sucsessful. other patients have had a decreasing of a-activity, an appearence of -waves for an hour and more, a short episodes of a-and e-activity. after that this patients had gas exchange and respiratory disorders with regression of the weaning right up to cmv. conclusion: eeg could be used as a method of the evaluation of patients ability for weaning from cmv. some eeg signs shows the overstrain of compensatory systems before the change to the worse of gas exchange and respiratory pattern. s. elatrous, p. aslanian, d. touchard, d. corsi, h. lorino, l. brochard. medical intensive care unit, inserm u , hopital henri mender, cr~teil, france. in vitro comparison of flow triggering (ft) systems demonstrated advantages compared to pressure triggering (pt) systems for some ventilators (puritan bennett ) but not others (siemens serve ). we studied the two types of systems in two groups of patients mechanically assisted with pressure support ventilation ( + cmh ). in the first group (pb ) the effort of breathing, assessed by the esophageal pressure time index, was significantly lower with the ft than with the pt ( + cmh .s/min - vs + , p< . ). by contrast no significant difference appeared in the second group (serve ), as predicted by the bench study despite marked interindividual differences ( + cmh .s/min - vs + , p = . ). we conclude that ) rigorously performed bench studies can predict in vivo effects, ) mild advantages can be found for the new triggering systems on some ventilators. objectives: pressore-volume curves (pv) of the respiratory system is of interest for the determination static compliance (cs , lower (lip) and upper (uip) inflection points which indicate zones of airway recruitment and overdistension. this study aimed to compare an "automated low flow inflation" method (alfi) to the reference occlusion (oc) method. the ability of the former method to identify cst, lip and uip was tested in icu patients. me,otis: ( arf and ards) sedated paralysed patients were studied using a serve c ventilator linked to a computer which automatically forced the ventilator to insufflate at a low constant flow a velum up to - ml or a maximum paw of cm h (alfi). the quasistatic elastic pressure (pel,qs was obtained by subtraction of the resistive pressure of tubing and patient and related to volume for calculation of compliance cqst. for oc tidal volumes (v from up to - ml were followed by a s post-inspiratury pause for determination of static pal (pel,st) in relation to volume. compliance was defined from the linear part of the p/v curves. lip and uip were defined from the consistent deviation of p/v data from extrapolated the linear part. ~,~ i~: in ards, mean cst was . + . and cqst . + . ml/cm h (us), lipst . + . and lipqst . + . cm h (us), uipst . + . and uipqst . + ~ cm h (us). nosocomial pneumonias (np) are frequent and often unsuspected during ards (bell, ! ). in the present study, we evaluated prospectively the onset of np during severe ards (group b of the european study). patients and methods: the charts of patients with severe ards have been prospectively recorded. a plugged telescopic catheter (ptc) specimen has been systematically performed every hours, for quantitative bacteriological analysis. the diagnosis of np was defined by a number > colony forming units / ml. results: for the patients studied, the mean saps score (+ sd) was +_ , the initial pao /fio ratio was -&-_ , the duration of mechanical ventilation (mv) was + days. the mean delay before the onset of the first np was . + . days ( - ), and the mean pao /fio ratio was +- . respiratory symptoms (purulent aspirates, new pulmonary infiltrates, or gazometric changes) were present in % of the patients studied. alteration of gas exchange was present in of the patients ( np) . a new pulmonary infiltrate was present in only np ( %). an increase of fever was noted in patients, an increase of leukocytosis > % in patients, an increase of volume and purulence of sputum in of the patients with np. the degree ofgazometric worsening (pao /fio before np minus pao /fio during np) during the first episode of np was + mmhg. excluding the bacteriological criteria of np, the number of criterias of np present was in / patients, ( / ), ( / ) or ( / ). two patients only had a pulmonary colonization (ptc: < cfu / ml) before the first episode of np. the incidence of np is high ( %) during severe ards. the first episode occurs in average:at the th day, and is the cause of a severe hypoxemia (pao /fio ) . the onset of a np may contribute to the high mortality rate observed in our patients ( %). each worsening of hypoxemia during severe ards should induce to suspect a np. respiratory system during mechanical ventilation. the me~hod quantifies the dissipative energy consumption of the respiratory system in terms of energy loss aek, inefficiency ~k~ and respiratory dissipative resistance rk~ over a given partition of the tidal volume. the method can be applied in intensive care units with no interference to ventilatory support. it allows for monitoring the combined effects of inhomogeneities, non-linearities and visco-elastic effects, that are subject to change in the respiratory system. the method is studied on pigs~ in the presence of a log-dose response curve of methacholine (mch) induced disease. in healthy pigs~ we find a mean value of energy loss, ae, of . • j/l, a mean value of inefflency, ~ of . ~= . and a mean value of resistance, ~, of . • cm h s/ . the respiratory resistance, rk, shows a variation over the partition of tidal volume with armax ---- . • . cm h s/l. during methacholine provocation~ ae rises more than five-fold up to . • j/l~ doubles to . • and t~ increases to a maximum of • cm h s/l, with armax : . • . cm h s/ . the variation in rk becomes more pronounced with higher doses of methacholine. methods: ards patients were prospectively studied. initially they were ventilated in the amv (assist mechanical ventilation) mode with the settings prescribed by their primary physician. after stabilization, ventilatory gas exchange and hemodynamic variables were determined. patients were then ventilated in the mrv (mandatory rate ventilation) mode with breaths as the target rate. in mrv the target rate is set and the ventilator autoregulates the pressure support level delivered ~o achieve this rate. after stabilization, the measurements done on amv were repeated. finally, patients were sedated and paralyzed and ventilated in cmv (control mechanical ventilation) with the ventilatory variables they had during mrv. measurements done in amv and mrv were repeated and respiratory mechanics were assessed with the constant flow end inspiratory occlusion method. results: two groups were recognized based on their response to mrv. tn group patients responded to mrv by decreasing their v and increasing the t/t t ratio. ve, vo , and aado decreased while paco increased and tda vo ume and co remained unchanged. on the contrary, in group v, vr and ve increased; ppeak and trr t remained unchanged, paco~ decreased while vo and aado increased with constant co, the pressure support level needed to achieve the target rate was much lower in group than in group ( , -+ . vs . _+ . ). obiectives : in the newly developed mode of ventilatory support ,,automatic tube compensation" (atc) the ventilator compensates for the flow-dependent pressure drop across the endetracheat tube (ett) thus allowing ,,e]ectronic extubation". the aim of the study is to investigate whether healthy subjects perceive atc in inspiration (atc-in) and in expiration (atc-in-ex) and whether atc provides an increase in subjective comfort compared with the conventional assisted spontaneous breathing mode (asb). methods : healthy volunteers (no preceding lung disease, non-smokers, male, - years)breathed spontaneously through an uncut ett of . mm id via a mouthpiece. the ett was connected with a prototype ventilator evita modified by the manufacturer (drfiger, lebeck) for atc. flow and airway pressure were measured at the outer end of the ett. three ventilatory modes, ( ) asb ( mbarover mbar peep), ( ) atcin, ( ) atc-in-ex were selected in random order. immediately following the transition from one mode to another the volunteers answered by hand sign how they perceived the new mode compared with the preceding mode: ,,better" (+ ), ,,equal" ( ) or ,,worse" (- ). inspiration and expiration were investigated separately by presenting mode transitions (in total; including ,,placebo" transitions). results : the difference between atc and conventional asb is perceived in inspiration and in expiration. atc is positively judged; asb is nega ively judged. the diagrams show mean values _+ sd of five volunteers investigated up to now. the new mode atc is perceived as an increase in subjective comfort. our explanation is that atc preserves the natural breathing pattern better than conventional asb. objectives: to determine the role of cerebral vasoconstriction in the delayed hypoperfusion phase in comatose patients after cardiac arrest. to correlate the results with indices of cerebral oxygenation and the levels of several vasoactive hormones in the jugular bulb. methods: in comatose patients after cardiac arrest we measured the pulsatility index (pi) of the medial cerebral artery by transcranial doppler sonography. the pi is a reliable indicator of cerebral vascular resistance. we also sampled blood from the jugular bulb and measured cerebral oxygen extraction ratio and jugular bulb levels of endothelin, nitrate and cgmp. the first measurement was done within hours after cardiac arrest and repeated , , , , and hours later. results: we studied patients, females, mean age , + , years. the pi decreased s!gnificantly between th~ first and the last measurement from . _+ . to . + . (p = . ). cerebral oxygen extraction ratio decreased also from . + . to . + . (.p = . ). endothelin levels were high, but didn't change during the studied period. nitrate levels varied in a wide range, but didn't change significantly. however, cgmp levels increased significantly from very low levels in the first measurement to very high levels hours later, rasp. . pmol/ml (median; th . - th . ) and . pmol/ml (median; th . - th . ) (p = . ). eighteen and hours after the first measurement we found a strong correlation between pi and cerebral oxygen extraction ratio ( r = . , p = . and r = . , p = . ). we.also found hours after the first measurement a significant correlation between pi and cgmp levels ( r = . , p = . ). we found no correlation between pi and endothelin or nitrate levels. conclusion.~; our results show a high cerebral vascular resistance in the first few hours after cardiac arrest, gradually decreasing during the next hours. this is accompanied by an initially high cerebral oxygen extraction ratio and low cgmp levels, suggesting that the cerebral vascular resistance is induced by active vasoconstriction because of insufficient cgmp levels, leading to a decrease in cerebral blood flow and a compensatory ~ncrease in cerebral oxygen extraction. objectives: sudden cardiac arrest is a major cause of mortality in western countries accounting for over half of all cardiovascular deaths. in most cases the mechanism of death is prolonged cardio-circulatory arrest due to ver:tricular fibrillation (vf) preceding final asystole. recurrent syncopes due to idiopathic vf with good neurological prognosis have been reported in patients with and without cardiac etiology ( , ). in the past measurements of cerebral hemodynamics have been repeatedly done in humans during cpr, but until today no studies of cerebral blood flow velocity (cbfv) have been reported during controlled cardiac arrest in humans not under-going cpr. it was the purpose of our study to evaluate the acute hemodynamic effects of untreated vf on cbfv. methods: after approval by the local university ethics comittee, five male patients aged - years without evidence of cerebral disease were investigated during vf while undergoing implantation of a pacer cardioverter defibrillator system (model d; medtronic| a standard anaesthetic regimen was used (propofol, fentanyl). after implantation of the automated cardiac defibrillator vf was induced by electrical countershock to test effective sensing, pacing, and defibrillation. to measure cerebral blood flow velocities (cbfvmca) the doppler probe was placed above the zygomatic arch between the lateral margin of the orbit and the ear and directed towards the m segment of the middle cerebral artery (mca). results: a total of phases of vf were investigated. duration of vf ranged from to seconds, with cbfvmc a (mean_+sd, cm sec - ) flow pattern changing from pulsatile to laminar flow immediately after onset of vf. conclusions: the underlying mechanism of the laminar cerebral blood flow observed during vf in our patients is uncertain, but it may provide insight into the prognosis of patients with idiopathic vf. theoretically, the laminar cerebral blood flow observed in our pulseless patients may provide a substantial amount of cerebral perfusion even during clinical cardiocirculatory arrest objective: to investigate whether the intensive care nursing staff can inflate more accurately a specific air volume with the laerdal resuscitation bag when they receive feedback after each inflation about the delivered volume compared to no feedback. method: icu nurses were asked to inflate a testlung model times with a specific air volume ( ml, ,ml or ml) under three different conditions (normal, decreased compliance and increased resistance) without and with feedback. we measured the mean absolute difference from the specific airvolume after each ten inflations. results: the largest absolute difference was found when icu nurses inflated ml ( ml). the mean inflated volume for this group was ml. when the icu nurses had to inflate ml the mean absolute volume difference was ml with a mean inflated volume of ml. inflating ml produced an absolute volume difference of ml with an mean inflated volume of ml. the absolute volume difference decreased when the compliance of the testlung was decreased and even more when the resistance of the used endotracheal tube was increased. when the icu nursing staff received volume feedback after each inflation the mean absolute volume difference was reduced between the ml and ml for all specific air volumes. % of the last inflations with feedback were significantly smaller than ml from the specific air volume (p < . ). conclusion: the majority of nurses overinflated the specific air volumes. the largest over inflation occurred when ml and the smallest when inflating ml. when nurses were provided with volume feedback the performed significantly better. we concluded that icu nurses are not able to inflate a specific air volume with the laerdal resuscitation bag without receiving volume feedback. feedback is desirable in order to reduce the volume trauma. objectives: a pro_found impairment in systolic and diastolic myocardial function following successful cardiopulmonary resuscitation (cpr) has been demonstrated by using langerdorff method in rats. in the present study we have investigated post resuscitation myocardial dysfunction in a porcine model of cpr. methods: ventricular fibrillation (vf) was electrically induced by alternating current applied to the ep{cardium of the right ventricle in domestic pigs. following rain of untreated vf, precordial compression and mechanical ventilation was initiated and maintained for min. electrical defibrillation was then attempted and of animals were successfully resuscitated. results: following successful cardiac resuscitation, stroke volume index (svi) decreased from prearrest value of . ml/kg to . ml/kg (p< . ), and left ventricular stroke work index (lvswi) from . to . mmhg,ml/kg (p< . ). both svi and lvswi remained depressed for another hours. these decreases were associated with increases in heart rate from bpm to bpm (p< . ). no significant changes from baseline in mean arterial pressure, mean pulmonary pressure, right atrial pressure and pulmonary artery wedge pressure were observed. prehospital resuscitation efforts c. k ppel. g. fahron, h. lufft, a. kruger, c. th(jrk, f. bertschat, f. martens dept, of nephrology add medical intensive care, virchow-klinikum, humboldt-universit~t, d- bedin, germany obiective: the success rate of prehospital resuscitation in patients with cardiocirculatory arrest in an emergency medical system (ems) may reach - % depending on the time of calling the ems, the distance to cover by the emergency ambulance and the training of the emergency physician and his staff. in the berlin ems, which is associated with the berlin fire brigade, the time between alarm and arrival at the scene ranges from - min, mean min. resuscftation is based on the advanced cardiac life support (acls) according to the guidelines of the american heart association. if resuscitation efforts fail to restore circulation, they are terminated after - min, depending on duration of cardiocirculatory arrest, pre-existing disease, age, absence of an even transient response to cpr. however, there is a lack of practical criteria for termination of cpr in individual decision making. patients: we report cases of prehospital cpr with primary asystolia terminated after - rain of frustraneous cpr efforts including highdose epinephrine and dopamine. results: after termination of cpr, the ecg monitor remained connected and showed permanent asystolia in all patients while the emergency physician completed his records. spontaneous resumption of respiration and circulation was observed in these patients after - min and cpr efforts were immediately resumed, nevertheless, of the patients died at the scene, while could be hospitalized with stable circulation. one of them died hours after admission to the icu, the other survived for weeks in a vegetative state. spontaneous resumption of circulation and respiration is most likely due to the development of extreme hypercapnia and acidosis, which -at least in some patients -seems to be a stronger stimulant of the circulatory and respiratory brainstem centers than cpr with high-dose catecholamines, conclusion: because of the legal and ethical implications of this rare phenomenon, emergency physicians should continue ecg monitoring for at least rain. after termination of cpr efforts. pulmonary artery catheterezation is used for patient's monitoring [ ]. we reported our results on such monitoring in [f.coaobbeb,r.fe enb~-kap~monorm~, ,n ,p. - ] .however not all of the received criteria assessments meet demands that are necessary for early diagnosis of critical states. here we report the data on po ,pco (mm rg),so ,ph levels in femoral [af) and pulmonary (ap) arteries blood, as well as on summary gas pressure (sgp) calculated from pe=(po +pco ) in mm hg in ap blood. these data were derived from:i) subjects free of cardiovascular pathology according to catheterization data during their spontaneous air breathing (n group in ap blood appears to be a measure of adequacy ratio between pc and sgp in ap blood during air breathing; partly its characteristics and variations ranges are presented earlier [ j. in control group it is equal to , • mm hg. tests on sgp neither exclude nor substitute conventional (pc and pco ) tests, but rather include them as a part choosing only additive characteristic -pressure. they appear to be a part of general system of human metabolism regulation by pressure (arterial,venous,intracardiac, tissue,liquor,onco-osmotic,etc ietraabdeminal pressure produces perturbations of cardiac, pulmonary, and renal physiology. this most often occurs fonowing eeliotomy for peritonitis or intestinal obstruction; bowel edema and distention prevent wound closure without unacceptable compromise of blood pressure or pulmonary compliance. a variety of temporizing measures have been reported for managing wounds that cannot be closed: ) using towel clips to reapproximate skin only, )i sewing silastic, marlex or other prosthetic grafts to the fascia to "enlarge" the peritoneal cavity, ) using loosely tied retention sutures for partial closure, ) simply packing the wound without attempts at c~osure. these techniques either traumatize the abdominal wall (complicating definitive closure), expose the bowel to damage, or allow excessive loss of fluid and heat. since we have evolved a suturelees technique which permits the abdomen to be partially closed in a quick, safe, sterile, sealed, atraumatic fashion -while providin! decompression of unphysiologic intraabdominal pressure. methods: whenever possible omentum is interposed between bowel and the open incision. viscera are covered by a layer of sterile, non-reactive plastic, placed deep to the fascia and extending we~t beneath the edges. sump tubes are placed above the plastic and covered in turn by two layers of an adhesive plastic drape which sticks to the skin and seals the wound in all directions, the patients remain intubated and paralyzed. results: we have used this technique in a total of patients, four of whom suffered from compartment syndrome. all of the latter were males and ranged in age from to . all four showed immediate physiologic improvement. all four incisions were eventually closed without complication. one compartment syndrome patient died t days later of multiple organ failure. there were no complications related to the closure technique in any of the patients. conclusions; . selected patients with abdominal compartment syndrome will benefit from decompression using this temporary sutureless technique. the technique a) is quick, safe, sterile, sealed, and atraumatic, b) minimizes loss of fluid and heat, c) facilitates eventual definitive abdomina| closure. although m. brunner m. mitllncr objectives: to determine incidence and predisposing factors for cardiac arrest occurring during the first hours after open heart surgery. methods: the study included patients who, following open heart surgery, had adequate cardiac function and in whom cardiac arrest was not anticipated. all data were prospectively recorded and analyzed. results: from / through / , pts underwent open heart surgery at our hospital. of th~se, pts ( %) (age _+ yrs) had a cardiac arrest during the first hours after transfer to icu. they were operated on for coronary artery bypass grafting (cabg) ( pts), valve replacement (vr) ( pts), cabg and vr ( pts) and aortic aneurysm ( pt). the preoperative ejection fraction was _+ % whereas bypass and aortic cross-clamp time were + and + rain, respectively. prior to arrest, they had a cardiac index of . _+ . l/min/m and were receiving . + inotropes. arrythmias leading to cardiac arrest were ventricular tachycardia/fibrilation ( pts) and bradyarrythmia ( pts). closed-chest cpr was initially performed on all pts and was followed by open-chest cpr in pts. eighteen pts ( %) survived to icu discharge. causes of arrest included perioperative myocardial infarct (t pts, %), tamponade ( pts, %), rupture of the proximal vein gra& anastomosis ( pt, %), graft occlusion ( pts, %); no cause was found in pts ( %). conclusions: postoperative cardiac arrest in stable cardiac surgery pts is relatively infrequent (- % incidence) and is associated with a high survival rate following successful cpr. perioperative myocardial infarct is the most common predisposing factor. group ~deptof anaesthesia and intensive care, semmelweis univ. medical school, buda military hospital intensive care unit, budapest background: when a cardiac arrest occurs in-hospital, the outcome can be improved by a higher quality of basic life support provided by the witnessing health care workers until the code team arrives. this basic life ~pport (bls) should include the best available method for airway management as well. since not all medical staff are ready for carrying out endatracheal intnbation, we investigated the effieacy of the use of different airway management methods during bls. methods: we have investigated the efficacy of airway management of doctors and nurses from different hospital wards: internal medicine, department of surgery, trauma, urology and gynaecolagy. comparing the bag-valve-mask, laryngeal mask and the endotracheal intubafion, we have measured the following parameters: time needs for correct application (sec.), number of incorrect applications (out of ten trial), efficacy of artificial ventilation provided by the device. we used a computerised als trainer manikin for the evaluation of the performance. total performance score was created after the measurement between - . after the first screening we held a x hours training. doctors and nurses were trained for the endotracheal intubation (group it , t ) , doctors and nurses were trained to use the laryngeal mask (group lm , lm ) . all respondent were trained to use the bag-valve-mask device. day, month and month after the training we have carried out retention study using the same method. results: we have found that the efficacy of the artificial ventilation using the above mentioned devices were poor before the training. the average after-training performance scores of the groups are presented in the table below. (bls) should be initiated by the witnessing health care professional. the cpr study introduced a multi level code system, which means bls included sophisticated airway management, early defibrillation and early epinephrine administration provided before the code team arrives. our previous studies confirmed a poor level of cpr performance and a high demand for cpr training among health care professionals. method: we established a cpr training course centre, where doctors and nurses are being trained for in-huspital basic and advanced life support. x hours of training were held. after the theoretical introduction a step-by-step training method ws used for trainees to be familiar with all sequences of basic and advanced life support. then we synthetised all separated sequences. afterwards, a r e play of rescue groups was taken in simulated situations. we also trained the multi level alarm system fur the in-hospital resuscitations. after the training all respondents had to sit for examination. the quality of performance was scored and compared to our previous results. semi-structured interviews were carried out before and aider the training among all respondents to collect information about the course. results: we have found a remarkably high interest among doctors and nurses in our cpr training courses. it was very important to use proper equipment for the training: audio-visual training facilities, computerised als trainer manikin, manual and automatic defibrillator units. the evaluation of the examination held immediately a~er the training course showed a significant higher quality of performance than before the training. the self.-eonfidence of the trainees for initiating and carrying out resuscitation had increased. their overall feeling about the course was positive and % responded the course "very useful". . % of doctors and . % of nurses claimed fur regular training facilities with als trainers, conclusion: the cpr training for health care werkers is mandatory including the training of sophisticated airway management and use of elad~l~ills~tt~r wlaa ~en ~r a~ti~atir ~nel r rm~a'*h*nr m~thnd for training will improve the efficacy, the satisfaction of trainees, therefore their compliance for further co-operation will also increase. s objectives: the effect of reinfusion in emergency surgery and gynecology. methods: we had an experience of autologous blood transfusion in patients whom was produce t an emergency surgical or gynecological interventions in occasion with break tubal pregnancies ( . %), penetrating abdominal wounds with injuries of mesenterial vessels ( . %), injuries of the liver ( . %), blunt abdominal trauma with lien ruption ( . %). in . % patients had the previous somatic pathology. blood loss volume was - ml, & the reihfuside blood volume was - ml, consisting - % of blood loss. it was needn't to fransuse donor blood in . % in further but - ml of contanined erythrocytes were frasfused for supporting of hb concentration on the g/l ( g/dl) rate at the other patients with isovolemie hemodiluttion. results: the arterial blood pressure fast stabilisation on the perfusion level had noted after reinfusion, excluding the case, when the volume of reinfused blood had conisted just % of blood loss at the patient with massive blood loss. complications have noted in two cases. one patient with slash wound, injury of arteria gastrica dextra and total blood loss of ml, has an episode of asystoly, dic (disseminated intravascular coagulation) syndrome, acute renal failure, and acute pancreatitis that we haven't connected to reinfusion. all the complications were successfully corrected and at thirty first day patient with subcapsular wound of the lien that has happened days before complicated with external rupture of the capsull & massive intraabdominal bleeding, has the hemolytical shock, dic syndrome, acute renal failure developed after reinfusion. he was died. all another have no complications. posthemorrhagic anemia had corrected rapidly than in case when hemorrange corrected exclusively by donor blood. conclusions: we consider that simplicity, accessibility, high effectiveness, quite well further results of blood reinfusion, except the case of blood reinfusing that was for time-expired out of blood vessels (more than days in our case) will promote to the wide spreading of this method, especially in emergency surgery, in massive injuries, & in disarters, all the cases of insufficiently of time for selection of lot of donor blood. objectives: study of a reaction of the oardioreepiratory system of pregnant women to i/v microperfusion of clophelinum which is known to eliminate hemodynsmic and endocrine nociceptive reactions and can be used for treating hypertensive syndrome in pregnancy and labor. methods: the following non-invasive methods were used: capnography, spirometry, oxygenography, indirect fick principle based on the circle breathing, plethysmography and integral rheography~ functional indices of cardiorespiratory function were evaluated. results: pregnant women with ~h-gestosis were examined before and after i/v infusion of i ml of . % clophelin solution, . mg/kg/hour. before the treatment intensification of carbohydrate metabolism, hyperventilation with moderate hypooapnia and complete respiratory compensation of metabolic acidosis~ increased alveolar ventilation, decreased alveolar volume, predomination of perfusion over ventilation, hypokinetio type of circulation with dominated load by peripheral vascular resistance to the blood flow was observed in this group of patients. microperfusion of clophelin imp~-oved the ventilation/perfusion ratio, ventilatory and gaseous exchange efficiency, resulted in a decrease of congestion in the pulmonary circulation, possibly owing to a decrease of peripheral vascular resistance by %, of the heart rate by io. %, of the oardial output index by . %. conclusionm: the resulted type of circulation with a decreased load on the heart both by resistance and volume allowed to improve the cardioreepiratory system function in pregnant patients. objectives: the injury severity score is a measure of severity of anatomic injuries. iss is a sum of squares of the highest degrees of the abbreviated injury scale (ais) for each of three most severity injured regions. the purpose of the study is to establish correlation between the iss values and mortality rate in older, polytraumatized patients. methods and results: iss was determined for patients. the mean iss value was . + . while the median value was . minor injuries were present in ( %) patients with iss less than , while ( %) patients with iss more than had severe injuries. increased mortality of the older patients was noted in the range - . all patients older than died while % of patients below yrs of age survived, indicationg correlation between iss and mortality rate in polytraumatized patients above yrs of age. conclusions: this mode of evaluating severity of injuries may help in triage, determining appropriate level of care and as an indicator of future outcome of polytraumatized patients. objectives : tissue hypoxia is a non exclusive cause of hyperlactatemia. other serious medical situations induce hyperlactatemia. therefore, lactatemia could be a non specific indicator of severity in patients admitted in emergency unit. the aims of this study were to examine the correlations between lactatemia with the short term survival course prognosis and the unit of hospitalisation; intensive care unit (icu) or medicine unit, in patients admitted in our emergency department. methods -lactatemia was measured as soon as the admittance, in arterial blood sample of patients which needed arterial blond gas. sixty-one patients were included during months. to assess the statistical performances of lactatemia, sensitivity (se), specificity (sp) and accuracy (ac) were calculated for the threshold determined by the youden's test (se+sp- ). results : fifteen patients were admitted in icu and in a medical unit. fifteen patients died. a group of patients had a lactatemia up to mmol.l" . in this group of patients, had acidocetosis, had asthma, had cerebral vascular ischemia, had neoplasia, had cardiogenic shock, was epileptic, had congestive heart failure, had acute respiratory failure, had septicaemia, had hyperosmolar status finally had medicinal intoxication. lactatemia was significantly higher in non survivor than survivor ( . • vs. . + . , p<o.oool, respectively), the cut point of lactatemia was . mmoll" se was %, sp was % and the accuracy was %. on the other hand lactatemia was higher in patients admitted in icu than in medical unit ( . + . vs. . • p<o. , respectively). conclusions : this preliminary results suggest that lactatemia is a good indicator of the short term survival course in patients admitted in an emergency unit. furthermore, hyperlaotemia is present in several pathology seen in emergency. objective: to determine the pattern of injury, total peripheral white cell, neutrophil, and lymphocyte responses, and the outcome of trauma patients who are leucopaenic on admission to the icu. design: prospective, descriptive study of consecutive admissions over months. setting: a -bed surgical intensive care in a teaching hospital. patients: thirty consecutive adults admitted to the icu following trauma. leucopaenia was defined as a total peripheral white cell count of < x , neulropaenia < x , and lymphopaenia < . x ~ cells per litre. measurement and results: the total peripheral white cell count was documented daily and the neurtophil and lymphocyte counts and differential percentages on days , , and . the incidence of leucopaenia was significanfiy higher in patients with gunshot wounds (p < . ) and hollow visceral intra-abdominal injury (p < . ). eight ( %) patients died. no significant differences were found in the initial mean total white cell, neutrophil, or lymphocyte counts nor in the differential percentages between survivors and non-survivors. the total peripheral white cell count increased significantly in survivors compared to those who died (p < . ) and significant differences were found in absolute neutrophil counts (p < . ) and differential percentages (p < . ) on days and . no significant differences were found in lymphocyte counts or differential percentages. conclusions: there is a signficant association between leucopaenia, neutrepaenia, and intra-abdominal hollow visceral injury and peritoneal contamination. survival is related significantly to resolution of these white cell deficiencies. these findings suggest a possible role of granulocyte colony stimulating factor in the trauma patient with intra-abdominal infection and persistent neutropaenia. amelioration of organization emergency care team in order to improve caring for urgent cases. objectives: emergency care team (ect), as integral part of health, respectively as activity of primary health protection care all acute difficult conditions which vitaly danger patients and distressed. the aim of our investigations was to indicate on the possibilities of amelioration of organization ect in order to improve caring for urgent cases. methods: in our investigations we used epidemiologicai and statistical metods all informations and matherials from terrain ects. results: the number of traumatized in traffic accidents etc. have a epidemic character. it is well known that . % traumatized died in first two hours. ect isn't enough qualified to care a traumatized on the place of accident and during transport. because that medical personnel must have an education with solid qualities. conclusions: . besides a physician specialized (vii --+ vii -~ viii gradus) in urgent medicine, it's necessary to introduce two ( ) medical technicians instead of one as is existing now ( ~ ). .the medical technicians can drive cars and one of them always, drives the ambulance car ("b" category). .the technicians have been specially educated for urgent cases (iv ~ v ~ vi). . such a new team structure should be more capable in professional sense. .we can see an importance of team-work in ects. . such teams should also be more economic in comparison with existing one. . we think, that on the general medical studies need to include a new discipline-urgent medicine! objectives: to detoxicate an organism since we have used biological sorbents: isolated from liver and spleen of human or animal cells or tissue fragments. methods: cellular dialysis ( dialyses) in patients with an acute hepatic insufficiency poisoning by hepatotropic poisons: cc , dichloethane, mushrooms -were conducted using "artificial kidney" apparatus, by means of arteriovenous shunt, formed at forearm with disposable dialyzers. hepatocytes suspension was poured into dializing circuit of dialyzer at - mg of cells per i kg of patients weight. dialysis was performed during - hrs. patients with purulent-septic states were treated as for hemoperfusion through prepared sorptional column: . ml of hemosorbent and . ml of fragmented spleen or hepatocytes suspension with the help of roller pump with the rate of - ml/min, during - min. average volume of hemoperfusion made . . conclusions: in all cases we used both native and cryopreserved biomaterial. analysis of the dynamics of clinical, biochemical, scintigraphic and us-investigastions allows to conclude that application of cellular-sorptional method of detoxication enable to prolong life and reduce lethal outcome in some severe category of patients with endotoxicosis. after infusion of diazepam ( . mg/kg),thiopentone ( mg/ kg) and vecuronium (lmg/kg),patient was intubated and mechanical ventilation was adjusted to mantain normoca= pnia. ct scan showed left parieto-occipital hypodensity with brain swelling. after admission in neurological icu,dexamethasone ( mg/ kg/die),mannitol ( .smg/kg) and diphenylydantoin ( mg/ kg/die) were administred. two hours later neurological status of the patien~ was normal and she was extubated. the risks of stereotactie radiosnkgety are related to: hemorrhgge during the latency interval;transient radia= tion effects;permanent radiatio~einduced complications; radiation induced neoplasia. no epilepsy is reported in pts with avm and no seizure before radiosurgery. in c nclusion, epilepsy can be a posmib~e delayed eompli c~t~n, ~fe~r rgdi surgery for cerebral avm. serum potassium deficiency is a frequently reported finding in the time course of acute myocardial infarction (ami). if this is also correct for patients with ami undergoing primary percutaneous transluminal coronary angioplasty (ptca) is unknown.for that reason we analysed in patients ( m., f., + y.) serum potassium concentrations on ad ,mission and directly after ptca.the reference intervall for potassium in our clinical laboratory is , - , mmol/l. although more than % of the patients with ami undergoing ptca showed normal potassium serum concentrations on admission a measurable decrease of potassium could be found in % of patients ( ) after ptca.therefore for the majority of patients with ami potassium supplementation prior to ptca can be justified to avoid electrolyte disturbances as a possible trigger factor for cardiac arrhythmias in the setting of ami and acute reperfusion due to primary ptca. objectives: diagnostic procedures are very important in the management of abdominal injures in trauma. the aim of this paper is to present our experience with peritoneal lavage as diagnostic procedure in abdominal injury. methods: we analyzed patients to whom peritoneal lavage was applied in the surgical emergency from st of january till st of december . results; in this four years period there were abdominal injures. there were blunt injures. among them in patients peritoneal lavage was applied. results were positive in patients and negative in patients. false positive finding were in patients and false negative in two patients. in patients with positive lavage there were more than , /mm red blood cells, more than , /mm white blood cells and the level of amylase was up to u/i. the gall, urine and stool were positive as well. in patients with negative lavage there were less than , /mm red blood cells, less than /mm white blood ceils and amylase were negative. conclusion: peritoneal lavage is useful and important diagnostic procedure in the management of abdominal injures in trauma. our experience with urgent surgical management of the acute gastric and duodenal bleeding s.se en md, z.milo~evi md, *s.srdi md, k.sar ev md. clinic for abdominal and endocrine surgery, institute for surgery; *clinic for cardiology, institute for cardiovascular diseases; school for medicine novi sad, university of novi sad, yugoslavia objectives: acute gastric and duodenal bleeding are very common complication of gastric and duodenal ulcer. the aim of this paper is to present efficiency of our surgical management of these acute conditions. methods: in this paper results of surgical management of patients with acute gastric and duodenal bleeding, treated in our clinic from the st of january till st of december , are presented. results: among operated patients there were females ( . %) and males ( . %). there were patients ( . %) with gastric bleeding and patients ( . %) with duodenal bleeding. bleeding from gastric ulcer were treated with the following methods: excision of ulcer with suture in patients ( . %), ulcer suture in patients ( . %), billroth i in patients ( . %) and billroth ii in patients ( . %). heinecke-mikulicz-weinberger pyloroplastica was the most frequently used in the treatment of the duodenal ulcer bleeding. bilateral truncal vagotomy was done in patients ( %), duodenotomy with ulcer suture was done in three patients ( . %) and three patients underwent billroth ii operation. we had three complicationsduodenal dehiscence in pyloroplasty. there were no lethal complications. conclusions: based on our own experience we conclude that acute bleeding from gastric and duodenal ulcer can be safely managed with urgent and modern operative techniques. dept. of anaesthesiology. emergency center of serbia, belgrade, srj b ectives and methods: cardiac contusion was evaluated by serial determination of cpk-mb fraction and co using non-invasive doppler technique in patients with blunt trauma of the chest. results: miooardial contusion was diagnosed in ( %) patients, while in ( %) it appeared unaffected. cpk-mb of % and more in comparison to total cpkwas . + , % in patients, and , + , % in pts (p< . ).c of . + . l/min in patients with cardiac contusion, measured hrs after admission at the latest, was significantly lower than in group of patients with co of . + . l/min (p< . ). conclusions: co values were significantly lower in patients with cardiac contusion and correlated with pathological values of cpk-mb fraction. objectives: extracorporal plasmophoresis (pph) was implemented by non-stop method in patients with obstructive jaundice. methods: changes of serotonin (s) and histamine (n) in arterial (ab) and venous (vb) blood were investigated before and after one-time session of pph. s and h in blood serum were determined with fluoremetric method. results: before pph the average s contents in ab and vb did not differ. after one-time pph session s in the blood outflowing lungs was % lower than in the blood inflowing. hours after extracorporal detoxication implemented the indices kept the same level. similar dynamics after pph was observed in h. before the session h contens was equal both in the blood inflowing and in the blood outflowing lunge. after pph h contents in ab was % lower compared to the vb and did not change for hours. conclusions: dynamics of changes of biogene amines shows that under the influence of pph there takes place not only mechanical removal of their surpluses together with plasm, but there sharply grows inactivating role of lungs towards ba substances, which is confirmed by reduction of their concentration in the blood outflowing lungs. this effect is probably connected with the "deplasmation" of the lung cellular elements. simultaneously lungs' cells are freed not only from plasm but from toxic adsorbents on their surface. as a result the lung cells activate absorption of the surplus number of amines from the vessel channel. it is not excluded that s inactivation is due to growing activity of monoaminooxidase resulting in deminishing of intoxication. acute pulmonary embolism: thrombolytic therapy or pulmonary embolectomy? i.lodiena md, phd, s.shevchenko md, pphd., medical university, kharkov, ukraine objectives: pulmonary embolism (pe) remains a challenging problem for diagnosis and management for the emergency physician. the aim of this work is to identify the best treatment for massive pulmonary thromboembolism. methods: during recent years patients with symptomatic acute serious pe were reffered to our observations. selective pulmonary arteriography confirmed this diagnosis in all cases. ( . %) underwent urgent surgery, of them ( . %) with cardiogenic shock and ( . %) with massive pulmonary embolism. patients ( . %) underwent thrombolytic therapy. results: in the patients who received thrombolytic therapy successful results were achieved in cases ( . %), in ( . %) patients subsequent pulmonary embolectomy was performed. mortality rate was ( . %) in the patients who underwent pulmonary embolectomy after unsuccessful thrombolytic therapy and ( %) in the patients with cardiogenic shock and massive pe. lower extremity deep venous thrombosis caused pe in % patients. pe mortality rate is repoted to be %, but all patients with cardiogenic shock and massive pe died. this very high mortality rate related to the clinical status of the patients whose condition became worse despite intensive treatment. conclusions: the results of this study show that in most cases thrombolytic therapy is an effective rapid method of treating pe. however, surgical treatment is preferable when the patients reveal adverse effects to drug therapy, when medical therapy is unsuccessful or when the patients are seriously ill with reccurent cardiac arrest. high-quality pulmonary angiography remains the most accurate and reliable means of diagnosing pe. this prospective study was conducted to investigate the serum thyroid hormone levels in traumatized critical ill patients. serum thyroid stimulating hormene(tsh),total thyroxine(tr ),free thyroxine(ft ),total tri-iodothyronine(tr ),free tri-iodothyronine (ff ) levels were measured within hr.of intensive care unit admission(first day) in multiple tratmmtized male patients(injury severity score higher than ). in fifth day the same hormone levels were repeated. tsh,et ,ft ,tr and ft levels were determined by radioimmueoassay(ria). the levels of 'i~sh,xt ,fr ,et and ft in survivors and nonsurvivors were compared with first and fifth days (table) . in conclusion, we are convinced that there was a high correlation between low ser~n thyroid hormone levels and mortality, serum thyroid hormone levels are prognostic value in traumatized critical ill patients. objectives: glucagon improves myokardium contractility, intensifies kidney blood flow, stops bronchospasm ( ), these were the reasons of investigating its effect on hemodynamics and metabolism in hypovolemic shock expermentally and in clinic. methods : in experiments on white rats with traumatic shock glucagon (novo nordisk) was injected intraperitoneally in dose rocg/kg. patients with hypovolemic shock (trauma, hemorrage) were injected glucagon intravenously in dose mg on the background of infusion therapy. results : glucagon hightened recovery indexes of glucose in rats and patients with shock, whereas in groups without glucagon hyperglycemia developed. rats with glucagon injection had double times urea content than the norm ( , + , mmol& norm - , + , mmol/i ), whereas rats without glucagon had urea content , + , mmol/ ( p < , ). osmolarity of blood plasma in rats having glucagon injections was , + , mosm/kg h , without the drug - , + , mosm/kg h ( p < , ), ldh activity - , + . and , + , ( p < , ) mcmol cec- accordingly. lethality in the group of rats without glucagon was % /n= /, with glucagon - (n = ). in patients with hypovolemic shock in minutes after glucagon administration stroke volume increased to % (sv), miocardium contractility -to % (mc), peripheral resistance of vessels ( vr ) decreased to %. in - , hrs sv increased to %, mc-to %, pvr -decreased to %. conclusion : the study provides the evidence that glucagon has an anti-shock effect, improves hemodynamics and metabolism indexes in cases of hypovolemic shock. reference : picazo j. glucagon in acute medicine : pharmacological, clinical and therapeutic implications (norwell, mass:kluwer publishing, ), p. n, vasina (t) ,n.sebbota hph ( ). dept; of acute endotoxicosis, n.v. s~lifosovslay scientific research institute of ermergency ltealth care, boscow, lk'ussia (i}. institute for problems of cryobiology and cryouledicine of the national academy of sciences of the f/maine, kl'k r-key, [ maine ( ), objectives: the investigation of isolated hepatocytes using's efficacy in patients with acute hepatic fai lln-e. methods: native and crioconsrved allo-and xeno-!mmatocztes fixed on semi;ermeable ~mbr~s were used. results: the artificial supporting system with isolated hepatocttes as metabolic ~its was. ap-plied in patients. during tl~ treatmen~ with this cytotherapz an improvement of clinic state and biochemical rates were observed even inthe first we~s. for instance, the kncreasing of glutamin acid's level in blood up to normal value and decreasing of ammontes -concentration from i ~ mmol/l down to # mol/l were discovered. ~ae diminution of ence,%halo;athy was noted too. general lethality was' equal z, there of i z concerned acute hepatic failure (/k~). conclusions: the using of sum~rting hepatic system is able to cope the ~nenomenon of ~i~. objectives: fat embolism (ee) is an important and insufficiently studied problem of the intensive care medicine. fe is clinically diagnosed in % and morphologically in - % of the victims with severe multiple skeletal injury that is accompanied by the shock. methods: during the last years patients with the cerebropulmonary form of fe were treated in the icu. the prognosis of the probability of fe development was done using the computer system "cite-prognosis" in which the triss-method, dynamic and statistical prognosis of the injury outcome~ and the values of the most severe injury in points were realized. the treatment consisted of the surgical stabilization of the fractures with the authors' design of the rod apparatus in the acute period, long-term mechanical ventilation with peep via tracheostomy, complex fluid therapy using perfluorochemical emulsions (pe), and electrochemically active solution of na hypochlorite (snh) via the central vein. results: the treatment of patients with fe gave a good result that was manifested by the complete regression of psychoneurologic and respiratory disorders. conclusions~taking into account the prognostic data~ it is necessary to provide early complex of intensive care to the polytraumatized patients. it includes the surgical stabilization of fractures, fluid therapy using pe and snh~ early long-term mechanical ventilation. dr. alexandr e. poladko, station of medical aid. kiev ukraine. objectives: the reason of investigation is to prove the necessity of beginning of the intravenous infusion of nitroglycerin before the hospitalisation. methods: from january i to june protocols of treatment myocardial infarction patients in kiev medical aid station. results: the results of treatment are better if infusion began early or prolonged during hospitalisation. conclusions: there were patients with acute myocardial infarction treated before hospital by the cardiological groups. patients were treated with the early infusion of nitroglycerin and without. the results of treatment were: in the group with infusion: mortality in the first hours % the full disappear of pain % in the group without infusions mortality in the first hours % the full disappear of pain % that's why our opinion is that infusion of n. is necessary in the treatment of the patients with myocardial infarction from the first minutes of illness. dr. gennady d. kyrzhner, station of medical aid, kiev, ukraine. object: looking for safe medication which is good for the treatment of arterial hypertension and is simple for use. we inspected the effect of prazosin in the conditions of the cail during the year. method: we used mg prazosin tablets sub lingua and measured blood pressure ones during hours. the parameters were registrated in protocol. result." one hundred patients took part in investigation. the middle age of patients was . the reason of hypertension was not taken into consideration. in two hours after beginning of the treatment we caught the reliable lowering of blood pressure in % of patients. the general condition of patients became better in - min. it was only one accident of complication during the treatment -the orthostatic hypoter~sion, conclusion: prazosin hydrochloride in the dose mg sub lingua is safe and simple for use in the urgent situations. objectives: hypomagnesemia is frequently observed in severely burned patients during the early period after injury. increased urinary excretion is insufficient to explain the magnitude of the magnesium (mg) depletion. the possibility of exudative cutaneous mg losses has been proposed, but not yet demonstrated. the study aimed at measuring the mg content of the cutaneous exudates and urine during the first week after major burns. methods: patients, aged _+ years (mean _+ sd), and burnt _+ % of body surface, were studied from day (d ) to d . serum samples were collected at do, serum and urine from d to d , and on dio, d , d . cutaneous exudates were extracted from the textiles surrounding the patients, collected over h periods from d to d , using bidistilled acidified water. mg supplements ( . to mmol/ h) were prescribed from d to dio according to the severity of hypomg (serum mg < . mmol/i). results: mg serum levels decreased below reference ranges in patients between d and d , and normalised thereafter during supplementation. urinary mg excretion was increased in patients, mean excretion being . _+ . mmol/ h until d . mean daily mg cutaneous losses, were mmol/ h, i.e. mmo; in days. large inter-& intra-patient variability: the daily exudative losses ranged from to mmol/ h. conclusions: the mean daily mg cutaneous losses after burns were larger than the urinary losses, and equivalent to the recommended intakes for mg; the addition of the exudative and urinary losses largely explained the increased mg requirements after burns. complex immunologic alterations occur following thermal injury. the activation and consumption of the complement and dotting systems are suggested to play an important role in the development of the capillary leak syndrome, tn burned patients, a generalized inflammatory reaction as well as the impairment of the host defense are considered to be the major reasons for complications, such as sepsis and multiple organ failure. in a pig model we investigated a possible protective effect of cl-inhibitor (berinert, behring). before conducting the animal experiments the human cl-inhibitor concentrate was analyzed for its inhibitory capacity on purified pig cls and its pharmacoldnetic behaviour in pigs (t / ,id ). pigs received anesthesia and analgesia and arterial, venous and pulmonary (swan ganz) katheters were placed into the carotis and jugular veins. the pigs were scalded for seconds with ~ hot water to achieve a % tbs partial-thickness burn. blood samples were taken prior and after surgery as well as , minutes, , , and every further hours after thermal trauma. two control groups (each n= ) included animals which were either scalded or not scalded and treated only by resuscitation of ringers lactat solution. besides various parameters blood samples were analyzed for complement. the pigs (n= ) received c -inhibitor concentrate at an initial dose of u/kg body weight either immediately or hours after thermal trauma (n- ), followed by three further applications (of reduced amounts) every hours. the clinical outcome as indicated by vital parameters and as well as demonstrated by reduced edema and inflammatory tissue destruction suggested a protective effect of cl-inhibitor. complement analysis revealed a faster recovery of the alternative and classical pathway activities in cl-inhibitor treated pigs as compared to the control group but only if the regulator was given immediately after thermal trauma. from these results a protective function of c -inhibitor on thermal trauma can be assumed. objectives: the aim of study was to characterise the pattern of secretion of interleukin- (il- ) and tumor necrosis factor alpha (tnf alpha) in multiply injured or not injured critically ill patients and to relate these results to their outcome. methods: blood samples of multiply injured ( ( ) ( ) ( ) il- (nis) ( ) ( ) ( ) il- (nin) ( ) ( ) ( ) conclusions: this data suggest tnf alpha is a better prognostic marker in patients with multiple injury, than in critically ill patients without injury. il- is not significantly higher in nonsurvivors of both groups. sepsis is associated with an increased production of nitric oxide (no), as reflected by a rise in plasma levels of nitrites (no ) and nitrates (no ). severe bum injury is associated with similar symptoms of inflammation like hypotension, high cardiac output low vascular resistance and increased vascular permeability so that an increased no production may be involved. the present study included patients admitted to the intensive care unit of the burn center of brussels (age : - years; burned surfaee area - %), and control (non-septic) patients hospitalized in the neurological rehabilitation unit of the erasme hospital (age - years). the patients in both groups were fed enterally with to kcal/kg/day of a standard solution. in the burn group, daring the study period, patients were mechanically ventilated, required vasopressor (dopamine) therapy, and received antibiotics; patients were discharged alive from the intensive care unit, and no patient died during the study period. plasma was sampled for no /no determinations (griess reaction) daily from day to day (n=ll) or to discharge (day , n= ; day , n= ) in the burn group, and once the control group. in the burn group, no /no levels were elevated at day ( _+ #moles/i), reached a maximal value on day ( - p.moles/l) and progressively decreased to day (fig). these values were higher than in the control group ( . :t: . #moles/l, all differences p< . ). however, no correlation was found between the plasma no /no levels and the age of the patient or the total burned surface area; burned patients who became infected tended to have higher plasma no /no levels than those who did not ( + vs - #moles/i, ns). the present study indicates that burn noa/noa (llmol**/l) injury is associated with increasedloo] [__ ] ~ no /no plasma levels, which are ao so consistent with an enhanced no pro- o duction, ao obiectives:urapidil has been recommanded for therapy of hypotension in neurosurgical patients, because it was found not to increase intracranial pressure in patients with compromised intracranial dynamics ( ). in contrast several authors reported an increase of icp after urapidil administration in patients with head injury ( ). our study was designed to determin the influence of urapidil on mean lumbar cerebrospinal fluid pressure (csfp) in awake humans with uncompromised intracranial compliance. methods: after approval by the local university ethics comittee, six volunteers (asa , male, female) were studied in the lateral decubitusposition with the vertebral column positioned horizontally. a gauge needle was inserted into the lumbar subarachnoid space at level l /l and connected to a trancducer (mx | medex inc.) for csfp measurements. the volunteers were advised to keep respiratory rate and etco constant. after a resting period of minutes basline measurements were performed including csfp, cvp, map, hr, etco (cardiocap | datex). then the volunteers were given urapidil . mg/kg over a period of minute. minutes later measurements were repeated. results: statistics: wilcoxon signed rank test, p< . significant; values: mean_+sd, si = mmhg. - _ " _+ * _+ * - _+ " _+ csfp: cerebrospinal fluid pressure, cpp: mean cerebral perfusion pressure. conclusions: during normoventilation urapidil leads to a decrease in map parallel by an increase in csfp and therefore in icp, most likley mediated by an autoregulatory dilatation of cerebral vessels. if this cerebrovascular response is suppressed by hyperventilation, no increase in icp is found despite a uredipil induced drop in map ( ). after longterm hyperventilation cerebralbloodflow is normalized. this might be the reason why the drop in bloodpressure following urapidil administration again led to an increase in icp ( background and objectives: the intestine is one of the most sensitive tissues to ischemia-reperfusion injury. reperfusion of the intestine is often associated with increase in mucosal permeability and ulceration. d(-)-iactate is produced by indigenous bacteria found in the gastrointestinal tract and mammals do not possess the enzyme systems to rapidly metabolize it. the present study was designed to determine the kinetics of plasma d(-)-iactate alteration in rats paused by acute intestinal ischemia-reperfusion injury. methods: following the anesthesia, the superior mesentcric artery (sma) was exposed and it was occluded by a micro-bulldog clamp applied at its origin from the aorta. after min of occlusion, the arterial clamp was removed and the supply area of the sma was allowed to be reperfused ( h). plasma d(-)lactate levels were measured by an enzymatic spectrophotometric assay. the endotoxin content of plasma sample was assayed by the limulus amebocyte lysate test with a kinetic modification of the test kit procedure. results: intestinal ischemia for min resulted in a significant increase in d(-)-lactate levels within the portal vein as compared to sham-operated animals. plasma d(-)-lactate levels had a tendency to further increase after reperfusion up to h. it was showed that significant elevation of endotoxin concentrations in portal vein was alread~r detected at the end of -min ischemia, reaching peak at . h post-reperfusion and decreasing gradually throughout the study period. at the end of ischemia, marked mncosai damaged such as edema, hemorrhage and necrosis was observed. there was evidence of injury to ti, e muscuiaris propria together with diffuse mucosal damage and destruction following reperfusion, particular at h postreperfusion. in addition, penetration of bacteria was commonly found in the intestinal wall at various time points following ischemia/reperfusion injury. conclusions: these data suggest that acute intestinal ischemia is associated with permeability change of mucosal barrier resulting in increased plasma d(-)qactate, which is also remarkably influenced by subsequent reperfusion. plasma d(-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insult. objective: to assess the clinical usefulness of two methods of intracranial pressatre (icp) monitoring: intraparonquimatous recording (icpc) and epidural recording (icpe), versus intraventricular icp (icpv) as a gold standard. we prospectively studied patients with severe head injury (glasgow coma score < ) admitted to our icu between fobmaly and december . icpv was monitored in all pativrats by means of a multipzffolated catheter connected to a water coinnm. six of patients were additionally icpc monitored by a fiber optic transducer (comma r~), and seven of patients were icpe monitored by a couplvd fluid system (plastimedr). icpc was placed homolatetal to the focal, lesion m two cases and contralateral in three; icpe was placed homolateral to the focal lesiou in two cases and contralateral in three. all three systems were calibrated at the ear level. stali~cs: correlation coefficient and lineal regression were done between icpe and icpv, and between icpe and icpv with the hourly p~rs of values obtained dttting assistontial period. results: of the six icpc -icpv studied pa~onts, we observed a correlation coef~cieut r = . (p < . ) with a regres~on line y = . + . x. four of ~hx lcpc -icpv patients had r > . when correlaliou eoet~dent was obtained indixddually. of the seven icpe -]cpv studied patients, we observed a cortelafiau ooeffioiont r = . (p < . ) with a regression line y = . + . x. corralalmu eoetfieiont was inwer than . in all seven patients. corrdation eoelfieients for levals of icpv > man hg, > mm hg and > tuna hg with icpe showed r = . , r = . and r = . respectively; and with icpe r = . , r = . and r = . . the obtained values did not change during the study. conclusdns: in our study icpe was considered a good type of icp monitoring. /cpe signiticantly infravalorates icp values. we observed a good correlatinn between icpc and icpv values in patients with high inttacramal presanre. objective: midazolam is a benzodiazepine agonist widely used for sedation in emergency medicine. few studies in animals and humans point to a direct analgesic effect of midazolam probably mediated by spinal antinociceptive receptors and/or peripheral benzodiazepine receptors ( , ). in our experience in the berlin emergency medical system (unpublished results) with anecdotal cases of extreme chest pain due to binge drinking but no evidence of acute myocardial infarction or extreme abdominal pain due to peritonitis, acute intermittent porphyria, peutz-jeghers syndrome or testicular torsion, we found that small doses of midazolam ( - mg i.v.) were much more effective in relieving pain than repeated administration of high doses of buprenorphine or morphine, which may be associated with a considerable respiratory depressant effect. the dose of midazolam required for pain relief in these patients is non-narcotic and allowed further communication on the character and localization of' the residual pain, which might be very important for the further diagnostic procedure. patients: ten patients with abdominal pain due to acute gastrointestinal bleeding, suspected pancreatitis, suspected acute porphyria, and chest pain with no evidence of acute myocardial infarction received first-line midazolam i.v. at an initial dose of mg and were asked how it affected the intensity and character of pain. results: at the chosen dose of midazolam ( - mg), all patients were responsive to detailed questioning on basic orientation, the character, intensity and localization of the pain, and medical history. none of the patients required an additional opiate. all patients stated that the pain was tolerable after midazolam alone. conclusion: our preliminary clinical observations suggest that low-dose midazolam might be an alternative to opiates in extreme pain of presumably visceral odgin. objectives: it is known that severe head injury in elderly patients is associated with higher mortality than in younger patients. it remains however to be clarified whether the preinjury pathology which is frequent among these patients, affects the outcome. methods: in an attempt to investigate this hypothesis, patients aged over years suffering from head injury, with glasgow coma scale (gcs) of or less, were studied retrospectively. twenty-six patients ( . %) had preinjury pathology i.e. diabetes mellitus, arterial hypertension, heart failure, alcoholism, parkinson's disease etc. (group a) and fifty-three ( . %) did not (group b). the following data were recorded: mortality in the i.c.u., duration of hospitalisation, incidence of infective complications and neurologic status at discharge. results: groups were comparable in terms of mean gcs ( . vs. . ) and median age ( . vs. ). the incidence of brain pathology in the two groups was the following: epidural haematoma . % vs. . %, acute subdural! haematoma . % vs. . %, intracerebral haematoma . % vs. . %, subarachnoid haemorrhage . % vs. . %, diffuse haemorrhage . % vs. . %, contusion . % vs. . % and non-visible pathology (normal ct) . % vs. . %. unilateral pupilary dilatation was found to be . % in group a and , % in group b. the mortality during hospitalisation in the i.c.u. was almost the same: % iu group a and . % in group b patients. however, group a patients had significantly more infective complications, required longer hospitalisation and had lower gcs at discharge. conclusions: the results show that the existence of preinjury pathology does not seem to affect the short-term outcome of elderly patients with severe head injury. it has however an impact on morbidity and perhaps long-term survival of these patients. the assessment of clinical development in intensive care patients with severe head injury still remains a problem. to optimize the monitoring of intracraniel prassure (icp) we rautlr~dly implant an eplduml measuring device in our hospital. the aim of this study was to prove the correlation of the icp-values with ct findings and clinical development. during a month period ( - r the icp was monitored in p~,tients ( male, female) with severe head injury by an eplclural measuring device (epldyn~/$plegelberg| the mean age was . years ( - ). the glasgow coma scale at admission was . ( - ). in all cases the device was placed wfihln the first hours after admission. the tcp was compared with physical examination, radioidglcal or intraoperatlve findings and cunlca! outcome. the average time of measuring was . days ( - ) . the traatment depended on the !cp values recorded. rising icp-valuea ~ed to radlologlcal c ntra!s by ct-scan. in case an intracranlai hemorrhage was detected and drained. the overall survival rate was . %. showed a complete resolutl n, in other . % psychological residuals like decreased mentatlon, in . % sensomotorlc residuals like cerebral nerve dysfunction and aphasia, and . % of the injured remained in a comatous status. in % of our cases the measured values correlated with clinical course and management. in cases ( . %) we observed a displacement of the icp-pevice. there was no icp induced infecllon. istituto di anestesiologia e rianimazione, universit& ,,la sapienza", rome, italy * istituto superiore di sanit& -servizio di epidemiologia e biostatistica, rome, italy objectives: acute renal failure (arf) can be a severe complication of trauma. the current incidence of post-traumatic arf is associated with high mortality . identification of risk factors and prevention of this complication could improve the outcome of trauma patients. methods: one hundred fifty three consecutive trauma patients (age . _+ . , injury severity score . + . ) admitted to icu were studied. incidence of arf was . % ( / ). arf was defined as persisteat plasma creatinine > mg/dl with or without oligoanuria . arf was defined as early when occurring within the first hours (earf) and late when the onset was after the first four days (larf). results: earf occurred in patients while larf developed in patients. age, iss, and incidence of rhabdomyolysis and acute respiratory failure were not different in the two groups. an higher incidence of multiple organ failure (mof) and sepsis ( . % for both) were observed in larf group, when compared to earf ( % and % respectively). abdominal trauma was more frequent in earf group ( % vs %). the gs for earf and larf were respectively _+ . and _+ . while in the group who not developed arf (narf) the gs was . • conclusions: gs score difference seems suggestive and can be that an abnormal cerebral activity (hipofisary hormones?) may play a crucial role on onset of arf in these patients. moreover the frequency of acute respiratory failure in the group of arf was higher ( . versus . ) than narf group. the early ipoxia in the early phase of trauma, then, may be another crucial point for development organ failure. these are preliminary data. a more exact statistical analysis must be perform to have definitive conclusions. to compare the active compression-decompression cardiopulmonary resuscitation (acd-cpr) with the standard cardiopulmonary resuscitation (s-cpr) in out of hospital cardiac arrest patients. is a controlled, randomized study. two groups of patients with cardiac arrest out of the hospitalwere formed. group i, (acd-cpr) and group ii (s-cpr). for the acd-cpr groupweusedthecardiopumpdeviceofambulnternational. asfortherest, the erc ( ) algorithms for acls were followed. the utstein style (for out of hospitat cardiac errest) was used for listing and evaluating all cases of the study. the cpr was contucted by the crew and the doctors of our mobile intensive care units (micu). we studied consequitive patients ( in group i) and ( in .group ii). demographics pre-cpr characteristics (e.g. ecg form of cardiac arrest) and procedures (eg bystanders or second tiers crew cpr, defibrillation, drugs) were quite similar for both groups. the mean arrival time of micu was min. in group i we recorded r.o.s.c. (return of spontaneous circulation) , %, death %, continuation of cpr efforts , %. while in group ii, %, %, and , % respectively (recorded percentage until the admission to the hospital). no significant difference was found in anyofthe short term outcome parameters. no complications related to the acd-cpr technique, were noted. not any significant difference between the two methods was proven (from this small evaluated sample). the results of previous clinical studies are controversial (i) . more sophisticated studies proved the superiority, in a certain number of parameters (e.g pressures, flow, etc) of the new technique although there are many difficulties for establishing clinical results. in the pre-hospital setting that is related to many parameters (speed of the intervention, effectiveness of bystanders cpr, education ofparamedics, etc.)the evaluation is even harder. the superiority ofthe acd-cpr can be proven when it is performed in almost times increased number of studied patients as w~ll as improvement of the technique could lead us to more established results. objectives; infectious morbidity is the major cause of mortality after burn injury, and is due to multiple factors. trace elements (te), which are involved in both humeral and cellular immunity, exhibit severely altered status after burns. te supplementation has been shown to be associated with increased leukocyte counts and shortened hospital stay. the trial aimed at studying the immune responses in severely burnt patients receiving normal te supplies or early large supplements. methods: patients, aged _+ yrs (mean_+sd), with burns covering + % of body surface were studied from day (d ) to d post-injury, were randomised in groups (g): g -control receiving recommended te supplies + placebo; g -receiving in addition large supplements of cu, se and zn from d to d . enteral nutrition was started within hours of injury in all patients. immunological parameters: peripheral leukocyte counts, proliferation of mononuclear cells to mitogens, cell surface molecule expression, and neutrophil chemotaxis at d and d . infectious episodes and micro-organisms were monitored until d . results: the patients' characteristics were similar g & g . the total leukocyte counts were higher in g between d and d , due to increased neutrophils (significant from d to d ). total cd + and cdlg+ cells did not differ, whereas cd + (monocytes) were significantly increased at d . proliferation to mitogens was significantly depressed in all patients. chimiotactism was not altered. the number of infectious episodes was significantly decreased in g with a mean of . _+ . infections during the first days versus . _+ . in the control group (p < . ). conclusions: the large te supplements for days was associated with a significant decrease of the number of infectious episodes. supplementation was associated with increases in total leukocyte, monoeyte and neutrophit numbers. further studies are required to determine the precise mechanism underlying the improved immune defences. objectives: evaluate the efficiency of local adsorption (la) with the use of carbon adsorbents in case of severe burns in expertment and clinic. methods: experimental studies on la were performed on a model of % body surface area iiib-iv burn in rats. a burn eschar was excised on the rd day after burn, the wounds were dressed with the gauze bandages (control) or with adsorptive dressings (la), dressings were regularly changed. clinical investigations were carried out in the course treatment of patients with severe thermal and radiation ilia-iv burn. in the dynamics of bum disease some indices of proteometabolism and intoyacation criteria were evaluated. results: the experiments have demonstrated that the application of la after early excision of a burn eschar exerts a pronounced normalizing effect on a protein electrophoregram and the activity of proteases and their inhibitors in burned tissues preserving vitality. thus, by the th day after burn infliction the activity of cathepsin d in injm'ed muscles is times lower under an adsorptive dressing than under a gauze bandage (control) (p< , ), the activity of trypsin-like proteases is . - . times lower and the antitryptie activity does not differ significantly from the normal level. the cytotoxicity of extracts of burned tissues after the adsorptive dressing application fn vivo and adsorption in vitro is - % and - %, respectively, of the toxicity of control extracts. a similar normalizing effect of la is ok~rved for an intact muscular tissue and blood serum. the dectron-spin-resonance studies have demonstrated that la allows to normalize antitoxic activity of liver and functional activity of kidneys. the application of la in the treatment of patients with severe burns have been shown to localize a region of irreversible tissue changes, accelerate rejection of a burn eschar, attenuate an endogenous intoxication level and, as a result, shorten the time for grafting of a burn wound and accelerate wound heating. conclusions: proceeding from the obtained results, we can consider la as an effective method of localization of a region of irreversible tissue changes as well as of correction of local and general metabolism failures and overcoming burn autointoxication during burn disease. c de deyne, t vandekerckhove*, j. decruyenaere, b. vaganee, v vandewalle*, f colardyn depts of intensive care and neurosurgery*-university hospital gent-belgium. jugular bulb oximetry is the first bedside available cerebral monitoring technique providing an estimation of the adequacy of cerebral perfusion. its routine use in all patients suffering from severe head injury admitted to our ic unit enabled an extensive analysis of all very early cerebral perfusion data in order to evaluate the incidence of abnormal sjo~ data (and their possible causes) in this very eady period after traumatic insult and to search for possible implications as to the emergency management. these very early data were defined as the first hours icu data and icu admission had to occur within h of traumatic insult. over the last years, pts with severe head injury (gcs< ) were monitored by jugular bulb oximetry, starting immediately after their arrival at the icu (mean of . h after trauma, range between - h). in a total of pts (= . %), jugular bulb desaturatiens (< %) were noticed during this early h period. in pts (= %), jugular bulb saturations higher than % were observed, whereas pts (= . %) revealed no abnormal sjo data ( - %) during these first h. concerning the periods with too low jugular bulb saturations (n: ), we found the following correlation ; in pts (= . %) cerebral perfusion pressure (cpp) was below mmng, in pts (= . %) paco~ was below mmhg and finally in pts (= %) we found primary intracranial hypertension. for the high jugular saturations (n: ) we found a primary intracraniaf hypertension in f pts (= %), and a pace level above mmhg in pts (= %). in all patients we could restore jugular bulb saturation within normal range ( - %) with the correct!on of the presumed causative factor. we can conclude that ultra early jugular bulb saturation data revealed a high incidence of abnormal values, with a predominance of jugular bulb desaturations, confirming once again the high incidence of disturbed and too low cerebral perfusion within the first hours after severe head injury. these jugular bulb desaturations were especially correlated to systemic causes, as a too low cpp (caused in the vast majority by primary map insufficiency, and not by intracranial hypertension) and hyperventilation were the major causes of the desaturation periods. as jugular bulb desaturatione are known to be significantly correlated to a worse neurological outcome after severe head injury, one might improve outcome by an emergency management avoiding these possible causes of jugular desaturation. therefore, extreme attention should be paid to the maintenance of an adequate mean arterial blood pressure (above mmhg?) even duhng the few time spent at the emergency department. one should be as attentive to the maintenance of normoventilation during this very early period of admission and hyperventilation without any knowledge of icp or sjo should be abandonned. recently, indomethacine has been proposed for the treatment of therapy refractory intracranial hypertension in pts suffedng from severe head injury ( ). indomethacine, a cyclo-oxygenase inhibitor, gives rise to a significant fall in cerebral blood flow by inducing cerebral vasoconstriction. therefore, its use could result in a drastic lowering of the intraeranial pressure (;cp) in pts suffering from intracranial hypertension secondary to cerebral hyperaemia and in whom the use of other cerebral vasoconstrictive drugs (barbiturates or hyperventilation) appears insufficient to control icp. for the last months, we included the use of indomethacine in our therapeutic flow chart for severe head injury management. pts revealing intracranial hypertension (icp> mmhg) and cerebral hyperaemia (sjo~> %) and in whom icp was not efficiently controlled by the combined use of hyperventilation and barbiturates were given indomethacine in a trial to control icp. a total of head injured pts received treatment for intracranial hypertension over the last months. six of them met the criteria set for the administration of indomethacine. in pts, no decrease in icp or in sjo was observed and both pts died due to therapy refractory intracranial hypertension. in the other pts, a significant fall in icp and in sjo was observed shortly after indomethacine administration. in pts we observed a catastrophic fall of sjo= even below %, indicating an extreme cerebral vasoconstriction with the possible risk of inducing cerebral ischaemia. in one of the pts, icp remained under control without further administration of indomethadne, but he died days later in multiple organ failure. the other pts, needed multiple indomethacine administrations (for pt even during consecutive days) to finally control icp. in all pts, icp was finally controlled, but only pt survived. both other pts died from systemic causes (multiple organ failure in pt, massive gut infarction in the other tat, possibly due to the systemic vasoconsttictive effects of the indomethacine administration). in conclusion, indornethacine might have a role in the treatment of intraoranial hypertension, especially when caused by cerebral hyperaemia. we observed however a poor final outcome and a threatening high incidence of systemic events (multiple organ failure, gut infarction) in those pts receiving indomethacine for icp control. therefore, indomethacine in the treatment of intracranial hypertension should be reevaluated in controlled study settings, before its routine use can be considered. untill recently, intracranial hypertension (ich) in pts suffering from severe head injury was managed in a staircase approach, with csf drainage as first therapeutic step, mannitol as second step, hyperventilation as third step, and finally, barbiturates as the last rescue step for therapy refractory ich. this staircase approach for the treatment of tch was only guided by the intracraniat pressure, and not by other parameters such as e.g. the actual state of cerebral perfusion of the concerned pt. jugular bulb oximetry provides us with the first, bedside and continuous available, estimation of cerebral perfueion. its implementation in a rigourous flow chart, based on as well icp-as jugular bulb oximetry-data might result in an altered strategy for ich management. we adopted a '~ugular bulb saturation (sjo~)-guided approach" for ich management in consecutive pts, suffering from severe head injury (gcs< ). we maintained csf drainage as first therapeutic step, but the decision for the second step was guided by sjo information. pts revealing ich and sjo=values above %, were treated with hyperventilation, and did not receive mannitol. if ich persisted, barbiturates were added as a third step. on the other hand, pts with ich and sjo= vales less than %, received mannitol administration as second step. hyperventilation and/or barbiturates were only added if ich persisted and if no cerebral hypoperfusion was discerned (sjo=> %). our objectives were to prospectively analyze this new therapeuticstrategy, as compared to the formerly used staircase approach of ich. we managed pts with ich, with an overall mortality of . % due to therapy refractory ich. all pts received standard primary care with head elevation, full sedation and normovenfilation. fer pts, csf drainage alone was sufficient to control ice of the remaining pts, pts received mannitol and pts were hyperventilated as second approach. in the third line, pts were managed with barbiturates, with mannitol and pts with hyperventilation. finally, barbiturates were used as the final rescue in pts. these results reveal a less frequent use of mannitol as only pts received mannitol, compared to the pts that would have received mannitol using the former staircase approach. hyperventilalien was used much earlier in the treatment course, as lots were already hyperventilated in the second line approach, were this was formerly exclusively reserved for the third line approach. finally, also barbiturates were used much eadier ( pts received barbiturates as third approach). we may therefore conclude to a important change in the management of ich, induced by a sjo -guided flowchart. however, future studies will have to elucidate if this new strategy for the intensive care management of severe head injury will also result in an improved outcome. obsectives: in a first series of experimental brain injury we investigated the course of brain po , icp and cerebral blood flow after traumatic brain injury (tbi), whilst accordingly there are very few data available and the mechanisms leading to secondary brain damage are poorly understood. methods: in piglets ( days old, , - kg) of either sex we produced a moderate brain injury ( , arm., msec.) using a lateral fluid percussion {fp) device. complete measurements were made before and min. after brain trauma and after , and hours including blood gases, cardiac output (htermodilution), heart rate, eeg, laser doppler flow probe (ldf} and icp values (camino), brain temp., po by a clake type oxygen electrode (licox) and coloured microspheres for regional blood flow. results: immediately after the trauma a typical "cushing"response to the icp peak up to mm hg being highly significant (before mean i mm hg, range - mm hg) could be observed: mean arterial blood pressure rose from appr. mm hg to ii mm hg for - min. in two animals this was followed by an ischemic period lasting min. accordingly icp values gradually returned to starting measures within hours; in the ischemic animals they remained at a level of about mm hg.-no secondary increase of icp could be observed, once icp dropped to starting values within hours. cerebral blood flow (ldf) fell from mean values being i before trauma to appr. zero and recovered to around . brain po started at mean values of mm hg (range - mm hg) and fell to around zero depending upon the severity of the ischemic reaction. on average values of mm hg were reached over the time course. conclusions: with our fp trauma model we can reproduce the well known "cushing"-response after brain injury; secondary icp elevations cannot be achieved, although local edema is observed. direct brain po measurement seems to be a very sensitive variable for detection of cerebral ischemia and anticipates eventually following icp elevations by far. pulmonary aspiration s,traoaras. v. sgountzos, p. agouridakis, m eforakopoulou, e. ioannidou. intensive care unit (tcu) of "kat" hospital, athens, greece ob!e=ives: the reported mortality rate after pulmonary aspiration is variable in several series. the purpose of this study was to find out the influence of preexisting disease or situation on morbidity and mortality of intensive care unit (icu) patients with pulmonary aspiration. methods: patients who were treated in icu and had pulmonary aspiration, were studied, entrance's criteria in the study, all of them obliged, were: ) suction of gastric contents from trachea during intubation, ) presense of a predisposing factor, e.g. coma. ) recent hypoxaemia or new infiltrates in xray. preexisting disease was recorded and correlated with complications and outcome. patients with glasgow coma scale , because of cerebral injury, and patients who died within days from cause other than aspiration, were excluded from the study. method of statistical analysis: chi-square test, results: one hundred forty five patients were studied. the trauma patients were and the non trauma patients . from the trauma patients, had cerebral injury and were polytreumatized without cerebral damage. from the non trauma patients, had malignant neoplasms, neurological diseases in terminal stage, old age, drug overdose, and several diseases. eighty seven from trauma patients ( %) and from non trauma patients ( %) manifested several complications (pneumonia, ards, etc), so there was no statistical difference in complications' frequency between the groups (p> , ). the severity of complications was also proportional in the groups. eighteen deaths were recorded in the trauma patients (mortality %). only deaths correlated directly or indirectly with the aspiration ( %). in non trauma patients, deaths were recorded ( %). twelve deaths were recorded in patients with neoplasms, deaths in patients with neurological diseases, deaths in aged patients, death in drug overdose patients, and death in patients with several diseases, the mortality difference in trauma and non trauma patients was statistically significant (p< , ). in patients with drug overdose the mortality was significantly lower from the other non trauma patients and the difference was statistically significant (p< , ). conclusion: the preexisting disease or situation plays a major role in the outcome of the patients with pulmonary aspiration. the mortality of patients with aspiration seems to be caused by severe preexisting situations rather, that lead to death, than from the pulmonary aspiration per se, which may be a final happening in a predetermined course. obiectives; the purpose of this study was to compare fluconazole and amfotericin-b in the treatment of fungal infections in severe trauma patients. methods: thirty five severe trauma patients who were treated in intensive care unit (icu), were studied prospectively. they all developed fungal infections, prooved with blood positive cultures and at least one of the following: fever, positive urine or bronchial secretions cultures, infiltrates in xrays. the patients were separated randomly in groups. the patients of group a ( patients) received fluconazole rag/day for days. and the patients of group ( patients) amfotericin-b rag/day for also days. compaiison's criteria were the clinical responce to treatment (fever etc), the fungal elimination (blood and other cultures), the relapses of the disease, the side effects of drug, and the outcome of the patients. as method of statistical analysis was used the chi-square test. results: nine patients from of the group a ( %), and from of the group b ( %), presented remission of fever (patients of group b had better clinical responce than patients of group a, and the difference was statistically significant, p< , ). all the patients before treatment had positive for fungi blood cultures. after days of treatment, patients of group a and none of group b had positive cultures. eight patients (from who had positive cultures of bronchial secretions before treatment) of group a. and (from ) of group . had positive cuttures of bronchial secretions after days of treatment, so positive bronchial secretions were fewer in group b than in group a, but this difference wasn't statistically significant, (p< , and p> , ): ten patients (from ) of group a and patients (from ) of group b had positive urine cultures, after days of treatment (positive urine cultures were fewer in group b than in group a and this difference was statistically significant. (p< , ). two patients of group a and none of group b had a relapse of fungal disease. in group a, no side effects were obsepced, while in group b were observed only minor side effects (small increase of serum creatinine in patients, chills and fever during infusion in patients, and hypokalemia in patients). three patients of group a and patient of group b died, because of sepsis. conclusion: amfotericin-b (even i~ short regimen of days), is superior to fluconazole in the clinical and laboratory responce and also in the relapse of fungal disease, fluconazole is superior to amfotericin-b as it has no side effects. ob!ectives: flail chest after thoracic trauma is a serious injury. it is controversial if flail chest by itself orthe concomitant intrathoracic injuries e.g. pulmonary contusion, is the cause of the reported significant morbidity and mortality. in this study we searched the influence of concomitant thoracic injuries in the course and outcome of patients with flail chest. methods: eighty five patients with flail chest after isolated chest injuries were studied, for the purpose of analysis, we separated the patients into groups, patients with isolated flail chest were included in group a, patients with flail chest and hemo-pneumothorax in group b, patients with flail chest and pulmonary contusion in group c, and patients with flail chest and hemo-pneumothorax and pulmonary contusion in group d. complications from the chest, duration of mechanical ventilation and mortality were compared in the groups. statistical comparison of results belween groups was made using chi-square and t-studend tests. results: the patients were . all patients received mechanical ventilation, twenty eight patients were ihcluded in group a, in group b, in group c. and in group d. seventy three patients manifested complications from the chest, especially pulmonary infections. there was no statistical difference among the groups as to number of complications ( twenty four patients had chest complications in group a, in group b, in group c, and in group d. p> , }. the duration of mechanical ventilation was not statistically different among the groups (the mean duration was , days in group a, , in group b, , in group c, and , in group d, p> , ). there was also no statistical difference in mortality among the groups (six patients died in group a. in group b, in group c, and in group d, p> , ). conclusion: flail chest by itself is a serious thoracic damage with many complications, regardless of the presense of other thoracic injuries, which don't contribute to greater morbidity and mortality. the present study investigated the correlation between blood lactate mortality and organ failure in trauma patients admitting between december , and july , in the icu. road traffic accidents were the most common cause of trauma in this studded population. brain damage was the main cause of mortality .nevertheless, of patients died from sepsis and multiple organ failure without significant brain damage and these deaths were potentially preventable. respiratory failure was the most common complication and was developed in ( %) of survivors and in ( %) of non survivors .we noted low fncidence of renal failure may be do to the early and aggressive ittv'asive hemodynamic monitoring and cardiopulmonary support. as part of our routine case protocol serial blood lactate levels were measured in each patient at least times a day until the valses returned within the normal range or until death. we analysed the blood lactate levels on admission, the highest value and the number of days until the first normal value (<l.smeq/i). initial lactate and highest lactate levels were significantly higher in patients with than without organ failure.( . vs . , . vs . meq/l, p< . )the duration of hyperlactemia also was higher in the patients with organ complications. ( . vs . days, p< . ). both initial lactate and highest lactate levels were higher in the non survivors than in the survivors.( . vs . , . vs . meq/l, p< . ) the present study demonstrated that not only the degree but also the duration of hyperlactemia can be related to the development of posttraumatic complications. serial blood lactate measurements are reliable indicators of morbidity and mortality following trauma. s current evidence suggest that peep only affects intracrenisl pressure (zcp)when it interferes with systemic arterial pressure, although the effects of peep over cerebral oxygenation remains unknown. objective: determine the effects of peep over icp and cerebral metabolism measured by sj , kjdo and ceo in severe head injured patients. meterial ~ methgds: patients with glasgow coma scale l at arrival, with difusse brain injury in the first gt, according to marshall criteria,lop and jo monitored, under analgesia and sedation, normoventilated with zeep, without mannitol treatment in the previous hours, normal x ray chest and within the first hours from injury, were considered candidates. peep value where increased fro~ zero to cmh , in three different steps, each one with min of duration. all date were analized on line, pmax p'p ..... p.._, from the ventilator, systemlc haemodynem]c data, cerebra perfuslon pressure (cpp), icp and sjo , in the case of hemodynamic deterioration, during the study, ppc ommhg, extra-volume were administered. if persistence, dopamine were begun or increased dosage. if no good response were obtained, patients were retired from the study. results. patients were candidates, of them were exc;uded due to haemodynamic instability, k total of completed all steps and were e~amined, men and women, age ! . yrs. at hospite; arrival, glasgow were < in patients, and > in the rest . patients mmhg at the beginning. zeep ob/ectives. critically ill patients are transpoded to an intensive care unit(icu), under conditions, which have not been systematically evaluated. therefore, we set suite investigate transportation and admission condition of these patients to our department. methods. we studied patients( females), aged (mean-..+-sd) . _ . yrs, which were consecutively (from august to march ) admitted to the icu, through the greek national emergency transporta~on service. apache ii severity score upon admission was . -+ . (range - ). the following data were evaluated: ) number of medical departments, where health care was provided until final admission to the icu, ) ambulance transportation conditions, ) catheters and tubes inserted before admission, ) vital signs upon admission ) information provided by referring physician (scored on a to scale: history, electrocardiogram, chest x-ray, laboratory data, drug therapy already administered), ) comparison of the state of the patient described by referring physicians, to the actual state u pen admission. resu/ts. one to four medical departments had provided health care before the palient was admitted the icu ( : . %, : . %, : . %, : %). thirty/ ( . %) patients were escorted by a physician. twenty-six/ ( . %) were transported on oxyge n, fio (mean__.sd): -+ %, pao : . -+ . mmhg. five of the remaining , for whom no oxygen was provided, had pao : . -+ mmhg. twelve/ ( . %) were intubated and ventilated during transportation. thirtyfour/ had a peripheral venous line, / had an arterial line, / had a nasogastdc tube, / had a urinary catheter. eleven/ were sedated and / were paralysed. three/ were on inotropes. vital signs upon admission were: arterial blood pressure, systolic . -+ mmhg, diastolic -+ mmhg, heart rate -+ bpm, temperature . -+ cc. patient information score was --. . . the actual state upon admission was found substantially different, as compared to the description of the referring physician, in / ( . %) patients. conclusions. we conclude that several aspects of the greek national emergency transportation service to an icu should be reevaluated and further improved, i. e. ventilatory support, adequacy of information provided and accuracy of prior description of the patient's state. a new perspective must be applied for critically ill patients transportation since . % of the patients were evaluated and treated in more than one, medical departments, mostly primary care, before they were finally admitted to our icu. dclhb is a human derived hemoglobin molecule that has been cross-linked to stabilize and permit heat pasteurization to remove residual proteins and inactivate viruses. dclhb is mixed with a lactated electrolyte solution to yield a total hemoglobin concentration of log/dl objective: to present an overview of four recently completed clinical safety studies of dclhb in the u.s. and europe, and to discuss the properties, actions and potential indications for dclhb. method: patient populations in the four studies included males and females ranging in age from to years. dosing ranged from mglkg to mg/kg. the controlled randomized safety studies were conducted in chronic renal failure patients, surgical patients undergoing total hip replacement or abdominal aorta repair and in hemorrhagic hypovolemic shock patients. these very diverse patient populations allowed safety evaluation of the product in patients who were generally elderly, often hypertensive with some degree of cardiovascular disease, and receiving medications for treatment of other conditions. results: over patients received dclhb in the four:studies. no product related sarious adverse events occurred during the clinical trials. conclusion: results from phase itll safety studies of dclhb in patients undergoing chronic renal dialysis, abdominal aorta repair, or total hip replacement and in patients in hemorrhagic hypovolemic shock, indicate that the product was well tolerated in these distinct populations. although these studies were designed to evaluate safety, the data suggest clinical benefit. follow-up efficacy trials are indicated. prehospital emergency services represent the extension of emergency care into the community and constitutes the manpower, communications, transportations and facilities used to provide care for patients outside hospital. one of the main points of the system is how to decide the hospitalization of patients and what kind of facilities to provide : emergency medical service, fire brigade, locat general praclitionner or ambulance officers. objectives : to realize guidelines for using the prehospital emergency medical service in case of patient'calls outside hospital. methods : from st june to july , all the calls for emergency care were analysed using a questionnaire of items (origin of the call, responses to the questions of an emergency practitionner, kind of emergency service provided and the issue of the patient). after taking account of the appropriatness of the decision, statistical method used was a logistic regression. results : calls were analysed. the criteria, for prehospital emergency medical service using, given by the logistic regression were as following : existence of a call for emergency, thoracic pain, dyspnea, seizures, cyanosis, drug intoxication, fall of the patient, fracture, age, the state of consciousness and the neurologic reactivity. the minimal and maximal predictive values of the model given by the logistic regression are respectively % and %. the performance of the model is %. conclusion : it seems possible to help medical decision of emergency medicine by using only some easy criteria and a predictive model. (italy) objective: to evaluate the incidence of blunt carotideal injury (bci) in patients admitted to our icu after head injury. methods: we reviewed the medical records of all patients diagnosed to have a bci. at admission, the severity of trauma was assessed either with glasgow coma scale (gcs) and with ct scan. bci was demostrated by doppler ultrasography (us) and by angiography (ang). results:since may to april , patients were admitted to our icu with bci ( m, f, age + ). a history of direct trauma was present in patients. admission gcs was in all patients, and was associated with hemiparesis in of them; the last became paretic hours thereafter. two patients had concomitant injuries (a homoiateral clavicular and a controlateral zygomatic fracture, respectively). the initial ct scan was negative in every patient, and showed signs of ischemia after a variable timespan ( - days) after the onset of the symptoms. the bci was diagnosed with us and ang, which demonstrated a thrombosis of the internal carotid artery (ic). in two patients, an intimai dissection was also present. three patients were treated with heparin associated with antiaggregating agents and were discharged alive. the last patient was referred to our icu after the development of a massive hemispheric infarction, and died three days after the admission. at necropsy, the ic thrombosis was associated to an extensive homolateral extra and intracranial venous thrombosis. conclusions:the presence of focal neurological signs despite a negative ct scan should address the diagnosis toward a bci, thus implementing the diagnostic workup with us and/or ang. tab i: distribution of l~tients (%) in the groups the outcome were monitorett results were sabmitted to statistical analysis using a continence table x in z test. res.cl~s: of patients were submitted to thrombolysts and died. the higher incidence of bracb, ar~lhmias (ii degree gg p t e and av block. i degree av block. avsb . <ii. sinus arrest) that requited the insertion of avsc . <cl temporar~ pace-maker was recorded in group a b vs c . ns in % of the cas ~. the rapid recognition of life tab li:;~ test. threatening conditions suggests the monitoring of v r-lead r b' in the course of inferior ami. the authors report their own expirience in application of ringer lact.(rl)and , %nacl/ %dextran . methods:in polytraumatized patients with developed hae morrhagic shock,injures of the chest(qg)and abdomen(q ) prevalid.replacement of the volume loss egan in institutions of general medicine,frequently by rl and dextran or haemaccel.after receiving necessary medical aid,polytraumatized patients wer transported to mma by helicopter,continuing replacing of circulation volume by the same solution. results:average quantities of the solution dministered ~o the injured wer~ - ml.a group of the inoured which,after the admission to mma was resuscitated by adml nistration of the , %nacl/ %dextran @(groupii)( -sml/kg observed to the final surgical management,had statistically higher map(increase of % in relation to admission), cvp(average increase of , cmh~o),diuresis(averagely omi after min.),better gas ~nalyses and acid-base status in relation to the group which was administered only rl(groupi)(increase of the map of q %,average increase c~ of cvp , cmh and average diuresis oml after omin). total quantity of the administered solutions was significantly smaller in the groupii( ml: ml).the only ob served complication was hyperhatr~f~a::and~moderat~hyper osmolerity of plasma which disappeared within hours. the quantity of replaced blodd was considerably smaller in the groupii(qooofnl: ooml).in the group i interstitial pulmonary oedema was observed in two patients(qo%),while: in the group ii no complication was observed.coagulation i disorder and hypotension were not recorded because of the fast infusion of hypertonic/hyperoncotic solution in the groupil as the infusion of , %nacl/ %dextran lasted minutes. w.scherzer(l~,k.lechner( ),r.simon( ). ll)dept.anaesthesiology,trauma hospital,vienna-meidlin !( )neurotraum.rehabilitation center,vienna-meidling both austrian workers'compensation board,vienna,austria what we usually call"unconcious" means only that the patient is not able to interact in any kind of way.experiences in intensive care medicine (robinson, ) ,in general anaesthesia (bennet, ) and with evoked potentials show,that unconcious patients are not automatically unhble to process and recall information.this implicates a challenge to start the efforts to restore the traumatica-!ly desintegrated brain function as early as possible in the acute phase ia (zieger, ) .we present a method to ~repare the patient for the rehabilitation goals of the postacute phase ib,the phase of stabilisation ii and of rehabilitation iii within one concept. to achieve sensory stimulation in phase la we use: attempt at some kind of dialogue by speaking to and tou-ching the patient,to make him experience his body limits, ~acio-oral therapy by ice application,tast and smell pro vocations and trials of feeding,early adaption to circadian rhythm and guiding the patient in every-day-life-ac-tivities e.g.:in the brushing of teeth,washing etc. to achieve motor stimulation and orientation in terms of ~-ace,time and gravity in phase la we use: avoidance of perceptual impairment as produced by air-:sack-beds or habituation to supine position,using method~ according to affolter( ) ,basal stimulation (bienstein, ) , bobath-therapy( ) and facilitation of a physiological moving pattern(pnf)according to knott( ) . conclusions: by integrating all these measures in the ~herapy and nursing even in the acute phase la one prei ares the comatose patient for multisensory stimulation nd motor training and all other rehabilitation activities in the following phases of therapy. s objectives." measurement of cardiac output (co) and stroke volume (sv) requires insertion of a central venous catheter and is associated with a considerable risk for complications. non-invasive methods for determination of hemodynamic parameters have been introduced recently. one of these methods is the aortic modelflow program, which provides co and sv continously using a three-element windkessel model. the aim of the study was to evaluate the accuracy of the aortic modelflow program in critically ill patients. methods: patients (mean age: ) admitted to the emergency department after cardiopuimonary resuscitation (n=ll) and for myocardial infaction (n= ), acute congestive heart failure (n= ) and anaphylactic shock (n=l) were included to the study protocol. after stabilization all patients received a swan-ganz catheter (baxter~; edwards swan-g-anz) via a central vein. co and sv were measured by the use of a cardiac output catheter and injection of rrd ice-cold glucose % non-invasive cardiac output measurement was done by using the continuous cardiac output software package modelflow (tno; portapres| results: overall, paired measurements were used for the evaluation of the accuracy of non-invasive obstained sv and co. mean values, standard deviation and range of co and sv evaluated by invasive and non-invasive methods are summarized in the aortic modelflow provides reliable hemodynamic data in critically ill patients. it may be a useful alternative due to its non-invasive approach and continous measurement. objectives: to determine the feasability and accuracy of a rapid urine screening test (triage tm, merck-diagnostika) in an emergency department. methods: prospective analysis of the triage tm testkit (tt) in patients admitted because of suspected drug abuse during an observational period of months. the tt is a eompetitve immunoassay which gives qualitative results within i minutes for methadone, benzodiazepines, cocaine, amphetamine, opiates, barbiturates and cannabis. urine samples were analysed with the tt and compared to the results of a enzyme-lihked tmmuno-assay (el.a) in our labratory (gold standard). results: during the study patients were enrolled, in of these patients substance abuse was proven by tt and verified by eia. we recorded no false positive or false negative results for benzodiazepines, barbiturates, opiates, cocaine and cannabis. two results were false positive and one false negative for methadone; one result was false negative for amphetamines. the triage-testldt had an overall sensitivity of . and specificity of . . conclusions: the triage tm testkit seems to be a a useful rapid test device in addition to quantitative tests for drugs of abuse in an emergency department. objectives: the purpose of this study was to evaluate the influence of several factors of the renin-angiotensin-aldosterone system on blood pressure response in patients with hypertensive crises. methods: patients with systolic blood pressure > rorohg and diastolic blood pressure > nunllg were included into the study. prior to treatment blood samples for determination of plasma renin activity (pra), angiotensin converting enzyme (ace), angiotensin ii (ang ii) and aldosterone (aldo) were collected. all patients received rog enalaprilat intravenously. success of treatroent was defined as a reduction of systolic blood pressure below mmi-ig and diastolic blood pressure below mmi-ig within minutes after start of treatment. results: patients were included in our study, ( %) patients responded successfully to treatment. mean arterial pressure decreased in responders by . mmhg and in non-respenders by . mmhg (p< . ). responders and non-respenders differed signii'icantly concerning pra (p= . ), ace (p= . ) and ang ii (p= . ). . . the extent of blood pressure reduction correlated positively with the pretreatment pra and ang ii concentrations (correlation coefficient for pra: r= . ; ang ii: r= . ). conclusion: our data confirm that in patients with hypertensive crises blood pressure response to ace inhibition is mainly determined by circulatory pra, ace and ang ii. as the extent of blood pressure reduction correlates with pra, ace-inhibitors in patients with suspected high renin status cannot be recommended, as excessive blood pressure reduction, which carries a considerable risk for further organ damage, may occur. f. staikowsky, n. grillon, f.pevirieri, c.jedrecy, c. zanker, f. michard, a. haft medical emergency department. hospital bichat, paris epidemiology of acute intentional self medications-poisoning (smp) in france is especially known by data of poison control centei,s and intensive care units (icu). the purpose of this study is pro~,ided characteristics of this problem in a med for adults. method: july to june , files of patients consulting to the ed for smp have been retrospectively analyzed. results: patients, women and men, . + years old (range - ) have been admitted for episodes of smp ( % of all consultations) whose relapses during the period of study. psychiatric disorders, drug addiction or hiv patients was found for respectively . %, . % and , % of patients. the interval of time between the ingestion and emergency consultation was noted for % of smp ( + min, ranges - ). the involved products name was known in totality in % of cases with an average number by episode of . + drugs (ranges - ). the most often, ( %) or ( %) different products were interfered. the nonbarbiturate psychotropic drugs accounted for . % of the products (benzodiazepines %, antidepressants . %, neuroleptics %, carbamates . %, imidazopyridines . %, cyclqpyrrol nes . %). analgesics and nonsteroidal antiinflammatories represented . % of all drugs, anticonvulsants . %, cardiovascular drugs %, antiinfective agents . %, drugs against cough . %, muscle relaxants . % and antihistamines h . %. the benzodiaz pines were present in episodes, alone in episodes. in . % of cases, there was a simultaneous intoxication with alcohol. the processing consisted of gastric lavage in . % of cases, activated charcoal in . % of cases, flumazenil in . % of cases, naloxone and acetylcysteine in . % of cases; orotracheal intubation was performed in patients. admission in hospital was effective for patients, in medical ward (n = ), psychiatry (n = ) or icu (n = ); no fatal case was recorded. conelusion: smp to ed are often benign. the benzodiaz pines are the most often incriminated but the new anxiolytics and hypnotics (imidazopyridines and cyclopyrrolones) take a growing place. the latsion burn center of athens. its planning constructive and functional refinements j. ioannovich, a. petalas-vourekus, d~ serbetis, h. carsin a bed burns unit is under construction following a donation to the general hospital of athens. the plan of the unit, covering a surface of approximately . m is based on the principle of three identical bed satelites which may function totally independent from each other. in the center of the unit the common facilities are installed, like operation theatres, storage rooms etc. this new modification in the plan of a burn unit is presented in this paper. the advantages from the fucntional, administrative and medical point of view are discussed. tiffs anisotropic conduodon could favour the ocenrence of a circular movement of the impulse that leads to tachyeardias by reentry. purposes of this work were to study, with the help of epicardial mapping, the influence of a trieyclie antidepressant, clomipramine (c), on the conduction velocity longitudinal (vl) and transverse (vt) to myocardial fiber orientation and on anisotropy (a = ratio vl/vt), and their modificutions by the sodium bicarbonate ( ). method: a plaque of electrodes, positioned on the left anterior ventricular wall of anesthetized dogs, allowed to deliver, thanks to central electrodes, programmed electrical stimulations inducing vcuttienlar complexes, and to collect them. each entailed unipolar dectrogram was processed by a computer system that drew the isochrones and a map of activation allowing the calculation of v. the c was infused ( . mg/kg/min iv) during rain; at t , dogs received the b until the retuni of qrs to its initial value fro). a lengthening of qrs of at least % of its value at to was demanded before the administration of b. results: dog was excluded because of an.~nsufficient prolongation of qrs before the administration of b. all values (map : mean arterial pressure, i-ir : heart rate, qrs andqt intervals, v) differed significatively ( < . ) compared to values control fro)except qrs at t . the b ( + ml/kg; ranges . and . ml/kg) modified no studied dements outside of the ( }rs. to ti t t t t t a , + , , + , , + , , + , , + , , + , , +- ,~ conclusion : the c slowed v l and v t without modify the anisotropy. the b did not modify the v of~conduction while the qrs prolongation was corrected. the c acts as a class i antiarrythmie drug on the inward sodium current during the phase of action potential; the gap junctions have shown to be important in the conduction and an action on the gap junctions such as a modulation of the junctional resistivity, can not be rule out. is the doctor a heroe ? p. t.schies~.he, t. bauer, m. seyr dept. of anaesthesiology and intensive care, aokh krems, austria objectives: helicopter emergency services (hes) are getting popular more and more. the results concerning outcome are encouraging. however, some recent accidents with dead or badly wounded hescrew-members have shown the relatively high risk for the crews. therefore we were interested to eval ate the motivation of physicians to participate in a hes. this survey was designed to investigate current concerns about safety and motivation of doctors on emergency call. methods: a questionnaire was sent to doctors of the austrian emergency system. the survey consisted of multiple choice questions and subjective scoring tables from (--full agreement) to (=disagreement). overall, "/. of the active emergency physicians participated in the survey. results: . % of the doctors assume the system is basically safe, experienced doctors tended to have less trust in safety. only % would not hesitate to go into action by dark. . % stdctly refuse night flights to accidents outdoors. although defibrillations are assumed to be safe dudng flight, only % would do it. . % of the doctors would rather stop flying. the most common reasons for ,uitting were wish of family and fear of an accident. . % conclusioq: short transportation times help to avoid trauma related stress, pain and shock-induced organ complications. therefore the physiologic and economic advantages of hes are undebatable. however, the survey data indicate a considerable concern about safety of the medical personal in a hes. crash landings within less than years with deadcases and badly wounded crew members in a small country like austda make desire for safe flying conditions understandable. obiectives: to evaluate the clinical usefulness of trachlight. methods: trachlight is a new device facilitating endotracheal intubation. a stylet with a lightprobe is inserted into the endotracheal tube. intubation is guided by the light glowing through the neck tissues, thus rendering direct laryngoscopy unnecessary. intubation using trachlight was studied in patients (age - years). the indication for intubation was elective surgery in patients (asa i-ii) and emergency intubation in patients. in the elective patients, anaesthesia was induced with thiopentone supplemented with fentanyl, and intubation was facilitated with vecuronium. the cause for intubation in the emergency patients was dyspnea in , cardiac arrest in , trauma in, and unconsciousness due to drug overdose or seizures in patients. intubation was facilitated with medication in patients. results: of the elective patients, ( %) were successfully intubated. six patients ( %) needed two attempts before successful intubation. the duration of intubation exceeded seconds in patients ( %). of the emergency patients, ( %) were successfully intubated. six patients ( %) needed two attempts, and the duration of intubation was more than seconds in patients ( %). in % of all patients, intubation was assessed as easy. no or insufficient glow, prolonging intubation or necessitating two attempts, was noted in patients ( %). oesophageal intubation occurred in patients. conclusions: trachlight may be a valuable adjunct for intubation in varoius settings provided that adequate training is provided. a learning curve was found to exist. objectives: to compare enoxaparin and standard heparin in cavhd and calculate the value of laboratory controls in the treaanent. patients and methods: twenty patients needing dialysis for acute renal failure participated in the study. the main exclusion criteria were massive bleeding or a thrombocyte level < x e /i. in each treatment the same type (av- , fresenius ag, germany) of a polysulfone capillary haemofilter was used. the study scheme consisted of two consecutive four-day cavhd treatments, one course for each type of heparin. the order of heparin administration was counterbalanced between patients. the standard heparin was given as a continuous infusion aiming at an activated coagulation time between and s. the initial enoxaparin dose was rag every :th hour intravenously, but was modified by any signs of coagulation in the dialysis blood lines or bleeding complications. results: the dialysis treatment was adequate in both treatment modes, with mean blood urea levels . and . mmol/l respectively (ns). the bleeding complications were moderate and similar in both treatment modes. the mean life-span of haemofilter using enoxaparin as an anticoagulant was some longer than using heparin ( . + . h versus . + h, ns). the mean aptt-levcl during heparin treatment was s and during enoxaparin treatment s (ref. - s). the mean daily dose of heparin was nag, that of enoxaparin lg mg. the mean anti-xa activities were . u/mi and . u/mi, respectively, reflecting a better bioavallability of enoxaparin. conclusions: both anticoagniation modes were equally effective and well tolerated. the amount of enoxaparin needed for a proper anticoagulation was, however, less than half of that of standard heparin. the changes in aptt level were too slight to make its use possible in controliing the dose of enoxaparin. the use of enoxaparin seems to be rather safe in cavhd even without laboratory controls. the adv~ucea in the management of computerized data of an intensive care unit have been petalled to the clinical advauces and the increasing sophistication of methods of diagnosis fop the clinical application an therapy. this has led our unit to design and develop a computational system called timbu which is used to help physicians assist patients. among its various uses, this system has a software for the hemodynsmic control of a critic patient. this program was carried out to get as fast as possible the hemodynamic data of the patients in an intensive care unit. as an example, we can mention that when we load data obtained through direct measurement from the monitors and the lab, the program calculates parameters that guide, intelligently, to the diagnosis and therapeutic behaviour of the hemodynamic problem through screen messages. the validation of this program in the unit of intensive care has demonstrated that its use allows a more efficient handling of the patient with serious hemodynamics and respiratory disorders. ohieetlve: traema is a heterogeneotm 'disease' that ecatr~ a~"o~s all age ~oupe with v~ying degrees of severity. this imerogeneity has made the di~e, trmma, diflkaflt to r the ehn of this stady wa~ to assr the fitaen of saps in ibis popeleties. methode: in order to compute the ~ probability, a model derived from logistic regression w~ developed. meam'e of calibration (goodaess-of-fit stetislj.r and di~'riminafion (roc ou~e) were adopted in developmm~ and validetlon set randomly taken from a database of pts eeeseemivety admitted in icu (arohidia). ~ witho= salm, p~ yom~ am is yam, with los ~horter thma hotam wore exr fa'om thi~ mmly~ir thi~ model v~s then evahmed on the ~per ~mbgro~ (i.e., trmma pts). if'it did t~t fit the data well ~, new model wm developed rer the logit only on trm=~apm. reims: data were availabte for pts during aperiod of three .y~m , treama pts were . %), teats of calibration iadioaled probability model did mot provide m adequate refle~on of the mortality ezperieace in pm with ireutae, being the observed mortality lower flma the expected (figm'o). a aew model was then variable. this oastomized model fit~ the de~t of trmara pts very well (g =- a p> . ; roc = , ). the di:lferencea between the two modele were evident. conclusion: this ltudy shows that mortality in iramna pts is over wcfe~d when ~se~ed by menm of saps. however the r mode! meets high standmcd in terms of calibration mid dil~'iminat'~o~ ']"he advaatage of ~imd models meaas the colleotion of the ~ set of variables for all pm admitted in icu e~einat the ase of diasma specific ~oring syatex~. ("sl"): effects on cardiovascular and hemostasis systems (cvs, hss) a.oborin~ph, ~.~yndiuk~ph, b.kondratsky ~pt. of'""su~gery and transfusiology, research institute of hematology, lvov, ukraine objectives: great interest has been shown recently in the use of hoss for the initial resuscitation of hypovolemic shock. methods: the study was carried out in dogs -~h hs was induced by jet momentary hemorrhage (h) from a. femoralls (the bloodloss volume made . + . ml/kg). the treatment was begun after .u+o. hrs of h. "sl", created on the basis of-sorblt and natrium lactate ( mosm/l) was injected into v. femofalls at the dose of io. ml/kg. results: it is established that before treatmen-~rterial blood and central venous pressures (abp, cvp) diminished to . mm hg and - . + . cm h (p .o ), while heart rate (hr)-increased to . + . per min (p<.o ). by this the indices of ~latelet counts (pic) and plasma fibrinogen (pf) lowered by . % (p<.i) and . % (p~. ), while fibrin degradation products (fdp) enlarged by . % (p~ . ). after - min of treatment termination abp and cvp increased to . + . mmhg and . +o. cm h (p<.o ), and ~[r diminished to t . + . per min (p>. ). at the same time the indtces of pic and pf enlarged by . % and . % (p>.i), while fdp diminished by . % (p>.i). one of dogs survived. life duration of the other dogs was . + . hrs. conclusions: the obtained data are ~he evidence of normalizing influence of "sl" on cvs and hss, and allow to recommend it as a mean of initial resuscitation of hs in clinic. oblectives: we prospectively studied icu patients with severe head injury (hi), which cerebral lesions monitorized with sjo through opljcal fiber and the cerebral flux with tcd. methods: since january until june , we collected ht admitted to the icu, and of them monitorized with optical fiber in the right jugular bulb and tcd. all patients needed mechanical ventilation related to gcs <__ , with ct in admission (classifing lesions according to marshall and al.) . we related the final results to the evolution of sjo and tcd, with other monitorizing methods like gcs, ct and icp. ~sults: conclusions: in patients with gcs _< , sjo is useful to evaluate the evolution towards vegetative state, still more in cases with ct type ii in admission and higher apache ill. elevation of icp implies an evolutive nsk to brain death and data of tcd is a good indicator of brain death, the complete monitorization of these patients can improve the therapeutic control of this neurologic problem, , ( m, f) , (m. age: + years), divided in two groups (a and b) under specific criteria(tremor and/or fever during admission in i.c.u., or not). the injury severity score was > in all studied patients. tbe group a ( m, ") had no tremor and/or fever on admisskm, while em group b (tin, the above criteria were ix)sitive. bhx~d samplings were taken - hours after accident and - rain. after admisskm in i.c.u. micro-eli~ method was used for measuring cytokinc-levcls. statistic analysis was performed by studcnt-t test. as control group, healthy people were examined. _resu!_ts-il-lct, il-ii~, il- and tnf-tt levels were similar to control group levels in both groups a and b. i!,- and g-csf levels were found increased in both groups (p< jxjl), while il- levels were statistically significant comparing to group a. in con_tin_skin, during immediate post raumatic period,proinflamatory cylokines il-i~, il-i~ and tnf.-ct, produced in an earlier stage than ,. , cannot be detected,whereas .- was increased significantly, especially in group b. g-csf was fimnd in increawal levels in both gr(mps, without statistically significant difference between gnmps a and i|. objectives-l~valantc proteolitic activity, disorders in" eariy, period after combined trauma and p(~.ssibilit, i' of their correction by injection of proteo[ysis inhibitors contrycal and s-fto~:nracil in combination with driving an isotonic snlu~ion of sodlum chloride and polig[ucine. methods: biochemicai studies of proteolitic activity in dogs with limited deep burn and acute bloodloss, . result:s: in case of deep % burn, cornplicated by bloodshed the of blood grows at - times. it; is the restdt of the pancreas glandischemi demage, caused by the centralised circulation of blood and intensifies the deviations of haemodiaamics and albumin exchange. the degree of endogene intoxication by mean mofecular peptides which are the products of albumin decay reses to %, and % in hours. in hours after the trauma the-process is accompanied b ! , % lower inhibitory activity of blood, where as at the peak of the trauma it was , ~ higher. that proves the nnfavuurahle process of the shock in case a combined trauma. conclusion: the vein injection of 'proteolysis inhihitotz cnntrycal and -fforuraei[ in cumbination with driving an isotonic solution of sodium chloride and p.dligh]cine to refill lhe loss of blood helps to lower at times the profeolitic activity of blood. but it still remains above the initial level. the degree of endogene intoxication lowers at times; [ emodinamics aml albumin exchange stahilised. objectives: nimodipine, a known calcium antagonist, has been shown to dispose a beneficial effect on patients with subarachnoid hemorrhage, but its efficacy on traumatic or spontaneous intracerebral hematoma has not been justified. therefore, we studied the effect of nimodipine on the histopathological changes following an experimental intracerebral haematoma in rabbits. methods: twenty-three new zealand albin rabbits of both sexes, weighing - , kgr and at age of - months were anesthetized and a small burr hold in the left parietal aerea was carried out under aseptic conditions. the dura was opened and . ml (this volume assuring a normal incranial pressure after kaufman ) of autologous blood was injected into a depth of mm via a needle of . mm bore. the wound was closed and the animals were left to recover. nimodipine, of , mg/kgr of by weight per day was given via a nasogastric tube to fifteen animals for a period of time of fifteen days (group b). six rabbits were given water and served as control (group a). both groups of animals weie sacrified on the fifteenth day, their brains were removed and immersed into % formalin solution. tissue sections of ~ were embedded into paraphin and stained with haematoxyline and eosin, mason and gfap stain for gliac cells. results: two animals died after the surgical procedure, because they developed large intracerebral bematoma. no animal developed neurological deficit except one of group a which manifested a right side hemiparesis. the results of the bistopathological changes are the following: i) the mean -+ sd diameter of the lesions in the group a was --. ~t while that of group b was + ~t (p< , ) ii) secondary ischaemic neural tissue changes, characterized by the extravasatlon of red cells, the presence of haemosiderin-containing macrophages and signs of low grade inflammation zpredominated in the specimens of group a and were totaly absent from those of group b. iii) a ring of gliac hyperplasia and a low grade local fibrosis was found, encircling the lesions in the specimens of group a in contrast to those of group b. conclusions: nimodipine when administered in rabbits following the development of a non increasing the icp experimental intracerebral haematoma, prevents the extention and the severity of the lesion. objectives: to study the efficacy and side effects of adding intramuscular clonidine (clophelinum) to analgesic regimen in early management of patients with serious burn injury. methods: pts with - % bsa second to third degree flame burns (respiratory tact injury excluded) to yrs of age were randomised to study (n= ) and control (n= ) groups. burn shock was treated with hypertonic saline -bicarbonate solutions ( mmol/l na +) ml/kg/%bsa for the first hours and ml/kg/%bsa for second day. analgesia in control group for the first hours was provided by regular hourly intramuscular administration of mg of morphine sulphate and mg of analgesic -antipyretic analgin with mg of diphenhydramine (dimedrol). from the rd day regular administration of morphine was finished. in the study group ixg of clonidine was added -hourly for hours and dose of morphine halved. vas, verbal rating scale for sedation (vrs, - ), sleeping time, spo , hr, bp, diuresis, vomiting and other complications were comparatively evaluated during patients' stay in icu. results: addition of ~g of intramuscular clonidine daily allowed to achieve better analgesia and sedation with halved consumption of morphine. mean vrs in study group for the first days was . - . vs . - . in control group with twice longer sleeping time. there was significantly less tachycardia in study group; dynamics of bp for the first hours did not differ considerably; later, there, was tendency for hypotension in study group without adverse effects on diuresis or other indices of tissue perfusion. because of high incidence of chronic ethanol abuse among study population pts of control group suffered from psychomotor agitation or delirium, probably as a sign of alcohol withdrawal syndrome (aws). this made regular evaluation of vas impossible. in the study group only pt showed sign of aws. mean vas score was in . - . range for first postburn days. pts appeared excessively drowsy due to clonidine, but it had no adverse effect on their overall clinical course. mean spo values in study group were in - % range, among controls - %; vomiting was absent in. cionidine group vs cases among controls conclusions: clonidine could be a valuable addition to analgesic -sedative regimen in burns, especially for prevention of aws and deserves further study in this regard. hemodialysis -hemoflltration modifications and/or intratracheal gas insuflation have been recently used for blood gas exchange in several models of respiratory failure. objectives: evaluate the combination of cavh-m and igi for respiratory support in experimental acute lung injury. methods: five mongrel dogs ( -+ kgr) were mechanically ventilated inroom air, paralysed, heparinized, connected with a cavh-m system (diafilter- polysulphone membrane) and remained stable for one hour (pao~= . • peco = -+ mmhg, ph= . -+ . , bp= -+ mmhg and pap= -+ mmhg). all was induced two hours after oleic acid infusion ( . ml/kgr) into the pulmonary artery (poo~= . _+ -p< . , paco~- . _+ -p< . , ph= . -+ . -p< . , bp= -+ -p=ns, and pap= _+ -p< . ). fio % for the next minutes did not significantly altered the b ood gas abnormalities. afterwards, pure oxygen applied simultaneously a) through the inlet of the filtrate's compartment of the hemofilter ( l/min) while filtrate and gas were removed from the outlet port (bypass flow ml/min) b) through a thin intratracheal catheter positioned cm above the carina ( l/min). the fio given through the ventilator readjusted to %. results replacement fluids/filtrate during the next four hours were not exceed . l/hour, whilst the blood gases and pressures were improved as follow: cavh-inlet:pao.= . objective. to compare the changes in humoral immunity in trauma patients following massive transfusion of autologous and homologous blood. methods. we studied randomised clinical groups of patients each containing patients with trauma and operation of large arterial vessels. the amount of autologous or homologous blood transfused to the patients was exceeding ml, while the patients in the control group did not recieve blood or blood products. results. we recorded most pronounced and characteristic changes on the -st and on the -th day in the group of patients recieving homologous blood transfusion, i.e. decreased amount of igg,iga,igm,c and c fractions of the complement system, haptoglobin and significant and sustained rise of circulating immune complexes up to the end of the study period. in the control group of patients the decrease was weaker and lasted only during the -st post-operative day; the dynamics of the circulating immune complexes level were almost the same as in the first group of patients. in the group of patients recieving autologous blood transfusion, the parameter values did not change significantly from preexisting levels after the -st day, while on the -th and on the -th day showed a tendency towards aslight rise. conclusions. autologous blood has a favourable effect upon humoral immunity and should be the transfusion medium of choice in cases where autologous blood reinfusion is technically possible. ivan petkov, m.d., rumen farashev, m.d. and dimitar terziiski, m. d. medicine, military medical academy, g. sofiiski str., sofia, bulgaria objective. the amount of blood lost during trauma and operation could hardly be forseen and donor blood supplies are not always available in sufficient amounts. rare blood group types and/or unexpected haemorrhage pose a great challenge to the transfusion therapy and the methods of intraoperative autologous blood transfusion. methods. we report a case of a -year old male patient with extremely massive intraabdominal haemorrhage ( m( blood loss ) during an abdominal aorta reconstruction following a traumatic injury of the abdominal aorta. we achieved a successful reinfusion of ml of autologous blood using an original autotransfusion system developed by us ( pat. no / . . ) . results and conclusions. the autotogous blood in the case reported here was the only and the most suitable transfusion medium for the rapid intraoperative compensation of the acute haemorrhage and the favourable outcome of the patient. the post-operative period was smooth and no significant disorders in the clinical course as well as in the laboratory tests ( morphological,biochemical,coagulation and immunological) were recorded. there were no complications during the postoperative period despite the fact that the amount of blood reinfused to the patient was slightly exceeding his own volume of circulating blood. objective. the haemoglobin concentration and the perfusion pressure value could not be the only criteria for the early signs of tissue and organ dysfunction. because of this, we employed the extensive monitoring of oxygen transport during severe trauma in order to. achieve dynamic evaluation of physiologic compensatory mechanisms and to assess the efficacy of intensive care management. methods. we conducted a prospective controlled trial on the blood oxygenation, oxygen transport and tissue perfusion during the first days after the trauma in patients with polytrauma. we used a swan -ganz pulmonary artery catheter (beckton -dickinson, u.s.a.), deseret cardiac output computer (medical inc., u.s.a.) and hewlett -packard monitor (hewlett -packard, germany) to measure and calculate all the parameter values. the severity of the injury was assessed using the apache ii score system. all the patients had scores over . results. the results show a significant decrease in the arterial blood oxygen content and in the arterio-venous difference, as well as an increase in alveolo-arterial oxygen difference and in the transpulmonary right-to-left shunt. the tissue oxygen supply and the tissue oxygen consumption reveal a tendency towards a decrease below the physiologic minimum of adeqate values. the erythrocyte current velocity and the ratio between oxygen transport and erythrocyte current velocity also decrease inspite of the optimal blood rheology. conclusions. the dynamics in the parameters values are most pronounced between the -nd and the -th hr after trauma, which predisposes patients to the risk of developing stable hypoxemia and characterizes this period as the most critical for tissue metabolism and organ dysfunction. posttraumatic changes in immune mechanisms in lung compartment in trauma were analyzed in ao and da inbred strains of rats which differ in their immunological reactivity: the former being low responder and lat-~er hiperresponsive. methods: the levels of tnf-alpha activity in the supernatants of cultured lung lobes and dynamics of cells migration from tissue explants in h lung cultures were assessed in ao and da rats subject ted to severe burn trauma. results: increased levels of tnf activity ( + pg/ml compared to + . pg/ml in control) were found od day following trauma in lung sups of ao rats while no changes in the levels of activity of this cytokine were found in lung-sups od da rats more pronounced extent and dynamics of cell emigration were noted in da rats, while almost unchanged in ao rats sharp rise in pmn percentages h following trauma ( - % compared to rare pmns in control), followed by increase in lymphocyte numbers at later time points among lung cell emigrants was detected in ao rats. slower but persistent increase ( %, h following trauma and % and % on days and after trauma infliction, respectively) in pmn numbers among da lung cell emigrants was detected, which appeared to be activated, as judged by their nbt reduction capacity. increased percentages of peripheral blood pmns and increased state of leukocyte aggregation/adhesion were detected in both strains, but different levels of plasma tnf: increased levels in ao rats on days and following trauma, and initially but persistently high levels of plasma tnf alpha in da rats ( - fold higher compared to initial levels in ao rats). conclusions:different patterns of local (lung) and systemic changes in cell numbers and cytokine levels implicate differential posttraumatic migratory capacity of pmns vs. lymphocytes in lungs in ao and da rats. early diagnosis of acute intestinal ischemia by color doppler sonography e. danse, b.van beers, p.goffette, f.hammer,aav.dardenne, f.thys, p-f.laterre, m,s. reynaert, .lpringot dept of radiology (profb.maldague) and dept of intensive care ( prof m,s.reynaert), st.luc univ.hospital, brussels, belgium ob emergeny medical squad service is the most important segment in the process of saving the people, in the cases of mass accidents, like industrial accidents caused by the: explosion, fire, chemical poisoning, traffic accident, elemental catastrophes and the war. because of that, each emergency medical squad service needs to have in its motor-pool vehicle for the mass accidents/ for provoding at least people, wounded as well as the people became ill/. objectives: presentation of such special vehicle, produced by "zastava-kamioni" and it's medical-technical equipment. methods: descriptive and comparative analysis of the medical and technical characteristics, based on the actual norms/din, , iso , yus.../ results: on the base of doctrinaired requirements of the emergency medical squad in the case of mass accidents, our researches resulted in the following medical and technical characteristics -the vehicles for mass accidents are gvw/with a payload off cca - t, with the fixed, closed body, type: universal van, -technical equipment aggregates, stretches, anti-fire device, equipment for pitching the tent and for maintaing technical conditions of the work -medical equipment: linen bags with complete sets of bandage material, means for the reanimation and immobilization, for the infusion, medical instruments and remedies as well as the tent for lodging at least wounded and sik people. in federal republic yugoslavia, it was proposed such vehicles for the emergency medical squad needs. conclusion: we suggest to introduce this vehicle in the production range of the ambulance vehicles for saving, especially in the circles where can occur serious accidents. introduction : carbon monoxide (co) poisoning commonly generates central nervous system abnormalities though an important cardiac morbidity and mortality must be considered. long-term exposure to co with cohb levels < % may be more dangerous than short-term levels of - %. we report a case of an adolescent who after prolonged exposure to co developed a severe reversible cardiac dysfunction with low levels of bloed cohe c a.ase history : a year old boy was found comatose at home. his mother in the neighbouring bathroom died severn hours earlier of what was later proven to be a co intoxication. on arrival the gcs was / and the patient was breathing spontaneously. a postictal status with eventual postanoxic encephalopathy was suspected. a coh'b level of % was objectivated. the cardiorespiratory situation quickly deteriorated requiring mechanical ventilation. chest x-ray showed diffuse bilateral patchy infiltrates. ecg revealed signs of ischemia. severe left ventricular dysfunction was evidenced by pulmonary artery catheterisation and echecardiography and later by isotopic angiography (lvef %). treatment was intensified with inotropic support, intta-aortic balloon counterpulsation and oxygen therapy. the clinical course was further complicated by a crush syndrome and renal failure. the patient's condition gradually improved and he fully recovered without any residual lesions (lwf %) conclusion : even after prolonged exposure cohb levels can be misleadingly low. high tissue levels of accumulated co can be associated with coma and fulminant cardiorespiratory failure requiring advanced life support facilities. introduction : both neuroleptics (nlp) and tricyclic antidepressive agents (tca) can induce arrhythmias, prolongation of the qt segment and the pr interval and hypotension. we report a case illustrating that combined overdose of these agents increases the toxicity of each compound and the risk for adverse cardiac events. .c, gse history : a year old male ingested mg doxepin (sinequanr), a tca and mg prothipendyl (dominalr), a potent nlp in an attempted suicide. upon arrival in the emergency department the patient was unconscious (gcs / ), breathing superficially, and presenting signs of recent vomiting. physical examination revealed a taehycardia of b.p.m., an arterial blood pressure of / mmh g. ecg showed a brood qrs complex tachycardia. a chest x-ray revealed the presence of an aspiration pneumonia. laboratory investigation demonstrated increased levels of crcatine phosphokinase, lactate dehydrogenase and aspartate transaminase ; hyperglycemia and leucocytosis were present. the plasma concentrations of doxepin and prothipendyl were respectively gg/l (toxic level #g/l) and i.tg/l (no reference). treatment consisted of mechanical ventilation, gaslric lavage and administration of activated charcoal and iv fluids and antibiotics. a hemodynamically well tolerated veatricular tachycardia developed / h later. nahco ( meq/ h) was administrated inducing an ectopic atrial tachycardia with a normal qrs complex and prolonged qt. h after admission a normal sinus rhythm was present; the prolongation of the qt segment persisted for days. the patient fully recovered. conclusion : the treatment with nahco~, alkalizing the blood and thus increasing the protein binding of the tricyclic antidepressant molecule, can readily correct the potentially life-threatening cardiac arrhythmias and therefore should be part of the routine treatment of combined tca-nlp overdose. ob/ectives: the development of diabetes insipidus (di) in patients with brain injury is a known negative prognostic sign. the aim of this study was to investigate whether this is also a reliable early prognostic sign of brain death. methods: this is a retrospective study of patients treated" during a two year period ( - - to - - ) in our i.c.u who meeted the following criteria: ( ) coma score _< gcs within the first hours, ( ) positive brain ct scan on admission classified according to marshall's diagnostic classification (classes - ), ( ) normal renal function during the entire icu stay. for the definition of di were used the usual di criteria plus hypematriaemia (serum na" >_ meq/l). survival was defined up to the th postadmission day. conclusions: according to the findings of this study, the development of diabetes insipidus in brain injured patients seems to be a highly specific index for brain death (positive predictive value = . ). however, further prospective studies are needed for the definitive evaluation of these findings in such patients. emergency care in italy, despite all efforts, is still lacking a nationwide organized prehospital care system and, until today, there are only different regional solutions. the majority of these realities imply rather simple ambulance first-aid services without attending emergency physicians and without resuscitation equipment. the emergency medical service (ems) system in falconara m., italy, was implemented in august by a collaboration between the school of anesthesiology and intensive care of the university of ancona and the, already existing, volunteer rescuer organisation "yellow cross". according to the guidelines pubblished in [ ] the pre-existing equipment of the volunteers was completed with type a ambulances and special equiped motorcar (patient monitor, defibrillator) for ambulance indipendent physician transpur[. a special data collecting schedule was created to memorise every emergency intervention in a computerised data-base. the intraining members of the school of anesthesiology and intensive care provide hour ready intervention. in this report the authors describe their experience concerning primary firstaid medical interventions. for a preliminary evaluation we considered, retrospectively, consecutive emergency interventions in the time period from novembre , to april , . the emergency physicians treated male ( %) and female ( %) patients, patients died before hospital admission and patients ( %) were treated at home by the ambulance indipendent physician and did not need any further medical treatment. in the same time period year earlier (november to april ) without attending physician the volunteer rescuers transferred all first-aid interventions to near-by hospitals. we conclude that the presence of an attending, iudipendently motorised physician in emergency interventions is essential for the establishment of precise priorities and may be helpful to reduce hospital admissions by ambulance intervention, though reducing primary" health care costs. we have developed the method of liquor filtration which allows to purify the cerebrospinal liquor from blood and its decay products in the subarachnoid bloodstroke. the hemipermeable dialysis membrane was used as a filter, which lets only in water, electrolytes and substances with small molecular weight. the liquor filtration was used for the treatment of patients with the subarachnoid bloodstrokes of different etiology. the perfusion of liquor was performed at the rate ml/min in the recirculatory mode. its duration was - min depending on the bloodstroke intensity. the filtration makes possible the most completely purifying of the hemorragic liquor, the reducing of the content of blood ceils and its decay products - times as less. the monitoring of the patient's state during the perfusion didn't revealed the departure from the norm of the main vital part. the liquor filtration technique compares favo-~ rsbly with the routine method of cleaning by the absence of toxical effect of heterogenous solutions on the central nervous system. the filtrstion of the cerebrospinal liquor in the subarachnoid bloodstroke sllows to provide the the early cleaning of liqour, the regression of meningeal syndrome and to improve the patient's state of health. e tabli~mczr bd ~ of rei~idnal medical first-aid zhoulittoing, ed., tan zi, m.d. dept. of sargery, the first teaching t[ospitat, yejin-l)a-l)ao, wuhan fltlna objectives: the medical first-aid is the most important task of the public hc atth department. in general, single hospital model couldn't fatty, effective ly rescue mony severe patients who need mergant treatment in the scene. bub establishing the medical first-aid network, the severe patients can be given the most timely und the most scientific emergent treatment. so that, the suc cessfut rate of the saving wilt be greatly increased. methods..; our hospital is a general big hospital. through developing and cons tructlng for more than ten years, the medical first-aid network distributed art over the area under our jurisdiction has been set up. it consists of thr ee units: the medical first-aid unib center comartd and mnagment unit, co m~nlcation and tiaison unit. the principle of the network operation is with oat having to far to mergoncy, specialized emergency and the best merge acy. results: the results of the network operation were notable. cmpari~ the to tat successful rate of the saving ( . ~), the successful rate of saving tra ma ( .~), the suscessfut rate of saving shock ( .~) and the successful rate of cardioputmonary resuscitation ( . ~) daring the three years after t he network operated with these before ( . ~), ( ]. ~), ( . ~) and ( ft. ~), the successful rates after operating were remrk~iy higher ( p<i).o ). conctusions~ the above results showed estabiishmnt and mena emont of region at medical first-aid network had very si~nificont action during mergentty s avin the severe patients. moreover, the regi~at medical first-aid network atso take an important part in prevention and health protection of the mass. objectives: se related mortality is due to the occurrence of both rv and lv dysfunction evoking cardiogenic shock and pulmonary edema (f. abroug, intensive care med ; s. nouira. chest ) . prospective evaluation of scorpion antivenon (sav), the only available specific treatment, is lacking. the aim of this study is to assess the effects of sav on the basis of a case-control study. methods:among consecutive victims of se presenting to the emergency department, were managed using sav (group sav+). these patients were matched to envenomated patients who did not receive sav (group sav- chest injuries are the cause of death in % of trauma fatalities and a major contributing factor in an additional %. pneumothorax is a major complication of chest injuries and can be initially overlooked bringing to additional morbidity and mortality especially in patients who require mechanical ventilation. the real incidence of pneumothorax in severe blunt chest trauma hasn't yet been established, as many pneumothorax can be missed on the initial chest x-ray (cxr) and computed tomography (ct) has not been routinely used. to evaluate the incidence of pneumothorax in patients with severe blunt chest trauma. methods: a prospective study. from january to december , all trauma patients with one of the followings conditions: fractures of four or more ribs, signs of lung contusion on the initial cxr or presenting a severe hypoxemia on admission (pao /fio < ) in the absence of pre-existing pathologies, were evaluated by initial cxr and subsequently submitted routinely to a ct. results: severe trauma patients were considered. of them, presenting a severe hypoxemia on admission, had no evidence of major chest trauma (ais< ). hypoxemia was the consequence of severe trauma in other districts; these patients were therefore excluded. patients with severe thoracic trauma (ais>= ) were admitted into the study. the mean iss was . ( - ). thirty-six patients required artificial ventilation for at least hours during the icu slay. three of them, who had a tension pneumothorax, were submitted to an emergency thoracic decompression on the field by the emergency helicopter team. in cases pneumothorax was diagnosed an the initial cxr more patients had a pnx which was identified only on the ct. in cases a large pnx with lung collapse was missed on the cxr. in our group of severe blunt trauma patients, % ( / ) presented a pnx that required the insertion of a thoracic drainage. only one third ( / ) of the pneumothorax could be recognised on the initial cxr, while other were decompressed before performing the cxr. as many as % of the cases of clinically significant pnx were missed on the cxr, and a ct performed soon after admission allowed an early diagnosis bringing to changes in the treatment. (as the patients were mechanically ventilated a chest tube was inserted in all these cases). in cases, the initial cxr overlooked a huge tended pnx which was the cause of hemodynamie instability. conclusion: in patients with severe blunt chest trauma even large pnx can be missed on the initial cxr. moreover due to the non compliant compressible lung, a % pneumothorax which can be recegnised only on a ct, can bring to high intrapleural pressure altering eardiopulmonary function. n. andoeli , .~osid, m.zesevid, m.risovid, d.stepi , d.djokid b~rga~yc~qterclinicalcaqterafserbia, belgrade cb~ctives:~lis study ~ the use of ~rq]ofol earbired with k~t~ine (aq a~sjgh~ic s@~qt widn inirjrsic armlgesic pro~mities) or with fsqtmtyl,with psrtial azgmsis an hgenxlyn-a~ic ~ durirg ~ ~ re:~ver~ f~m ~ in hxh ~ of ~ti~. ~: yali~mial and ~bod: a~it p~tie~ts a~ i-ii were included in ibis shxly. patients were rsrd]nly dieided in two ~ns. all d~tie~ts ~me given - prcpofol bolus doses (o, ~gkg) for ird~iqn of ~. ~ia ~s m~sjn~ with an infusion ~ ~ropafol. as sdflitianal were given fan-i~l (o, n]g) ~tely before ~ anj trad~e~ irfojoation followad by feasted bolus of o,i mg in ~ro o l.patients in gr~ o received i~ (an initial bolus dose of rg slowly intcavax~ rd mg as infusion over ~ rain) .infusions of pro~fol or imcpofol with kg~mine ~ stopfsj - rain ]:~o~ extuhation.arterial blood ~ (sistolic arterial blood preassu-re~zap,mean ~rterial blood pr~,d~lic arterial preassure-[zp a~ h~art rate-~) ~ m~ before induction of a~ io, snd rain aftem ~ intutation. results: arterial blood preasstre ~s decreases duri~ irn~ction of sn~wd~sia in hy~ ~n~s,tnt mare in th~ ~ who r~eived fsqtanyl.~ere w~s statisticslly sifnific~ntly difemerme dmir~ m~ of an~ia. arterial blood r~easatre and heart rate were stable in the t-..e~min -~a ~. all th~,fl-e keta'nire grcqo hsd e~rly :~e~y time. ctrmlusi~s: ~e ombiretion of protxfol wilh keta/ne for irduorion a~d ~ of sn~sd~esis w~s yell accept~ by p~tierfcs anj coald he ~ as an alterrstive ~o ccnva~icrsl a~es -d~sia. objectives : assess the relation between cytokine or endotoxin release and indices of splanchnic malperfasion after hemorragic shock in multiple trauma patients. ]~r study was approved by the local ethical committee. trauma patients admitted to the emergency room who met the entrance criteria of more than hour map < mmhg or use of vasoactive agents or blood lactates > mmol/ were selected for study. a nasogastric tonometer (tonometrics, inc, plastimed, france) and a swan ganz catheter were placed on admission. phi, lactates, hemodynamics, plasma cytokine and endotoxin concentrations were measured on admission and at . , , , hrs. an immunoradiometric assay was used to determine plasma concentrations of il (n< . ng/ml) and tnfc~ (n< pg/ml). plasma endotoxin concentrations were measured using a chromogenic limulus assay (n< . eu/ml)( endotoxine unit= pg). results : severe multiple trauma patients (age = _+ yrs, iss = -!-_ , saps = +'~, mean-+sd) were studied. they received + packed red cells during the first h. mean duration of collapsus before inclusion was . _+ . hrs. death occm'red in ~tients. ~ pglml, *: ng/ml, etox : endotoxin(eu/ml), lact: lactate (retool/l) a significant correlation between initial il level and saps was observed. in the early post-injury period phi, sao , svo , vo were significantly associated with ;il release (p< . at ho, h , h ). later a significant correlation existed between lactates and ii (h , h ). a peak of tnf was detected at and hrs. it was associated with low phi and low arterial ph of the early post-injury period (p< . iat ho, h , h ,h , h ) and with high lactate levels of later period (_>h ). only the late release of endotoxins (i{ ) was correlated significantly with initial !oxygea-delivered parameters. iconclusion : there was a marked increase in il in the early phase of trauma . i and tnf release after major trauma iwith hemorragic shock is associated with splanchnic malperfusion, as assess by the ivery low values of phi. lactates seem to be a later indice. toxic effects are a well-known complication of an overdosage of prescription theophylline. what is less known is that over-the-counter (otc) asthma medications contain theophylline, and that in some cases this might cause toxic effects. a case seen by us involved toxic effects from theophylline in an otc medication and to date is the only published case in the english literaturet the rationale for this study was to delineate the otc products containing theophylline from whatever data sources available. hyperthermia frequently occurs in intensive care treated patients and intentional application of whole body hyperthermia together with chemotherapy is a therapeutical access to treatment of malignant disorders. anaesthetic support is required in either condition. due to the marked decrease in systemic vascular resistance seen in hyperthermia an additional vasodilatory effect of the anaesthetic is unwanted. the vascular effects of anaesthetics in hypertherm organisms is not known in detail. therefore, we performed an experimental study to detect the effects of inhalational anaesthetics in whole body hyperthermia. in sprague-dawley-rats katheters were inserted into trachea, jugular vein, and carotid artery. for continuous monitoring of cardiac output a flow probe was placed around the aortic arch. the rats were mechanically ventilated with different concentrations of inhalational agents in oxygen. we compared the effects of enflurane, isoflurane, and halothane in stepwise increased body temperature by submerging in a temperature controlled water bath. results: isoflurane lowers arterial pressure more than halothane or enflurane. the inhalational anaesthetics lower the cardiac output similarily and independently of temperature. isoflurane decreases systemic vascular resistance independently of core temperature and the decreasing effect of halothane on the resistance is completely abolished in hyperthermia. conclusions: the influence of hyperthermia on the systemic vascular resistance is dangerous. this allows no additional effect of the anaesthetic management. in spite of the vasodilating effect of inhalational agents in normotherm subjects, this effect is abolished in hypertherms using halothane. the condition of management of analgosedation in hyperthermia is different from normothermia. objectives: to evaluate a bedside computer processed cerebral function monitor for assessment of brain wave activity when clinical/visual clues are not present. methods: ten icu patients undergoing neuromuscular blockade monitored with the aspect brain wave monitor from january to june , . results: time to onset and depth of sedation were readily apparent to icu physicians not specifically trained in eeg reading. objectives: to determine whether non-depolarising neuromuscular blockade reduces oxygen consumption (vo ) in sedated, apnoeic patients. methods: haemedynamic. metabolic and oxygen transport variables were determined in sedated, apnoeic patients with severe acute lung injury. all patients were ventilated using a puritan-bennett ae ventilator with integrated metabolic monitor. inclusion criteria were; ) stable cardiorespirator s" status; ) systemic and pulmonary artery catheters already in situ; ) inspired oxygen < %. patients were sedated with midazolam or propofol to abolish response to verbal stimuli, and sufficient morphine or alfentanil to abolish all spontaneous respiratory efforts. following baseline measurements, neuromuscular blockade was induced with intravenous vecuronium, ug/kg, followed by an infusion of ug/kg/h to maintain the train-of-four ratio at . a further four sets of measured and calculated variables were obtained at min intervals. results: statistical analysis was by repeated measures anova. there were no significant changes in any variable over time. the changes in calculated oxygen consumption (vo fick) , and measured oxygen consumption (vo gas), and in energy expenditure (ee), are shown in the table. objetive: to study the effects on coronary hemodyrtamics and myocardiai metabolism of administering propofol during postoperation sedation of patients with normal coronary circulation and good ventricular function undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mi~-a/ valvular cardiac surgery were selected, with an ejection fraction greater than . and normal coronary circulation. for postoperation sedation propofol was administered in . mg/kg i.v. bolus, followed by a . mg/kgth perfusion. all data were registered before administering propofol and after minutes, the patients being hemodynamically stable and a rectal temperature of _+ . -~ systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabofic variables were measured. results: the patients studied were about years old, and the average period of aortic cross-clamp was . min. the adminstering of propofol caused a decrease in the coronary blood flow (- %), great curonary vein flow (- %), myocardial oxygen consumption (- %), regional myocardial oxygen constanption (- %), myocardial oxygen extraction (- %), regional myocardial ooxygen extraction (- %), while coronary vascular resistances and global coronary vascular resistances did not change. oxygen saturation increased in the coronary sinus (+ %) as well as in the great cardiac vein (+ %). in no patient were significant changes suggestive of myocardial ischemia objectified. there was also found a decrease in systolic (- %), diastolic (- %) and mean (- %) arterial pressure, systemic vascular resistance (- %), and cardiac output (- %). conclusions: in accordance with the clinical conditions of this study, the administering of propofol is not likely to cause changes in coronary autoregulation, oxygenation and myocardial metabolism. obietive: analyse the effects of . % "end tidal" isoflurane (sedative dosage) on the metabolism and coronary hemodynamics during the postoperation period of patients undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mitral valvular cardiac surgery, with an ejection fraction greater than . and normal coronary anatomy, were selected. after the surgical operation, . "end tidal" isoflurane was administered for postoperadon sedation. the determination of variables to be studied was carried out before and minutes after administering isoflurane, die patients being hemodynamically stable and a rectal temperature of _+ . -+c. systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabolic variables were measured. results: the average age of the patients studied was -+ . years. during surgical operation the period of aortic cross-clamp was . _+ . rain. the administering of isoflurane was followed by a statistically significant drop in coronary perfusion pressure (- %), coronary vascular resistance (- %), regional coronary vascular resistance (- %), regional myocardial oxygen consumption (- %), regional myocardial oxygen extraction (- %) and accompanied by a significant rise in oxygen saturation in the coronary sinus (+ %) and in the great cardiac vein (+ %). myocardial oxygen consumption, myocardial exu'action of lactate and regional myocardial lactate extraction did not change. in no patient were enzyme or electrocardiograph changes objectified. systolic (- %), diastolic (- %), mean (- % ) arterial pressure, and systemic vascular resistances (- %) decreased, while cardiac output did not. discussion: the administering of . % "end ddal" isoflurane, in the clinical conditions of this study, produced a decrease in systemic arterial pressure due to a reduction of systemic vascular resistance without deteriorate cardiac output. at coronary circulation level, has and effect on coronary autoregulation but had no effect on oxygenation and myocardial metabolism. the idea of tiva implies the realisation of major anesthesia components (los of consciousness, neurovegetative inhibition, analgesia, myorelaxatiou, providing the adequate gas-exchange) through i.v. introduction of drugs exclasively. aim: providing for the main tiva components with minimal side effects of the drugs used, taking into consideration the patients characteristics and the surgery specific character. methods: anaesthesias have been conducted in patients aged years ( females, males), undergoing planned and urgent operations with the pathology of lower, extremities, perinaeum, small pelvis, hypogastrium and with reserved spontaneus respiration against a background of % insnffladon through mask. operations lasted from . - . h. anaesthesia adequacy was assested by constant monitoring: "cardiocap" (nibr hr, rr, sao , t), through glykhaemia level and mimicry reactions. standart premedicatioo of m-cholinolytics ( . mg/kg) and h -blockers ( . mg/kg) on the operational table was sumplemented by administration of . - . mg/kg of lidocaine, . . mkg/kg of clonidine, . - . mg/kg of pentamidine by the tachifilaxia method. the premedication adequacy was assessed through haemodynamics characteristics. sedation: . - . mg/kg of droperidoi, .l- . mglkg of diazepam and analgesia: - mkg/kg of phentanyl, . -- . mg/kg of ketamine were introduced fractionally according to indications. infusion rate of ringer-lactat solution was - ml/kg/h and depended on the intraoperational blood loss volume and on the patients preoperational condition. the duration of postoperative analgesia was registered. results: clinical assessment of analgesia according to this techniques allowed to decrease the anaigetics dosage to the subauaesthetic levels. smooth stabilisation of haemodynamics (bp) at proper age norms in patients with the initial hypertension by the -th min. of anaesthesia as well as the absence of its increase in response to the additional introduction of anaesthetic have been achieved. (hr) had no abrupt changes and remained in the range of - per rain. adequate external breathing: decrease (rr) by - per rain., with sao increase from % to - %. hypoventilation was avoided by respirate ventilator. according to unauthentic data the glykhaemia level had been lowered by -t % to the end of the operation with the initial moderate hyperglykhaemia of up to mmol/l the cutaneous covering grew warm and got pink colouring. no mimicry reactions. in the postoperative period patients were in the superficial sleep state ( - ) and analgesia lasted - b. there were no complications due to anaesthesia. conclusion: combined using of bz, opiates, neuroleptics potentiate the i.v. anaesthetics effects allowing lowering of each tiva component dosage and, as a consequence avoiding their negative influence on respiratory and heart vascular systems. complex application of adrenergetics (therapeutic doses of cionidine and pentamini with using of taehfilaxy effects) permitted to provide for analgetic and neurovegetative components of general anaesthesia under subanacsthetic doses of tiva main components, and manifestation of hyperdynamic reactions of haemodynamics decreased while using of lidocaine -the economicai activity of heart-vascular system. good level of muscle relaxation was achieved allowing for widening of surgical intervention extent without respirator ventilators and inhalation anaesthetics application. anaesthesia is easily controlled due to fractional introduction of drugs with quick recovery of cns functions after anaesthesia. postanaesthetic analgesia is increased while concurrent opiates doses are decreased. absence of marced haemodynamic, endocrine and metabolic reactions during the operation and after it resulted in shortening the period of patients staying in hospital. a yo white man was admitted to hospital for dyspnea and a productive cough. he had cabg in past, but no recent cardiac ischemia. physical exam: decreased breath sounds over right lung. chest xray: consolidation of right lung. admission medications included diltiazem, furosemide (both were continued) and trazodone (which was discontinued). admission ecg: sinus rhythm, qt . /qtc . sec, with st and t wave abnormalities similar to prior tracings. he required intubation and mechanical ventilation for progressive hypoventilation and hypoxemia. between icu days and he received haloperidol, - mg/d (cumulative dose rag) for agitation and delirium. icu day : qt . /qtc . sec. icu day : for better control of delirium, trazodone " mg q hs was added. icu day : he developed frequent nonsustained ventdcular ectopy. icu day : qt . /qtc . sec, pha . , paco mm hg, pao mm hg, k . meq/l, mg . meq/l. later in icu day the patient had brief episodes of torsades de pointes, each responding to precordial thump, and finally rhythm stabilized with i.v. lidocaine and magnesium. haloperidor and trazodone were discontinued. ecg was unchanged and myocardial infarction was ruled out. next day, icu day : qt . /qtc . sec. torsades de pointes, a form of ventricular tachycardia characterized by a twisting qrs axis, is commonly associated with qt prolongation. haloperidol is used frequently in icu for control of agitation and delirium, with reported doses up to mg/day. over past decade, cases of torsades de pointes with prolonged qt related to haloperidol have been reported. trazodone may also prolong qt and cause ventricular arrhythmias, especially in patients with pre-existing cardiac disease. in this patient, trazodone likely exacerbated qt prolongation from halopeddol leading to torsades de pointes. critical care physicians must be aware of this interaction. it is imperative to follow the qt interval for patients receiving halopeddol, especially when another drug also known to prolong qt is added. one must consider discontinuing the drug when qt/qtc becomes prolonged. objectives: analgesics and intravenous anesthetic drugs are routinely used in critically fll patients, who often suffer from a secondary impairment of the immune system. previous in vitro studies have demonstrated inhibitory effects of these drugs on polymorpho nuclear cells (pmn). the potentially important role of endothelial cells (ec), however, was not investigated, since suitable test systems were not available until recently. therefore a physiologically more relevant in vitro migration assay through cultured human endothelial cell monolayers (ecm) we established. using this assay system, the comparative effects of fenlanyl, sufentanil, propofol and the known pmn inhibitor thiopontal were tested. methods: human umbilical vein endothelial cells (huvec) were isolated and cultured on microporous membranes (cyclopererm) until an ecm was grown. pmn from male and female volunteers were separated by standard procedures. ecm and pmn were preincubated with clinically relevant concentratious of thiopental ( m), propofol ( p_g/ml), the solvent of propoful (intralipid), fentanyl ( ng/ml) and sufentanil (sng/ml). after preincubatiun (ecm minutes, pmn minutes) with the reslx~tive drug, leukocyte migration towards the chemoatfractant fmlp ( o - m) was measured in a two chamber well system for hours. the migration rate of untreated (untr.) and treated (treat.) pmn through untreated and treated ecm were determined. as a control untreated pmn and untreated ecm were used. results are given as means from independent duplicate determinations and expressed as a percentage of control (table) . statistical analysis was done with student's t-test. results: clinical concentrations of fentanyl, sufentanil and prupofol showed similar inhibitor~ effects as the known pivin inhibitor thit e ). % conclusions: for the first time we could show that analgesics and anesthetics exert their inhibitory effects not only on pmn, but mainly on the interaction of pmn with endothelial cells. moreover, we could shmv a significant suppressive effect of the opinids fentanyl and sufentanil on both ec and pmn. the known inhibitory effect of thiopental obtained in ec-free test systems were also confirmed in our physiologically more relevant assay system. objectives: to investigate when and how sedation is used in a consecutive cohort of patients admitted in a large sample of italian intensive care units (icus), gathered in a network named giviti, representative of the italian icus system. methods; the study called for a recruitment period of one month, from january to february , , data collection included age and other demographic variables, acute diagnostic broad profiles, severity of illness scores, treatments, lenght of stay and vital status at icu discharge. as concerned sedation, each patient was observed until discharge or for a maximum period of seven days. information on all the drugs used for analgesia/sedation, the route and modalities of administration, the timing, dosages and purpose of the administration have been recorded. results: the study involved the cooperation of icus, of which enrolled at least one case. the total sample included patients. overall, . % of patients analyzed (t / ) received at least one prescription of sedative during their stay. globally, at least one sedative drug was prescribed to these patients in days in icu. although over drugs were reported to be used, pharmacological principles accounted alone for % of all prescriptions. opioids were actually used in % of prescriptions; propofol in % and benzodiazepine in . %. as regards the way of administration, intravenous administration was applied in % of cases and, followed by intramuscular in . %. moreover, non-steroidal anti-inflammatory drugs (nsald) were used in % of patients and neuromuscular blockade agents (nmba) in %. detailed analysis on certain subgroups (surgical, trauma, ventilated patients etc.) have been also carried out in order to describe the practice of sedation in these peculiar subgroups. findings will be widely discussed during the presentation. conclusions: these results should be interpreted keeping in mind how peculiar is the intensive care setting compared to many other less complex settings of hospital care. in conclusion we thought it was important to present the data currently available in the most neutral form, to start moving in a direction which will enable us -by means of more specific and detailed studies, and with the cooperation and involvement of all those participating in the project -to shed light on one of the many aspects of medical practice in the field of intensive care which deserve closer attention. introduction: the aged run perilously high risks in cardiac surgery: among others, of haemodynamic fluctuations, respiratory depresskm and organ failure. response to anaesthetics is a crucial determinant for post<)perative complications, none the less being reintubation due to mechanical ventilation difficulties which increase morbidity, mortality and intensive cdre unit (icu) stay. objective: we wanted to assess our a,aesthesia window (selection, and a view of the induction -extubation period) for predicting safe and swift awaking, thus: icu dismissal for the aged. methods: in , selected patients (pts) (> y, f) followed a regular elective cardiac surgery protocol (propofol given at precisely designated time intervals). upon cu arrival, they were subjected to an admission protocol. our predictive criteria for early extubation at h included: a) alertness and ready response to commands; b) adequate gag reflex and sufficient protection for respirak)ry tract; c) pao > mmhg with flu < . ; d) stable ph> . with spontaneous respiration; d) stable haemodynamics without dysrhythmias; e) adequate perfusion and diuresis (> .(i ml/kg/h); f) mediastinal bfeeding< ml/h for at least h; g) normothermia (core temp> ~ and no shivering). subsequent reintubation was for: ) rr> /min; ) spontancx)us ventilation for rain with paco > mmhg; ) pao < mmhg with fio > . ; ) ph> . ; ) heart rate>] bm; and/or ) non mental alertness; and ) other medical disorders, after which adequate weaning therapy was necessary. then, successful weaning after h was considered: ) spontaneous breathing without any forrn of mechanical assistance; ) stability in haemodynamics; and ) elimination of fever threat. results: pts ( %) were extubated at h without complication; other pts ( %) at h but had to be reintubated because they were hypoxic and began weaning therapy; finally, they were all re-extubated by h. only pts ( %) proved problematic. conclusion: a,aesthesia wimhlw options (selectkm, extubation, reintubation and weaning) predicted quick (times propofol administration) and safe (rigid criteria) extubation ( %= h and %= h), exempting pts with developed post-operative complications ( %=extubation< h) unrelated to al~aesthesia window or icu protocol. dismissal and recovery then became an abbreviated question of time. fifisetll p, domeneg~i ~, sforzini i., veronesi i~, maconi a.g. *, breg~ massone p.p h [] ic+pca request conclusions:using e~aprenorphine, a synthetic,long-acting, ago-antagemist opinid drug as analgesic, in the major surgery we obtained the best clinic results with association of conttheus infusion of haft dose drug with bohts of pca in the first - hours and just pca in the secmad day after surgery when the patient is less sleepy. in this way we dent have a great sav~g of suppled drug but the major well-belng of patient without ~erious side-effects and quick mobilization; the dosage used don't compromise a good awake of patient: all patients are sleepy but ready for answer, no allueinatian, bradipnea but not less than b/m without ipoxia. also the patient proffered this kind of truit meut than the traditional at demand. the ward staff feel it useful] and rehabl~ the negative feed-back technology of the electronic infuser system makes possible to use it safe in the ward with high drug's concentration too. the infusion rate of low dose of drug assure a continuative analgesic covering ~n the first postoperative periad; the pca mode involves the patient him-self in the managemenl of therapy and enables him to choose the best way to confront the dll~icuity of postoperative period without call medical stall using pca-device we have had no probicm~ no accident. analgesia during extracorporeal shook wave lithot ripsy a .levit, b.grinbezg regional hospital, ekaterinbu~g, russia b~ectives: our task was to compare ~he analgetic effect of norphin and tramel. methods: study was made of two groups of uro-li~patients aged - . group a ( patients) received baprenorphine hydrochloride (norphin) at dosages of #. • mg/kg. group b ( patients) received tramadel hydrochloride (t~aasl) st dosages of . z . mg/kg. before the procedure diazepam was administrated i.v. ( . ! . mg/kg). blood saturation (spoz), hemodynamics incides (bp, hr,sv,co,sap,svr) were examined and the patients' subjective assessments of snsesthesis quality were analyzed. the hospital ethics committee approved the investigation. results: when using norphin hr increased by . % on the onset of the procedure while sap and sv decreased by .%% and . %, respectively (p< . ). however, there were no reliable co chsnges. spoz ~educed by @. % (p< . ) and remained lower than the initial one after the procedure was oyez. when administrating tramsl min. after ste~ting the procedure sap and svr increased by ~ . % and . % respectively. sv and co decreased insignificantly. nine patients in group b saffeting some dlscomfo~t needed additional tm~msl in~ection. in the course of the whole p~oced~e spo, was constant and was highez than that in ~he case of nozphin (p<o. ). conclusion: respiratory suppression by no~phin can limit its use in case of lithotzip@y while the advantages of tremsl a~e: lack of dyspnoe and good contact with the patti-b_ the role of uncommon agents of antinociception, placed epidurally, in the control of pain transmission in the spinal cord is well documented. somatostatin as an inhibitory agent is found in the dorsal horn of the gray matter of spinal cord. the effects of somatostatin is similar to the opiates if injected into the epidural space (ref. i, , , ) . the aim of the present study is to present the clinical effect of above mentioned palliative therapy in the case of cancer and non cancer pain. informed consent had been obtained from every patient before treatment was initiated under the legalisation of the local ethics committee. using the permanent epidural catheter and continuous infusion pump, we administer somatostatin in the dose of up to microgram per hour for one up to three days. the patients paln feeling was evaluated using a vas (visual analogue scale). we found that the opiate resistant pain level decreased by %. the rest pain could be controlled by pereral opiate analgetics or by combination of somatostatin and an opiate plus a local anaesthetic agent epidurally. theoretically, it seems that epidural administration of somatostatin and local anaesthetic agent is useful in the control of acute pancreatic pain and systemic effect of somatostatin is beneficial in the treatment of acute pancreatitis. few studies have been performed in the critically ill (ci) and because of the complex pharmacodynamic and pharmacokinetic changes that occur, it is difficult to predict accurately drug responses and interactions in individual patients. midazolam (m) is a watersoluble benzodiazepine with a rapid onset and short duration of action in normal individuals; however its metabolism is decreased in the ci. critical care physicians every day experience suggest that among the ci there is a different pattern of response to m; here it is hypothized that such a response could be due to different metabolic behaviours of ci. m (i.v.infusion rate - rag/h) and antipyrine ( rag p.o.) were infused to ci with ( patients -group ) and without ( patientsgroup ) endotracheal intubation. blood samples were collected at fixed times during and after m infusion. total urine nitrogen and antipyrine elimination half-life demonstrated different metabolic characteristics in group chypermetabolizer") as compared to group chypometabolizer"). results follow. the results of our study are preliminary and more kinetic data in critically ill patients are needed to statistically confirm our approach of "hypometabolizer" and "hypermetabolizer". objectives: some clinieai and experimental studies suggest that propofol decreases myocardial contractility in coronary artery bypass grafting (cabg) patients. the intrinsic negative inotropic action of the drug may be independent from changes of preload and afterload, whereas the myocardial depression induced by propofol may depend on changes in ca ++ ious availability. aim of this study was to verify the hemodynamic effects of propofoi in a group of cabg patients with uneompromised contractile function and to minimize myocardial depression, during induction of anesthesia, choosing to associate calcium chloride (cac ) in an other group and to define its role in producing this effect. methods: fourty patients, randomly divided in two groups ( pts a and pts b), undergone elective cabg, were enrolled in this study. anesthesia was induced by senior anesthetist in both groups by means of fentanyl mg• kg < in ", pancuronium . mg x kg - and propofol mg • kg - in ". a blind investigator administered via another venous way at same speed ( ") saline in patients of group a and mg x kg - cac in patients of group b. hemodynamic data (heart rate hr, mean arterial pressure map, mean pulmonary artery pressure pap, pulmonary capillary wedge pressure pcwp, central venous pressure cvp, cardiac index ci, stroke volume index svi, systemic and pulmonary vascular resistances indexed svri and pvri) were obtained at baseline (to), ' after anesthesia induction (t ) and " after tracheal intubation (t ). results: hr decreased moderately in both groups (p = ns). map decreased as well, more markeatly in group a at ti and t . this trend was statistical significant (p < . ) in both groups. pap, pcwp and cvp unchanged following induction in any of two groups. ci decreased in group a (p < . ) dramatically dropping at t , while in group b it showed a negligible decrease at t (p = ns) and value similar to baseline at t . svri and pvri did not exhibit statistically significant changes. conclusions: the use of propofol as a starter of anesthesia in cabg patients allows to reduce total dose of fentanyi, dramatically reducing post-operative intubation time. propofol-fentanyl association prevented the hyperdynamic response to stress (i. e. laryngoscopy, intubation) but severely depressed ci and svi. cac simoultaneous administration effectively minimized the negative inotropic effect of propofol. moreover no unwanted side-effects due to cac were observed. diseoordinated labor activity (dla) is one of most serious in obstetric pathology.medication sleep effect to a woman in birth is of limitation of pathologic impulsation from the central nervous system, but it does not influence processes resulting in and supporting dla on the organ level. constant discoordinated uterine contractions during medication sleep (ms) imerease disturbances of uterine blood flow, organ hepoxemia connected with hyperergia of vascular wall and myometrium to catecholamines, that reduces efficiency of anesthesiologic protection. we applied hexoprenalin in complex with ms to primaparas. efficiency control was being accomlished through hysterograms, grade scale of analgetic effect where hemodynamics reaction to pain, significance of emotional reactions and their vegetative manifestations before and during ms were registered, and also through hydrocortisone level in plasma before and during ms. the examined women's average duration of ms was hours more than in control and made hours, though their average labor duration and in control was the same and made hours. % of the examined women experienced independant labor, as for the control group -only %. supplementary methods of anesthesia were required in % in control,that increased medicamentous depression of the fetus, but for the examined group -only in %. the examinees's newborns experienced favourable terminations, in control newborns were in state of light rate asphixia. analgetic effect was complete in control just in i %, and of examinees -in %. on the women's hysterogrnms before ms discoordinated contractions were registered on the background of increased tonus. during ms in control similar uterine contractions were constantly registered, but for the examinees they were not marked at all or had the proper character. the examinees' hydrocortisone level was reduced for % and in control only for %. the study has allowed to make a conclusion that hexoprenalin applications in complex with ms in case of dla make anesthesiologic care safer and more effective, promote simultaneous removal of patholgic processes in the central nervous system and uterus, which lead to dla development. objectives: the aim of report is to present a clinical study results for the evaluation of anesthesia for a patients in unconscious states by eeg examination: methods: the study was conducted on patients after a severe abdominal operations on stomach and intestine and on one patient after traumaticat exarticulation of upper extremity. all patients have different unconscious state levels from somnolence to coma ]. also thay hav~ had respiratory insufficiency and control mandatory ventilation have been used. we were used intrave,~ous injections of morphine hydrochloride from initial dose of mg. than we were increased the dose to mg i.v. by drops with an accompanying eeg monitoring and fourier spectral analysis. initially all patients have had -rhythm with slow and a-activity. an c~-activity index have been lower than %. results: after anesthesia the o-and a-activity have disappeared. the or-activity index have increased to %. also we have noted decreasing of the unconscious state levels to a possibility of a verbal contacts ( - points gcs). conclusion: the quality of anesthesia could be evaluated by eeg monitoring. a regaining consciousness afte~ the injections of high doses of morphine, probably, may be a result of an opiate deficiency (full or partial). anesthesia with the following drugs: clonidine, l-arginine, l-n-arginine-methyl-ester (l-name), and their combinations. tail-flick latency (tfl) was determined at time zero and min after each treatment. clonidine (i- ~g/mouse) prolonged tfl in a dose-dependent manner. at a clonidine concentration of gg/mouse, tfl increased . -fold compared to time zero. l-arginine increased tfl at a high concentration (i gg/mouse). l-name suppressed tfl . -fold compared to time zero at a concentration of gg/mouse. conclusion: we have found that no is involved in clonidine spinal analgesia. studies are currently being undertaken to assess the effect of combination treatment of the above drugs on clonidine supraspinal analgesia. objectives: hemodynamic changes ussualy accompany laryngoscopy and tracheal intubation.the aim of this prospective study vas tu present the effectivness sufentanil in preventing reflex circulatory respone of laryngoscopy and tracheal intubation and provides stable hemodynamio condition for induction of balanced anaesthesia. methods: adult asa i-ii patients sheduled for elective surgery.they were allocated randomly and divided into two groups:fifteen patients received single bolus of placebo prior to laryngoscopy.and tracheal intubation. anaesthesia induction was then performed with thiopental (smg/kg) and atracurium ( , mg/kg), followed by neurolept anaesthesia. mean arterial preassure (map) and heart rate (hr) were measured before, during and min after intubation. althought ecg was recorded at the same time intervals. results: the groups were compared with regard to the changes in arterial blood pressure,heart rate and electrocardiogram. mean arterial preassure and heart rate were incresed significantly during and after laryngoscopy and tracheal intubation in control group but remained unohange the baselin values in the group who received sufentanil. control group ecg suggested more changes than sufentanil group. conclusions: the results indicated that , mg/kg sufentanil for anaesthesia induction reducing the pressor response to laryngoscopy and tracheal intubation. obiective: the aim of this experimental study was to evaluate morphologically the influence of anesthesia in liver as well as in isolated hepatocytes (hc). methods: a total of female swine ( - kg) were used as liver donors and were randomly assigned to one of two groups regarding anesthesia protocol: group a (n= ): induction with intravenous sodium thiopental in a dose of mg/kg, group b (n= ): propophol in a dose of mg/kg for induction'and mg/kg/h for maintainance of general anesthesia. both groups were under the same preanesthetic regimen (diazepam, ketalar and atropin) and received standarised doses of fentanyl and pancuronium during anesthesia. in beth groups total hepatectomy was performed and the liver was perfused with - it of cold ( oc) university of wisconsin solution for a period of hours before hepatocyte isolation. liver tissue samples were fixed in formalin for the morphological study and stained with hematoxylin-eosin and pas. for hc isolation collagenase solution (type v, sigma, c- , . mg/ml) was infused via portal vein and the liver was incubated at oc for rain. cells were filtered and then washed in cold hanks' solution. isolated hc were fixed and prepared for staining or simply cryopreserved (- oc). results: histology was completed in / experiments ( in group a and in group b). mononuclear infiltration (halothane type injury) was found in all specimens ( / ). focal zonal necrosis and acidophilic bodies were found in specimens from group a ( / and / respectively) while portal inflammation with piece meal necrosis was found in one specimen from group b ( / ). smears of hepatocytes -beth formalin fixed and cryopreserved at - oc -were stained with hematoxylin-eosin and showed morphologically intact hepatocytes. conclusion: pre[imineq~' study of our material reveals mote frequent livet injury in the thiopental group, but this finding has yet to be established by increasing the number of observations. objectives: in this paper we present our experience and point out the importance of sedation of those patients who suffered severe head injuries/contusic cerebri with signs of decelebration/and who were put on ventilatory machine to obtain better mechanical ventilation in neurosurgical intensive care unit of emergency center in belgrade. methods: patients were treated from jan. till dec. results: in patients we successed to reduce agitation and decelebration. conclusions: the major demand of sedation in neurosurgical patients are that the patient should be calm, comfortable and painless. references we compared three analogous groups of patients in each, with orthopedic operations on lower extremities. in each group we applied different kind of analgesia: first group rece-ned local anesthetic ( ml . ~ bupivacaine) when analgesia was first demanded; second group received ml fentanyl via peridurai catheter when analgesia was first demanded, and third group received m] fentanyi intravenously on demand for analgesia. we used visual analog scale (vas) for estimation of pain intensity and success of applied therapy. statistical data analysis was performed using student's t-test. tha best vas had group in which local anesthetic was applied periduraly. second was the group with periduraly applied fentanyl, and third was the group with intravenously applied fentanyl the longest duration of the effect of analgesia ~/as in the second group. there were no adverse effects and complications, apart from mild sedation in the third group. for orthopedic operations on lower extremities, application of peridural catheter for anesthesia and successful postoperative analgesia with local anesthetic, or opioid analgesics is acceptable. background and obiective : tympanic temperature measurement (ttm) is a relatively new procedure which provides accurate estimates of core temperature in stable postoperative patients and in patients admitted to the emergency ward. however, experience with this technique in hemodynamically unstable adult icu patients is limited. design : prospective study with patients serving as their own control. se:ttijlg : adult medico-surgical icu in a tertiary care hospital. patients : consecutively enrolled patients with thermodilution catheters in place and without contraindieation for rectal temperature measurement and without hypothermia (core temperature < ~ interventions : tympanic temperature, measured by a commercialized tympanic thermometer (genius a first temp) was compared with pulmonary artery (pat) and rectal temperature (rt). within minutes, core temperature was assessed in each patient by the same trained individual using the three techniques in random order. measurements and main results : mean bias (ix~ and its variability (sdr of method comparison pairs were calculated using the methods comparison analysis as described by bland and alunan (lancet, ; i : - objective: to measure the prevalence of pressure sores on the intensive care unit and the effect of risk calculation on pressure score prevalence and pressure score severity. method:in during a period of months a series of prevalence studies was carried out on the sicu to investigate how many patient days with pressure sores were taken care for by the icu nursing staff, what kind of preventive interventions were done and what the patient risk was on developing a pressure score. results: on average there was a prevalence of pressure sores on the buttocks of . % on the short stay unit and . % on the long stay unit; preventive interventions increased when the pressure score was visible for the nurse and the majority of patients had a high risk or extra high risk for developing pressure sores according the pressure score risk calculator. as a result of these findings the nursing management decided in that nurses had to complete daily on every patient the pressure score risk assessment in order to be able to take adequate preventive interventions. when the results of the two studies were compared, the most important results were that: ) there is no indication of a reduction in patient days with pressure sores (short stay unit: %, long stay unit: %); ) there is a reduction in severity of pressure sores (grade iv decreased from . % to . %) because adequate preventive measurements are initiated by icu nurses in an earlier stage. possible explanations for the increase of patient days with pressure sores on the long stay unit are that the average pressure score risk score was increased from . to . and the mean frequency of nursing patients on alternate sides decreased from . to . times each day. conclusion: daily assessment of the individual patient risk on developing pressure sores does not decrease development but reduces the severity of the developed pressure sores. method: the conventional woundcare method of patients with an open abdomen is to change frequently the saline soaked ribbon gauze pads ( - times each day). this method is labour intensive for the itu nursing staff and rather uncomfortable for the patient. problems that often occur are: insufficient hygiene, frequent nursing interventions, a progressive risk for deterioration of the skin and underlying tissues, difficult to measure abdominal output and in case of bowel fistulas enteral feeding is hardly possible. in using the new method, stomahesive is applied on the skin surrounding the wound. a large size of surgical film dressing, opsite | is applied over the abdomen. two or more foley ~ catheters ch are inserted through an opening in the surgical filmdressing. the application of several lateral openings in the catheters is advised. the drains are held firmly in place between two layers of sterile opsite | "flexigrid ~'' x with the so called bookend method and are connected to a low vacuum suction system ( - kph) results: we studied the frequency of dressings changes on patients in the itu. in total they had days with an open abdomen. during this period there were dressing changes. this means one dressing change every days. further advantages of the new method are; more hygiene in patient care, no maceration and irritation of the skin, nursing on alternate sides is possible, output can be measured, in case of bowl fistula, enteral feeding is possible and an abdominal lavage is possible on the sicu by opening the opsite | conclusion: this new method of woundcare management is more patient friendly, prevents several nursing complications and decreases the work load for the nursing staff. objective: to investigate the interaction between the ventilator and the closed suction system related to possible induced negative pressure by this sytem. method: we studied in a testlung model what the effect was of the different ventilators (evita: dr~iger; servo c: siemens), ventilation modes ppv, simv) and ventilator settings (tv, trigger level, frequency, peep level) on the induced negative pressure by the closed suction system during suctioning. results: when using the evita the magnitude of the negative pressure increased when the ventilation frequency and tv decreased.. the largest negative pressure (- cm h ) was produced with a tv of ml and a frequency of /min in the ippv mode with trigger level on - cm h and a peep level of + cm h . the servo c showed a complete different pattern. the largest negative pressures were measured when no trigger level was set ( cm h ), the induced negative pressure was not depended on the tv or ventilation frequency but more depending on the ventilator mode. the simv mode produced the smallest negative pressures ( - cm h ) and the ippv mode the largest ( - cm h ). conclusion: the effectiveness of the closed suction system is very much depending on the kind of ventilator, ventilator mode and ventilator setting that is used. if the interaction with the used ventilator is not known by the icu nurse this piece of equipment can cause damage to the patient by inducing large negative pressure in the comprimised lung and there fore creating the possibility of alveolar collaps and atelectasis or oedema. introduction : ethical problems are daily and disturbing preoccupations for the icu staff. objectives : improving ethical management in icu by creation of an intelprofessional group of ethical reflexion ( iger ). methods : existing was evaluated by a preliminary formulated series of questions sended to the whole staff (q , n = , items) after two training sessions (laws, deontology, professional values, culture, norms of quality) followed by persons ( %) and directed by an external chairman, satisfaction and needs of the staff were evaluated by a second series of questions (q , n = , items). at the issue, iger was created. results : q : responders ( %). law's misinformation : to %, disagreement for limitation of intensive cares : %, hope to improve collective decisions and creation of iger : % q : responders ( %) : satisfied by the training sessions : %, non satisfied : %, want to continue the project : %, refuse : %. iger was constitute by physicians, nurses, secretary, dietetic (n = ). the first working theme was {< therapeutic's withholding and withdrawing decisions in icu ~>. four subgroups of iger's members (having access to an ethical library) worked independautly and submitted their reflexions in a tdmestrial plenary session of iger in the presence of an external chairman, allowing a synthesis. at the issue a report was writted to be used as a reference for bedside and individual decisions. conclusions : constitution of iger seems to improve ethical management in icu. the first result of iger is that it is now possible to began collectively a reflexion concerning therapeutic's withholding and withdrawing in icu. the work is going on and further subjects will be studied. objectives: ) to compare the value of heat-moisture exchangers with bacterial filters (hmef) and without bacterial filters (hme) in the prevention of colonization of ventilator tubing and ventilator-associated respiratory infections. ) to asses the temperature and relative humidity of inspired all using both types of heat-moisture exchangers. methods: mechanically ventilated patients were randomized, to either hmef or hme. endotraeheal aspirates, pharyngeal swabs and samples from tubing were collected for bacterial cultures on the st, nd day mechanically ventilation and weekly thereafter. temperature and relative humidity were measured in patients ( hmef and hme) h and h after placing the hme or the hmef. results: both groups were comparable as regards age, mechanical ventilation period, severity score (saps ii), leukocyte count, and number of patients with prior antibiotic treatment. from the hmef group, ( %) ventilator tubing yielded microorganisms in, at least, one sample as compared to ( %) of the hme group; p=ns. the incidence of respiratory infection was similar in both groups ( % vs %, p:ns, for hmef and hme respectively). among the bacterial species isolated from ventilator tubing in the hmef group, ( %) were not isolated from pharyngeal swabs. a similar ratio was shown in the hme group ( / , %). both heat-moisture exchangers were efficacious in keeping a good relative humidity of inspired air ( % • vs % • .%; p=ns, for hmef and hme respectively). relative humidity was significantly higher after h of mechanical ventilation in the hme group as compared to hme group ( . % • vs . % • %; p= . ). conclusions: both types of heat-moisture exchangers have the same effect on the prevention of colonization of ventilator tubing. similar relative humidities are achieved when using either type of heat-moisture exchanger. results: tumor and nontumer enhrgements of the thyroidea were present in ~ of the operated, surgicel adrenal disease in io!, hyperplssle or persthyroid gland tumor in ~ end endocrine pancreatic tumors in %. in the intensive oere unit, these patients wore screened by noninwsive monitoring in ~ of cases: and invasive monitoring was applied in % of ceses.the basic noninvesive methods included: electrocardiogram with standard end precerdial leeds, percutaneous eutomotlc measurement of systolic, diastolic and mean arterial pressure, measurement of hourly diuresis and body temperature, frequency, hearing capacity and rhythm of one s own breathbng bs well as pulse oxymetry. a special plece in monitoring and control of vital parameters in postoperative period belonged to the nurse, thoroughly trained for enelysis end interpretation of the observed parameters which would be discussed in the paper. it has been believed that the leader sits at the pinnacle of power. over the years, this has proven to produce frustruation and anguish instead of the expected results. leaders have not been able to produce the changes they know are essential to their organization's survival with this command-and-control paradigm. through literature reviews and evaluating leadership styles, one can clearly see the most effective form is that of empowering people to a new level of performance -not ordering it. changing the leadership paradigm to a manner/style that has been shown to be effective and one of people empowerment shifts the focus to personal responsibility for performance. removing obstae}es~ stimulating self-directed actions, and determining focus and direction are just a few elements used to create the successful environment of empowerment. with increasing pressure in the health care arena, it becomes critical that a leader's job is to get the people to be responsible for their own performance. developing ownership, creating an environment where people want to be responsible, being a mentor or coach, and learning faster while encouraging others to do so demonstrates the commitment to effective leadership. this presentation will illustrate the critical components that are achieved when every person in the institution is empowered to perform at a level that is directed toward positive, effective results. herrera m. (md) . icu. hospital regional. malaga. spain. the systems of veno-vanous continuous haemofiltration (wchf) have a high cost and a limited life span. in an attempt of lengthening their mean life it has been proposed to accomplish programmed washes of the ~-stems. this practice supposes an increase in nursing workload. in order to evaluate the real efficiency of this practice we have accomplished this study. material: prospective randomized study of all the filters of vvchf used during the last year in our icu. we have determined two groups of filters, in the first (group a) we accomplished washed in a programmed way, and in the other (group b) only when the alarms of the system suggested a clotting of the filter. for the statistical analysis we used the kaplan-meier test for survival analysis. results: we have studied a total of patient submitted to wchf during the last year. we used a total of filters with this results. objectives. sounding out the nurses about the need to inform patients" relatives and the rigth kind of such information, like a preliminary approach to an information cuality assessment, methods: we inquired all the nurses of the intensive care unit of an regional hospital by an semiestructurated questionary which included personal data: age, sex, contractual relation, professional experience.., and opinion data: do you think to inform relatives is a nurse task?. which of the next informafions do you think is more important?, please, write others topics about information you think are relevant. we process the data on epi-info estatistical program and use x test to compare the results. results" from nurses of staff refused to flu the quetionary, and were not available. of the remaining, %were v~men and % men. the mean age were . % had an svable contract and ( eventual, the mean professional experience were of years and % worked in the unit since more than years. the % answered that offer information to relatives is part of the nurse activities. we did not find differences with nurses who answered negatively comparing by sex, age, contractual relation or proffesional experience. the three information topics found out like more important were: ) to inform about patient mood. ) to inform about happenings from the last visit. ) to inform about dressing instrument required by the patient, nurses who answered negatively think that to inform is a doctors task or that nurses are not competent. conclusion~ intensive care unit teams (nurses, doctors and auxiliar personnel) should get accord on who and how to inform relatives, we consider the nurses' role on information as unquestionable. objective: investigate the respiratory and cardiovascular response after discontinuing oxygen therapy durir~ intr~/]o~pital transport. desiqn: fifty-one patients ( male and female, aged + , and , , years respectively, ~+sym) being on therapy were studied prospectively in two consecutive intrahospital transports. oxygen therapy was continued in the first transport while the second one was performed as usually, i,e, without . during transport each patient was monitored by pulse oxymeter and holter whereas arterlal blood gases were tested just before a~xl aft~-trar~portation. results: compared to daseline, pa and sa were signif~canthy decreased in the case of oxygen discontinuation (p< , i). paco was significantly inur~ds~i only in the subgroup of patients with obstructive lun[ disease (p< , ) . heart rate increased in all phases of the transport when administratlon was discontinued. blood pressure remained stable in either case. the percentage of supraventricu!ar extrasysto!es, ectopic v~r[hicui~r contractions and st-s ~ment depression was progressively increasing and became very high at the end of transport in the case of therapy discontinuation. other arrhythmias did not change significantly. conclusion: discontinuation of oxygen therapy during intrahospital transport causes severe drop of pao and sa , increases the heart rate and contributes to the appearance of arrhythmias which were not present before. methods:for evaluation of the functional state of brain the complex of methods was used,whieh included electro encephalngraphy ( brain mapping ), rheoencephalography, tetrapolar transtorax rheography. for the estimation of humoral status the level of histamine and serotonine, products of free-radical oxidation,enzimatic markers of ishemic damage of brain and of endogenous intoxication was investigated. results: patients with encephalopathies after resuscitation were observed.asystolia was as a result of:shock, trauma, asphyxia,poisonings,appiication of drugs, eclamp sia,injury of the heart,diseases of fhe cardiac vessels. all patients with postasystolic syndrome entranced in comafose condition.in the group (reconvalescents) the depth of coma by glasgo~ pittsburg"s scale was , +- , . the duration of coma was from rain. to hour,average , +- ,sh.ln the group (the deads) the depth of come was , +- , .the artificial lung ventilation was used in all patients:in the group , +- , days,in the ~ , +- , days.apallish syndrome developed in cases,in patients diagnozed <<brain death~. the th degree encephalopathy (coma) was found to be associated with disorganized eeg-pattern with predomi nant alpha-( group) and slow ( group) activity. the relative power of delta-and theta-ranges was about - per cent.the patients with apallich syndrome demonstrated greatly elevated theta-range power, that of beta -range was essentially decreased. the degree of disturbances of circulation in the both groups was different.cardiac index (ci) and stroke index (si) in the group decreased on , % and , z, in the -on , % and (; , %.general peripheral resistance (gpr) increased in the group on , %,in the -on (; , %.in the group brain blood flow was increased, in the -decreased on , n.in the group there was the normotonic type of reg-curve,in the -atonic or hypotonic type (without reaction on pharmacologic influ ence).disturbances of permeability of cellular membranes (enhanced free-radical oxidation with an increase in di enic conjugates on and n) and vascular ones (an increase of serotonin concentration on and %, hi stamine content on and %) resulted in hyperfermentia (an increase of concentration of creaune phosphoki nase in the group on %,in the - %.the level of middle molecules (mm) increased in the group on , %, in the -on , %,of polyamines (p) (spermidin,spermin,putrescin).coefficient of correlation between mm and p was , . immediate correction of neurocyte metabolism is impossible due to marked brain oedemaswelling,severe dis ordes of cerebral circulation, disturbances of membrane permeability.thus,the following treatment algorythm might be advisable: . protective inhibition of brain and reduction of its energy requirements. . recovery of cell and vascular membrane fuoctions. .recovery of blood circulatiom .oxygenation of nervous tissue and drainage of brain disintegration products.in patientshbo carried out. .active methods of detoxication (homo-and enterosorption). .correction of cerebral metabolism. . dehydrative therapy must be very cautious. conclusion: the activation of energetic metabolism in neurocytes must be carred out only under neurophysiolngical control and after definite preparation. ( ). the clinical estimation of acute cerebral failure carried out by olasgo-pittsburg"s classification of coma. we studied such groups of patients: poisoning co ( ), asystolia ( ), eclampsia ( ), acute renal failure ( ), control group ( ). methods: electroeneephalngraphy (brain mapping) was fulfilled by means of encephalograph <,medicor ~ in monopolar channels. the estimation of eeg patterns by zhirmunskaya method ( ) was carried out. there were analyzed and changes of eegb by results of rapid transformation furie after rhythmical photostimulation(phts) , , , hz. we studied also the figures of absolute and relative power in such diapason : delta ( - hz), theta ( - hz), alpha ( - hz), betal( - hz), beta ( hz and more). results: all eeo changes were divided into following types: -organized ( , groups); iii -asynehronic ( group); iv -disorganized with prevalence of alpha-waves ( , , groups); v -disorganized with prevalence of delta-and theta activity ( , , ; , groups) akkording to our model of hormonal-metabolic disbalance in pregnancy , one of the main reason of destosis is hypoergos , reesults in endotoxemia and neuro-endokrine disregulation. so, stady of central nervous system function give us the information about adaptation processes. the aim of our work is to study the degree of neurologikal deficit in destosis when olifen and lipin were used. there were studied pregnants with different severe forms of gestosis. the degree of neurologikal deficit was valued by datas of neurologikal status . eeg with ,~brain mappinng~, , electrikal resistance of the skin. the komplex inteensive therapy with applikation of olifen and lipin allowed to improve the patient,s condition , decrease the degree of neurolodikal deficit and mortality . kostenko v.phd,kabanko t.,phd,galalu s.md,beliavtseva n. ,shramenko k. phd intensive care department,donetsk medical university, donetsk, ukraine plasmapheresis (pph),as other extracorporal methods of detoxicatin,has a great importance in contemporary medicine. the role of pph is special,because of its simplicity, effectiveness, atraumatic.we incalcated pph in obstetrical clinic. there are rough changes in agregate condition of blood in more of pregnants.these changes lead to disturbances of central,organ and peripheral hemodynamic.the therapeutic effect of pph is due to influence on agregate condition of blood. we considered that application of pph is very effective in pregnants with:bronchial asthma, severe forms of diabet, psorias, gestosis, allergic diseases. we used the membrane pph in pregnants: apparatus-,,hemos-pf>,, plasmofllter pmf- ,with effective area- cm,the volume of extracorporal contour- ml.such pph has no the ~ agressive effect,,, as in cases of application another extracorporal methods. this method was incalcated in our practice recently, so results will be reported in further publications. ( ). post-operative cerebral neoplasm ( ), post-operative subdural hematoma ( ). icp was monitored via a catheter inserted in the lateral ventricle and values were continuously digitally recorded by means of a bedside computer data acquisition system (maclab). the fiberoptic tracheobroucosenpe, which guided the procedure, was passed between the nasotracheal tube and the trachea in order to avoid hypoventilalion. the patients had stable baseline hemodynaimcs. propofol infusion and fentanyl boli were administered to mantain stable mean arterial pressure values. peak (mean(sd)) icp duping the minutes pre-ciaglia procedure (baseline values) were compared with values during ciaglia procedure, and the minutes p st-ciaglia procedure. data were compared with repeated measures anova. results: ciaglia procedure duration was (mean(sd)) ( ) objectives: transient global amnesia (tga) is a syndrome caracterized by impairment of short-term memory, inability to form new memories, retrograde amnesia and repetitive queries, without other neurological signs and symptoms. the pathophysiology of tga is unknown; thromboembolic, epileptic, migrainous and metabolic mechanisms have been suggested. to address some of these issues, we undertook a study of cases of tga in whom we examined clinical, laboratory data, electroencephalogram, ct of the head, ultrasonography ecodoppler. methods: patients were included in this study: men and women. the mean age was years. all cases underwent a standard clinical examination, electrocardiogram, routinary humoral tests and x-ray, electroencephalogram (eeg), ct scan of the head, ultrasonography ecodoppler. results': the mean duration of amnesia was h. m. +/- h. m. hypertension was found in patients ( %), ischemic heart disease in patients ( %), hypercholesterolemia in patients ( %), hypertrigliceridemia in patients ( %), smoking in patients ( %), atrial fibrillation in patient ( %), history of epilepsy in patient ( %), migraine history was not recorded. ct scans of the head showed multiple small deep infarcts in patients ( %), a single hypodense lesion in patients ( %). in patients electroencephalogram was normal ( %), in patients there were widespread nonspecific electrical changes ( %), in patients there were focal nonspecific eeg abnormalities ( %). conclusion: in our study tga was more common in women ( %). we showed a prevalence of hypertension, hypercholesterolemia and cerebral infarcts compared to normal controls. we have demonstrated a higher incidence of nonspecific electrical changes in tga of lower length, while ischemic lesions in ct of the head were more frequent in tga of greater length. these data seem to be in agreement with the hypothesis that tga is a heterogeneous clinical syndrome, consisting of pure, epileptic, and ischemic types. however we did not find any correlation useful in discriminating pure from associated tga forms. from our study it is tempting to speculate that pure tga is a rare event, underlying still unknown mechanisms wich differ from ischemic, epileptic, migraineous causes. objectives: aneurysmal subarachnoid haemorrhage (sah) is special condition increasing intracranial pressure (icp) in various ways. at the other hand cerebral vasospasm and related delayed ischaemic deficit (did) could answer for the poor outcome. triple h therapy seems today a basic option to prevent did, but it may increase the icp worsening the altered intracranial pressure condition and thereby the cerebral perfusion pressure (cpp). is there any way to individualise the triple h therapy when it is necessary? methods: between sept. march thirty-seven patients with intracranial aneurysms were operated on within hours following sah. five patients were in hunt-hess iv at admission. all patients received triple h therapy in a preventive fashion following surgery and were monitored by daily transcranial doppler ultrasonography (tcd). icp and cpp was measured in twenty-four cases. twenty-two of them received lumbar liquor drainage (lld) and nineteen were administered induced hypertension. the other group was treated by basic triple h therapy. results: in group with monitored icp the outcome was twenty-one excellent, one poor, two died (one of them died from extracranial decease). in the other group four had excellent, six moderate, two poor outcome, and one died. conclusion: according to our recent observation the patients can be divided into two groups of therapy. in group i, the patients with elevated tcd values and either low or high icp reacted to lld. we are concerned that haemodilution and slight hypervolaemia should dominate in the triple h therapy. in group ii patients having high icp with tcd and/or symptomatic vasospasm should be managed by the induced hypertensionhypervolaemia dominated therapy focusing on cpp (icp) and focal neurological signs. air emboli were detected in lo% (n= ) of natients undergoing coronary srtery bypass craftin~ (cabg). central nervous system ~ysfunction occured in ~$ of the nstients with air embnli and in none of those ~ithhout air embo!i. hvtothermia is the classic form of oro-tect~on used dur~nc ~"~" " ~ ~ ca~.,~modu] :r, on~_,_. bj/oass. the surf~eon sho,;,ed thorough!~: evecnnte air from the heart, but the onesthesio!o[[ist can signifieamt!y influence the outcome by emt!oyin ~ methods to detect and treat air emboli. the changes in head rate are primarily due to alterations of autonomic tone. the heart rate variability (hrv), that express the degree of heart rate fluctuation around the mean heart rate, reflects somehow the condition of central nervous system. hrv may be measured by a number of techniques. short-term time-domain variables of hrv are reflect generally the vegal activity. in this study the changes in hrv variables of patients with brain damage, and in addition the changes in hrv measurements in comparison with the clinical evolution were evaluated. eight patient with brain damage and six normal individuals as control group were studied. a elecrocardiographer with availability of computation the sequence of beat-to-beat intervals for one minute was used. the following variables of hrv were measured: ) standard deviation (sd) of beat to beat r-r interval differences that reflects the respiratory control, )the maximum/minimum (max/rain) interval that reflect variability related to baroreflex and thermoregulation and ) the coel~cient of variation (cv), the results are shown in the in the patients with brain death and in vegetate state there were virtually no hrv. increased hrv pattern was found with clinical improvement, the changes of hrv precede of the changes of gcs, we conclude that time-domain hrv could reflects the degree of brain damage, it is good prognostic index of the brain damage and may change earlier than the gcs. objectives: cerebral co vasoreactivity is an important determinant of cerebral blood flow (cbf) and has been shown to be of prognostic value in head trauma (acta anaesthesiol. scand. ; : - ) . we wondered whether co vasoreactivity could be selectively altered in one hemisphere in comatose patients. methods: patients ( m/ f, age - yrs, glasgow - ) in coma due an acute brain lesion (trauma, hemorrhage, or infection) were studied. cbf was measured bilaterally using jugular thermodilution at paco , , , and mmhg by increasing pico with mechanical ventilation kept constant. normal co vasoreactivity was defined as an increase in cbf of at least i ml/min. g per mmhg paco . results: patients had normal co vasoreactivity bilaterally, patients had altered co vasoreactivity at both sides, and patients had a normal response at one side (left or right) with an altered response on the other side (dght or left). for the patients left cbf was in mean ! ml/min. g lower than right cbf (figure methods: following institutional approval piglets (body weight :tl . ) were anaesthetized by % fluothane. a catheter was placed in the right femoral artery for blood pressure monitoring and a fiberoptic catheter (oxymetncs- abbott) was advanced via the right internal jugular vein to the jugular bulb for sjo determinations. another catheter with a balloon on the tip was advanced in the right atrium via the right femoral vein. a mean arterial pressure (bp) at mmhg was achieved by appropriate balloon inflation for rain and two groups were cleated: i) the hypoxemic group by respirator disconnection (*) and it) the hyperoxemic group by fio =l on respirator (o). samples were obtained at time ( ), ' min at hypoperfusion ( ) arid at reperfijsion at ' ( ), ' ( ) and ' ( ). pao , pjo and oxidative brain stress evaluation was performed from jugular bulb blood. the latter included: i) no synthase (nos) and xanthine oxidase (xo) activities by a method based on the oxidation of scopoletin detected fluorometrically, it) no levels estimated as onoo-by luminol enhanced chemiluminescence in the presence of ~tm hydrogen peroxide (h ). resul'~s: the mean pao was mmt-ig for group i and methods: we retrospectively reviewed all upper gi-endoscopies, performed in the period january -july in patients ( men and women) admitted at the icu's of our hospital. results: it concerned surgical, medical, eardiological and neurological patients with a mean age of . yrs (range: - ). in %, the endoscopy was performed at the icu and in % at the endoscopy department. in % of the cases, the endoscopy was primarily diagnostic, of which % was performed for localization of upper gi blood loss. in % the endoscopy was primarily thempentic, of which % was performed for placement of a duodenal feeding canula. location of the upper gi bleeding was: variees ( %), duodenal ulcer ( %), oesophagitis ( %), gastric ulcer ( %), others ( %) and none ( %). as coincidental findings were noted: cesophagitis ( %), gastritis ( %), gastric deer ( %), duodenal ulcer ( %), duodenitis ( %), oesophageal ulcer ( %) and others ( %). conclusions: there were marked differences in indications and findings of endoscopy at the different icu's. these differences reflect an admission bias and differences in populations and treatment preferences. compared with cardiological and neurological icu's, substantially more endoscopies were performed at surgical and medical icu's. in a considerable number of cases, no source of upper gi blood loss could be found endoscopicaiiy. when upper gi blood loss was the icu admission diagnosis, the main cause was needing varices, which could be controlled endoscopically in the vast majority of cases. when upper gi blood loss was ndt the icu admission diagnosis, peigie ulcer and oesophagifis were the main causes of bleeding. because of the considerable number of coincidental almom~adities found at endoscopy, there is still room for debate whether antacid medication and/or motility stimulating agents should be given prophylactically at icu's. many studies have shown that blood lactate levels in survivors and nonsmvivors of traumatic and septic shock are significantly different. the degree of multiple organ failure is related to the duration of lactic acidosis ( ). the aim of this study was to evaluate blood lactate level as a prognostic marker of high risk postoperative patients who may benefit from invasive hemodynamic monitoring and aggressive fluids administration and early inotropic support based on oxygen transport parameters. methods: patients undergoing elective long term vascular and abdominal surgery (asa i-bi) were studied. blood lactate levels were measured after icu admission. in the case of blood lactate level above mmoltl, measurement was repeated every hours for hours or until normaiisation (blood lactate level less than mmol/ ). type of surgery, length of surgery, amount of fluids delivered intraoperatively and postoperatively, hemoglobin levels, hemodynamic variables, diuresis, postoperative complications, length of icu stay and clinical outcome were recorded. because no attempts were made to randomisr therapy or change our standard therapy protocol institutional approval was not required. rebuts: the frequency of postoperative complications was , % and mortafity was , % in a group of patients with blood lactate level less than , mmol/l (n = ). frequency of complications ( , %) was significantly increased in a group of patients with blood lactate levels , - mmol/l (n = ), mortality was , %. mortality ( %) and frequency of complications ( %) were significantly increased in a group of patients with blood lactate levels above mmol/l (n = ). conclusion: blood lactate levels can serve as early marker of high risk postoperalivr patients and may predict increased risk of postoperative complications mad ~e death. objective.~: investigated practicability and clinical value of the routine measurement of hepatic venous oxygen saturation (shvo ) after major liver surgery, as shvo is considered an indirect parameter for splanchthc and hepatic blood flow. methods: consecutive patients were included in this study after liver resections for primary or secondary liver tumors. patients suffered from liver cirrhosis (childs a). immediately after post-operative admission on the icu a pa-catheter ,was inserted under fluoroscopy via the right jugular internal vein into the hepatic vein contralateral to the resection area. hepatic venous and arterial blood samples were drawn every two hours. shvo was correlated to the clinical course, macro hemedynamics, abgs aug other established lab parameters. results: in out of attempts the catheter could be placed correctly. in four cases after right hemihepatectomy the left hepatic vein could not be intubated due to a dorso-lateral tilting of the left liver. this is also reflected in a significantly longer time of fluoroscopy for catheterization of the left hepatic vein ( . _+ % rain vs. . + . rain; p < . ). the procedure requires a total of between and minutes. relevant clinical complications were not observed except for short term supraventricular arrhythmias during passage of the catheter through the right atrium. hemodynamics and pulmonary function could be considered normal in all individuals at time of measurement. shvo showed a span from . % to . % with a mean of . % -+ . %. the following statistically significant findings could be obtained: (a) patients with liver cirrhosis showed a significantly lower shvq than patients without ( . % • . % vs. . % • . %; p < . ). (b) a negative correlation between shvo immediately after operation and the duration of intraoperative hepatic vascular occlusion could be observed (r = - . ; p < . ). this correlation could also be seen for the first post-operative hours (r = - . ; p < . ). (c) a negative correlation between shvo and the difference between arterial and hepatic venous lactate levels was found (r = - . ; p < . ). conclusions: the routine measurement of shvo appears to be a promising extension of post-operative monitoring after major liver surgery. it is a safe method easily feasible on any major surgical icu though relatively time consuming. a further validation of this method is necessary in larger studies. therapeutic recommendations on the basis of shvo findings cannot be given yet. methods: in cases after major liver resection, in which abnormally low readings of shvo suggested an impaired hepatic blood flow, pgi was applied at a dose rate of ng/kg/min. as shvo can be considered an indirect parameter for hepatic blood flow, the effect of pgi infusion on shvo was measured. moreover, the changes of macro hemodynamics and pulmonary function were monitored. results: before the application of pgi z mean shvo for all patients .was . % ( - - - ). in three cases without major structural alteration of the remaining liver tissue the continuous intravenous administration of pgi lead to a sustained increase of shvo z to an average of . % ( . - , ). the postoperative course in these three cases was uneventful. in two cases with compensated liver cirrhosis after hepatitis c no change in shvoz under pgi infusion could be observed. both patients died and days respectively after operation in protracted liver failure. side effects of pgi included a slight decrease of systemic and pulmonary vascular resistances. consequently map decreased by up to % as did intrapuimonary right-left shunt increase. in none of the observed patients did these side effects posed a limitation of continuous application of pgi z. conclusions: in patients without structural alteration of the liver the systemic application of prostacyclin at a dose rate of ng/kg/min could significantly increase an abnormally low hepatic venous oxygen saturation after major liver resections, tn two cases of severe liver cirrhosis a similar increase could not be observed. after first clinical investigations and with the results of recent studies in animal further controlled clinical studies of prostacyclin in the postoperative management after liver surgery appear justified. any delay in gastric emptying can promote micro-aspiration and give rise to ventilator associated nosoarnnial pneumonia. h -receptor antagonists have been suspected of promoting pneumonia by changing the gastric ph. in a few tri',ds on humans ranitidine was noted to delay gastric emptying. the aim of this prospective, randomised, blinded study was to evaluate in a ventilated icu population if there was a difference between cimetidine (c) and ranitidine (r) on the gastric filling index (gfi conclusion: in this population there was no difference in gfi between c and r; however the age and creatinine were significantly different and could have favoured the c group. also the very long t/ could have hidden smaller differences between c and r as has been described in volunteers. between april , and april , , patients with severe acute pancreatitis were admitted to participating hospitals. patients were entered into the study if severe acute pancreatitis was indicated, on admission, by multiple laboratory criteria (imrie score >_ ) and/or computed tomography criteria (balthazar grade d or e). patients were randomly assigned to receive standard treatment (control group) or standard treatment plus selective decontamination (norfloxacin, colistin, amphotericin; selective decontamination group). all patients received furl supportive treatment, and surveillance cultures were taken in both groups. results: fifty patients were assigned to the selective decontamination group and were assigned to the control group. there were deaths in the control group ( %), compared with deaths ( %) in the selective decontamination group. (adjusted for imrie score and balthazar grade: p = . ). this difference was mainly caused by a reduction of late mortality (> weeks) due to significant reduction of gram-negative panreatic infection (p = . ). the average number of laparotomies per patient was reduced in patients treated with selective decontamination (p < . ). failure of selective decontamination to prevent secondary gram-negative pancreatic infection with subsequent death was seen in only three patients ( %) and transient gramnegative pancreatic infection was seen in one ( %). in both groups of patients, all gram-negative aerobic pancreatic infection was preceded by colonization of the digestive tract by the same bacteria. reduction of gram-negative colonization of the digestive tract, preventing subsequent pancreatic infection by means of selective decontamination, significantly reduces morbidity and mortality in patients with severe acute necrotizing pancreatitis. ieco by sodium hypochlorite (nacio) infusion is considered to be a model of microsomal oxidation in liver on cytochrome p- . active c provides oxidation of toxic metabolic products in the blood and exfused during plasmapheresis plasma, and also hydrophobic to hydrofilic transformation of substanses. sterile nacio in necessery concentrations was obtained by electrolysis of saline ( , - , % naci solution) in electrochemical set e~io- (russin,moscow). methods: . the nacio in concentration ragfl ( - ml/ h ) was administred into central veins in patients with extensive peritonitis and endotoxicosis - /t. erytrocytes resistance to nacio, circulating blood volume glycemia and hemostasis were initially estimated. . after plasmapheresis exfused toxic plasma was mixed with nacio conccantration of i mg/t in : ratio in sterile "hemacons".the effectiveness of plasma detoxication and possibility of its reinfusion were evaluated by determination of albumin effective concentration (eca g/l), the concanlration of medium molecular oligopeptides (mm , ) and other biochemical tests (bilimbin, creatinine, carbomide and so on). results: . the intravenous administration of nac excels detoxicative effect of hemosortion by - % provides effictive presentation of protein components and blood cells and improves the transport function of albumin by %. . the return of exfused plasma after its purification ieco was - %. only the remaning - % of deficient plasma were compensated by fresh cryoplasma and albumin solutions. ischemic hepatitis (ih) is a severe complication in critically ill patients. acute circulatory failure of multiple etiology can lead to splachnic hypoperfusion and cause acute and reversible anoxic damage. over a period of mos pts, m and f, mean age + . yrs developed liver disease compatible with ih. eight pts had a documented hypotensive episode (six pts with septic shock and two hypovolemic shock), while cardiogenic pulmonary edema in the absence of hypotension was responsible for ih in the remaining four pts. all the pts had a rapid striking elevation of ast, &lt and ldh with equally rapid resolution of these parameters to near normal wimin days (mean . ). the mean peak level of ast, alt and ldh was iu/l (range to ), iu/l (range to ) and iu/l (range to ) respectively. serum total bilirubin levels rose transiently with a moan t:eak level of . mg/dl (range . to . ), while altered coagulation paran-,ete's (pt> . times normal) was observed in four pts and clinically significant coagulopathy with fibrin degradation products occurred in one pt ( . %). renal impairment (cr> . mg/dl) was manifest in all pts; six pts developed non-oliguric renal failure ( %) while two pts required hemodialysis. ten lots required vasoconstrictor inotropes [dobutamine (range - pg/kg/min) and dopamine (range - pg/kg/min), while replacement of circulatory blood volume was performed in two pts with hypovolemic shock. eight lots expired ( . %), but none died as a direct result of hepatic damage. the mortality rate was higher among pts with concurrent renal failure ( %). it is concluded that: ) ih is not uncommon complication in the icu with the prognosis depending on the underlying disease. ) clinically significant coagulopathy is uncommon complication of ih. ) titration of inotropes is required to obtain optimal cardiac output support and subsequently liver blood flow. it is difficult to ascertain the perfusion of free flaps such as jejunal loops after surgery. objectives: to assess ischaemia as evidenced by intramural ph of jejunal free flaps used for reconstructive surgery following total pharyngolaryngectomy. methods: the sigmoid ph tonometer ( tonometrics inc.,usa ) was used to monitor intramural ph of the jejunal free microvascular flaps ( phig ) in patients who underwent total pharyngolaryngectomy. a standard general anaesthetic was given and all patients were admitted to the icu for controlled ventilation and monitoring. all had similar postoperative care. phig was measured pre, post-revascularization of the flap and on icu admission, , and hours postrevascularization. objectives: to classificate the wide spectrum of itc of anp into distinct pathophysiological patterns according to presentation and course. patients (pts) and methods: pts, ~( , %), ( , %) were admitted in the icu because of anp and acute respiratory failure(arf), ilean age: , • years. hean stay in icu: , • days. pts were operated, of them twice. hean value of ranson's scale: , • ( - ). we analyzed hemodynamic measurements,arterial blood gases(abg), x-ray findings(xrf), ct-scans and operative records. results: patterns of pleuropulmonary complications were identified: a)early hypoxia without xrf - pts. b)early ards with typical xrf - pts( died), c)early arf with xrf(atelectasis,infiltrates)- pts( died). d)late ards with typical xrf- pts( died), e)pleural effusions in various combinations with the above patterns - pts. overall mortality rate: / = , %. conclusions: l)frequent x-rays and abg are important for the classification of itc of anp. )even though patterns of classification in anp are not clearly distinguishable,they facilitate an anticipatory management. )deterioration of abg and xrf indicates that preventive measures for arf must be intensified and agressive surgical therapy is required. )delay of surgical therapy is related to worse prognosis(p<o, ) and prolonged hospitalisation time(p<o,ol). in the contrary, the early timing of the operation before infection and extrapancreatic necrosis is essential for a better prognosis (p<o, ). objectives: the development of cholestasis during intensive care treatment is allied with an inferior prognosis. this study investigates the sensivity, specification and also the positive and negative forecast of patients survival -exemplary for bilirubine. methods: during a period of months all surgical patients on icu were registrated prospectively (n = ). for documentation of disease development a standard foldcrform based on a computer-data-system was used. the results of this kind of documentation showed aapprax. , m!ll. of single patient informatioas. results: of patients didn't suffer from liver disease or have any operation on liver or bile tract. of them have had a normal scale of bilimbine in the postoperative period, a higher scale of bilirabine was regisu'atcd by patients. at a ,,cut-off" of rag% (total-bilirubine) the sensitivity was , , specivity , , positive predicive level , , negative predictive level , for survival criteria of a patient. the max. reached level of bilirubine, also the daily increase turned out almost the same results as they were found for other parameters nf cholcstasis like ap or gamma-gt. objective: the aim of this experimental protocol was to evaluate the morphological and functional parameters of isolated pig liver grafts, perfused in an extracorporeal liver support system. methods: the system consists of the graft liver, a membrane oxygenator (oxygenation surface . cm z, flow= itlmin), a heater, a centrifuge pump and a fluid reservoir. twenty pig livers, mean weight gr (min , max gr) were obtained and after a mean cold ischemia time of min were perfused fo} a mean of . h (min . , max h). perfusion solution consisted of r/l and hemacell. inflow to the graft liver was performed through the portal vein at a mean pressure of ( - ) mmhg at ~ while outflow was secured through the suprahepatic inferior vena cava. during perfusion the following parameters were evaluated through pre-and posthepatic hourly (to-t ) sampling: po , " + + " pco , ph, hco -, na , k , ca , osmolality, glucose, lactate, ast, alt, alp, u bilirubin and coagulation factors i, v and viii. biopsies were obtained periodicallty. b_p_~: results were as follows: mean ph fell from . at t o to . at t while mean output po fell from at t o to at t . mean output ast values increased from at t o to > at t while mean output alp values increased from . at t o to at t . mean output k + values increased from . at t o to > at t . histology revealed lesions of ischemic necrosis, more prominent after t . conclusion: results show that the isolated liver graft presents satisfactory function and morphology at least for a five hour perfusion period in the described extracorporeal circuit. correction of ph contributed to an increase in bile flow. between and the practice of transplantation has changed drasticaily in switzerland -besides kidneys also hearts, heart and lung, lung, iiver and pancreas transplantation has started in several centers. major information efforts have been made, organ exchange rules were set up and a national coordination center was initiated. the aim of this retrospective single center study was to assess the influence of transplantation on organ donation. in the past eleven years organs were donated from potential donors i single, multi organ donations) analysis of refusal was evaluated categorized into medical and/or familiar reasons. the number of potential donors increased from ( ) ,to ( ) with a concomitant drastic reduction of donations from % in to % in ; amounting to a net unchanged number of donations over the last years ( = ; = ) . the import and export of donor organs was balanced since the introduction of the national coordination center. in contrast multi organ donation increased from % in to % in despite of the more stringeant selection criteria, in conc]usion the introduction of a full range of transplantation procedures at several new university programs and the increase of multi organ donation has not had the forecasted impact on organ donation despite a sustained informative and promotional campaign, objective: monitoring hepatic venous oxygen saturation (svho ) provides online information about hepatic-splanchnic oxygen supply-demand ratio [ ]. previously, x~ reported hepatic venous catheterization in patients undergoing orthotopic liver traru~lantation (olt) [ ] . in the present study, we assessed the effects of nitroglycerin (ng), a vasudilator that affects the venous capacitance vessels more than arterial vessels and prostaeyclin (pgi , flolan r~, wellcome, uk), an arterial and splanchnic vasodilator on hemodynamies and hepatic venous oxygen saturation (svho ) in human liver transplantation. methods: with institutional approval and informed consent, consecutive patients, mean age - -_ years, were studied following olt. postoperatively, fiberoptic pulmonary artery catheter was inserted into the right hepatic vein. timed infusions of ng at a rate of . gg/kg/min and pgi at ng/kg/min were initiated for a rain period. each sequence was followed by baseline therapy for rain. results are expressed as mean=tsd. statistical analysis was performed using friedman's-two-way-anova-test, significance was accepted at p< , . results: ng at . gg/kg/min induced a decrease of mean arterial pressure (map) ( _ [baseline] vs. + mmhg) and pulmonary artery wedge pressure (pcwp) ( j: [baseline] vs. : mmhg). cardiac index (ci) ( - vs. + l/rain/m ), oxygen delivery index (do i) ( -+ vs. + mgnfin) and svho ( _~ vs. -l-_ %) were decreased (p< . ). pgi at ng/kg/min induced a reduction in map ( • nm~. _g) and pcwp ( + mmhg). ci ( _+ l/rain/m ), do i ( : ml/min) and svhoz ( + %) were increased (!o< . ). vasedilatation induced by ng decreased systemic oxygen supply and impaired splanclmie oxygenation. pgi increased systemic oxygen delivery in parallel with svho , suggesting a corresponding improvement of hepatic-splanchnic okygenation. thus, if vasedilator therapy is indicated in th orient receiving liver grafting, pgi appears to be advantageous. however, due to its platelct aggregation inhibiting properties, the usefulness and safety of pgi in olt patients has still to be determined. objectives: to analyze the effect of steroid treatment given to donor on the early function of transplanted kidney. methods: from january, until now donors were involved into this prospective study. every other donor was treated with mg/kg solu-medrol one hour before organ retrieval. according to the steroid treatment of the donor the recipients were divided into two groups: group -steroid pretreatment goup (y~= ), and group -control group (n= ). the donors and the recipients were treated using the same kidney transplantation protocol onl~r the adults, and the first cadaver kidney transplanted patients were involved into the study. the daily routine parameters were analyzed pre-and intraoperafive, and on the - th, th and th postoperative days. results: we could not show any clinically important differences between the two groups in respect of donor parameters. preoperative, the patients in group had slightly lower ereatinin level ( -+ g.,non vs. -+ gmol/ ) which persisted into the early postoperative phase. the values of the other examined pre-and intmoperativc parameters were almost the same. during the first postoperative days the patients in group i needed less diuretics (furosemide and renal dose of dopamine) and their sodium excretion was closer to the physiological range than in group . the other parameters did not differ significantly. the less furosemide need in group ! pe~isted to the end of the first month. conclusions: according to our data the steroid treatment of the donors improves the early function of the transplanted kidney in some respects. to prove the real benefit of the donor steroid treatment needs more data and further analysis. objectives: severe infections may compromize the outcome of liver transplantation..determination of new parameters may increase the knowledge of pathophysiologic mechanisms and may lead to changes in postoperative therapeutic management of patients at risk. methods: between august and september , patients with transplants were monitored for cytokines and extracellular matrix pammeters on a daily basis. serious infections (n= ) included microbiologic evidence and more than secondary organ failures. patients with cholangitis (n=ll) or uneventful postoperative course (n= ) referred as control groups. results: -year patient survival was . % ( / ): patients died due to serious infections, while died for other reasons. mean bilimbin, stnf-rii-, ifn- -, il- -, il- -, il- -, laminin-and neopterin levels were significantly elevated in patients with serious infections compared with patients experiencing mild cholangitis or with an uneventful postoperative course. a further increase of all parameters was observed in patients who subsequently died; tnf-ri/: _+ pg/ml vs • pg/ml; ifn- : _+ pg/ml vs . -+ . pg/ml; il- : -+ pg/ml vs -+ pg/ml; il- : -+ pg/ml vs _+ pg/ml; il- : _+ pg/ml vs • pg/ml; laminin: -+ ng/ml vs -+ ng/ml; neopterin: _+ nmol/ vs _+ nmolb for non surviving vs-surviving patients. a significant decrease of sialic acid yeas observed in patients with serious infections; and a further decrease occurred in patients who subsequently died: -+ mg/l vs • mg/ . conclusions: the increase or decrease of various cytokines and extracellular matrix parameters may be indicative for severity of infectiolx routine monitoring of these parameters may improve current diagnostic tools and poss~ly lead to changes in therapeutic management of patients at ~k. objectives: evaluation of the cytokine network after liver transplantation may give some insight in pathophysiologic mechanisms of rejection and may lead to detection of patients at high risk. methods: patients with transplants were monitored for various cytokines on a daily basis between august and september . rejection was assessed by histology in combination with clinical signs of rejection and laboratory investigations. results: during the first postoperative month, patients ( . %) developed rejection; patients were successfully treated with methylprednisolone (steroid-sensible rejection), while further patients required additional treatment with fk or okt (steroid-resistant rejection). patients subsequently developed chronic rejection. mean levels of various cytokines and extracellular matrix parameters including tnf-rii, ifn- , il-ib, il- r, il- , il- , il- , hyaluronic acid and neopterin were significantly higher in patients with steroid-resistant than in patients with steroid-sensible rejection. a further increase of some parameters was observed in patients who subsequently developed chronic rejection; bilirubin: . -+ . mg/dl vs . -+ . rag/all; tnf-rii: -+ pg/ml vs _+ pg/ml; il- : +- pg/ml vs -+ pg/ml; neopterin _+ nmol/ vs -+ nmol/ ; hyaluronic acid: _+ ~tg/l vs _+ ~tg/l for patients with chronic versus patients with acute steroid-resistant ~ejection. sialic acid levels decreased in patients with acute steroidresistant rejection; and a further decrease was observed in patients who tieveloped chronic rejection: _+ mg/l vs _+ mg/ . ~onclusions: various cytokines and extraeeuular matrix parameters were indicative of severity of rejction. the extensive increase of bilirubin, tnf-ii, il- , hyaluronic acid and neopterin may indicate subsequent chronic ection. monitoring of these parameters may, therefore, lead to changes in immunologic management after liver transplantation. background : combined kidney and pancreatic transplantation is being performed with increasing frequency in patients with diabetes mellitus and renal failure, as it offers more chances of success and better results than kidney transplantation alone. mycotic arterial aneurysm constitutes a devastating complication following pancreatic transplantation. all cases of mycotic arterial aneurysms have been however reported with exocrine pancreatic drainage into the gastrointestinal tract. intervention : we describe a series of consecutive whole kidney-pancreas transplantation performed at the university of geneva hospitals ( beds) between december and may . exocrine pancreatic drainage into the bladder (epdb) was performed to improve early detection of rejection episodes. epdb was hypothesized to reduce the risk of contamination from the gastrointestinal tract and the subsequent possible occurrence of potentially fatal infectious complication. in all patients the dual transplantation was performed through a median incision according to the procedure described by nghiem. results : two out of the patients who received kidney-pancreatic transplant developed arterial mycotic aneurysms and days following surgery. aneurysms developed at the site of the arterial anastomosis used to rearterialize the homograft. both patients had peritonitis caused by candida albicans requiring surgical drainage and intravenous antifungal therapy. rupture with hemorragic shock occured in both patients leading to graft removal in one patient, and three episodes of lffetreateniug hemorragic shock followed by graft failure and removal days after transplantation in the other. conclusion : arterial mycotic aneurysm constitutes an early, lifetreatening complication of kidney-pancreatic transplantation; it mandates graft removal. although exocrine pancreatic drainage into the bladder consitutes a definitive advantage for caller diagnosis of graft rejection, it does not eliminate the risk for retrograde colonization and subsequent severe infection in our experience. s. bocharov, i. teterina, regional clinical hospital, irkutsk, russia acute profound loss of blood can result from the very different injuries and hepato-pancreato-duodenai operations enter such a rank. ill-timed and inadeguate correction of operation hemorrage is one of the reasons for postoperation complications, including polyorganic insufficiency. the pathogenesis seems to be very complex. in early stages of bleeding the liquid enters the vessel bed, followed by hypoproteinosis and hematocrit fall. however, as decompensation develops, the fluid leaves the vessel system in the result of increasing postcapillary resistance and lowering col-ioidnooncotic blood pressure (cop). the resulting hypovolemia causes primarily acute disturbance of central hemodynamics and then of microcirculations and transcapillary exchange. central hemodynamic failure after acute loss of blood manifests itself through cardiac output lowering and capillary blood flow deceleration. taking into consideration, that % is critical value for cpv loss and for cev it is %, we consider arising the level of cop to the immediate task. cop raising allows to normalize transcapillary exchange, which we assess through cop and mcp (mean capilary pressure) gradient. the next task is to make up for globular volume till homeostasis providing level. considerable attention is given to catabolism inhibition and maximum possible enegry provision. control over high proteolitic activity of blood and callicreinkinin system activity implies direct proteases inhibitors. reologic, membrane stabilizing, antihypoxanthine and anticoagulant therapies are obligatory. virehow clinic, dept. of surgery, humboldt university berlin, germany regarding a high mortality up to % of fulminant hepatic failure orthotopic liver transplantation seems to be the only promising therapeutic approach in many cases. this study shows experiences from a transplantation center. between june and april patients suffering fulminant hepatic failure were admitted to our surgical intensive care unit all patients showed severe liver dysfunction with grade ii to iv encephalopathy. after a period of diagnostics and conservative treatment ranging from few hours to days (mean . days) we reported of these patients as possible organ recipients to eurotransplant. all of these patients were transplanted within hours, ( %) of them even within hours. the principal aetiologies were hepatitis b ( ), hepatitis c ( ), nanb hepatitis ( ), mushroom poisoning (amanita phalloides ). after transplantation patients suffered from initial-non-function and underwent re-transplantation. the one-year-survival rate was %, patients died within months after transplantation due to various reasons. patients were not referred for liver transplantation. of them never met transplantation criteria, improved by conventional therapy and could finally be discharged from hospital. the known reasons for liver failure in this group were mushroom poisoning ( ), paracetamol intoxication ( ) and fulminant hepatitis a ( ). patients suffering from fulminant hepatitis ( ) or intoxication ( ) were excluded from emergency liver transplantation for various contraindications. of these patients ( %) died despite conventional intensive care. we don't know if some of the patients in the transplantation group would have survived without transplantation, because whenever we decided on transplantation we could perform the operation within hours. but the good survival rate in the transplantation group ( %) the % recovery rate in the group, where there was no transplant-indication in our opinion and the fatal outcome ( % mortality) in patients with contraindications are an encouraging proof of a successful therapeutic strategy in acute liver failure. these results are based on a close cooperation between experienced transplant surgeons, hepatologists and intensive care doctors, using sophisticated laboratory and imaging techniques in a specialized center. introduction: during brain death patients suffer from multiple endocrinologic disturbances. one of the most important are those related with thyroidal axis. it is well described the euthyroid sick syndrome whose more frequent pattern consist of decreased triiodothyronine (t ), increased reverse t (rt ) with normal levels of tetraiodothyronine ( " ) and tsh, this lacking in " " levels lead to a change from aerobic to anaerobic metabolism which results in tissular damage. objective: .to study thyroidal pattern in brain death patients potential organ donors. .to avoid organ impairment by administration of t . .to study the hemodynamic and hormonal changes after the administration of t in these patients. material and methods:population: brain death patients of any etiology potential organ donors admitted to the intensive care unit. patients were classified in hemodynamically stable (group ) and unstable (group ). group received a bolus of . p.gr/kg. and a perfusion at a dose of - . p.gr]h of t . hormonal assays: total t (tt ), total " (tt ), tsh. fxee t (ft ), free " (ft ) and rt were determine at the moment of clinical brain death ( hrs) and in group two these assays were repeted at hours , and . results: patients ( male) with a mean age of years (range to yrs.) were studied. the clinical brain death was confirm later with other explorations (eeg, doppler). there were patients in group ( , %) and patients in group ( , %). hormonal pattern: at the moment of brain death tt was normal in cases ( , %) and decreased in i ( , %); tt was normal in patients ( , %) and decreased in ( , %); ft was normal in cases (i , %), decreased in ( , %); fl' was normal in patients ( , %) , decreased in ( , %) .rt was normal in cases ( , %) and increased in cases ( , %). there were no statistically significant differences in hormonal pattern between the two groups. only t levels at hours , and were significant in group . in the cases with ft decreased, the tt was normal in ( %) and decreased in ( %), tt was decreased in ( , %) and normal in ( , %), tsh was decreased in i ( , %), normal in ( , %) and increased in i( , %) and ft decreased in ( , %) and normal in ( , %) and rt was normal in ( , %) and increased in ( , %). there were no statistically significant differences in cardiac index, vascular resistances and pulmonary shunt before and after the administration ef t . conclusions: . the hormonal pattern most often find in brain death patients was: normal tt , decreased tt , normal tsh, decreased ft , normal fr and normal rt . . there were discrepancies in the values of ft and tt . there were no statistically significant differences in hemodynamic and pulmonary parameters. objectives: magnetic resonance angiographie (mra), a non-invasive procedure, provides flow-related information additionly to the anatomy of the vascular system. measurement of signal intensity and edge detection of vessel structures permits to calculate blood flow velocity and vascular diameters. we examined whether cerebral hemodynamic changes by altering the arterial pressure of carbon dioxid (pace ) could be detected by mra. methods: following institutional approval and informed consent, mechanically ventilated patients without elevated intracraltial pressure underwent mra with defined periods of hyper-, hypo-and normoventilation (pace : , , mmhg; arterial blood gas probes; avl). mra was performed with a . tesla magnetom (vision, siemens). two different mra techniques were used: a conventional time-of-flight- d-angiography (tr: ms; te: ms; fl: deg; slab: mm) for vessel diameter detection and a flash- d-gradient-echo-sequence (tr: ms; te: ms; fl: dog) for measurements of blood flow velocity. an axial view parallel to the ac-pc-iine (anteriorposterior-commissur-line) was used for repeated imaging of identical regions of interest toi) of the proximal part of the internal carotid (ica) and middle cerebral artery (mca) as well as of peripheral branches of the mca and the posterior cerebral artery (pca). results: changes of pace correlated with changing signal intensities, whereby under hyperventilation a decrease of , % (p . ) and under hypoventilation an increase of . % (p . ) was observed compared with normoventilation. blood pressures were stable throughout the whole study period, pace dependent changes in vessel diameters were more pronounced in peripheral branches of mca and pca. a change from normo-to hyperventilation produced a decrease in proximal vessel diameter of - . % (p _< . ) and in peripheral diameter of - . % (p _< , ). a change from normo-to hypoventilation produced an increase in proximal diameter of + . % (p < . ) and of + . % (p -< . ) in peripheral diameter. conclusions: pace related changes of cerebral vessel diameter can be easily detected by mra without injecting a contrast agent. the results confirm that co -reactivity is more pronounced in peripheral cerebral vessels, which are subjected to greater changes in diameter than major basal arteries. hyperventilation leads to a decrease and hypoventilation to an increase in signal intensity thus reflecting the corresponding changes in blood flow velocity, intensive care unit (icu) of "kat" hospital, athens, greece, ob!ective$; the value of bronchoscopy in pulmonary atelectasis of icu patients is under question the presence of an air bronchogram sign in xrays, which is considered as evidence of central bronchus patency, is referred in several studies as a negative criterion for bronchoscopy, whereas its absence as a positive one. it is also referred that air bronchogram sign correlates with delayed resolution of atelectasis, probably because of obstruction of many periferal airways (not central). the purpose of this prospective study was the evaluation of the air bronchogram sign on frontal chest film as a negative criterion for bronchoscopy and as criterion of delayed resolution of atetectasis, methods: icu patients with atelectasis were studied prospectively. they underwent bronchoscopy, bronchoscopic findings, presense of air bronchogram sign, and outcome of atelectasis were recorded, correlations were made, between: ) bronchoscopic potency of airways and air bronchogram sign } resolution time of atelectasis and broncoscopic potency of airways. ) resolution time'of atelectasis and air bronchogram sign, methods of statistical analysis were the t-student test and the chi square test, results:the patients were , men women , seventeen patients had atelectasis of whole lung, of upper lobe, and of lower lobe. ten patients had atelectasis in right and in left lung. eight from patients had air bronchogram sign in x-ray, there was no statistical correlation between air bronchogram sign and bronchoscopic potency of airways [ from patients with air bronchogram sign ( %) and from without air bronchogram sign ( %), had bronchoscopic potency of airways, p> . ], resolution time of atelectasis didn't correlate statistically with bronchoscopic potency of airways (mean resolution time in patients with bronchoscopic potency , days and in bronchoscopically closed bronchi , days, p> , ). there was also not a statistical correlation between resolution time of atelectasis and air bronchogram sign (mean resolution time in patients with air bronchogram sign , days, and without air bronchogram sign , days. p> ). conclusion~i; the presense of an air bronchogram sign in x-ray of icu patients with atelectasis, does not coexist obligatorily with bronchoscopic patency of airways and cannot be used as a negative criterion for bronchoscopy, neither as a criterion of delayed resolution of atelectasis. th. wertgen chest sonography (cs) is routinely used in our department to examine icu patients with clinical symptoms of pulmonary embolism, pneumonia, pleural effusion or unclear chest pain. we perform cs with a sector transducer ( . mhz) and a linear transducer ( . mhz) using acuson xp/ c. the sonographic signs of pulmonary embolism and infarction are most well demarcated, mainly wedge shaped and triangular pleural based lesions, more roughly structured, observed with a hyperechoic reflex in the center corresponding to the bronchitic (fig. ) . pneumonia is characterized by homogenously hypoechoic, wedge shaped parenchymal lesions, containing air or fluid bronchograms; they move with respiration (fig. ) . pleural effusions are spaces of various echogenicities, from anechoic to homogeneously echogenic, which may contain floating strands or complex septa, located between visceral and parietal pleuras (fig. ) . from march to april we did examinations by cs in icu patients ( male, female; age from - ). patients examinations pulmonary embolism pneumonia pleural effusion us-guided thoracic punctions were performed in patients. in two patients we found pneumonia or pleural effusion caused by a lung carcinoma. another two patients showed a normal cs (diagnosis: inflammation of the gall bladder, inflammation of the myocardium). conclusion: cs is a very useful method for icu patients with chest diseases. it takes less time and is less expensive than ctand sometimes of a higher diagnostic value than x-ray. last but not least cs is invaluable for the icu patient, because the examination is done save and quickly at bed side and the results of cs are very helpful in diagnoses and treatment. results : inter-observer reliability was evaluated as an % concordance. results of the tee classification were : class : n = ( %) ; class : n = ( %) ; class : n = ( %) ; class : n = ( %) class : n = ( %). therapeutic implications of tee in class patients were : cardiac surgery in patients (two cases of acute mitral regurgitation, two valvular abscesses and one hematoma compressing the left atrium), discontinuation of peep in one ventilated patient with an atrial septal defect, weaning of mechanical ventilation in one patient with an atrial septal defect, prescription of antimicrobial therapy in patients with endocarditis and prescription of anticoagulant therapy in patients with left atrial thrombus. the only noteworthy complication was a case of spontaneously resolving supraventrieular tachycardia. conclusion : tee is safe and well tolerated, and is useful in the management of icu patients with shock, unexplained and severe hypoxemia or suspected endecarditis. the aim of this study was to determine whether ultrasound guidance can help interns to improve the results of jugular vein access in icu. methods : in a prospective and randomized study, we compared, in patients admitted to the icu, an ultrasound-guided method (ultrasound group : patients) with an external landmark guided technique (control group : patients). all jugular vein accesses were performed by young interns with an experience of < procedures. results : internal jugular cannulatian vein was aci~ieved in all patients in the ultrasound group and in patients ( p.cent) in the control group (p < . ). average access time was longer in the control group ( • sec. vs • see. ; p = . ) and puncture of the carotid artery occurred in patients in each group (p = . ). patients ( p.cent) in the ultrasound group and patients ( p.cent) ia the control group (p < . ) were cannulated in rain. or less. the cannula was therefore unabie to be inserted within minutes in patients in the control group, with failure of eannulation in of these patients ( p.cent). failure was due to thrombosis (n = ), small calibre of the internal jugular vein (< ram) (n = ), abnormal vascular relations (n = ) or cervical irridation (n = ). among the primary failures of cannulation, an internal jugular vein catheter was able to be inserted in cases by an experienced physician on the side initially selected and with ultrasound guidance in cases. the catheter was inserted into the contralateral internal jugular vein under ultrasound guidance in the remaining cases. jugular cannulation was obtained at the first attempt in p.cent in the control group and p.cent in the ultrasound group. conclusion : ultrasound guidance improved the success rate of jugular vein cannulation by inexperienced operators in icu patients. when the internal jugular vein has not been successfully eannulated within minutes by the external landmark guided technique, the authors recommend the use of the ultrasound guidance. in the majority of cases right atrial or ventricular thrombi represent pulmonary emboli in transit. these may be fatal in patients (pts) treated conservatively with anticoagulation only. in literature the incidence of right heart thrombi in pts with proven pulmonary embolism (pe) is said to be in the range of - %. extremely mobile, long, worm-shaped masses in the right heart cavities carry an especially high early thrombus-related mortality rate which ranges from - %. current therapeutic strategies favour fibrinolytic therapy with consecutive anticoagulation. we report five cases ( male, i female, - years) of right heart and pulmonary thromboembolism. in these pts diagnosis and regression of thromboemboli following systemic intravenous lysis therapy with recombinant tissue-type plasminogen activator (rt-pa) was documented by transesophageal echocardiography (tee). a submassive pe occured in pts, a massive pe in pts. one patient (pt) had a cardiac arrest. in all cases tee clearly identified the extensive thrombns formation in the right-sided cavities of the heart and in the central pulmonary artery in cases. all pts were treated with mg rt-pa, pts in a front-loaded regimen over minutes, pt over minutes, and, due to the life threatening situation, in one case a bolus injection as ultima ratio was performed with no intracerebral bleeding complication. regression of thromboembolic masses after fibrinolytic therapy was demonstrated by transthoracic and transesophageal echocardingraphy after to hours. all pts survived and were put on coumadine, pt developed an intracerebral bleeding with persistent hemiplegia. conclusions: the use of thrombolytic therapy is highly efficacious for the therapy of pts with pe and concomitant right or ventricular thrombus formation. transthoracic and especially transesophageal echocardiography are powerful bed-side diagnostic tools for the immediate diagnosis and follow-up of successful treatment in this life-threatening condition. although widely used, catheterisation of the femoral vein in the groin using "landmark" technique is frequently complicated by accidental arterial puncture. suboptimal hygiene and patient discomfort are also associated with this technique. with regard to these last two factors cannulation of the femoral vein - cm below the inguinal ligament would seem an attractive alternative. as "landmark" technique is not possible for the cannulation of the femoral vein in this part of the thigh, ultrasound was used to locate the vessel and the results of this technique were evaluated. methods: a portable compact ultrasound device (site rite,dymax corp.) featuring a . mhz transducer (ultrasound depth - cm) fitted with a needle guide and a cm screen was used by residents with no previous experience in ultrasound guided cannulation. patients consisted of a surgical icu population. results: in patients catheters were introduced.in cases more than one ( - ) attempt was made and in patients the procedure was unsuccesfull due to the fact that the vessel was situated out of reach of the ultrasound (vessel depth > - cm), during the procedures one accidental arterial punction was registered. the catheters remained in situ for a mean of days (range - ) and were used for volume suppletion, medication, parenteral nutrition and haemodialysis.co-ionisation rates compared to those of subclavian catheters in our icu. in the first patients cases of asymptomatic thrombosis of the femoral vein were seer on ct-scans performed for other indications, in the following patients duplex scanning performed after removal of the catheter yielded another cases of asymptomatic femoral vein thrombosis. conclusions: ultrasound guided femoral vein catheterisation - cm below the inguinal ligament is a safe and simple technique that can easily be performed by residents without prior experience. the incidence and impact of thrombo-embolic complications associated with this technique are still subject to further investigation. objectives: to estimate the cost of antibiotherapy (ab-cost) in a multidisciplinary -bed greek icu and to correlate ab-cost with total cost of drugs and consumables and with patient's outcome, severity of illness and type of admission. methods: prospective data from consecutive patients admitted to the icu from / / to / / were studied. a tick chart was designed to record all drugs, materials and consumables regularly used for icu patients, but did not include low price drugs and consumables, which are provided from hospital's pharmacy as stock and were included in a fixed icu cost calculated for a month period. the chart also contained demographic details and data necessary for the calculation of several illness severity scoring systems. obiectives: over years evaluate the necessary efforts and expenses to implement a cis in the routine of a -bed stcu. methods: in june a commercially available, unix-based cis was installed on a -bed surgical icu. the goal was a paperless documentation at the bedside. after more than years clinical experience two aspects were investigated: what effort is necessary to install and support a cis, and what is the benefit for patients and personnel on the icu? results: the installation and support of a full-fledged cis requires a considerable effort: (a) the conceptual framework for the cis has to be defined. this includes the definition of documentation standards, as well as nursing and therapeutic standards, which is the essential basis for the configuration of any cis. (b) configuring a cis, i.e. "fine-tuning" it to the user's specific needs, is always a laborious task. moreover, constant maintenance is necessary. these tasks require the following personnel: experienced health care professionals for defining the conceptual framework, - trained health care professionals for configuration, system administrator. on a single icu ( - beds) these are not considered full-time jobs. (c) training is best done employing the "train-the-trainers" approach. (d) beside the necessary amount of man power and money to install and purchase a cis, administrative and mis support is needed, especially when interfaces to the hospital and laboratory information systems have to be set up. in general, a cis needs the commitment of all people involved. without a really professional approach with a longterm goal any major cis can turn into an unnecessary but inevitable night mare. after years clinical use and a thorough implementation of a cis on a major sicu it can be said that full-fledged cis offers an opportunity to dramatically improve the working environment on an icu. moreover, it adds to patient safety, quality of care and cost efficiency in one of the most advanced and expensive areas of medicine. conclusion: a major investment in man power and money is necessary to install and maintain a full-fledged cis. a sincere professional commitment to the goals of a cis is necessary. in exchange, a well configured and well maintained cis dramatically improves the quality of therapy and care on the icu. even return of investment and financial profitability of a cis seem feasible todayl from the clinical perspective it appears that the users themselves are the central determinant whether a cis makes a dream come tree or turns into a night mare. objectives: to establish a relationship between the activities of the staff and the occurrence of auditory alarms on the i. c.u. ard to evaluate confusion between auditory alarms. methods: laboratory based studies which investigated aspects of confusion between alarms in current use on the i. c. u. the observational studies were conducted over an month period and examined the frequency and duration of alarms together with the concurrent activites being undertaken by staff on the unit. the laboratory based studies showed that there were enduring confusions between the alarms on various items of medical equipment, for example a ventilator alarm and an e. c. g. monitor alarm. the results of the observation studies demonstrated that alarms are activated when specific activities are being undertaken by staff. sounds could be used in future recommendations for alarms on medical equipment. suggestions are also discussed for improving and rationalising auditory warnings in the i. c. u. obiectives: we investigated inferior petrosal sinus (ips), the lowest affluent to jugular bulb (jb), as a possible source of contamination of samples in jb for monitoring oxyhemogiobin saturation (sjbo ). pulling back the catheter the oxyhemoglobin saturation usually rises indicating extracerebral contamination (jakobs en met al: j cereb blood flow metab ; : ). methods: the study was carried out on patients undergoing ips sampling to differentiate cushing disease from ectopic acth syndrome and to lateralize any resulting pituitary lesion. we studied the value of oxyhemogiobkn saturation high in jb (sjbo ), at ips (sipso ) and at mid jugular vein ( th cervical vertebra) (smj ) bilaterally. results: we found significant differences between right sjbo and both right sipso (p= . ) and right smjo ( p= , ) and between left sjbo and both left sipso (p= . ) and left smjo (p= . ) we did not fred any difference bilaterally. objectives: we studied various methods of receiving and editing of clinical datas in critically ill patients (different ethiology). patients were investigated in regional intensive care center. methods : the following datas were studied : anamnesis, status praesens objectivus ( organs and systems ) ,. clinical and biochemical markers of critical condition , datas of eeg ,rheography . the medical information complex contained : channel electroencephalograph, -channel roencephalograph, ad-converter ( analog inputs, bit resolution, k hz), ibm dx , software includes set of routines for spectral eeg analysis, eeg-mapping, correlative analysis, and brain bloodstream reg-monitoring (written in turbo pascal . ), expert programs for estimation objective and humoral patient status (written in clipper . ) and statistics. there were used following programme-language instruments : borland c++ . , nantucket clipper . , ca-clipper tools ii. as the methods of statistical processing of dates were used: t-students criterion , fisher criterion, methods of correlation analisis, calculation of the regression levels, dispersion analysis, results : there was created the optimal structure of hard and sofware complex of search steady objective regularity in dynamic of critically ill patients condition. conclusion : the created system allowed to value effectiveness of intensive care and give us new opportunities in study pathogenesis of systems disorders in critical condition . over a five year period a patient data management system has been installed which allows individualised patient data to be accurately collected. using this data a costing system has been developed which ascribes costs thus: . direct costs -drugs, fluids, consumables, interventions. these are ascribed to individual patients, according to data collected from the pdms. . indirect costs -energy, depreciation, admm costs, maintenance etc. these are summed for the year and ascribed as an overhead per patient day. n.b staffcusts contain art element of both cost types the aim is to make as many costs as possibie 'direct', hence 'activity costs' have been calculated winch comprise staff time, drugs and consumables -these are direct costs. these costs of patient care are then searnlessly integrated into the financial and budget management of the icu environment. it was found that by calculating costs in this manner % of the total cost of icu are captured within the 'direct' element, and so are able to be ascribed to individual patients. this is much more accurate than simply dividing the total costs of ~cu by the number of patient days. temporal costs (variations during patient stay) and cross sectional costs (cost differences between admitting specialities) were also noted with interest. results of the initial analysis of data captured by the system will be presented. little is known about the resource costs (not simply cash costs) of icu. even less is known about individual patient costs, with previous estimates of these costs varying widely. however, if cost effectiveness studies are to be undertaken accurate calculation of individual, group and total icu cost is an essential, prerequisite, which, via this system of costing, is now achievable. information about intensive care of cancer patients is limited in the literature, despite the increasing use of such facilities in oncology over the two last decades. in order to determine if and how critical care facilities can be used specifically for these patients, we performed a world-wide inquiry in anticancer centers selecting the hospitals by using the international directory of cancer institutes and organizations. we mailed a questionnaire to centers and we received responses ( . %). there was at least one uncological (i.e. with > % of cancer patients) icu in (% % an -year old woman with graves disease presents with sore throat, vomiting, diarrhea, sinus tachycardia at /minute and a temperature of ~ several weeks before, treatment with propylthiouraeil had been stopped (rash and fever) and replaced by methimazole and ledide prior to a minor surgery. however, both drugs were discontinued by the patient two weeks before admission. shortly after arrival in hospital, patient's condition progressed to respiratory failure (upper airway edema), delirium and shock requiring icu admission, intubation and resuscitation with fluids and vasopressors. white blood count was /mm ~ with neutrophils. patient's hemodynamic data showed initial hyperdynamic profile followed by low output state with decreased sv ( %) (n - %) and cardiac index ( , ) (n , - ). echocardiogram confirmed cardiac chambers dilation as previously described in thyroid storm. lithium carbonate, corticosteroids, antibiotics and beta-blocker perfusion were given. plasmapheresis was started. free t& (n= , - pmo/l) went from , to , after the first two pheresis. after a remarkable clinical recovery, sub-total thyroideetomy was done i days after admission. in life-threatening thyroid storm, plasmapheresis is a very effective therapy when anti-thyroid drugs are counterindicated. purpose: to compare the reliability of prognostic indexes in crhically iu patients admitted in an intesive care unit (icu) who had acute renal failure (arfi and were treated with different dialytic techniques. material and methods: patients were included in a prospective study from june to november . patients presented arf defined by creatinin serum leve(s greater than pmol/l and previous normal levels. patients were divided in three groups. group i (control) : patients with arf who did not receive substitutive techniques. group ih patients under intermittent hemodialysis (hd) or peritoneal dialysis (pd). group ii : patients under continuous hemodiafiltrstion (hf). the statistical analysis was chi-square test and analysis of variance. results: the table shows the results we obtained, we did not find any significant difference betwen the two groups of patients undergoing dialysis. d(fferences were observed only between group i and the other groups as shown below. we did not find any significant association between the theoretical mortality predicted and the observed mortality according to saps in the three groups. due to exposure to a wide variety of unpleasant stimuli, for example, tracheal suctioning, venipuneture and physiotherapy, most pataents admitted to the icu will require some form of sedation. this review will describe the suggested properties of an ideal sedative agent for use in the icu and review the current limitations of some of the available agents from this perspactive. methods used to quantify the level of sedation, such as the ramsay score, glasgow coma score, newcastle sedation score and visual analogue scores, and their deficiencies will be examined. consideration will be given to defining the optimal level of sedation and the circumstances under which sedation might be varied over the icu course will be discussed. preliminary results from an ongoing study examining the role of light versus heavy sedation and ischaemia in a cardiac surgical icu population will be presented. the pharmacceconomics of icu sedation will be briefly addressed. finally, the role that sedation may play in increasing morbidity, pastieuiarly nosocomial pneumonia, in the icu will be discussed. objectives : therapy cost(tc) in icu patients is a substantial component of total hospital care cost. estimation of tc during this year, partitioning to various groups of drugs used and attempt to minimise it, were considered practically useful. methods : in collaboration with the hospital pharmacy we were able to have a complete report of au drugs used for icu patients (including enteral and parenteral nutrition). mean apache ii severity score upon admission was . and mean length of tcu stay was . days. price per drug unit and cost per group of drugs were also available drugs were divided into two groups: antibiotics ( ) cardiovascular drugs ( ), gastrointestinal system drugs ( ), enteral and parenteral nutrition ( ), respiratory system drugs ( ), sedative, analgesics and paralysing agents ( ), parenteral solutions with electrolytes, vitamins and trace elements ( ), anti-inflammatory agents ( ), protein substitutes and immunomodulation agents ( ), anticoagulative agents ( ). antibiotics were further subdivided into those "freely" prescribed (a) and those whose prescription and administration requires filling of a relevant form (b). results : !) tc for icu patients/day was . drs ($ ). total tc/patient was . drs ($ . . ). ii) partitioning total tc per group of drugs reveals : ( ) %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %. t ) concerning antibiotics which consist the major cost component, group a and group b contributed by . % and . % to the total icu tc respectively. group b were administered to . % of all icu patients. conclusions : i) for the above studied patient population antibiotics consist almost half of total tc followed by protein substitutes and immunomodulation agents. ii) if tc control could be attempted in the icu, prescription of beth groups must be reviewed. appropriate treatment should be prescribed and readily provided to any patient. clinical significance of routine protein substitution, currently controversial, should be re-evaluated. new antibiotics (third & fourth generation cephalosporins, quinolones, carbaponems) should be prescribed on the basis of strict diagnostic procedures using modern technology available. rationalisetion of antibiotic therapy will lead to cost control, redistribution of icu expenses and substantial contribution to infection policy in our country. objectives: i -to investigate the clinic efficiency of the monitoring of the rso cerebral, in relationship to the stroke prevention, in patient undergoing carotid surgery. -to determinate the variations of the rso during the different surgical and anesthetic procedures in these patients methods: ten patients undergoing carotid endarterectomy. precise neurological exploration previously to the surgery and in the immediate postoperative period. angiography evaluation to the extend of carotid artery disease. invasive blood pressure, ecg, pulse-oximetry ( pso ) and rso were collected previousty to the induction of anesthesia. the premedication was administered intravenously -midazolam ( mcgr/kg) and fentanyl (i rncgr/kg) -. thiopental ( mg/kg),fentanyl ( mcgr/kg) and atracnrium ( , mg/kg) have been used for induction of anesthesia. co te is monitoring al~er the orotraqueal intubation ! the anesthetic maintenance is accomplished with lsofluorane ( , - , %) and bolus of atracurium and fentanyh the surgical procedure is standard (without arterial shunt during the carotid cross-clamping). we register each minutes: blood pressure, cardiac frequency, pso , co te and rso . the rso cerebral variate in relation with: the anesthetic induction, blood ~ressure, co te, cross-ulampping carotid and with the modifications of the head position. the maximum decrease of rso cerebral was in relation with the :ross-clampping carotid ( minimal value: ). no patient had neurologic complications and postoperative stroke after carotid endarterectomy were not observed. objectives: there are more than anesthesia in chelyabinsk emergency hospital every year. to % patients of it emergency anesthesia is applied. more than patients have ishemie heart disease (ihd), hypertansion (hp) and previos miocardial infarction (pmi). more than % of all patients are old patients (op). the resalts deep noninvasive bioimpedance monitoring (nbm) in surgical patients have been studied by us. methods: our nbm system "kentavr" includes parameters of cardiac and vessels function. it is realised by monitors in operation theatres and computer network. moreover we are able to examine surgery patients before anesthesia and perioperatively by using special computers system for cardiovascular reflex control by fast fourie transform (fft) of parameters simultaneously. results: pathients extremly needed peryoperative monitoring of hemodinamics. from these patients more % had stroke volume (sv) less than ml, n -co less than . /mim/m , % -ejection fraction (ef) less than n and % -puls bioimpedans microvessels (pbm) less than morn. patient had intensive care in special department. out of died. comparing with survived with these patients before operation hr was larger, sv, co,ef, pbm and puls bioimpedance aortha was smaller. much more of these patients were with ihd, pmi, hd, op. even with survived patients these parameters decreased the towards the end of operation. surgery patients had different variability of basic hemodinamical parameters with common tendency to increase power amplitude in low frequency by fft. conclusions: using of bioimpedanee noninvasive parameters allows to have criteria for corrections (infusies, vasodilatators, inotrops and others) and then us the final goal, to have more sucssesful surgery. with survived patients was perioperatively and postoperatively care more intensive. obiectives: the aim of the study was to compare the phi with the hemodynamically derived tissue oxygenation indexes as: oxygen delivery (do ), oxygen consumption (vo ), cardiac index (el), and arteriovenous difference in oxygen [(a-v)do ]. methods: patients ( males and females) with major trauma or major abdominal surgery were studied. on admission, a nasogastric tube allowing phi measurement was introduced and a pulmonary artery catheter was inserted for optimal hemodynamic management. each phi measurement was accompanied with a complete hemodynamic study comprising systemic and pulmonary artery pressures, blood gases, and cardiac output measurements with the thermodilution method. derived parameters vo , do , ci, (a-v)do were measured according to the standard formula. hemodynamic parameters were opt• as soon as possible with fluids, inotrepes, and vasopressors according to repetitive hemodynamic measurements. all patients were under mechanical ventilation. after hemodynamic stabilisation phi and hemodynamic measurements were repeated every eight hours, during a -hour study period. a total number of measurements were obtained and compared. statistics: results are presented as means + sd, correlations were performed between phi and the hemodynamically derived oxygenation parameters. a p< . value was considered as significant. results: mean values were phi= . + . , do = + , vo = + , c. = . + . , (a-v)do = . + . . no correlation was found between phi and do , phi and vo , phi and c.i, phi and (a-v)do . on the contrary in patients phi remained below . for more than hours despite adequate hemodynamically derived tissue oxygenation parameters. mortality in this group of patients was very high ( %). conclusion: no correlation was found between phi and the hemodynamically derived tissue oxygenation parameters our data suggest that phi is a better oxygenation indicator than the hemodynamically derived tissue oxygenation parameters, because it is closely related to the patient's outcome. objectives: the pathogenesis of septic shock and multiorgan failure is believed to be related to tissue hypoxia of the gastrointestinal tract. therefore new monitoring techniques, preferably organ specific, are required to establish the adequacy of tissue oxygenation. peep is used to reduce pulmonary shunt volume and improve blood oxygenation, but is accused to impair splanchnic perfusion. we studied mucosal oxygenation and perfusion on the capillary level in the stomach and the duodenum. methods: we used the erlangen microlightguide spectrophotometer (empho ll) together with a specifically designed fibre probe (bodenseewerk ger~tetechnik, berlingen) in combination with a standard gastroscope. measurements were performed on ventilated, traumatized patients (ages - years), with no evidence of shock or severe infection, after informed consent was obtained from the relatives. all patients were hemodynamically stable without inotropic support. an area of cm was analysed in the gastric corpus, the antrum and in the duodenum. in three patients we simultaneously measured the muc sal blood flow using a laser doppler flowmeter ( objectives: to investigate the influence of hb-o affinity in the monitoring of svo~ during improvement of cardiac index (ci) in cardiogenic shock. design: to state whether changes in svo: were associated in changes in actual pso (p~ ) and standard p~ (ps st) consecutive measurements of artero-venous bga, before an.d after therapy-induced changes in ci, were evaluated in patients (mean age -* y) suffering from cardiogenie shock, all under mechanical ventilation in psv modality. methods: together the hemodynamic measures, m~xed venous samples were analysed at ~ c using the abl radiometer for po , pco: and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the p~ at ph= . , pco:= mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood as was the ps "in vivo" (i.e. the pso at the patient's value of ph, pco and temperature), using siggaard-andersen's computerizated algorithm. mean time between paired measurements was . -* . houm. the data were compared by anova test for linear regression and t-test for paired samples. results: a dose linear relationship was found between svo and oxygen extraction ratio (oer), r= . ,p= . . the improvement of ci ( . -* . to . + . l/min/m , p< . ) induced a significant increase in svo~ ( . -* . to . • . %, p<. ). a significant decrease in p ( . • . to . • . mmhg, p< . ) without any significant change in p~ st ( . • . to . • . mmhg, p=ns) was also found. these data show that either oer or the shift to the left of the oxygen dissociation curve account for increase in svo occurring with restoration of systemic blood flow. the program is intended to help the intensive care unit interne providing him with a practical tool when making decisions concerning patients in a critical condition. in his daily practice in intensive care unit, in this case the interne of the unit, uses this program for each patient as follows: on the first stage of data collection he should complete the following modules: ( )personal data ( )patient's pathology ( ) laboratory and~ monitor lug data ( )drugs prescribed or toxic elements ingested. in this way, the system allows optionally the consult with a computerized data base about the drugs prescribed, standardized parameters and techinques performed by the central laboratory. ( )reference to an antibiotics guide regarding becterian sensitivety in our unit, whitch ee checked every six month ( ) access to de questionnaired apache ii to load up new data. ( ) statistcs about patient's admission and discharge. results: once all data collection is finished the system performs the followin duties: ( )detailed drugs interactions, including toxic elements ( )diagnosis starting from the clinical, laboratory and monitoring data. in some cases, it also establishes therapeutic strategies, e.g. a coagulopathy ( ) give the l~narmacological incompatibilities between the drugs p~escribed and %he diagnosis established, and ( )perform dosage adjustments based upon the personal and pathological data. objeatve: to assess the power of diseri~,~ion ofa multiperpose severity score (sai~) when applied to subgroups ofpatieals (pta) according to their lemg~ of ~ay (los) in icu. design: in order to compute the saps probability, a model derived fi~m legible regression was developed. meaumree of calibration (goodmem..of.fit statistics) end discrimination (roc cm've and relative area under the cm've) were adopted in develotammtul asd validation set. the whole databue was ~ati~ed in five gronps reeked on los as follows: los = days, los = - days, los = - da~, los = - days, los > day~. area under the carve (auc) was ud~ninted for each ro~. s~ing: imlimlcus. patents: of ~ pts comec~ively admired ~ a period of three yeet~ ( ) ( ) ( ) , a total of was i~leded in this study. pts without saps, p~ yolmger them yearn, p~ with los shorter ~ hom'~ were excluded from this maly~is. iaterventinns: nose mema'onm~ end result: the logistic model developed gave good remits in terns of calibration md discrimin~on, both in developmental set (do.s g : . , p > . ; auc = . i- . ) and in validation ~t (g.o.g g : . , p > . ; auc = . ..+ . ). auc of each grottp showed a loss in di~zimination (i.e., prediaton) closely related with los, being . i- . in pts with los = days el . ~. ia tm with los > da~ (figure). following the present guidelines of integral management, in order to achieve optimization of sanitary resources and better use of facilities, we feel that the setting up of objetives is a key factor in the continuous process of improvement of quality care. postsurgical intensive care services maintain an interdepent relationship with other hospital services. within the general plan of the hospital it's of the utmost importance to delegate autonomy to the various depertments and service units in determining and achieving objetives. it's also necessary to establish mechanism for coordination of the activities in order to assure the succes of the program. the objetives cannot be improvised, they must be carried out in a specific manner in the following stages: .-analysis of the present situation (starting point). where are we?. defining objetives and making explicit the activities and methods to achieve them is to anticipate the future; it is of the utmost importance to comunicate said plans to all whom affect by encouraging them to attain the desired results. in the present paper we intend to show the guidelines to follow in carrying out a course of objetives. introduction:we presents results related to the quality of life (qol)of critical patients, from paeec project data. material and methods: the paeec project is a multicentre study define the type of patients cared for in spanish icus, and the therapeutic activity provided. ninety-five icus from spain are taking part. this study analyzes the qol of critical patients prior to their icu admission.for the evaluation of qol a questionnaire designed by our team for critical patients was used, with items grouped in sub-scales: physiological functions ( items); functional capacity ( items) and subjective aspects ( items). qol is classified in levels: normality ( points); slight deterioration ( - points);moderate deterioration ( - points); significant deterioration (>i points). the we present results related to therapeutic activity in critical patients and their age, from the paeec project. material and methods: the paeec project is a multicentre study to define the type of patients in spanish icus, and the therapeutic activity provided. ninetyfive icus from spain are participating. this study analyzes therapeutic activity in the first hours as evaluated by tiss, and related factors. results: the sample was , patients, sge . ~ . years. severity by apache ii system was . • points. the tiss score was . • points, distributed as follows: i (<i points): %; ii (i - points): %; iii ( - points): %; iv (> points): %.there is a positive correlation between the level of therapeutic activity and severity by apache ii (r = . , p < . ), and a very weak but negative correlation between tiss and age (r = - . , p < . ), so that an increase in age corresponds to a lower level of therapeutic activity.patients the multivariate analysis of the relationship between tiss and age took into account: severity, existence of previous history, need for mechanical ventilation, size of hospital, diagnosis and mortality. it indicated that there continued to be a relationship between therapeutic activity and age, so that as age increased, therapeutic activity diminished. conclusions: therapeutic activity performed on critical patients is less in the oldest patients, in whom excessively aggressive procedures are limited. a relational data base management system in the icu. c. kotsavassiloglou*, d.matamis, g. dadoudis, j. kioumis, d. riggos. icu dep., g. papanicolaou gen. hosp., exohl, thessaloniki, and * a' neurological clinic of aristotelian university, thessaloniki, greece. objectives: the introduction of the information technology in the i. c. u seems to be unavoidable because of the large amount of produced data and the need for their systematic analysis. such an information system should be a) easy to use, b) friendly to the user, c) powerful and d) modular. on that basis, we created a patient data management system (pdms) according to the expectations of the medical staff of an eighteen bed multidisciplinary icu. methods: we selected paradox for windows v . for the implementation of a relational data base because this program meets the above mentioned criteria. informations regarding the patients include a) demographic data, b) previous medical history, c)diseases upon admission, d)complications during hospitalization and e) outcome data. the diseases' registration consists of items classified in categories upon the principal system affected. specific informations about the need and duration of mechanical ventilation, nutrition, renal replacement, right heart catheterization and icp monitoring are also available. an extension was added concerning icu infections and related informations about antibiotic-resistant pathogens. all icu pathogens can be matched to their resistance or sensitivity and cost of antibiotics. the program can perform queries and various statistical analyses based on complex criteria. new modules can be added later according to the future needs and remarks of the users. results: the program was well accepted by the medical staff and patients were registered as a test. the first analysis of the data related a) observed mortality versus the apache ii predicted mortality, b) mortality according to the age, gender, pathology aud duration of icu stay and c) pathology upon admission and icu related complications. conclusions: the long term use of this pdms can be an efficacious research tool. it can be used in retrospective or prospective studies by addition of necessary modules. the first data analysis revealed the iack of an international diseases' classification system. the development of a worldwide common classification system is essential for the compatibility of the data analysis among various icus. this will allow the realization of multicenter trials on a large scale. s. nanas= n. sphiris, a. precates, a. lymberis, m. pirounaki, and ch. roussos dept. of critical care, university of athens, athens, greece the complexity of the cases submitted to an icu, the variety of underline disease, tbe severity, as well as the large number of substances administered to each patient constitute obvious the need of support with an easy available dss. this system will assure the safety of the administered treatment will help to adjust the dose according to the situation of each patient and it will screen for possible interaction and incompatibilities between the administered drugs. the goal of the present effort is the design and development of a software system acting as a decision support tool to physicians of icu. the application is organised around a relation database management system (rdbms) that consist of: a) all available substances ( . ), b) all generic names of medications available in our country for each substance, c) incompatibilities ( . cases) and d) interactions with other substances ( . cases). the following figure shows the structure of the rdbms. y ta~ortato~ [ c~rs using the stored parameters for each patient the dose and the rate of administration of selected substances will be possible to calculate. the continuous monitoring of the treatment for each patient supports the medical staff to make the necessary changes of the prescriptions. the application is currently developing in wireless pen based computer systems which place patients at the centre of "islands of information" located throughout icu. in conclusion this dss is a powerful and useful tool for icu staff because it provides without additionai work to the routine of daily practice, the currently available information for each order concerning drug interaction and incompatibilities as well as treatment monitoring is to obsea~ among critically ill pfdieats, stdjdivided following the diagn~s at the adn~ssio~ the diffmeax:es in the ~ and oxyplx~efic l~mmems bawe~ strvwors [s] and non sumvors ins] and to test the pc~'bih'ty to have soar survival criteria, as earliest as tx~able. method~ :we made a ~ study on consexa~e ~ilically ill paliffas, subdivided in series following the diastases at the admission: medical pafiea~ ( s and ns), surgical patients ( s and ns), a~d poliwauntas ( s and ns). follow up was done at d,.ays from the admission in ice. all the patienls were ramitored with a ~ c~eter and laeno:lymmi. "c and o .x.xyphorefic txuamaers va:~e couected at fin~es (t): at fiae ~draission (t ), at x~ars from t (t ), at (f ), (y ), (t ), % (t ) and horus from t cf ). in~,h ~ies, for ~y ~ a all the lin'~ n~an and sandaid d~viation was ~ tx~h for s and for ns. th~ betw~ s and ns tl~ roeaas of ~h porarneter ~e ccmpared tt~ng t-lest and p < . w~ considered ska~ significant in each series in the t wheae the mast significative diffemx:as ~goeamd bet~en s and ns, we made a txedictive criterion, asamting as predictive indices for stnvival the i:r values, higher or lower than flae treans of the ~rar~ers of au flae patients, axx)rdhlg to those ones t~iatistically diff~'e~ betw~m s and ns. fhmlly xse co:weatxt onaong the series the nrametees of the st~rs with the analysis of variance, to daserve the lxjsable differealt irea~ of sty hflices, following the diagn~s of admission: :nedkal, angical patient or poll~tam results: we c~ld not find ~ predictive criterion for politraonaas, perhaps ixx:ause of the few ntanber of l~fients. for high ri~ saw~cal patieras the following criterion at t has a sensitivi .ly of ~ ,and a ~ecificity of . %: sv > . nffmin/n~, map> mmhg, pmap< nmalqg cvp<i nunhg will nmah& lvswi> g m/m , sxo > ~ do > mlhnin/m , o er< %. for lx~dical l~tienls at t the following criteric~a has a ser~tivi.ty of % and a ~zificity of . ~ cvp< . mn~g, sao > %, s,g) > ~ vo i< ml/nfin/m , o er< %, shunt< % survlvops' data of the series ~ signitic~atly differenl~ both for the t~mody~nic a~ for fl~e ox rphomfic lxlmn~s; moreover we ~ that the vatt~ of hemodynamic mad ox.~ho~tic indices were higher in politrautms. conclus'ions: acx~ording to the fftffe~mt patho!o~es, the ~ rnelabo~c needs are diffeten~ so that it is juslified to mash ~ the~alceutic goals, following the type oflmthology. hen~ we foru~d for high ~k mrgical pmka~ and for medical patier~s assme, ff mllslied, a good prognosis while, if n [ ntljsfled~ the plinsliclioil ofdl~tth is no[ g(ioct finally, ab~ high iis~ supgical palieaats, according to what other atmhors say, txatws sh ~'n~ers ' therapeutic goalsvvould seem inadeqt~te, bec~jse they need a gear physiologic and themtx~ic elth~ in rdation to the rretabolic needs. figure ) . thus, the smaller european nations had a greater participation than ~e larger ones, with the exception of norway. a similar result was evidenced for contributions to intensive care medicine (figure ). these findings can be explained by different submission policies and language banners. however, there was no significant correlation with the gross national product of each country. conclusion: we conclude that the smaller european countries generally contribute more to international intensive care journals than the larger ones. objectives: to evaluate the agreement between a new and three old methods measuring ctp and to assess their reproducibility. methods: we studied patients ventilated with a siemens c respirator. we measured ctp by dividing the tidal volume with the increase in airway pressure (paw), either with the respirator setting used (ca) or with a fixed setting (cf). by modifing the inspiratory time (ti) without changing inspiratory flow, we were able to deliver two series of inflations ( , ,... ml) before and after curarisation of the patient. the same volumes were also inflated in paralysed patients with a super syringe. at the end of each inflation a plateau of sec was performed and paw was recorded. the above three sets of pressure-volume (pv) points were used to reconstruct the corresponding pv-curves (( , c , c the new method for ctp measurement without a super-syringe had the best reproducibility in paralysed patients and gave similar results without curarisation in the majority of them. however, agreement between the methods tested was unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of ctp measurement in icu patients. m kunert, r.sorgenicht, l.scheuble, k.emmerich, h.g ker med.clinic b (dept.of cardiology) i heart center of wuppertal/university witten-herdecke,germany objective to determine the accuracy of activated partial thromboplastin time (apl-l) and activated clotting time (act) studies when samples are drawn through heparinized central venous catheters (cvc). methods a total sample of paired act/p't-/" values was analysed in patients ( m., f., + y.) for monitoring heparin therapy.all patients had a cvc (certofix trio,braun,frg) in the internal jugular vein receiving a continous infusion of . u heparin via the central catheter.act (hr-act, hemotec,usa) and ap'i-f (neothromtin, behring,frg) samples were drawn from the cvc using the double syringe technique (removing and discarding ml blood before drawing the sample). these blood samples were compared to act/ap'cf blood samples obtained by venipuncture (v.fem.) at the same time, act values were analysed directly in the intensive care unit (icu),api-i samples were measured in the hospital laboratory within minutes. results ac-i -~ pi-f~ cact/~pi r = , ) cvc samples + + . v.femoralis samples " + + p-value n.s. n.s. conclusion there is no difference in heparin anticoagulation studies drawn from heparinized central venous catheters compared to those obtained by femoral venipuncture,withdrawing ml blood prior to obtaining the blood specimen is a safe way for eliminating heparin contamination.not only the aptt test but also the act test is a useful method for heparin anticoagulation assessment in the icu. objectives: evaluation of the delicate balance between filter-coagulation and patient-hemorrhage using heparin as anticoagulant in continuous renal replacement procedures. methods: from january through august , we studied filter surviva[ and hemorrhagic complications during filter periods in critically d[ patients, treated with continuous arterio-venous hemo(dia)filtration, with special emphasis on the heparin dose, concurrent use of coumarins, systemic activated partial thromboplastin tirne(aptr), platelet count, mean arterial bloodpressure and the type of filter used. results: filters ( %) were disconnected because of coagulation. mean survival of multiflow an filters was twofold shorter compared to survival of fh gambm filters. a total of hemorrhagic complications occurred of which three patients died at aptt values of respectively , and seconds. after adjustment for mean arterial bloodpressure, platelet count and the type of the filter, the risk for filter-coagulation decreased % (relative risk . , %c . - . ) for each ten seconds increase in aptt. the risk for patient-hemorrhage increased % (relative risk . , %ci . - . ) at an aptt-increase of ten seconds. the occurrence of filter-coagulation and patienthemorrhage was not correlated with the administered dose of heparin. concurrent use of cournarines had a positive effect on filter-survival, without increasing the overall incidence rate of patient-hemorrhage. conclusions: the systemic apt]" is a good predictor of the risk for filtercoagulation and patient-hemorrhage. heparine therapy seems optimal at an aptt between and seconds, although one should realize that fatal hemorrhagic complications still can occur. objectives: the alterations in vascular tone which are primarily regulated by adreno-sympathetic tone(ast) are compensatory responses in hemorrhagic patients. this study was designed to evaluate the correlation between vascular tone and ast in patients with hemorrhage, methods: the vascular tone was expressed by volume elastic modulus (ev) that is defined as; ev = ap/(av/v) (ap; the arterial pulse pressure, av/v; the volume change ratio). ev was measured using a non-invasive transmittance infrared photoelectric plethysmography (tipp) and a volume oscillometric sphygmomanometer . we prospectively studied patients with hemorrhage. the initial ev measurement was performed on arrival and repeated for a hours duration. as a parameters of ast, serum concentrations of adrenalin (ad), noradrenalin (nor), plasma renin activity(pra) were measured simultaneously. we analyzed the correlation of ev and conventional parameters to ast by multivariate statistical analysis. results: ev values at transmural pressure mmhg on admission and hours later were respectively . + . mmhg, . +_ . mmhg (mean + sd). systolic pressure(pas) and serum hormones on arrival and hours later were respectively, pas; . _+ . , + . mmhg, ad; . _+ . , . _+ . ng/ml, nor; . _+ . , . + . ng/ml, pra; . _+ . , . _+ . ng/ml/hr. the ev values correlated significantly with ad (r= . , p= . , n= ), nor (r= . , p= . , n= ), pra (r= . , p= . , n= ). by multivariate statistical analysis, ev correlated more significantly with ad and nor and pra (p= . ) than the conventional parameters such as pas, heart rate and pulse pressure. conclusions: the alterations of ev correlates closely with ast. the compensatory mechanism in hemorrhagic patients can be detected noninvasively by ev monitoring. obiectives and method: autologous oxygenator blood was processed at the end of cardiopulmonary bypass (cpb) by either hemofiltration (hf , , m , fresenius) or by cell washing with a onntinous autologous transfusion system (cats, fresenius). prospectively the blood of patients for each group was processed and then retransfused intravenously to the patient. besides, volume and time requirements, standard hematologic chemistry, coagulation and complement activation were measured. results (mean values for oxygenator blood at the end of cpb, and results of concentrate after processing by filtration or washing): both processing techniques show excellent hemoconcentration of the diluted cpb blood with a good transfusion effect for the patient. filtration retains all plasma proteins and large molecular weight plasma bound waste products. in contrast, cell washing with cats significantly depletes plasma proteins and waste products. the newely developped cats machine gives eonsisinnt laboratory result in a fully automatic continuous processing mode. in conclusion, both filtration and washing are effective for processing cpb blood. filtra tion yields a highly concentrated whole blood, whereas cats washing produces a high quality autologous erythrocyte concentrate. soluble fibrin has during the last years gained interest as a marker for the activation of the coagulation in connection with various clinical conditions, e.g. disseminated intravascular coagulation, deep venous thrombosis and myocardial infarction. elevated levels of soluble fibrin in plasma can be detected by the chromogenic assay coaset fibrin monomer, relying on the ability of fibrin to enhance the tpa-catalyzed conversion of plasminogen to ,plasmin. using this test, it has been shown that the level of soluble fibrin can be correlated to severeness of illness in critically ill intensive care unit patients. a revision of the coaset fibrin monomer kit has now been made and the new product, coatest soluble fibrin, is considerably more convenient to handle and gives higher resolution at low fibrin levels. the test is performed by the addition of a buffer dilution of the plasma sample to a microstrip well containing the colyophilized mixture of tpa, plasminogen and the plasmin specific cbromogenic substrate s- . the reaction is allowed to proceed at,. room temperature for minutes before discontinuation. the absorbance at nm, measured in a microplate reader, is proportional to the content of soluble fibrin in the sample. the assay is carefully standardized and calibration curves are provided in the kit. the convenient and rapid assay procedure makes the coatest soluble fibrin test well suited for single test analysis in acute situations. objectives : blood coagulation abnormalities have been reported in the systemic blood of patients with cerebral lesions. the physiopathology of such events is not yet completely understood. we compare the coagulation profile of blood from the right jugular bulb with systemic blood of patients with head injury. methods: we studied patients, who were admitted to our neurosurgical intensive care unit between january and march with head injury and no other associated pathology (age - yrs), a glasgow coma score <= g, no abnormality in baseline coagulation profile and no history of coagulopaties. the patients did not undergo angiography. a one-way gauge certofix catheter was inserted through the right internal jugular vein up to the jugular bulb. an identical catheter was inserted through a subclavian vein. blood was sampled from either catheter (a=atrial; j=jugular) - hours after trauma (t ) and t hours later (t the inddence dpontolx'rative thmmhi~e and haumord~gic complieatiom were assessed in padents treated with indobefen, heparin calcine caeca), low mollecolar weight heparin (lmwh) (f.nosheparin) and undergoing hemodiludun, blood predeposhing, intra mad postoperative blood saving. ]'he indolmfon tempota~.norks platelet aggregation through ,,elective inhibition of the cyclatygenasis and thus atacbldonicadd( ).tbe n'mimum effect occurs after hours from the fast administration and is still present after hours. ~- patients, mean age --- yrs., weight --- kg were studied. ( . %) were male and ( . %) female. onderwent hip prosthesis ( previously plate and screw removal) hip revim'un ( stem, cop and stem + cop), tutal knee prosthesis, in the st anaesthesidogy depl from - to - - . as for antithromboembolic ptephylam, apart from hemodihitiun pts were with treated indobufen ndo), with heparin ealdum caeca) and with low mo!lecular weight hepam (lwr, ). as the slightest clinical and/or imtmmental suspidon of deep vein thrombosis (dv'i') or polmonary umbolism(pe), a phlebogram or sdndgram were respectively carried out. -the inddence of homologom transhisiom was significandy lower (p= . l) in the padeats treated with indobufen ( . ) compared .'ith heca ( . %). the con~gency table shows statistical signifleance for the use of heca in patients with vein deficiency in the lower limbs, past dvr and/or pe, coronary heart disease (cdh'), while there is no correlation for renal, cardiac or liver defidency, obesity, systemic hypertemion, atrhythmy, diabetes, chronic bronchitis and rheumatoid arthritis. by comparing the postoperative cumplications with the risk factors, there ks a highly significant correlation (p= . l) between cdh and thrombotic and humord~agic complieatiom (pe, death, he~atoma, die use of hum_ologous blood). thee data show that hep~in, preferred in patients with c'dh, roost likely for leagal-tuedical reasons, did not have the de~'ed effect. conclusions -the stastisfical aar~ais shows ~nifieanfly different efflea~ (pro . ) between the therapies (see table) : it can be seen that in patients undergoing autotramfusiun and hemedihidon, indobufen produo~ a lower incidence of haemotrhagic complieatiens compared to heca and lmwh and is more effective in the prevention d ~c complications at clinical e~idence. the duration of i~toperadve hospital stay is signi~cantlylonger for patients transfused with homologous red ceils and treated with hec, .a ( . -+ . days) and lmwh ( . +- a days) compared with indo(ll. _+ a days). one of the main causes for postoperative complications in major orthopaedic surgery is postopemtive bleeding with local effects in the operation site (hematomata, pain and delayed mobilization) and/or systemic and subsequent cardiodrculamry repercussions that are sometimes severe. the aim of this study is to assess the possibility to apply a new system of monitoring, control and saving postopemtive blood loss from the drainage. the bt recovery dideco (marandola, modena-italy) ~ used since it is the only apparatus capable of doing this. the apparatus consists of a pressure transducer, adjustable from - a + mmhg, which activates a peristaltic pump connected m drainage robes. the bt recovery display shows hourly bleeding in the first hours, total bleeding, time passed since the start of monito~g and subsequent salvage and the aspimtioo pressure on the drainage robes; the latter is inserted at - mmhg and then modified according to bleeding/minute, g bt recovery also has an alarm that sounds automatically if.' blood loss is more than ml/hour; air is in the circuit; the batteries are running low. materials and methods: pts were studied ( m and ~), aged . -+ .lyears, basal hemoglobin . -+ (range . - . )g/all, treated from st january, to mst december, in the st service of anesthesia and intensive care unit of our hospital. the patients underwent the following surgical treatment: total hip revision ( pts), cup revision (~ipts), stem revision ( pts), total knee revision ( pts). the average dumtion of the operations was -+ min. intranpemtive monitoring and blood salvage was applied to all patients. genera! anesthesia was used on pts. and integrated (epidural analgesia + light general) on the remaining t . anttthromboembolic prophylaxis consisted of external pressure bandage, isovolemic hemodilution with iodobufen in ( . %)pts., calalc heparin in ( . %)pts., low molecular weight heparin in ( . %)pts.; pt did not give a predepoalt of blood, gave unit, pts units, pts units, pts units. the data obtained was statistically analysed using contingency tables and anova. results: average intmop salvage was -+ ml, average postop salvage was -+ mi the average intra+postop +- ml. average postop loss was -+ ml. the global incidence of postop complications was: h~natomata . %, dvt . %, pulmonary thromboembolism , , myocardiac ischemia . %, acute myocardic infarction . %, respiratory deflciecy . %, arrhythmia %, cystitis . % there were nn complications in . % of pts. postop bleeding over ml in under minutes (with bleeding alarm activation) occurred in pts ( . %). this sta~tically correlates only with the type of operation performed (more frequently in total hip revision p= . ) and with a significant decrease (p~ . ) in the pruthrombic activity detected about hours after the operation. this bleeding, also made the alarm sound, calling the attention of staff who could act accordingly, by making the drainage pressure positive and incre~sthg the tension of the external pressure bandage. conclusions postop monitoring, control and blood loss salvage combined with predepoalting and intmop salvage has enabled allogenic transfusions in % of cases to be avoided in operations with high postop blood loss like hip or knee revision. the usefulness of the system can be seen by the fact that in the patients with so much bleeding to set off the alarm, there was no significant difference in the incidence of allotransfusions and complications. references )borghi b., bassi a., de simone n., laguardia am., fonnaro g. an injury of the brain may result in various disorders of hemostasis caused by the release of • into the circulation through a damaged blood-brain bar tier. disseminated intravascular coagulation(dic) is one of these disorders. it is a freguent but relatively rare ly diagnosed complication of subaraohnoidal haemorrhage. the aim of this study was to evaluate some parameters of both blood coagulation and fibrynolisis in patients with sah.in addition one wanted to find out wh~ther potential changes correlated with the pa• condition in the acute phase of sah and whether they influenced the course of this disease. patients with sah were studied. in of them sah was due to closed eraniocerebral injury and in the rema ining resulted from vascular malformation. the following parameters were evaluated:the prothrombine time,the activated partial thromboplastin time, the thrombine time,level of factor v,fibrinogen degrada tion products and fibrin monomers. the results let us show the presence of oic in patients with closed craniocerebral injury and in with vas. cular malformation despite the lack of clinical symptoms the tests in posttraumatic patients and in patients from second group showed incomplete dic.on admission patients with such changes in measured parameters were in poor condition.the course of the disease and the effe cts of treatment were also worse in these patients. the results showed ihal in patients with sah complex disorders of both coagulation and fibrynolisis occur, and they depend on clinical condition of the patient. they also influence the course of the disease. methods : charts of all patients admitted with d.i.c. over a ten year period ( - ) were reviewed. diagnosis of dic was based on the association of fibrinogen < g/ -platelets < / -fpd > ~tg/ml in the hours of the admission. results : patients -mean age + y -saps +_ -gestanional age _+ weeks -the two first conditions associated with d.i.c. were placental abruption ( %) and preeclampsia or eclampsia ( , %). bleeding episode was present in pts ( %) and surgical treatment has always been necessary. pts ( %) were given packed red ceils ( + u) and fresh frozen plasma ( + u). patients were given platelets packs. heparin was never administered. pts required mechanical ventilation and two patients hemodialysis. all the patients survived. correction of prothrombin time (p.t.) and fibrinogen (f) was quick (p.t. at t h ~ % -f at t h , + , g/i). but platelets count remained low (plat. at t h + / ) -no difference was observed in patients who received platelets. conclusion : prognosis of critically ill o.p. is good. blood loss is the main complication. correction of hypovolemia and anemia with concomitant surgical treatment are essential. the administration of coagulation factors or platelets is still under discussion. objectives: to evaluate the effects of antithrombin iii i at-iii) and a protease inhibitor, gabexate mesilate foy), on the coagulation and fibrinolysis in disseminated intravascular coagulation (dic). methods: after the approval of our institution and consent from patient's family, patients with a dic score ( , japan) more than points (dic or having a risk for dic) entered this study. they were randomly divided into two groups, foy (i- mg/kg/h for days or more) treated group and no foy group, each of patients. platelet count (plt), fibrinogen (fen), at-iii fibrin degradation product (fdp), d-dimer (do), fibrin monomer (fm), thrombin-antithrombin complex (tat), plasmin-plasmin inhibitor complex (pic), and prothrombin time ratio (ptr) were measured before the start of treatment (at admission) and i, , and days after the admission. at-iii at units for days was administered if the at-iii at admission was less than %. finally the patients were divided into four groups: group a, foy (+) and the at-iii ~ %; group b, foy (+) and the at-iii < %" group c, foy (-) and the at-iii %; group d, foy (~) anffthe at-iii < %, each of patients, to match the patients for backsrounds. all parameters, dic score and survival rate in a month following treatment were compared among the four groups. results: the at-iii and plt from day to were significantly higher in groups a and c than in groups b and d. the fdp, dd, tat, and pic after treatment decreased significantly from the baselines in groups a and c but not in groups b and d. the fgn and fm were not significantly different among the four groups. the ptr decreased in groups c and d but increased in group b. the dic score decreased significantly in groups a and c than in groups b and d. survival rates were %, %, % and % in groups a, b, c and d, respectively, although not significantly different. conclusions: in patients with dic or a risk for dic, foy had no expected effects but at-iii had suppressive effects on the coagulation and fibrinolysis mechanisms. a prognostic factor ? carbon monoxyde intoxication is a classical complication of inhalation injury. carbon monoxyda is also physiologically produced during the heme metabolism: heme is conversed to bi]irubin by the hemeoxygenase which is an intracellular stress protein. icu patients (pts) were studied prospectively for apache ii score and carboxyhemnglobin (hbco) arterial level to assess if hbco level could be correlated with the severity of the pts. objective: to evaluate a new technique of non-surgical tracheotomy. patients: adults, mean age years and children, mean age months ( me.- yrs). method: through a needle inserted in the trachea, a guide wire is retmgradely pushed out of the mouth and attached to a special device formed by a flexible plastic cone with pointed metal tip joined to an armoured tracheal cannula. this device is then pulled back through the oral cavity, larynx and trachea, and outwards across the neck wall by applying traction on the wire with one hand and counterpressure on the neck wall with the fingers of the operator's other hand. when the cone and / of the eannula have emerged, the cannula is cut off from the cone, straightened perpendicular to the skin, rotated and advanced caudally to its final position. results: endoscopic control facilitates and improves the safety of all manoeuvres. the pointed cone easily pierces the tissues, and the cannula is extracted without difficulty since it has the same outer diameter as the cone. tissue adherence around the cannula is absolute thus preventing local inflammation. the time in apnea required for dilation and cannula placement does not exceed see., and it is well tolerated because within safety limits in patients hyperventilated with oxygen. only one case of bleeding occured in a patient on dialysis with severe coagulopathy. autoptic findings in subjects who died due to progression of primary disease showed a very regular stoma with an almost complete lack of hematic and flogistie infiltration in recent tracheotomies. .conclusions: translaryngeal tracheotomy (tlt), by virtue of its greater inherent safety and lower tissue trauma than percutaneous techniques, can also be carded out in infants and children, a severe test bench for any tracbeotomy technique. further specific indications are recently stemotomized patients, since tlt is associated with a low rate of infection, and short term tracheotomies after laryngeal surgery, to prevent obstructive complications. references: fantoni a., translaryngeal tracheotomy, apice, ed. gullo, trieste, , . background: inhalation of no has been shown to reverse hypoxic pulmonary vasoconstriction , to reduce pulmonary pressure in pulmonary hypertension of different origin and to improve gas exchange. in putmoflary embolism, pulmonary hypertension is caused by mechanical vascutar obstruction and by reactive vasoconstriction. the effects of inhaled no in putmonary embofism has been partiatly studied' the purpose of this study was to investigate and determine the effects of no inhalation on pulmonary hemodinamica and gas exchange in a hypoxic canine model of pulmonary embolism. methods: two groups of adult mongrel dogs were studied: group (control} dogs and group (no inhaled) dogs. both groups were anestesized with tiopental, mechanically normoventilated with an hypoxjc mixture of and n~ (f[q , ) and instrumented (swang-ganz catheter, femoral artery catheter) pulmonary embolism (pe) was induced by fisher's method s. no inhalation ( ppm) in group was started rain. pdor to pe and kept constant throughout the experiment. no inhaled concentration was analyzecf by chemiluminiscence technique. pulmonary artery pressure (pap), central venous pressure and sistemic arterial pressure were continuosly recorded. cardiac output, artedat po~ (pan ) and mixed venous po~ were measured in both groups under hypo)dr conditions, before pe and , , and rain. after pe. pulmonary vascular resistance (pvr) and gas exchange (pao fio:~ ratio), were calculate using standard formulas. data were process and analyzed with non pararnetdc test, and reported as mean -so and statistical significance was considered if p < , . : no produced an increase in arterial oxigenation (pao /fio~ ratio) and reduced pap before pe induction in group . after pe we found no significant difference with .respect to the time eour.se of pap, pvr and gas exchange between beth groups throughout the experiment. probably, the severe mechanical obstruction produced in pulmonary embolism masked the small effects of no inhaled. obiectives: blood volume measurement would be useful in critically ill patient management if it were easy to perform. this is not the ease and current methods are based on radiolabelled red cell dilution. inhalation and uptake of a known mass of carbon monoxide (co) gas and measurement of earboxyhaemoglobin increase can give results accurate enough for clinical use. this requires a rebreathing system providing oxygenation and carbon dioxide removal, yet complete retention of all carbon monoxide administer&l, and so most authors hand ventilate with a bag and waters soda-lime canister, adding oxygen as necessary. we aim to popularise this method by; i)design of an automatic co administration system driven by the itu ventilator and ii)writing of software for a portable computer to perform all necessary calculations method: we show the computer is use estimating the co dose required and later estimating the blood volume. we also show the new gas administration system. this is a fully closed circle attached to a "bag in bottle", driven by the ventilator. the novel feature is the mechanism by winch driving gas (set to % ) spills automatically into the circle, balancing o uptake by the patient, yet allowing no co loss. conclusions: this equipment is easy to use, reduces human error and allows optimum ventilator settings to remain. the operator merely administers the volume of co determined by the computer and takes blood on two occasions. carboxyhaemoglobin measurement is easy to perform, thus there is a cost saving also. with our modifications use of this technique may potentially become more widespread, the video demonstrates the method in use in our itu. - ( %) underwent conventional surgical therapeutics. " ( %) with resection of tracheal stenosis with end-to-end anastomosis(rts). i ( %) with broncoscopic dilatation. one patient died and the others still have stable patency(sp) without continued treatment. - ( , %) have received endoscopic laser ablation with or without calibration tubes. of them ( , %) are receiving continued endotracheal treatment until now. ( , %) have sp wihout continued treatment. -i ( , %) endoscopic laser therapeutic case turned to rts and is having sp. conclusion: conventional surgical aproach has been progressively replaced in our hospital by endoscopic laser ablation and silicone calibration tubes. this study suggests that these technics are effective and could be the elective treatment for iatrogenic stenosis. obiectives: hemorrhagic disorders due to thrombocytopenia and thrombocyiopathia remain one of the most serious complications during long-term extracorporeal membrane oxygenation (ecmo) in patients with severe acute respiratory distress ~drome (ards). in the presented study, nitric oxide (no), kwown as a potent endogenous platelet antiadhesive, disaggregating and antiaggregating compound, was evaluated for its possible antagonistic effect on platelet trapping when added to the gas compartment of membrane oxygenators (mo). meti~ods: two parallel separated extracorporeal circuits, consisting of heparin bonded hollow fiber oxygenators (minimax, medtronic, carmeda eioactive surface), tubing systems, low pressure reservoirs, and roller pumps were prepared. for each measurement, a pair of circuits was simultaneously filled blood from the same volunteer. low-heparinized fresh warm blood was obtained from four healthy volunteers, who had no drugs for at least two weeks. the gas inlets of both oxygenators received dry gas ( % oxxygen, % carbon dioxide, % nitrogen); gaseous no ( ppm) was added to the gas of one of the oxygenators (no-mo), whereas the other one (mo) was used as control. after minutes no gas was switched off, so that the no-mo received no more no, and no was added to the gas inlet of the membrane, which had no no before_ to assure iutracircnit volume stability, drawn blood for measurements was replaced with saline, and platelet counts were corrected for dilution by hemoglobin values. the mean of four platelet counts (coulter counter) of each timepoint (start, , , , , , , , and minutes) was used for statistical analysis (paired sample t-test). results: in the no-mo platelets remained at + , % (percentage of baseline value, mean -+ sd) until min. in contrast, platelets of the mo continuously decreased after start and were significantly lower after minutes ( , + , % vs _+ , %(p< . ); min. , -+ , %vs , _+ , %(p< . ); min. , _+ , % ( p < . ). after switching of no gas to the mo, further decrease of plateleta was stopped and platelets remained at , +_ , % until termination of circulation. platelets of the former no-mo decreased slightly after cessation of no gas to , _+ , %. conclusions: these data indicate that gaseous no significantly attenuates platelet trapping in hollow fiber oxygenators, when added to the gas compartment. this might be a new therapeutical approach for membrane oxygenator induced thrombocytopenia during long-term ecmd. objectives: nitric oxide (no) plays a pivotal role in regulation of vascular hemostasis. several studies elucidated the antiadhesive, antiaggregating, and disaggregating properties of endothelially synthesized no to platelets. additionally, agonist-induced no production in platelets by the l-arginine-no pathway was found as a negative feedback mechanism after platelet activation. although noplatelet interactions were intensively studied by several investigators, no data exist, about changes in platelet surface molecule expression in no-modulated platelets measured by flow cytometry using monoclonal antibodies (moabs). methods: p-selectin (alpha-granule-membrane protein, gmp- , cd p) and glycoproteiu (gp , lysosomal protein, cd ) are expressed only after platelet activation and degranulation. activation was quantified in thrombin ( . u/ml) and adp ( . ram) stimulated platelet rich plasma samples (prp). blood was obtained from healthy volunteers (n= ), who had no drugs for at least days. for evahiation of no-modulated activation, the spontaneously noreleasing compound sin-i ( . mm) ( -morpholino-syndonimin-hydrochlorid) was added in parallel prepared samples prior to the addition of agonist. platelet surface molecule expression was evaluated with moabs directed against cd a (gpilbliia, fibrinogen-receptor, phycoerythrin(pe)-conjugated), cd p (fitcconjugated), and cd (fitc). only cd a-positive signals were gated in sideangled light scatter, and assayed for activation marker expression (defined as percent of gated population). results: basal p-selectin expression was . + . %, and increased to . _+ . % after thrembin-activation, and to . + . % in adp-stimulated samples. addition of sin- attenuated p-selectin expression to . - - % in thrombin (p<. , two-tailed paired t-test), and . + . % (p<. ) in adpactivated platelets. basal gp expression was . _+ . % and increased to . + . % in thrombin, and to . _+ . % in adp-stimulated samples. with sin-l, gp expression decreased to _+ . % (p<. ) in thrombin, and . : . (p . ) in adp-stimulated samples. conclusions: these data implicate, that no leads to a significantly reduced activation of surface molecule expression in thrombin and adp-stimulated platelets. in addition, flow cytometry might be a useful tool for studying modulation of platelet activation by no or no-releasing compounds. introduction: acute cadmium poisoning is very rare. on initial presentation may mimic metal-fume fever, but acute inhalation cadmium toxicity may produce fatal chemical pneumonitis. case report: we present a case of acute fatal respiratory failure secondary to cadmium-fume irthalation. a year old patient was trasferred from another hospital with acute respiratory failure presumably due to pneumonia. the last days before he had had commom cold symptoms. he had been cutting with a welder during one hour without any respiratory protective measure. three hours after exposure he developed progressive dispnea and was admitted to hospital. with presumtive diagnosis of respiratory infection, antibiotics were begun, however be failed to improve. all microbiological studies were negative. chest x-ray showed bilateral diffuse infiltrates. on seventh day he needed intubation and mechanical ventilation and on th he was admitted to our icu. antibiotics were stopped and new microbiological studies were performed including brochoalveolar lavage and virologic studies. all results were negative. he developed progressive hipoxemia and hipercapmia and finally, multiorganic disfunction syndrome. he died days after exposure. the metal he had been working with was a % cadmium alleation. blood cadmilam concentration days after exposure was . mcg cd/g cr, and urine cadmium concentration was . mcg/l. on postmortem examination, tissue cadmium concentrations were: blood ng/ml, liver ng/g, kidney ng/g and lung ng/g. these values confirm that cadmium was the cause of the fatal respiratory illness in this patient. conclusion: this case evidences the considerable hazard of acute poisoning after inhalation of eadmium-fume and stresses the need of appropiated safety measures against metal-fume poisoning. aim : lactic acidosis is considered the hallmark of cyanide poisonirig. however, the relationship between plasma lactate and blood cyanide levels has not been determined. the aim of this study was to determine the significance of plasma lactate concentration (plc) during the course of cyanide poisonings. methods : the patients were included according to the clinical suspicion of pure cyanide poisoning at the time of presentation. fire victims were excluded. serial blood samples were collected before and after intravenous hydroxocobalamin (hoco). blood cyanide concentration (bcc) was measured colorimetrically. plc was measured enzymatically. results : patients were studied. on admission, plc ranged from . to mmol/l, and bcc from . to gmol/l. mean systolic blood pressure was • mm hg, mean arterial ph . • . , mean anion gap was . + . mmol/l and mean pao . • . kpa. three patients died. before antidotal treatment, there was a significant correlation between plc and arterial ph (p = . ), anion gap (p = . ) and bcc (p = . ) but not with heart rate, pao , paco and blood glucose, or blood pressure. during the whole course of the poisoning, a plc _> retool/ was a sensitive and specific indicator of a blood cyanide concentration > ~tmol/ . sustained catecholamine administration reduces the correlation coefficient. conclusion : baseline measurement of plc allows assessment of severity of acute cyanide poisoning. thereafter, plc may be used to assess the adequacy of antidotal treatment, more especially in patients not requiring sustained infusion of catecholamines. aim: the aim of this case report was [o study the correlation between the plasma lactate levels and several clinical, biological, and toxicological parameters serially measured during the course of a cyanide poisoning treated with a high dose of hydroxocobalamin. a -year-old male ingested potassium cyanide leading to cardiac arrest. cpr was performed prior to hospital arrival where the patient received g hydroxocobalamin. sbp rapidly returned to normal allowing withdrawal of epinephrine. the patient remained comatose and died from brain injury days after the ingestion. methods plasma lactate and blood cyanide levels were measured serially. blood cyanide levels were measured using a colorimetric method.~ plasma lactate levels were measured using an enzymatic method. for correlation spearman rank correlation test was used. results. initial plasma lactate and blood cyanide levels were mmol/l and gmol/l, respectively. there was no overall correlation between sbp and either blood cyanide or plasma lactate levels. similarly, there was no overall correlation between arterialvenous oxygen saturation difference with either blood cyanide or plasma lactate levels. in contrast there was a strong correlation between blood cyanide and plasma lactate levels (r= . , p< . ). the time-course of the blood cyanide concentrations was described by a mono-exponentiai decay (r = . ) with a blood half-life of . h. similarly, the time-course of plasma lactate levels was described by a mono-exponential decay (r = . ) with a blood half-life of . h. discussion. in this case of acute human poisoning, sbp was a much poorer indicator of continuing cyanide effect both before and after antidotal treatment, than was lactate production. this suggests a potential clinical role for following serial plasma lactate levels as a marker of the evolution of cyanide toxicity. aim : cyanide (cn) poisoning in fire victims is frequent and rapidly fatal. in a prospective study we tried to assess the clinical tolerance of a high dose of hydroxocobalamin (hoco) administered at the scene of the fire in fire victims suspected of cn poisoning. methods : inclusion criteria : soot in mouth or sputum ~ any degree of neurological impairment. exclusion criteria : children, pregnant women, burns of total surface body area > %, multiple trauma. protocol desigrl following examination and the collection of a blood sample in dry heparin, a g dose of hoco ( g in case of cardiovascular collapse) was administered intravenously over min. the systolic blood pressure was monitored before and after the administration of hoco, and one hour later. results : there were females and males. the mean blood cn concentration was • pmol/ . the mean blood carbon monoxide was . • . mmol/ . nineteen fire victims eventually died. among the non-cn-intoxicated patients (blood cn < ~mol/ ), there was no significant change in arterial blood pressure. in the cn-intoxicated patients (blood cn > gmol/ ) a significant increase in blood pressure was observed both immediately (p < . ) and hour later (p < . ) after the admistration of hoco. no allergic reactions were observed. conclusions : in fire victims with cyanide poisoning, the administration of a high dose of hydroxocobalamin was associated with an improvement in systolic blood pressure. hydroxocobalamin is well tolerated in fire victims without cn poisoning. objectives: tricyclic antidepressant (tca) overdose can lead to serious complications including cardiac arrhythmias [ ] . because of the known risk of early deterioration and the implication for management, emergent evaluation is essential. we determined the diagnostic usefulness of the electrocardiogram (ecg) in tca poisoning. methods: retrospective study of all patients with tca intoxication (pos. ,toxicology screening in urine and/or pos. history) in a -beduniversity hospital from through . the severity was graded with mild= no symptoms or agitation; medium= disorientation, somnolence, tachycardia, or convulsions; and sever~ coma, significant arrhythmias or death. we analysed the first ecg after admission with a special emphasis on qrs-and qtc-intervals and the terminal ms frontal plane qrs-vector (tqrs), which, was reported to lie typically between + and * + + • the best correlation with severity grade was found with qrs-and qtc-duration (p= . ), the tca-dose (p= . ) and hf (p= . ); tqrs did not correlate. patients died ( . %). conclusion: qrs-and qtc-prolongation in the admission ecg, and the reported dose of ingested drugs are useful predictors for severity of poisoning due to tricyclic antidepressants. we did not find additional benefit in determining the terminal ms frontal plane qrs-vector. objectives: since treatment of amphetamine poisoning is usually symptomatic and often associated with a fatal outcome, a search for specific drugs to help the amphetamine-intoxicated victim is sorely needed. methods: we report a case of a suicidal ingestion of large amounts of the amphetamine-derivative , -methylenedioxy-ethamphetamine (mdea) and heroin (diacetylmorphine) and present the hypothesis that the two drugs produce opposing clinical effects. results: a year old caucasian male was admitted to the emergency ward because of acute-onset confusion. at presentation, he was agitated and showed increased muscular rigidity. he had taken tablets of "eve" (mdea, approx. g) and g of "smack" (heroin) by oral route approximately h before admission. because of rapidly progressive tachypnea and exhaustion, the patient was intubated and ventilated. the serum concentration of "eve" on admission was ng/ml (lethal range - ng/ml). trace amounts of cocaine and substantial amounts of heroin ( ngtml; mean value in heroin-related deaths: ng/ml) were also found in the serum. the patient was successfully weaned from the ventilator by day and recovered without persistent neurobehavioral disturbance. despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. amphetamines in general, and mdea in particular, have opposite clinical effects to heroin or diacetylmorphine. none of these were however present in the case presented despite the high ingested doses and the serum levels in the lethal range. conclusions: the fascinating fact that, apart from the respiratory depression, none of the clinical signs reported after massive overdose with these two drugs were present, might be attributed to the opposite pharmacological effects of mdea and heroin. we believe that the patient unwittingly saved his own life by the oral coingestion of both mdea and heroin. our clinical data raise an interesting point about the pharmacological treatment of acute poisoning with amphetaminederivatives. introduction: the acute attack of aip still carries a significant risk of mortality of around %. a succesful outcome depends on early diagnosis, removal of pricipitating factors and provision of intensive supportive therapy. objectives: twenty one patients ( females, male) with documented aip were seen over a -year period in the university hospital. patient was in clinical remission and were with the acute attack of aip, among them with respiratory paralysis were required artificial lung ventilation and -assistant ventilation with peee pathologic treatment during the attack was normosany, adenil, androgenes, glueosa, riboxin parenteral and enteral nutrition via nasogastric tube. symtomatic treatment -pethidine, propranoton, antibiotics, bronchoscopia. methods: intermittent phasmapheresis was performed on patients. the following measurements were peformed: level of porphobilinogen (pbg) in the wire and delta-aminolevulinic acid in the blood. hematological and routine chemical evaluations, hepatic, hemodynamic and respiratory function. results: after plasmapheresis the median pbg excretion (normal range - mkg per/ kgr creatinine) fill from mkg on admission . mkg, then on - day raise to mkg and then during treatment with normosong and prasmapheresis lowest level was . mgk. fatalities occured in two females during attacks with proforma cerebral involvement and patients attained clinical remission. conclusion: after therapy with plasmapheresis normosong we found that there was consistently reduce the urinary excretion of pbg and shortening the duration of the acute attack. objectives: pigs has been reported to present with a higher pulmonary arterial pressure (ppa) and stronger pulmonary vascular reactivity than many other species, including man. aim of the present study was to compare pulmonary vascular impedance (pvz) before and after embolisation in weight-matched adult dogs and minipigs. methods: we investigated pvz spectra in anaesthetized and ventilated (fio . ) minipigs and dogs. after baseline measurements the animals were embolised with autologous blood clots to reach a ppa above mmhg. results: flow ( and ppa matched pvz data (mean-+sem) are shown in the table. [zo = hz impedance (z; {dyn.sec_em- }); zl = first harmonic z; zc = characteristic z; z phase = first harmonic phase a@e {radians}; fmin = frequency of pvz the first m{n~mam; *, f p at least < . between dog and minipig, and before v~. after embolisation respectively]. before case report: a -yr-o]d woman affected by legs recurrent thmmbophlebitis, was admired in medmine department for tach.~pnea, chest pain, tachycardia and cyanosis. before starting two-dimensional transesophageal echocardiography (tee) to confirm the suspicion of pulmonary embolism, she suddenly had ventricular fibrillation. resuscitation and defibrillation were readily performed. when sinus rhythm was reinstituted she was in superficial coma with preserved corneal and light reflexes: right hemiplegia, poor perfusion and h~posphygrma of the left arm. tee showed dilation of rigth ventricle (rv), incomplete occlusion of pulmonary arter~ (pal at it~ hifurcation, severe tigth-to-left shunt through a patent foramen ovate, paradoxical embolism with incomplete occlusion of left subclavian artery mechanically ventilated with vt= ml, rr= /mm, fio =l, the patient had ph= . , pao = mmhg and paco = . systemic bp was / mmhg and hr= b/min with low dose epinephrine ( . g/kg/min) a thrombolytic infusion (rtpa: mg/ h) through a peripheral vein was started tee imaging and clinical status hours later were unmodified. a new rtpa infusion was performed through the pulmonary hole of a swan-ganz catheter with the tip close to the embolus. one hour later pa pressure decreased from / mmhg to / mmhg, etco increased from to mmhg and sao improved from % to % three days later the parietal, spontaneously breathing and with normalized tee scans of rv and pa, was transferred to rehabilitation service to perform physical therapy. conclusions: massive pulmonary embolism in a patient with patent foremen ovale, paradoxical embolism and refractory hypoxaemia was unaffected by systemic rtpa infusion, while intrapulmonary rtpa administration dramatically improved gas-exchange, hemodinamics and the general conditions of the patient. the presence of a large rigth-to-left _atrial shunt and the rapid rtpa metabolism could likely explain the effectiveness of its intrapulmonary administration in front of failure of systemic thrombolysis. introduction. cardiogenic shock during massive pulmonary embolism (blpe) is due to an acute increase of right ventricle (rv) afterload and possibly rv ischemia causing a failure of rv pump function. the rec~;mmended therapeutic strategies are: xoiume augmentation ~n ~rder m }ncrease rv pre-h~ad, adrenergic drugs to increase t'ontractillly and maybe coronary perfusion, fibrinolytic drugs to delermine clot lysis. there have been several reports of noradrenaline (na) as a useful drug in this setting for its sluing ~z, but also ~, properties. case report.an obese },ears old woman was transferred to our icu for tetanus. she was given the usual antibiotic and immunoglobuline therapy. l'wo thoracic epidural catheters were put in place at different levels and replenished with marcaine qid. a continous infusion of sedation (diazepam § was started together with mechanical ventilation. curarization ~,as given occasionally. fraxiparine . /die was used for prophylaxis of thrombotic disease, on day th at . a.m. she started to be hypoxic (sa %), tach ,tardic l l(i b/rain.), her blood pressure(rp) dropped frum norma~ values to r mm/hg, the central venous pressure (cvp) raised [rom lb to mm/hg and the end tidal co was mm/hg lower than one hour before. the physical examination of the chest revealed a clear bilateral ventilation and the chest x-ray was normal apart from an elevation of the :tiaphragm as compared to the previous. an e.c.g. showed sinus tachycardia, right bundle branch block and a possible inferior necrosis (which was already present on admission). a trans-thoracic echozardiography was performed which showed "an acute overload of the right centricle wilh remarkable dilatation. tricuspidal regurgitation ++. paradoxical movement of septum. small left ventricle with normal wall kinetics". the cardiac enzymes were later shown to be normal. an acute massive pulmonary embolization was assumed m be present.. a bolus of streptokinase x i(i u. was given fonowed by a continous infusion . two liters of colloids were also given in a sh~rt time, two hours later the patient was still deeply hypotensive, hypoxemic and anurir(bp / mm/hg, cvs mm/hg, spo %) despite a cominnus infusion of dobutamine fag/kg/min and adrenaline . ~tg/kg/min. at this stage a bolus of aoradrenaline ,g was given followed by a cnntinous infusion of . !*g/kg/min. an immediate improvement of the hemodynamics was noticed and one hour later the bp was / mmhg, the cvp mm/hg, the sao % and a brisk diuresis started. the hemodynamics kept stable and weaning from vasoactive drugs was achieved within two days. one month iater the patient was discharged home in good conditions.. con c i u sio n.ne administration may help to restore rv coronary flow and ;~ump function during mpe. aeute putmonary t~omboembo~sm [ffe) cou be mamfeslated with either respiratory or cardiovascular syndromes or both. the arm of the study was to establish leading respn'atory symptoms, frequency and form of the roendganographic (rig) changes as well as blood gas disturbance degree in acute pte with dommam respiratory disease appearance. the study includes retrospeotive analysis of i pte patients (pts), males (average age , yrs) and .q females (average age , yrs). they were admitted at university, olinie" with suspection ofpleuropnlmonary disease, including pte. final diagnosis of pte was based o~ evident risk factors in , % of the eases (deep venous thrombosis, surgery, trauma, imobilisation, malignancy ere), acceptable clinical, rtg, sdntigraphic and laboratory findings, as well as deep veins examination by dopple~-sonographie and radioisotopic -~enogmphy. respiratory symptoms appeared in all cases: sudden pleural pain ( %), dyspnea ( %), hemoptysis ( %), cough ( %) with association of two or more symptoms in %. chest xrays findings were abnormal in % with diaphragmal elevation ( , ~ lung opaeilies ( , %), atelectasis ( , %), plemal effusion ( , %), main pulmonary brancah asimetry ( , ~ oligemia ( %), heart shadow changes ( , %) and pulmonary arteries "cut off' ( , %). the association of two or more abnormalities was found in , % while normal chest x-rot was found in ~ of the cases. hypoxemia with pao < , kpa was found in , % followed with hypocapnia and respiratory alealosis in , % in , % of the gas exchage analysis were within normal limits. among cardiovascular symptoms short syn~cpa appeared in i , %, ecg changes-st q t type in "~ , %. results show high frequency of positive ~g findings in pte pts that is opposite to oppinion that chest x-ray in acute fie is the most ofran normal. leading symptoms are pleural pain and dyspnea, while hemoptysis were found in a half of the study group. blood gas changes were present in two thirds of the cases. kakkar, in his classic work ,clearly demonstrated the efficiency of low doses of heparin in prevention of deep vein thrombosis (lancet : , ) .after this first study the application of heparin prophylaxis became more and more diffused until to be considered a routine in many surgical departement.actually application of blood saving technique induces postoperative hemodilution effect. in that condition prophylaxis routinely applied seems a nonsense and can be at risk for postoperative hemorrhage. methods: to analize this problem we compared patients arrived in our intensive care unit (i.c.u.) in. : (group a) with arrived in : (group b) .every patient was operated for major abdominal surgery.in each one we considered the hemoglobin (hb) value,hematocrit(hct), and coagulation pattern (c.p.) at the arrive in i.c.u. and hours later. the patients was also divided in those receiving heparin prophylaxis (i) from not treated patients (ii) results:the application of blood saving technique clearly appears from the hb and hct level wich have a mean value of , +/- , (hb) and +/- (hct) in group a while in group b mean value are , -/- , (hb) and +/- (hct).patients of group a (ii) are the only one where a pathologycal c.p. with statistical significance has been demonstrated.in this goup we got four cases of evidence of venous thrombosis and one of pulmonary embolism.in patients of group b(i) we encontered the incidence of two cases of severe hemorrhage despite the absence of statistical significance in c.p.modifications. oxygen desaturation during broncho-alveolar lavage: role of oxygen saturation monitoring in prevention of acute respiratory insufficiency g. galluccio, b. valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the broncho-alveolar iavage is a diagnostic procedure employed in interstitial diseases of the lung. it requests the introduction through the working channel of a fiberoptic bronchoscope, after occlusion of a segmentary bronchus, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove cells and proteins from elf (endoalveolar lining fluid), which is related to interstitial medium. bronchoalveolar lavage induces deep effects on pulmonary function: -lowering of the alveolar surface of exchange; -shunt effect, depending on the perfusion of non-ventilated districts; -increased pulmonary arterial pressure, due to hypoxic vasoconstriction; -decrease of lung compliance. in this report the authors present the result of oxygen saturation monitoring in a group of patients with interstitial lung disease, who underwent diagnostic broncho-alveolar lavage. in most patients with severe interstitial involvement, the lavage performed without supplement of oxygen induced a severe fall in the oxygen saturation during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. in patients without thickening of interstitium, in whom the lavage was performed in order to obtain material for bacterial or cytologic examination, no modification of oxygen saturation was observed in standard procedure. as conclusion the authors strongly reccomend monitoring oxygen saturation in patients with radiologic evidence of interstitial involvement also in patients with no evidence of dyspnoea. g. galluccio, b.valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the treatment of choice in patients with alveolar proteinosis consists of pulmonary lavage. this procedure requests the introduction, through the working channel of a fiberoptic bronchoscope, segment by segment, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove the proteins deposited in the alveolar spaces. the method is very similar to that used in bronchoalveolar iavage, a diagnostic procedure used to obtain cells and substances from elf (endoalveolar lining fluid), which is related to interstitial medium. as known, bronchoalveolar lavage induces oxygen desaturation, because of shunt effect. understandably, one lung lavage has remarkably more deep effects on pulmonary function than bronchoalveolar lavage, for the amount of fluid introduced, the length of the procedure and the conditions of controlaterai lung. in this report the authors present the result of oxygen saturation monitoring in a patient who underwent pulmonary lavage for alveolar proteinosis. in the lavage performed without supplement of oxygen a severe fall in the oxygen saturation was observed during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. as conclusion the authors strongly reccomend the subministration of supplementary oxygen in pulmonary lavages, also in patients with excellent respiratory conditions. a. b. dublisky prof., m. r. isaakjan ass., v. a. zasukha, s. m. vinichuk prof., v. p. tserty ass. prof., chair of anaesthesiology, resuccitation and medicine of catastrophes, neurology of ukrainian state medical university, kiev, ukraine. objectives: detection of plasmophoresis's influence of results in treatment of ishemic insult. methods: we ve investigate patients with ishemic insult, treated with reverse plasmopheresis in complex treatment. after primary infusive therapy we took ml of patients' blood and separated it within min with rotation frequensy of /rain. after separation of erythrocytes from plasma, the latter has been returned to patients. we made - procedures during - days. hemoglobin, hematokrit, time of blood coagulation were determinated. the brain blood flow in internal carotid arteries, regional volum brain blood flow and total brain biood flow were evaluated with tetrapotar chest rheography and tetrapolar rheoencephalography. obtained date were comparised with control group after traditional treatment. results: it was found that after reverse plasmopheresis the hemoglobin and hematokrit levels decreased significantly in studied patients' plasma (from + . g/l to _+ . g/ and from + . % to _+ . % respectively). the time of blood coagulation by lee-white has increased by - . times (up to - rain). the level of brain blood flow has been increased significantly after reverse plasmopheresis in comparison with control group. the following tests of brain blood flow have been increased: a) the total volume brain blood flow from . + . ml/min to . _+ . ml/min (p < . ); b) the regional brain blood flow from . _+ . ml/min to . + . ml/min (p < . ); c) the brain blood flow in internal carotid arteries from . _+ . ml/min to . + . ml/min (p < . ). conclusions: the use of reverse plasmopheresis in complex treatment of patients with ishemic insult aiiows to improve rheological blood patterns, helps to increase volume brain blood flow. it results in quicer reparation of neurological functions. objectives: a prospective evaluation of the efficacy of continuous infusion of verapamil in reducing the incidence of postoperative atrial fibrillation after pulmonary surgery. methods: a total of consecutive patients, on verapamil, on placebo was included after lobectomy or pneumouectomy. a loading bolus of verapamil ( mg over minutes) was followed by a rapid loading infusion ( . mg/min) for minutes and finally a maintenance infusion ( . rag/rain) for hours. results: a mean plasma level of verapamil of ng/ml was obtained only after more than hours. atrial fibrillation occurred in five out of patients who tolerated the verapamil infusion, and in out of patients on placebo (p = . ). verapamil infusion was not tolerated in patients because of hypotension or a heart rate of less than /min, within hours of the start of the therapy. when atrial fibrillation occurred, the ventricular response, mean _+ sd, was not significantly slower during verapamil infusion ( + ) compared to placebo ( + ). conclusions: because of its frequent side effects and the only modest efficacy verapamil should not be considered for prophylactic therapy of atrial fibrillation after pulmonary surgery, and is probably not a good first choice for slowing the heart rate in case of rapid ventricular response once atrial fibrillation has occurred in these patients. results: study of haemostasis in these patients has showed deep disturbances of blood coagulation. fibrogen level has reduced to . + . g/l, fibrinogen and/or fibrine degradation products concentration have enhanced to . _+ . g/l, monofibrin soluble complex concentration to . -+ . g/l, blood plasmin level was enhanced to . + . mmol/ , plasminogen proactivator level was also enhanced to . + . ram, plateletes aggregation has decreased to %. after plasmopheresis aggregation was decreased in . times. it has been connected with decrease of fibrin and/or fibrinogen degradation products level and level plasmin in . times, and plasminogtnt activator level in . times. at the same time we have observed increase in total antifibrinalitic activity of blood in . times. activity of activators plasmine and plasminogene proactivators has decreased in . times and in the same time activity of activation inhibitors and antiplasmines has increased in times. conclusions: plasmapheresis leads to considerable improvement of a general condition and reduction of the haemorrhagic syndrom's sings (controlling of gastrointestinal haemorrage, reduction of intensity of subcutaneons haematoma). evaluation of continuous cardiac output (cc ) monitoring based on thermodilution technique in critically ill patients. methods: cardiac output (co) was monitored continuously using a modified pulmonary artery (pa) catheter, on which a heating filament is located and by which energy is transmitted to the circulating blood. a microprocessor calculated co by a new algorithm. standard bolus thermodilution technique ( ml of ice-cold saline solution) was used to compare cc with intermittent bolus cardiac output (ic ) measurements. the following subgroups were prospectively studied: i. heart rate (hr) > beats/min, . cardiac output > i/min . cardiac output < . i/min, . rectal temperature > . ~ and . pa catheter was inserted for more than days. results: a total of pairs of ic and cc measurements were obtained from the patients. bias (ico measurement minus cc measurement) of all measurements were . • i/min and the % confidence limits (mean difference• were - . / . i/min. also in the subgroups, cc measurement agreed closely with ico measurement (c > i/min: bias= . • i/min; co < . i/min: bias=- . • i/mln). elevated temperature and prolonged lay-days of the pa catheter did influence agreement of cc measurement with ic measurement neither (> ~ bias= . • i/min). conclusions: monitoring of cc using a modified pulmonary artery catheter with a heated filament has proven to be accurate and precise also in the critically ill when compared with "standard" intermittent bolus thermodilution technique. this method enhances our armamentarium for more intensive monitoring of these patients under various circumstances. background: the number of patients who need coronary artery surgery was) grows every year. most of these surgical operations are with extrar eircuiation (ecc). since january , this surgery is made without ecc in selected patients in our hospital. this technique is exceptional in spain. this type of surgery has proved useful in patients requiring revascularization of the left anterior descending, eireunflex or right coronary artery (not for grafting the pos~tefio~r descending branch}. blethods and results: since , patients aged to years (mean years) underwent cas without ecc. the mortality in programmed surgery was %. no patient was reexplored for hemorrhage. the mean values of some clinics parameters v~ere: a) blood requeriments: units per patient, b) need of mechanical ~entilation: i , hours, c) postoperative bleeding: cc, d) days at icui , . we used the student % t test or fisber~s exact test to compare these results with the mean values of surgery with ecc: a) blood requeriments per patient (p< , ), b) need of mechanical ventilation: hours (p< , ), c) postoperative bleeding: cc (p< , ), d) days at icu: (p< , ), e) programmed surgery mortality: % (p< , ). conclusion: our limited experience shows that this surgery is an alternative in the treatment of coronary disease, especially for aged patients with associated pathology and in jehova's witness. the need of mechanical ventilation, days at icu, blood requeriments and morbi-mortality were fewer than surgery with ecc. to study the hemodynamic and antiarrhythmic influence of ace-inhibitor enalapril in acute myocardial infarction (mi). methods: holter ecg monitoring, heart rate variability analysis, echocardiography ( and l days after beginning of the treatment), stress-echocardiography and stress ecg ( - -th day after the onset of mi). enalapril was included into the treatment of pts with mi (study group), with normal or increased blood pressure, from the -st day of the disease. the data were compared with pts treated without enalapril (control group). results: silent ischemia during stress-test was registered in pts of the study group and of control group, the arrhythmia episodes during stress test -in and pts and episodes of silent nocturnal isehemia -in and pts correspondingly. enalapril importantly attenuated the hypertensi~re re~aetioh % stress test. in pts of the study group the number of perifocal hypokinesis zones decreased; in the control group it didn't change. the quantity of ventricular extrasystoles in the patients of the study group decreased by %; the heart rate variability indices improved as well; in the control group the character of ventrieulir arrhythmias, heart rate and its va]~i~bili%y didn't change significantly. conclusions: the inclusion of enalapril into the treatment of mi is a useful t ol to improve hemodynamie parameters and decrease the incidence of ventricular arrhythmias. objectives: to study left ventricular (lv) systolic function in the patients with acute myocardial infarction (ami) before and after peroral captopril test. methods: the original echocardiographic parameter of lv contractility, "coefficient of effective systolic function" (cesf), was proposed in the study. cesf is calculated from lv stroke volume (sv), obtained from doppler aortic flow in lv outflow tract and lv end-diastolic diameter (edd): cesf =sv/edd. the study included patients with ami, who had local lv dyskinesia and global lv systolic dysfunction (ef< %). besides cesf, the ejection fraction was calculated before and after administration of mg eaptopril (on the fifth day of ami) by methods of bullet and simpson. results: the dynamics of these parameters, as well as heart rate (hr) and mean blood pressure (bp), is shown in the tabte. before cal~topril ef (bullet) . • . ef (simpson) . introduction: the cold system is a monitoring system for measurement of right (copa) and left (coart) ventricular cardiac output, cardiac function index (cfi), fight ventricular ejection fraction crvef), fight ventricular cnddiastolic volume (rvedv), intrathoracic blood volume (!tbv), global enddiastolic volume (gedv), lung water (etv) and excretory liver function (pdr). patients and methods: pts have been monitored by the cold system. above mentioned parameters are measured by thermal dye dilution and a fiheroptic femoral artery catheter. copa, rvef and rvedv measurements additionally were compared to measurements by the baxter explorer. :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ;;;k;;;;i cov (%) explorer ! ! [ gedv, itbv and pdr showed a significant decrease dufing the first - h after the operation, cfi and rvef si~canfly improved after k wheras etv showed a i~ in the early postoperative phase and fell to normal ranges at h. comparison of cold/explorer m~ements sb wed good correlations. discussion: concerning m ~toring of ri,ght ventric~ar function cold and explorer can he seen as equal. rvef gives an ar report about the performance of the right ventricle without use o f echocardiography. measuring itbv and gedv ~ improve ~gement and con~ol of th.e volume status, monitoring etv helps preventing lung edema. pdr shows good corre|ati n to liver blood chemistry and is bedside avai|ab|e. thus the cold system offers additional parameters for comprehensive m~nitofing of pts. ~e~ ~c surgery. obiectives: to evaluate the influence of an a!'~ered cardiac function on the cardiovascular response to the increase in oxygen demand induced by an increase in core temperature. methods: this preliminary study included adult critica!ly ill patients monitored by arterial and pulmonary artery catheters in whom thermodilution cardiac index {ci) and arteria! and mixed-vef)ous blood gases measurements could be obtained before and after an acute change in core temperature of at least . ~ (max rain apartl the patients were separated in two groups according to their cardiac function: patients had an impaired cardiac function as defined by a history of cardiac disease and an ejection fraction below % and patients had normal cardiac function. results: individual data are shown in the figure. in contrast to the control group (continuous line) in which c! increased without changes in oxygen extraction ( er), the q er in patients with impaired cardiac function (dottled line) increased without changes in ci. conclusions: the increase in oxygen demand associated with changes in temperature is met by an increase in c! in patients with unaltered cardiac function and in an increase in o er in patients with altered cardiac function. temperature should be taken into account in the assessment of the adequacy of cardiac output in patients with impaired cardiac function. objectives: to define the hemedynamic and metabolic response to physical therapy(pt) in relation to the type/level of sedation and the cardiac status in icu patients. methods: we studied mechanically ventilated icu patients ( • years) in stable hemodynamic status (no change in vasoactive treatment for at least hours), separated in groups: group = deep sedation, cardiac dysfunction required dobutamine (n= )r group = deep sedation (barbiturates), unaltered cardiac function (h=lo), group = moderate sedation, altered cardiac function (h= ) and group = moderate sedation, unaltered cardiac function (n= ). complete hemodynamic data, arterial and mixed venous blood gases, respiratory gas analysis (metabolic cart ccm, medgraphics) were obtained at baseline ( x) and twice (q. min) during leg mobilization. data were analyzed by anova. calcium channel blockers were used in complex preoperative preparation of hypertensive surgical patients. patients were allotted to groups based on their hemodynamic profile: hypokinetic: ejection fraction (ef)< . , patients; eukinetic (ef> . ),i patients and hyperkinetic (ef> . ),i patients. the most noticable change in hemodynamics was in the hypokinetic group: ef and cardiac output (co) were significantly decreased (p< . ) while systolic arterial pressure (sap) (p< . ) and peripheral resistance (pr) (p< . ) were elevated. the results showed that in hypokinetic patients on nifedipine ef (p< . t) stroke volume (sv) (p< . l) and co (p< . ) were increased while pr(p< . t), sap(p< . ) and diastolic arterial pressure(p< . ) were decreased. eukinetic type patients also showed an increase in ef,albiet to a lesser extent,than in the hypokinetic group. increased sv and co(p< . ) were observed in eukinetic patients though this was to a lesser extent than in the hyperkinetic group. in the hyperkinetic group of patients nifedipine had no effect on the aforementioned parameters except for a decrease in sap(p< . i). nifedipine increased ef in all hypokinetic patients. comparative results show that isoptin was less effective than nifedipine in decreasing peripl~eral vascular resistance and had a depressive effect on the myocardium. it can be concluded that the action of calcium channel blockers normalizing the circulation in the hypertensive surgical patient depends on: the condition of myocardium, the patients hemodynamic profile and their pharmacological properties. they were most effective in the hypokinetic group. zalo/nthinos e., daniil z. zakynthinos s., armaganidis a., kotanidou a., nikolaou ch..,roussos ch. critical care department, university of.athens, evangelismos hospital, athens, greece. introduction : surgical is the optimal treatrnent for ioculated effusions and the preferable procedure when multiple bands are seen in the pericardial sac by echo. patients : palients, post cardiac surgery, uremic ( men, women) with large pericardial effusion and clinical or echocardiographic findings of tamponade or both. these particular patients displayed numerous linear echo-dense bands and s~'ands crossing the pericardial space (in one of them a ioculated effusion compressed the left ventricule). one had aptt increased, four were mechanically ventilated. technklue : a fr polyurethane catheter with end and multiple side holes over ga needle was echo-guided to the ideal site (fluid abundant and closest to the transducer). the catheter was attached to a close system with a heimlich valve for continuous drainage (pneumothorax kit). subcostal entry was selected in one patient and chest wall in five. the patient's position was changed every hour at least. (we believe that the small changes in the position of the catheter and the mechanical breaking of the bands in relation with the movement of the heart assist the pericardial fluid to remove). results : in all cases only a small quantity of fluid was withdrawn in the first minutes( - ml) with some clinical and echo-findings improvement. the fluid was bloody or serosanuginous with high protein content (ht= % ,protein , gr/dl) in all cases. in first hours the mean volume of fluid removed was ml ( to ml). in that period echo showed no residual fluid. the catheter remained within the pericardium to days .. no complications are mentioned. conclusion : cardiac tamponade due to hemorrhagic high protein pericardial effusion in uremic and postcardiac surgery patients,, as it is revealed by echo dense bands, can be faced by -d echo guided perieardiocentesis. a -fr polyurethane catheter with multiple side holes, attached to a heimlich valve was effective to evacuate the pericardial fluid. no catheter was occluded though heparin infusions were not used. multiple changes of the patient's position may be fundamental. this -d echo guided pericardiocentesis performed in in~nsive care unit seems to be useful , safe and quick technique. determining the best inotropic drug represents a very serious problems. the use of more selective and potential inotropic and vasodilatative drugs does not always lead to improvement of hemodynamic parameters in patients with low cardiac output syndrome. this paper presents patients with acbp who need an inotropie support after extracorporeal circulation in first hours. the patients were divided into dobutamin et dopamine groups. the heart rate (hr). mean sistemic arterial pressure [map), central venous pressure (cvp). and termodilution cardiac index (ci) were measured. the measurements were without using inotropic drugs, and then using them after rain, min, and finally with one hour rate, within first hours. the statistical analysis shows that both drugs lead to an increase in hr in the first hour of the application. the final effect of dobutamine is no change in hr, whereas the effect of dopanime is very significant increase in hr. thus. an absence of taehyeardie response selects the dobutamine as a better choice. backeround: pulmonary vascular eadothelium possesses major metabolic functions, which when altered contribute to the development of serious pathologies such as ards. one such function is the conversion of angiotensin i to angiotensin ii, catalyzed by angiotensin converting enzyme (ace), located on the luminal surface of the endothelial cells. ace activity has been extensively studied in animals in vivo, by means of indicator-dilution techniques, providing: i) under toxic conditions, an early index of lung injury, and it) under normal conditions, estimations of dynamically perfused capillary surface area (pcsa). objectives: to validate the use of these techniques in matt: i) for pulmonary endothelial function assessment, and it) for pcsa estimation. methods: ace activity was estimated in ten adult haman volunteers, with no pulmonary medical history and normal pulmonary artery pressures, undergoing cardiac catheterization for coronary artery disease assessment. single-pass traspulmonary hydrolysis of the specific ace substrate hbenzoyl-phe-ala-pro (bpap; p.ci) was measured by means of indicatordilution techniques, and expressed as %metabolism (%m) and v=-hi( -m). bpap was injected as a bolus i) into a main pulmonary artery, and it) inside the right atrium, to assess ace activity in one and both lungs. we also calculated a,~,/i~, an index of pcsa. pulmonary plasma flow (fv) was determined by thermodilution. fp in one lung was estimated as . xf v. results: similar values of %m ( . + . vs . • and v ( . • vs . • were observed in both and one lung respectively. a~k~ decreased from • ml/min (both ltmgs) to :~ (one lung). conclusions: i) pulmonary endothelial ace activity and thus pulmonary endothelial function may be assessed in humans by means of indicator-dilution techniques, it) our data denote homogeneous pulmonary capillary ace coneentratious and capillary transit times in both haman lungs, iii) the % reduction of a=~/k~ in one lung suggests that this procedure can be used to quantify pcsa in man. (supported by the fonds de la recherche en saute du quebec and the national health system of greece). objective: verify whether antioxidant activity is higher in reperfused than in no-reflow myocardium after i.v. thrombolysis for acute myocardial infarction (ami). methods: patients with ami were included. blood for estimation of catalase (cat), glutathione peroxidase (gpx) and mn-superoxide dismutase (sod) was drawn before initiation of i. the mechanism of myocardial cell defence against free radicals is probably identical in both reperfusion and no-reflow phenomena. therefore, antioxidants cannot be used as reperfusion markers. objectives_ to evaluate the precipitating factors of hypothermic phrenic nerve injury following cabg with lima. methods: fifty two consecutive patients ( females), with a mean age of + (mean +sd) years were studied. during the ischemic arrest time topical hypothermia was obtained in al~ patients wffh ice slush and no cardiac insulation pad was used. all patients received a lima graft, with or whithout additional vein grafts. supramaximai, bilateral phrenic nerve stimulation was performed percutaneously preoperatively and whithin hours postoperatively. square wave stimuli of . msec duration were applied at the posterior border of the sternomastoid muscle. the compound muscle action potential of the diaphragm was recorded, using surface electrodes on the anterior chest wall. the time interval from the application of stimulus to the onset of diaphragmatic activity, phrenic nerve conduction time (pnct), was measured. values exceeding . msec were considered as abnormal. besults: preoperatively, all patients had normal (mean+sd) pnct, . • msec for the left nerve and . • mseo for the right nerve. on the first postoperative day, right pnct was normal in atl patients ( . • msec) , whereas left pnct was normal in patients ( . • msec) and abnormal in patients (incidence . %). in patients the left phrenic nerve was inexcitable and in patient left pnct was prolonged ( . msec). comparing patients with normal and abnormal pnct there was no difference in age, gender, number of grafts used, aortic cross-clamp and bypass time. however, patients with abnormal pnct had a lower preoperative ejection fraction ( • vs • p= . ). moreover, in all of them lima was dissected from its origin ligating all upper arterial branches, which provide the blood supply to the left phrenic nerve, whereas in those with normal pnct the small vessels originating from the upper to cm of lima were preserved (p= . ). conclusiojel~ a hypoperfused left phrenic nerve seems to be more susceptible to hypothermic injury during cabg with a lima conduit. objectives: to test if necessary interventions on systemic vascular resistance (svr) along with preset pump flew (q) during cpb could adversely affect autoregulatory response and cause vo shifts. methods: we studied males ( - yrs) who underwent cpb for cardiac surgery. at o oesophageal temperature - c we set pump flow at . i.m~ .min - . when map was higher than mmhg we calculated vo by using fick equation. then we infused sodium nitropruaside (sn) to control map at - mmhg for min and we calculated vq . without changing the sn infusion rate we set q at . i.m' .min " . ten min later we measured vo . we took vo changes into consideration if greater than %. statistical analysis using students-t-test for paired data and analysis of variance was used as appropriate. results: depending on the biphasic vo response to sn infusion during low and high q we classified pts in four groups (table). i. vo increases with sn and increases further during high q unmasking hypoperfusion and supply dependency. ii. vo increases with sn but the addition of high q results in systemic shunt. iii. vo increase during high q proves that vasodilatation can turn flow insufficient. iv. vo does not change with any intervention. the small number of pts and the wide standard deviation did not allow any statistical significance. conclusions: cpb is an interesting model for the behavior of microcirculation. intervention on svr and q can improve or impair effective regional oxygen delivery, resulting in either better perfusion or systemic shunt. vo monitoring seems necessary during cpb. preoperative cardiovascular optimization (opt) to ci > . l/min/m , _< paop < mm hg,and svri __< mmhg/ll/min/m decreases cardiac events (events) and mortality (mort) in peripheral vascular surgery patients (pvs). objectives: to determine if opt to the same endpeints decreases events in patients undergoing abdominal aortic aneurysm repair (aaar) and to study the r predictive value in pvs patients. methods: aaar patients and pvs patients were admitted to the s cu monitored with e pa and arterial catheters and treated to achieve opt. patients underwent surgery independent of success of opt data included demograph cs, incremental risk factors, laboratory and hemodynamic data pre, intra, a~nd postoperatively events, and mort. events included arrhythmias requiring treatment or prolonging the sicu stay > hours, a st depression > !mm or t wave inversion, an acute mr defined by a new q wave > . sec or cpk-mb > %. results are presented as means _ -. sd. opt was achieved in of ( %) and in of ( %) in the pvs and aaar group, respectively. events did nat differ between groups of ( , %) and of ( , %) in the pvs and aaar group, respectively (p>o. ). mort was of ( %) and of ( . %) in the pvs and aaar group, respectively (p > . ), while there was no difference in endpoints of opt between patients with and with.out events in the aaar group, there was a significant difference in ci between patients with and without events in the pvs group. of note, of ( %) patients who developed events in the pvs group had a ci < . in contrast to of ( %)in the aaar group. the positive and negative predictive value were % and % in the pvs and % and % in the aaar group. conciusione: f. the endpoints of opt used for pvs patients cannot be ~sed to reduce events in aaar patients; . pvs patients who have net achieved opt are at extraordinary risk of perioperative events; . preoperative card ovascu ar opt in aaar patients makes no difference in cardiac related events, background : comparison of the right and left filling pressures (cvp/pcwp ratio) is considered as a useful diagnostic clue : the normal ratio is _< . ; ratio >_ . may suggest right ventricul~ infarction while equalization of the cvp and pewp is a classic sign of tamponade ( ). however after cardiac surgery, many conditions (diastolic dysfunction, pulmonary hypertension, positive pressure ventilation) are susceptible to modify the '*normal" cvp/pcwp ratio. material and method : we determined cvp/pewp ratio in consecutive patients (pts) after uncomplicated cardiac surgery ( coronary artery bypass grafts; valvular replacements) measurements were made before and after tracheal axtubation. results :cardiac index : . _+ . /minlm~; laotate: + rag/i; cvp range : - rnmhg; pewp range : - mmhg. mean cvp/pcwp ratio before extubation is . ( % confidence imerval : . - . ) and after extubation, . ( % confidence interval : . -. . ), (ns, paired t-test). in % of the pts, cvp was higher than pewp. there are no correlation between the cvp/pcwp ratio and c! before (r = - . ) and after extubation (r = - . ) nor between the cvp/pcwp ratio and mean pulmonary arterial pressure (mpap), before (r = . ) and after extubation (r = - . ), discussion : cardiac performance is adequate according to ci and lactate. however the cvp/pcwp ratio is markedly higher than the "normal" (_< . ) ratio. this difference is not related to mechanical ventilation because the ratio is similar before and after extubation, nor to pulmonary hypetaension because of absence of any correlation with mpap, post-cpb diastolic dysfunction of the right ventricle could be an alternative explanation. in this group of pts, increased cvp/pewp is not associated with any impairment of cardiac performance (absence of correlation with ci), conclusions : cvp/pcwp ratio as high as within a large range of cvp ( - mmhg) and pcwp ( - mmhg) may still be considered as normal after cardiac surgery. this emphasizes the limitations of the hemodynamic monitoring after cardiac surgery (in comparison with echographic technics). careful analysis of the morphology of the cvp and right ventricular pressure curves (x descent, y descent, dip-plateau) is mandatory rather than relying on the quantitative assessment alone. reference : ( ) ntensive care.-university hospital -m~laga (spaink introduction. fibrinolitic treatment (ft) permits the treatment of acute myocardial infarction (ami) addressing the etiology, thereby eading to mproved ventncular function and a marked reduction m mortality. the main clinical oroblem is the reduced time of application. delay in hospitalization, which can be from to minutes, is potentially the most avoidable delay. method. to reduce delays in hospitalization, the following was carried out in two chases. audit: analysis of the time lapse from onset of symptoms to start of ft. showed that during "(he period june to december , patients with chest paros were treated within a eriod varying from minutes to hours from onset of symtoms. ages ranged from to (average , ), oelng males and females. they were glved initial ecgs to determine st mcreases suggesting ami. median t~me for this orocedure was l m.. potentia ami patients were then admitted to the coronary unit, [)atients, under age with no contraindications received ft the median time apse from admission to corona-y care and administration of ft was minutes ( . ), -he total median delay was minutes ~ -i h. min,~ delays n start of this procedure are grouped as follows: extra-hosdita delays (from onset of symtoms to arrival at hospital) diagnostic delays (from hospital arrival to ecg). treatment delays (from diagnosis to ft). objectives: protocol of procedure to implement a fast-track method. a protoco was drawn up with the object of reducing diagnostic delays to -i minutes and treatment delays to less than i minutes results. following rmplementatlon of this protocol in january , fts were glven, with an over all average delay of minutes. this fast-track method did not reveal any inappropnate ft or any increase m complications, conclusions: detailed study of the various times taken for diagnosis ane treatment of ami patients, showed up weaknesses in the system and improvements througn the protocol based on performence orocedures which led to a % reduction in the start of ft background: the importance of the early use of thrombo!ytic agents in acute myocardial infarction (ami) is based in the better remaining ventrictjlar function and smaller mortality rate because of the greater reperfusion and sma!ler infarction size, therefore, it is very impodant to apply this treatment to the maximum number of patients without thrombolytic contraindicati n, and within the minimun period of time. the "thrombolytic fast track" implementation allows to optimize the time to administrate thrombelytic agents avoiding multiple delays~ methodology: we anal!ze the application of thromboly c agents to patients with suspect of ami from the begin!ng of september until the end of february . in this time there are two different periods, during the first months thrombolytic agent were admin!strated at intensive care unit (icu), and during the second period we carried out a protocol of quick detection and thrombolysis therapy in susceptible patients at the emergency room in order to reduce the time to treatment. ma!n results are shown in the faffewins de ay h=hours m=minutes the implementation of the fast track does not need supplementary personal or equipment but a protocelized approach and training of the personal involved the main problem detected was the usual attendance overload of the emergency department that makes difficult to follow many structurated actions. conclusions: pratocqlized changes in the management of ami can significantly reduce the detay in the administration ef thrombolytic agents. it is not necessary to eomplet the procedure iq the emergency department, as the use of bolus schedules allows to begin the treatment in this area and to transfer the patient to icu afterwards. elective cardiac surgery. b calvet, f ryckwaert, p trinh duc, p colson. anesthesia -reanimation, hopital arnaud de villeneuve, montpellier, france. obhectives: the study was aimed at analysing the incidence of renal dysfunction following cardiac surgery and its prognosis (acute renal failure, post-operative morbidity and mortality). methods: two hundred and thirty seven patients (aged from to ) were consecutively operated on for elective cardiac surgery and retrospectively included in the study. patients with preoperative infections and operated on in emergency were excluded. each patient had preoperative invasive cardiac investigation with angiography and calculated ejection fraction (ef). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest management were similar in all patients. general body temperature was reduced to - ~ c. renal dysfunction was defined as a % increase from baseline of serum creatinine. demographic data, asa, treatments, pre-operative creaunine level, cpb and clamping (axc) times, intra and postoperative use of inotrope, serum lactate level before surgery, at the end of cpb, at the time of admission in intensive care unit (icu) and on post operative day one and apache score were compared in patients with or without renal dysfunction using anova test for repeated mesures and x when appropriate. data are expressed as mean +__sd. p value less than . was considered statistically significant. results: thirtytwo patients ( , %) suffered from renal dysfunction. age, serum lactate level at the end of cpb, at admission in icu, at pod and apache level at admission in icu, intra-operative use of inotropes were statistically different in patients with or without renal dysfunction (p< , ). mortality rate was statistically different in patients with or without renal dysfunction(~, , % and %, respectively, p= , ). incidence of acute renal failure following renal dysfunction was , % ( patients required hemodialysis). conclusions: although our cdteria for defining renal dysfunction were very sensitive, the incidence of renal dysfunction following elective cardiac surgery was lower than communly accepted in the litterature ( ). however renal dysfunction appeared significantly associated with a poor prognosis. reference: -settergren g, ohqvist g current opinion in anaesthesiology , : - r ; , tzelepis, g. , , late complications were observed in % of cannulations: local infection in (i, %), catheter displacement by the patient in cases ( , %), catheter displacement during nursing care in ( , %) and malfunction in cases ( , %). conclusions: central venous catheterizations are followed by immediate and late complications in almost the same percentage acute poisoning with amphetamines (mdea) and heroin: antagonistic effects between the two drugs methods: after institutional approval and informed consent, selected patients ( _+ years) undergoing peripheral vascular surgery (n= ) or carotid endarterectomy (n= ) were investigated. patients included had either documented cad (n= ) or two or more (n= ) dsk factors (age > years, smoking, diabetes meltitus, hypertension, hypercholesterolaemia > mg/dl). -lead ecg recordings were carded out preoperatively, on ardval in the postanaesthetic care unit, and h, h, h, and h postoperatively. ecg recordings were analysed by an independent blinded cardiologist for signs of pmi (new st segment depression > . mv and/or new t inversion). in addition results: of the patients investigated developed ecg-documented pmi, % occurdng in the immediate postoperative phase. troponin i levels > . ng/ml were found in of these patients thus, comparing a cardiac troponin i cut-off level of ng/ml with intermittent -lead ecg recordings, we found a sensitivity of % and a specificity of % methods: demographic, clinical and ecg data were analyzed. . % of patients were male; . % female. cad was the most common underlying cardiac disease ( . %) and . % underwent open heart surgery. % received proeainamide for supraventricular and % for ven~cular arrhythmias. % received a loading dose. maintenance was provided by iv route in . % and by po in . % ( . %sr end . % ir). . % of patients were obese right ventricular function following cardiopulmonary bypass: is important the mode of myocardial protection we underwent this study in order to examine its safety and usefulness in pts with trustable coronary conditions (unstable angina ua the mean age for group a was • years, for group b • years, and for group c • years. a history of previous myocardial infarction was present in pts of group a, in of group b and in of group c. three pts in group a, in group b and in group c had previous coronary artery bypass grafting. the median time between the onset of symptoms and a was days ( - ) for group a we used a continuous fixed intravenous a infusion at a dose of the sn was % in groups a and b, % in c, and sp % for group a, (fixed defects included) and % for groups b and c. there was no difference of side effects among groups: chest pain (i pt -group a, pts -group b, and pts -group c), transient hypotension ( pt -group c), headache ( pts, group c), dyspnea ( pt -group a), while st depression was seen in pts of group b and in pts in group c. the rate of a infusion was decreased to /kgr/min in one group b pt due to development of chest pain s five year follow up of humoral immunity in paced patients athens polyclinic hospital, department of cardiology athens, greece author index a abiad ch bertschat, e betbes blanch, l del nogal saez e -meneza nolla, j. nolla-salas pilz~ u puig de la bellacasa e scarpa, n. van de wetering objectives: only % of patients suffering from acute guillain-barr@ syndrome (gbs) respond promptly to established therapies like plasma exchange or intravenous immunoglobulines. in contrast to serum, cerebrospinal fluid (csf) of gbs and ctdp patients contains enriched portions of antiexcitatory factors(i) and cytokines ( ) able to induce pronounced conduction block ( ). to reduce or remove such pathologic factors we introduced a technique with direct access to the subarachnoid space. methods: with informed consent we lumbally inserted g catheters in gbs-and cidp -patients under sterile conditions. some of them had not responded very well to established therapies. - ml of csf were withdrawn and retransfused by a bidirectional pump (flofors) after passing newly developed filters (pall). daily filtrations with several cycles were performed ( - ml) over one week. results: the gbs patients improved after days (median) for one grade (according to the gbs-scale from the gbs study group) . the ventilator dependent patients were weaned after days (median). patients not at all treated before ( / ) responded better than patients that had been pretreated ( / ) with plasmaexchange or intravenous immunoglobulines. / cidp patients drew benefit from treatment, stabilized iongterm. conclusions: csf-filtration is a relatively save and well tolerated additional procedure. the costs are considerably lower ( / ) than those for plasmaexchange or intravenous immunoglobulines. references:( )wsrz aet al: csf and serum from patients with inflammatory polyradiculopathy have opposite effects on sodium channels. muscle nerve ( ) . ( ) clinical observations were made in patients admitted to the clinic. they were in coma associated with acute alcohol intoxication.standard evaluations (ecg-monitoring, electrocardiography, neuromonitoring, studies of acid-alkali condition, biochemical and toxicologic investigation of blood and urine) prior to and following the treatment conducted were undertaken in all the patients.to correct irreversible impairement of functions twofold laser blood irradiation by means of alok- apparatus, the exposure within minutes, was carried out.the data obtained confirm more rapid coma withdrawal of the patients, reconstruction of the heart and central nervous system electrophysiologic indeces, reliable reduction in complications compared with the control group. objective: to know the actual incidence of the critical illness polyneuropathy(cip). setting: fourteen intensive/critical care unit beds, in bed university hospital, covering . inhabitants (majority rural area). the icu patients are medical, surgical and coronary, excluded the neurotrauma and neurosurgical. design: a conseculive and prospective study. all the patients admitted during three months, from january lth to march th , were eligible (patients with admittance diagnosis of polyneuropathy were excluded ). methods: patients with apache ii score > , at the admission and six days after admissions were included into the study protocol. diagnosis of sepsis, mof, and all the drugs administered days before were recorded. a complete neurological exam, by a neurologist, in absence of ssdatives and muscles reliant ( th, ~ and th days after icu admittance) was made. we evaluated the nerve and muscles function with and electromyography study in all patients, at same days. in some paeents with cip we performed a nerve biopsy. results: from patients ( apache ii score: . ) admitted in the icu, ( . %) enter the study protocol. seven ( , %) had an axonal polyneuropathy(cip), three very severe. only four of the patients with cip had pathologic clinical exam. apache ii score: cip vs non-cip was . vs . . the incidence of cip by diagnosis (cip/diagnosis) was: sepsis, / and mof, / . conclusions: . -we think that it is necessary to define the "critically ill" for some score, before designing a study to know the incidence of this syndrome. . -we think that the incidence of the cip is lower that the latest papers say. objectives:acute pancreatitis(ap)is becoming a more important problem among the elderly as the population ages. the increasing presence of gallstone disease,as well as the use of certain drugs,may also contribute to the occurrence of pancreatitis. methods:all patients(> years)admitted to our medical department over an eight year period were included.pancreatitis was confirmed by biochemical tests and imaging techniques.scores were developed using ranson's criteria and a multiple organ system failure(mosf)index . overall, patients were evaluated; ( %)had pancreatitis of unknown etiology . results:( )patients with pancreatitis of ~nlqnown etiology were sicker and had greater morbidity( % vs %),mortality( % vs %),and longer hospital stays than p~tierf~ with pancreatitis of known cause.( )the best predicto~of severity and outcome was the mosf index and not ranson's criteria;the higher the score,the greater the associated disease,the worse the outcome.( )curlously,no difference existed in associated medical conditions between patierts withknown and ur ~own causes of pancreatitis. conclusions:greater organ dysfunction exists in patients with pancreatitis of unknown etiology, even though age and associated medical conditions do not differ . the application of the total enteral nutrition in the burns disease has minimized the complication rate and consequently increased the survival rate of children and adults. time of initiation, composition, duration and way of administration are very important in obtaining the optimum beneficial effect from the treatment and diminishing the complication rate and side effects. the above features will be discussed in view of our experience in cases. ta buckle?,, ra freebalm, c gomersall g joynt, r young. tg short. department of anaesthesia and intensive cm+e, prince of wales hospital. the chinese university of hong kong, shatin, hong kong introduction: gastric mucosal ph (phi) monitoring has been proposed as a relatively noninvasive index of the adequacy of aerobic metabolism in the gut. to examine the accuracy of gastric intramucosal pit measurements as a function of time and as a function of the catheter itself to determine whether the measurement error between catheters is clinically acceptable. patients with a gastric tonometer (trip tm, tonometrics, worcester. ma) insitu for > days were studied. following informed consent two new tonometers were inserted equidistantly & correct position was confirmed radiographically. measurements of intramucosal gastric ph were then performed over a hr period. eight -ten measurements were made in each of ten critically ill patients.percent differences between the two new catheters were . % ie at ph . _+ . ( % limits) and between old & new catheters were . %, ie ph j _+ . ( % limits). conclusions: the results suggest that the function of the tonometer deteriorates over time and that the absolute values of phi m~ not ~ufficiently accurate. however as a trend monitor phi may be useful in the clinical setting. despite a continuous decline both in li'equency and severity of gastro-intestinal stress-lesion/-bleeding (gisb) due to both improvement in preclinical support and in intensive care medicine, patients with cerebral lesion are still considered at high risk for developing gis . therefore the question arises, whether m> specific (}lsb-prophylaxis besides general and neurological intensive care, specific pharlnaeothcrapy or even the combination of two specific drugs reveals any protective efli~ct on frequency and severity of gisb.this pntspcclive randomized study has been perfornted in patients snfrering t'rttna head-injury/cerebral lesion and with a glasgow-coma-scale on admission (gcs:,)of < . according to randomization the patients have been grouped as tbllows: h analgesia/sedation (n= ); ih analgesiajsedation plus pirenzepine mg/day (n= ); .[ih anatgcsia/sedalkm plus sncraltate x [ g/day (n= ); iv: analgesidsedatkm plus pirenzcpine mghlay plus sucralfate x e/day (n= ). slalislical analysis has been performed by chl:*tt~sl. rank correlatinn and unpaired t-test; statistical significance has been set with p < . . / patients ( . %) developed gisb. although the mean gcs~-value (x -+ sd) did not reach significance between patients with and without gisb ( . + . vs . -+ . ). a significant inverse correlation between gcs:, and the incidence of gtsb (rs~ = . ) has been shown. the frequency of gisb among the groups is as follows: h . %; lh . %; llh . %; iv: . % (ch -~ = . ; not signilicant). no gisb-induced blood translusion or mortality, respectively, could be demonstrated. survival rate between the groups did not differ significantly (chi-" = . ; p= . ) and reached an overall-value of . %.drug-specific glsb-prophylaxis -administered either as monotherapy (pirenzepine, sueralfate) or in combination of these two specific-drugs -reveals no additional significant influence on the incidence of gisb in patients with cerebral lesion compared to no specific prophylaxis besides the general trauma-/disease-specific intensive care measures. critical care dpt, evangelismos hospital, athens university scho~" of medicine objectives: the correlation of longterm presence of nasogastric tube (ngt) to gastroesophageal reflux (ger) is still in question. in case of positive correlation, peg should represent an alternative to tube feeding in patients unable to be fed orally. therefore, we investigated: i) the correlation between ng and ger and ii) the effect of peg on ger. methods: a -h esophageal ph-metry was performed in patients in recumbent position at ~ who had a ngt for more than days and were on sucralfate for gastric mucosal protection. the tip of the ph-probe was lied cm over the esophagogasttie junction, confirmed by x-rays. patients who presented a percentage of ger-total (i.e. with a ph less or more than ) (ger-t) more than %, underwent ~t peg. the presence of a creseent-notch on the esophagogastric junction persisting on inspiration and the grade os endoseopic and histologic esophagitis (scale= - ) was noted. two ph-metrles repeated on h and on days post-peg were compared to the pre-peg one, with the followin~ parameters taken in consideration: i) % ger-t, ii) number of ger-total per hour (no/h ger-t) and iii) the duration that ph was less than (tph< ). in case ot ger persistence at the ph-metry on ?th day post-peg (group ii) another endoscopy was performed, while patients with reduced ger (group i) were considered as esophagifis-free.results: out of patients presented a ger-t> %. eleven out of group i group (n= ) i ( objectives: the aim of the present study was to compare the performance of a specially modified version of a photo-and magnetoacoustic (pa/ma) gas analyzer (br~)el & kjaer, denmark) with a conventional quadrupole mass spectrometer (ms) (innovision, denmark) in inert gas rebreathing (rb) tests such as determination of functional residual capacity (frc), pulmonary capillary blood flow (pcbf) and lung tissue volume (vtc). methods : from simultaneous readings of inert gas concentrations with the ms and the pa/ma analyzer during rb experiments a comparison was made of the pcbf, vtc and frc values. the rb tests were performed during rest and exercise ( , and w) in ten healthy subjects. results: the differences (mean +/-sd) between simultaneous estimates of rebreathing parameters were the following (pa/ma -ms) for pooled data, pcbf: . +/- . i/min, vtc: - +/- ml and frc: . +/- . liters. conclusions: smell but significant differences were found between the estimates of pcbf, vtc and frc using the ms and pa/ma, respectively. reference: p. clemensen, p. christensen, p. norsk, and j. gr~nlund. a modified photo-and magnetoacoustic multigas analyzer aplied in gas exchange measurements. j appl physiol ; : - . objectives: because transcranial doppler (tcd) has been proposed to explore cerebral co vasoreactivity in brain injury (stroke ; : - ), we compared this technique with the kety-schmidt reference method to assess cerebral vasoreactivity in comatose patients. methods: mechanically ventilated patients (age - yrs, glasgow - ) in coma due to acute brain injury were investigated during stepwise changes in paco ( , , , and mmhg) by increasing inspired pco . middle cerebral artery velocity (vm) was measured by tcd. after insertion of a catheter in the ipsilateral jugular bulb, cerebral blood flow (cbf) was determined by the kety-schmidt method, using the inhalation of % n through the inspiratory line of the ventilator. for each patient a cerebral co~ vasoreactivity index was calculated as the slope of linear relationship between vm or cbf and paco . objectives: after cardiac surgery the fluid shill, between interstitial and intravasal space may be marked. this is due either to the intraoperative volume loading by the extracorporeal circulation or the increased postoperative diuresis. therefore, infusion of a large amount &fluids is necessary during the first postoperative hours. it still remains unclear which of the substances at disposal is the best for this purpose. aim of the present study was to compare the different fluids with special regard to postoperative bleeding and rheological behaviour. methods: patients undergoing cabg-surgery were investigated and randomizedly distributed to three different groups of postoperative volume replacement to stabilize the mean arterial pressure at mm hg. . ringer's solution, . . % gelatine solution, . % hydroxyaethylstarch (mean m.w. . ). we evaluated the following parameters within intervals of min: arterial and central venous pressure, heart rate, postoperative bleeding, urinary output, volume replacement. results: there was no statistically significant difference between the groups with regard to urinary output and bleeding. in spite of larger amounts of fluids necessary in the ringer treated group patients of this group showed symptoms of hypovolemia. hematocrit was increased in the ringer patients. this was statistically significant. introduction: pulmonary wedge pressure (pcwp) and central venous pressure (cvp) are frequently used as parameters for cardiac preload, although it is known that both are poorly correlated to the cardiac index (ci). it has been claimed that intrathoracic blood volume (itbv) measured with the thermal dye dilution method reflects cardiac preload better than pcwp and cvp. we studied the correlation between itbv and ci in a mixed population of critically ill patients. methods: in consecutive patients ( sepsis/sirs, acute heart failure, ards, transjugular intrahepatic portosystemic shunt) monitored with a pulmonary artery catheter, itbv was measured on regular intervals using the pulsion cold z- system (pulsion, munich, germany). ci, pcwp, and cvp were recorded simultaneously. results: a total of ol measurements was made. pcwp and cvp did not correlate to ci, nor did apcwp or acvp correlate to aci. itbv was correlated to ci in a non-linear fashion (f - , df = , p < . , (figure) ). aitbv was correlated to ac in a linear fashion (r = . , f = , df = , p < .o ). a rapid and efficient circulatory support system may save a patient in cardiogenic shock. left heart bypass with percutaneous and transseptal placement of the aspiration canuia simplifies the circuit and avoids the need for an oxygenator. we assessed this preclinical set-up in anaesthetized pigs using a centrifugal pump with a f arterial catheter and a f left atrial aspiration line. animals were supported for two hours at a mean flow of . liter ( ' rpm), a mean hematocrit of % and low heparinisetion (act double baseline). hemodynamic and laboratory samples were taken at baseline (a), minutes (b), one hour ( pulmonary hypertension (ph) usually involves obliteration and loss of functional pulmonary microvasculature. the microvaseular endothelium normally acts as a major metabolic organ, converting angiotensin i to angiotensin ii via the angiotensin-converting ectoenzyme (ace). it is unknown whether the loss of functional vasculature and altered pulmonary blood flow seen in ph will affect lung ace metabolic activity. we therefore estimated pulmonary vascular ace activity in patients with ph of various causes: primary; post atrial septal defect closure (asd); chronic thromboembolic (te); anorexigen; iv drugs; collagen disease. single-pass transpulmonary hydrolysis of the specific ace substrate h-benzoyl-pbe-ala-pro (bpap) was measured and expressed as % metabolism (%me . we also calculated an index of peffused functional capillary surface area (amax/km). all patients with ph had an abnormality of %met or amax/km, or both. as compared to control humans (mean %met = . % _+ . % s.d.), the mean %met in ph patients was . % _+ %. the %met in ph patients correlated inversely with cardiac output (r= . ), possibly reflecting more complete bpap hydrolysis with longer pulmonary transit times. amax/km was markedly decreased in ph ( + ml/min) as compared to controls ( _+ ml]min), consistent with a significant loss of functional capillary surface area. patients with collagen disease, asd and anorexigen-induced ph had the most marked abnormalities. in conclusion, patients with pulmonary hypertension have decreased pulmonary endothelial angiotensin converting enzyme activity, likely due to a loss of functional or perfused pulmonary microvaseulature. supported by the funds de la recherche en same du quebec and the national health system of greece. objective: to investigate adrenocortical function in patients with ruptured aneurysm of the abdominal aorta (raaa). studies investigating adrenocortical insufficiency in critically ill patients report an incidence ranging from % to less than %. this may in part be explained by difference in methods used (single cortisol measurement vs short acth stimulation test) and populations studied (heterogenous groups of patients with great individual variation in underlying disease as well as duration and severity of illness). methods: we investigated the adrenocortical function in patients with (raaa).a short acth stimulation test (synacthen test; ug - acth iv) was performed at hrs within hrs of admission. plasma cortisol was measured before (cort basal) and after stimulation (cort stim). a plasma cortisol level > . umol\l before or after stimulation was considered normal, severity of illness was assessed using apache ii. results: of the patients investigated died and survived. mean cort basal in nonsurvivors was significantly (p< .o ) higher than in survivors; . (range . - . ) vs . (range . - , ). this difference between nonsurvivors and survivors was also present for cort stim but lacked significance; . (range . - . ) vs . (range . - . ). while patients showed a cort basal < . , no cort stim < . was found. there was no significant difference in mean age or apache ii score between survivors and nonsurvivors; vs and vs . conclusions: single plasma cortisol levels were inadequate to assess the adrenocortical function in the patients studied, judged by a short acth stimulation test, our investigation in patients with raaa showed no adrenocortical insufficiency. mortality in raaa is associated with elevated plasma cortisol levels. obiectives: mortality in acute myocardial infarction (ami) prinicipally depends on hemedynamic impairment. thus, patients (pts) with elevated pulmonary wedge pressure (pwp) present high in-hospital mortality. however, the complete right heart catheterization is laborious, so the central venous pressure (cvp) alone is frequently used to assess the severity of ami. the accuracy of cvp in estimating pts with ami was tested in this retrospective study. methods: pts. aged + years, admitted to our ccu from to with their first ami, were inctuded in this study. all had undergone right heart catheterization because of overt or suspected heart failure. swan-ganz catheters ( f, cm, abbott, il, usa) had been used, every treatment had been temporarily interrupted l h before the calheferization. based on ecg findings the pts were retrospectively divided into groups. in group a we included pts with anterior ami, in group b, pts with inferior ami, and in group c, pts with inferior and right ventricular ami. the initial values of cvp and pwp were considered for the linear regression of the pwp variable on cvp and p< . was accepted as statistically significant.results: in g~oup a, the cvp and pwp vaiues were + mmhg and _+ mmhg respectively. despite the signifanf correlation (p< . ) between the two variables, it was not possible fo predict the exact value of pwp based on cvp value, pts ( %) presented cvp> mrnhg and of these ( %) had pwp_> mmhg. in group , the cvp was _+ mmhg and the pwp, _+ mmhg. significant correlation (p< . ) between the two variables also existed, however it was impossible to predict the pwp value. pts ( %) had cvp> mmhg but only of these ( %) had pwp> mmhg, similar was the relation between cvp and pwp in group c (p< . ). cvp averaged + mmhg, and pwp, _+ mmhg. pts ( %) had cvp> mmhg and from these ( %) presented pwp> mmhg,conclusions: a single measurement of cvp in ami does not ensure an accurate assessment of pwp. because every pt with ami needs optimal values of pwp in order to prevent pulmonary congestion or manifestations of low preload, the significance of complete right heart catheterization becomes apparent. in patients (pts) with advanced hf the need and the prognosis for heart transplantation (ht) can be predicted from vo= max. indirect measure of functional capacity with the six-minute walk test can also predict smvival in moderate hf. to predict vos max from indirect astinmtions of functional capadty such as - ~q~/, pulmonary and heart function tests, and to assess the prediddve value of the above parameters in hf pts survival. we evaluated pts (age + yeats nyha class: ii, hi, iv) with hf for pit. they underwent a pmgmmive exercise test on cycle ergometer for vo max determination, a -mw, a right heart catheterization and a spirometry and dlco estimation. introduction: brain death causes myocardial impairment by mechanisms that are not well understood yet. the aim of this work was to assess the echocardiographic features found in these patients from the clinical onset of brain death to somatic death, methods: seven brain dead patients were studied (patients" relatives refused to allow them to be used as donors). mean age was . ( - ) years old. four of the patients were female, none of the patients had any history of cardiac disease. transthoracic echocardiogram (echo) and electrocardiogram (ecg) were obtained at the onset of clinical brain death and were repeated every hours until somatic death. we we detected severe diffuse hypokinesia (ef< %) in patients and mild hypokinesia in others (ef - %). systolic function was strictly normal in only patients. corrected qt interval (qtc) in ecg was . _+ . msec (normal range - msec) just before somatic death (b). conclusion: in patients with brain death we observed a significant increase of left ventricular mass due mainly to ivs "hypertrophy" without any important change in the dimensions of the left ventricle. to our knowledge, this finding has never been reported before and its importantance in heart transplantations may be of particular interest. predict right ventricular outcome. l. jacquet, r. dion, p. noirhomme. m. van dijck. m. goenen cardiothoracic intensive care unit, st-luc univ. hospital(ucl) we have registred: heart rate (hr), blood pressure (bp), pulmonary artery pressures (pap), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), pulmonary and systemic vascular resistances (pvr, svr), right ventricle end-diastolic end end-systolic volume (redv, resv), right ejection fraction (ref), right sistolyc ventricular work (rsvw) and cardiac output (co) using a thermodilution thechnique and a microprocessor (model ref- ; baxter-edwards laboratory); duration of cpb and aortic clamping, and the requirements of haemodynamic support after cpb.results: in the c group an increase post-cpb of the fc ( + . + . , p < . ) was produced without significantly changes in the redv, resv, ref, rsvw neither co. in the w group, hr increased from . + . to . + . (p < . ); redv was reduced from . -+ to . _+ . (p < . ); resv was reduced from • . to + . (p < . ). there were not changes in the other haemodynamyc parameters. there was a trend (no significantly) to an increase of ref in the w group ( . + . |• . ) compared with the c"group ( • . ($ . • . ) post-cpb. the need for haemodynamic support was similar in both groups.conclusions: the warm, continuous, anterograde-retrogade myocardial protection has obtained a decrease of preload, hr, and a trend to an increase in the ref, making an improvement in the right ventricular global performance when is compared with the classic form of cold myocardial protection. objective: to evaluate the effect of dobutamine on gastric mucosal ph (phi) after coronaly artery bypass surgery. design: prospective study in a university hospital intensive care unit (icu). subjects: elective cardiac surgery patients. interventions: dobutamine was infused at ug/kg/min for hours immediately after admission to the icu. hemodynamics were measured every minute periods until hours and again hours after stopping dobutamine. results: there were no significant differences in mean gastric phi between the groups but mean phi decreased in both groups during the study period. oxygen delivery and consumption both increased during dobutamine infusion but decreased to the control group level after stopping the dobutamine infusion. lactate levels did not change. baseline objectives: the aim of the study was to evaluate the usefulness of a low dobutamine dose in conjunction with intraaortic balloon pumping and mechanical ventilation in cardiogenic shock. we studied patients . -+ t . years of age suffered of post infarction cardiogenic shock characterized by a systolic arterial pressure< mmhg, urine output< ml/h and mental confusion or purpueral signs of low output, non responded to dobutamine infusion up to pg/kg/min. all patients underwent mechanical assistance by the intra-aortic balloon pump (iabp). five patients were additionally placed on mechanical ventilation due to blood gases disturbances. the end points in our study were: reversion of cardiogenic shock, improvement of patients survival or both on the th post infarction day and months later. results: three patients refused iabp treatment and / survived on the th day. on the th day / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p < . ). on the th month / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p< . ). conclusions: in conclusion, the combined use of mechanical ventilation and iabp assistance in severe cardiogenic shock might improve survival. obiectives: the study was aimed at analysing predictive factors of swan ganz pulmonary catheter (pc) requiremen t during elective cardiac surgery according to the need of sustained inotropic support after surgery. methods: three hundred patients (aged from to ; females and males)were consecutively operated on for elective coronary artery bypass surgery (cabg, n= ), valvular replacement (vr, n= ), combination of both (vr-cabg, n= ), or others (n= ) and retrospectively included in the study. each patient had preoperative invasive cardiac investigation with calculated ejection fraction (ee). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest managements were similar in all patients. pc requirement was estimated from the need of either dobutamine, adrenaline, dopamine or enoximone use during the first hours after cardiac surgery. demographic data, asa and nyha classifications, preoperative ef and treatments, type of surgery, cpb and aortic cross clamping (axc) times, and postoperative incidence of complications were compared in patients with or without inotropic support using either student's t test or x with continuity correction when appropriate. results: seventy hree patients ( . %) required inotropic support after surgery. axc .and cpb times, mean stay in icu were significantly longer in patients with inotropie support (p< . ). type of surgery, preoperative ef, and nyha classification are the first significant factors related to inotropic support (p< . ). most patients operated on for double-vr or vr=cabg required inotropic support ( and %, respectively). postoperative mortality was higher in patients receiving inotropic support ( , % vs , % 'overall mortality, p= . ). conclusions: since pc insertion is most.often justified because inotropes are required, these results suggest that elective rather than routine systemic pc insertion could be helped by considering several but selected preoperative factors. background: cardiovascular depression due to anaesthesia, old age and major gastrointestinal surgery is becoming an increasingly frequent challenge .to the anaesthesia-surgory team. deliberate preoperative manipulation of haemodynamics and oxygen transport parametres towards prede~t~mined optimal values may prove to be effective "in reducing morbidity ~nd mortality in high risk surgical patients,. a new concept of using conlimaous perioperative measurement of cardiac'output to obtain and maintain supranormal oxygen delivery (do i) is presented. methods: continuous measurement of cardiac output is a relatively new form of on-line monitoring, in which trains of impulses are emitted from a thermal filament mounted on a pulmonary artery catheter. computer software recognizes patterns generated by minute changes in blood temperature and ealoalates cardiac output every - seconds. cardiac output and mixed venous blood oxygen saturation are displayed graphically on line. in tins tm study cardiac output was measured continuously by vigilance cardiac outpu t compl/ter (baxter). preoperative haemodynamic optimization was performed with the goal of increa- sing do i to at least ml/min/m accordfing to shoemaker's algorithm . this was.done by infusing colloids (albumin or hydroxy ethyl starch (haes-steril| until the desired do was reached. infusion was stopped if cardiac output ceased to increase with infusion, if there were signs of pulmonary oedema or if wedge pressure reached mmhg. vasoactive or inotropic drugs were infused if the desired do was not reached by infusion alone. anaesthetic technique included continuous thoracic epidural and isoflourane anaesthesia. expected mol:bidity and mortality rates were calculated by the "possum" score aasing preoperative clinical and paradinical estimates of organ function as well as surgery characteristics . materials: asa group ill-iv patients with a mean age of years (range - ) and a mean weight of kg (range - )) scheduled for major abdominal surgery were included. results: patients were excluded because do i could not be raised at all. mean do i was increased from ml/min/m (range - ) to ml/min/m (range - ). mean volume of preoperativdy infused colloid was ml (range - ). during surgery ml (range ) of colloid was infused. mean length of surgery was minutes (range - ). mean blood loss was ml (range ). expected mortality and morbidity rates ("possum") were % and %, respectively, whereas patient follow up upon discharge or at death revealed mortality and morbidity rates of % and %, respectively. conclusion: based on experience from the present study, continuous measurement of cardiac output has proved to be a valuable tool for perioperative optimization of do in asa group ili and iv patients during major surgery. however further studies including a greater number of patients are necessary to confirm the promising preliminary findings. we studied the hemodyn~c effects of three different combinations of positiv inotropic .agents, vasodilators, diuretics and av-filtration (av) in patients (pts) with severe left heart faille (left veutrieul x filling pressure (lvfp) > mmhg) due to acute myocardial infarction. hemodynamic measurements (intravascular pressures (lvfp), thermodilution (cardiac index (ci)) were made before (control) and after each therapy. in furosemide (f) + d butamin (d) + nitroglycerin (ni) reduced lvfp and a small increase of ci occurred. in of these pts :(group a) nitroprusside (hip) instead of ni increased ci significantly, in the other pts adding of amrinone (a) resulted in a pronounced increase of ci. group c (n= ): the combination of ni and av reduced lvfp but did not increase ci which was achieved by av+d+ni. in order to optimize the treatment of acute heart failure a combination of inotropic agents, vasodilators, diuretics and av-filtration should he used guided by hemodynamic monitoring. arias jr, miragaya d, sandard, san pedro dm ~, herndndez d, valenzuela . objectives: to evaluate the variation in nomdrenaline (na) plasma concentrations in patients with acute myocardial infarction (am ) after thrombolytic therapy with noniltvasive reperfusion criteria (clinical, electrocardiographic and enzymatic), in relation to infarct size and location.methods: consecutive patiens with ami, from october , to february , , admitted within hours alter onset of symptoms, undergone successfull systemic thrombolysis. of them were anterior (group a) and inferior (group b) . noradrenaline plasma levels at (na ), (na ) and (na ) minutes after admission were compared with ck-peak plasma levels by linear regression. differences were tested for significance by student-t-test for paired and unpaired values. na plasma concentration was measured by high-presssure liquid chromatography. p< ns . ns means -sem (normal limit for our laboratory: na < / pg/ml; ck < u/i ) conclusions: . the na plasma levels at admission (nai) are more increased in anterior than inferior amis, probably in relation to infarct size. . the decrease in na is more evidence in amis with anterior location. . this decrease is probably due to the major efficacy of thrombolytic therapy in amis with anterior location. arias jd, miragaya (group b) , probably due to certain degree of t~cg'rfueion. . there is not significant variation in na in conventional treated ami (group c). v.suchanov, a.levit, p.trofimov, icu, regional hospital, ekaterinburg, russiaobjectives: our task was to improve the technique of preservation of platelet rich plasma. methods: patients scheduled for multiple cardiac valve replacement in were divided into two groups: group i ( patients) -without pp; group ii ( patients) -pp was performed preoperatively. the first pp was made ten days and the second - days before the operation. prp was preserved by cryoconservation. our technique of cryoconservation is distinguished by the speed of freezing ( - ~ and absence of dmso. this made it possible to preserve % functionally active platelets during days. the prp was transfused back after heparin neutralization. the hospital ethics committee approved the investigation.results: the blood loss through the st p. o. d. was significantly greatest in the group i ( _+ ml) and all the patients required transfusion of the donor blood ( + ml) whereas the blood loss in group ii was +_ ml and olny patients required the donor blood. the number of platelets on the st p.o.d, was _+ . /l (group i) and + . /l (group ii), p < . .conclusions: our technique of prp cryoconservation makes it possible to avoid the crystallization phase during freezing of prr thus the infusion of prp may improve hemostasis after open heart surgery and limit the use of the donor blood. in-hospital outcome of women suffering an ami is generally considered worse than that of men, but it is still debated whether female sex is per sea negative prognostic factor or is merely associated with other negative determinants of prognosis. the purpose of the present study is to evaluate the independence of the association between female sex and mortality (in the patients of the swiss centers) and in the patients randomized in the isis- trail mortality rate in women was . % ( / ) compared to . % ( / ) in men; in switzerland: in-hospital mortality for women was . % ( / ), for men . % ( / ).the table shows the results of isis- in terms of odds ratios and their % confidence intervals either after unadjusted analysis or after adjustment for age, known to be the major confounding variable when prognosis of women after myocardial infarction is considered, and for all the available clinical and epidemiological characteristics collected at trial entry: these observations suggest that there is a small but independent effect of female sex on short-term mortality after acute myocardial infarction. ( ) and bubble ( ) oxygenators a, ere used. anaesthesia was balanced and pts were extubated to hrs after cpb. pts were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that time qs/qt was calculate( according to )be standard shunt equation. after the sgc had been removed, an estimated shunt was calculated. measurements of qs/qt were performed: before induction of anaesthesia ( ), after induction of anaesthesia (i[), mins after cpb (iii) (iv) and (v) hrs afiter cpb, rains after extubation (vi), hrs after cpb (v[ ) and on the nd, rd, th, th and tb postoperative day (pd) (viii, x, x, xi, xi , respectively). analysis of data was performed by two-way analysis of variance, p < . being regard as significant.results: the figure shows the values for qs/qt expressed as means + sd. there was a significant increase in qs/qt above b~setine throughoul the whole investigated period except on the th pd. qs/qt reached maximum at rains after extubation (vi). objectives: many stndies have shown advantages of membrane oxygenalors over ubbie type oxygenators. the aim of this study was to evaluate the influence of x 'genator type on pulmonary shunt (as/at) after coronary surgery. methods: patients (pts) gave their informed consent to the study which was approved by the university ttuman research committee. pts were divided into two groups: a (n = ) with a membrane o~genator and a (n = ) with a bubble oxygenalor used during cardiopulmonary bypass (cpb). ths were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that tfme os/ot was calculated according to the standard shunt equation. alter the sgc had been removed, an estimated shunt was calculated..measurements of os/qt were performed: betore induction of anaesthesia (i), mins after extubation ( ), hrs alter cpb ( ) and on the nd, rd, th, th and th postoperative day (iv, v, vi, vii> viii, respectively). analysis of data was performed by one-way analysis of variance, p < . being regarded as significant.results: the figure shows the values for qs/qt expressed as means _+ sd. os/qt was significantly greater at rains after extubation (ii) in a group. the difl'ereuce between the two groups was no more significant from hrs after cpb (iii) to the end of the investigated period. ! i * p < a. s betw~n ~o~ conclusions: membrane ox 'genation during cpb is accomplished by reduction in blood cellular destruction and less alteration in blood. the results of our study show the influence of oxygenator type on value of qs/ot only after extubation ( to hrs after cpb). the difference in qs/qt disappeared his after cpb and since that time the oxygenator type had no influence on qs/qt. it may be of particular importance in patients with severe forms of cardiopulmonary disease who are at risk of higher postoperative morbidity and mortality. objectives: hypomagnesemia has been reported with a variable prevalence ( to % ) in icu patients. magnesium deficiency can induce a number of climcal symptoms (primarily cardiovascular and neuropsychiatric) but can also be clinically silent ( - % are asymptomadc), methods: we measured whole blood ionized magnesium (lmg++) in patients on admission to the icu, using a nova electrolyte analyzer (nova biomedical), containing an img++ electrode. blood was collected in syringes with dry heparin (radiometer qs ). normal range of img++ was found between . - . mmot/l (healthy volunteers). results: for the entire population, we found a % prevalence ( / ) of hypomagnesemia (figure ) . among the surgical patients, the prevalence was highest after cardiac surgery ( %) and after thoracic surgery ( %) and was lowest after neurosurgery ( %). hypomagnesemia was also common in patients after liver transplantation (lvtx) or with hepatic failure ( % for both groups). conclusion: our findings confirm that hypomagnesemia is common in acutely ill patients, especially in those after cardiothoracic surgery or those with liver disease. nevertheless. it is difficult to define the associated factors with sufficient specificity, so that measurements of img++ are warranted to diagnose hypomagnesemia. hepariu influences platelet function and may lead to thrombocytopenia called heparin-associated thrombocytopenia (hat) regardless of the dose and route of administration. additinnal venous and/or arterial thrombosis may lead to life-threatening complications. the incidence of so-calied heparin-associated thrombocytopenia and thrombosis (hatt) ranges between i- %. hatt is confirmed by a heparin induced platelet activation assay (hipa). results: from / to / consecutive patients of our icu were reviewed retrospectively. all patients were treated with heparim the incidence of hatt was % ( ). in all cases diagnosis was proven by a positive hipa. / patients died. in / hatt could be confirmed before severe thromboembolic complications occured. / patients developed a deep vein thrombosis (dvt), / dvt and pulmonary embolism (pe), / dvt, pe and arterial thrombosis (at) and / a dvt, pe~ at and a sinus thrombosis. conclusion: the incidence of hatt in a r series of pts. is %. presence of thrombocytopenia and thrombosis of the great 'vessels is associated with a significant mortality ( / ). computed tom graphy (ct) and transthoracic/transesophageal echocardiography (tte/tee) are important tools in diagnosing and monitoring the extent of cenlrai venous and arterial thrombosis. a. cabral md, m. shahla md c. meneses-oliveira md and jl vincenl md.phd. department of intensive care. erasme university hospital, brussels, belgium objective: to determine extreme hemodynanuc patterns in cardiogenic shock. although ~.~xdiogenic shock is characterized by a low cardiac index (ci), high systemic w~,scular resistance index (svri), and high cardiac filling pressures, some patients may develop art atypical pattern. we reviewed the hemodyuamic pattern of patients with cardiogenic shock, as defined by an initial ct below . l/rain/m: in the presence of myocardial dysfimction attributed to ischemic heart disease (n= ), heart failure (n= ), valvulopathy (n= ) or recent cardiac surgery (n= ). after exclusion of patients with concurrently suspected/documented infection, this study included patients, of whom ( . %) survived. treatment of shock included dopamine (n= ), dobutamine (n= ), norepinephrine (n= ) and epinephrine (n= ). patients with arterial hypertension (ah) and initially law plasnla renin activity (pra) had been studied. in all patient changes of arterial pressure (ap) after single administration of enap was studied. nypotensive reaction wiht deereasin e of average ap about - mm hg ayter single drug administration observed only in patients. ezap monotherapy accomplished during one week with mg daily dose. hypotensive effect observed in patients including ones which were susceptible to single enap administration. after that first stage of therapy all patints began to combinate enap with hypothyazid in dose of mg per day~ after week of treatment such drugs combination lead to veritable ap lowering in addition patients. in the remaining resistant to such drug combination patients was add corinfar in daily dose of mg. this new drug combination permits to lower ap in patients. subsequent discontinuation of enap administration to such patients aid not connected with increasing of again.therefore the most of the patients with ah and law pra( , %)did not susceptible to enap therapy and enap and hypothyazid combination. on the contrary-combination of corinfar with hipothyazid was effective in % patients with ah and low pra. methods: in patients with cardiogenic shock due to ischemic heart disease (n= ), heart failure (n= ) and valvulopathy (n= ), hemod aamic data including measures of intravascular pressures, cardiac output and mixed venous gases were collected at regular times intervals, at least times a da?. all measurements were obtamed in a relative steady state and in the absence of severe anemia or hypoxemia. treatment of shock included dobutamine (n= ), dopamine (n= ), norepinephrine (n=i ) and epinephrine (n= objective: based on our previous studies of the function of isolated liver grafts, this experimental protocol aims at developing a novel extracorporeal liver support circuit, with an incorporated pig liver. methods:the graft liver was obtained from pigs weighing - kg. under general anesthesia the aqimals underwent total hepatectomy,following cannulation of the portal vein, the infrarenal aorta and the infrahapatic vena cava and peffusion wit h it of heparinised r/l solution at ~ the circuit consisted of the graft liver connected to a fluid reservoir and a centrifuge pump. ten healthy pigs weighing - kgr were connected to the circuit as follows: the rt carotid artery was connected to the portal vein of the graft and the rt jugular vein was connected to the fluid reservoir, through the centrifuge pump. the fluid reservoir collected the outflow from the graft's suprahepatic inferior vena cava. the cystic duct of the graft was ligated and the bile.duct cannulated for bile collection and measurement. bridges were adapted to the circuit to bypass the graft liver when necessary, in cases of by pass blood perfusing the graft was oxygenated through a bubble oxygenator. mean total priming volume of the circuit was ml. temperature was maintained at ~ and portal vein pressure at ( - ) mmhg. the flow was . - . ml/gr of graft liver mass per minute. observation period was hours (t ). results: results of the hemadynamic and metabolic monitoring of the recipients [map (t = mmhg , t = mmhg), hr (t = , t = ), rap (t = mmhg , t = mmhg), pap (t = mmhg, t = mmhg), pcwp (t = mmhg, t = ~mhg), svr (t = dyn'sec/cm ' , t = dyn'seclcm~ pvr (t = dyn.sec/cm o, t = dyn.sec/cm ,'~), co (t = . t/min, t = . t/min), do (t = ml/min, t = . ml/min), vo (t = ml/min, t = ml/min), o er (t = . %, t = . % ), ph (to= . , t = . ), po (t = mmhg, t = mmhg), pco (t = mmhg, t = mmhg), pvo (t = mmhg, t = mmhg), svo (t = %, t = %), be, na, k, ca ++, lactate, osmolality, ast, alt, pt, aptt, revealed hemodynamic and metabolic stability of the animal. consumption, co production and tissue oxygenation of the graft were also studied. conclusion; the described circuit proved to be safe and well tolerated by healthy animals but its value for temporary liver support is currently being estimated, in a surgically induced experimental fulminant hepatic failure modal. introduction: prosthetic materials like silikone, dacron, teflon e.tc. produce auto immune responses and may even trigger clinical syndromes like scleroderma, sjogren, sle el.c. in our study we followed the evolution of humorial immunity parametrs for up to five years in a cohort of paced pts with implanted metallic and silicone materials. method: paced pts (mean age +- yrs) without clinical or laboratory findings of malignancy or immune disorders were included. we measured the immunoglobulins, the complement, the auto antibodies and the proteins involved in inflammatory reactions every months. the initial and final mean values are shown in the obiectives: hsp, a systemic leucocytoclastic vasculitis and anaphylactoid purpura can be accompanied by abdominal pain and life-threatening intestinal bleeding. recently we could disclose, that these patients develop severe fxiii-deficiency and immense haemorrhagic oedema of the intestinal wall. by the following case report we will demonstrate and discuss the importance of fxiiideficiency for pathogenesis, therapy and outcome in hsp. case report: a year old man developed typical skin manifestations of hsp following an episode of severe (biliary ?) pancreatitis and percutaneous draining of a pancreatic pseudocyst. two days later he had a paralytic "ileus with immense hemorrhagic wall-oedema and massive dilatation of the small bowel. he got fever up to . ~ and developed severe gastrointestinal haemorrhage (blood transfusions necessary). the coagulation data disclosed a severe fxhi-deficiency (activity %), whereas quickvalues, platelet count and atiii-level were found to be within the normal range. elastase was markedly elevated. substitution of fxiii to normal levels leeds to the cessation of bleeding symptoms and abdominal pain, later resulting in a restitutio ad integrum. conclusions: hsp with intestinal involvement is a life-threatening vasculitis, in which careful and frequent examinations of the coagulation system, especially of fxiii are necessary. detailed analysis of the coagulation data suggest, that the severe fxiiideficiency is due to a specific degradation by proteolytic enzymes (like elastase) as well as consumption within the immense haemorrhagic oedema of the intestinal wall. knowing these facts, even most severe cases of hsp with intestinal involvement can be successfully treated by substitution of fxih. a -year-old woman presented a year history of occasional self-limited episodes of weakness, generalized edema and o!!~aria. the immunologic testing showed no~nnai levels of complements, clq inhibitor, and serum chemistry values, between or during a attack, she was not treated. she was a~mitted to the hospital with symptoms including nausea, vomiting, weakness and ol!guria. on examination, the patient presented facial and g~neralized edema. the systolic blood pressure was mm hg, pulse beats/mir~ute, hematocrit . , seln~n protein /i, and se~um albumin q/l. an leg-kappa pa[apfotein was demostrated ( . g/l) and urine was neaative for puotein. c~'stalloid and colloid don't increased the blaod pressure but resulted in anasarca, with a total of ii lit[as of in~ravenous fluids. therapy wink flozen plasma, . units of clq inhibitor, cortlcosteroids, annihistwnines and antifibrinolytic agents was uns~iccessfull. the a~minist~ation of dopamine, norepineph~ne and epinephrine was inefective. the patient died at the bores, only a few cases have been reported, all had igg paraprotein, the pathophysio!o~] is urd~no~n% but is possible that the paraprotein may be zesponsib!e for the increased capillary pe~leabilityo despite efforts to res~scinate the patients during an acute attack, the syndrome is often fatal. the variable course of systemic uapiliary leak syndrome and the unpredictability and self-limited nature of attacks cloud assessment of therapeutic inte~-vention. the purpose of the present work is to provide some information about the nursing care and results from our experience in continous arteriovenus hemofiltration (cavh).cavh is an extracorporeal technique, especially applicable in the critically ill patients, for disturbances, and for the control of azotemia.we used this method in critically ill patients men and women ages from - who had sepsis -arf congestive heart failure postoperative multiple organ failure and polytrauma .this method was applied to these patients from to hours. % of the patients recovered completely their kidney function, % improved their kidney function and % died.we concluded therefore that this method was very effective for the critically ill patients to whom it was applied, but it requires excellent and continuous nursing care; under the above mentioned circumstances the method works effectivelly. an animal model with rats undergoing a dialysis procedure was designed to test the hypothesis that recovery from ischemic acute renal failure (airf) may be affected by the type of membrane used in hemodialysis. male sprague dawley rats were allocated to groups: in group i, (n= ) airf was inducted by bilateral renal artery clamping for rain. group h (n= ) rats underwent a sham procedure. in each group, rats were dialyzed twice ( th and th day) with either a cuprophan (cupro), a hemophan (hemo) or a pan (an ) minidialyscr or stayed nondialyzed (no hi)). renal function was monitored daily by measuring urea and creatinine values and by two single shot inulin clearances on the days following dialysis. additionally hemolytical activity of complement was determined. inulin clearance on day was reduced significantly but there was no difference in the degree of decrement in glomular filtration rate (gfr) between dialyzed and undialyzed rats, nor between the dialyzed animals with different membranes (gfr: no hi): . _+ . ; cupro: . _+ . ; hemo: . _+ . ; an : . _+ . ). the evaluation of renal function by day nine revealed significant recovery for all airf-groups compared to day (p< . ), irrespective of wether they underwent dialysis or not, or the type of dialysis membrane. complement activation could be detected in all dialyzed groups but no statistical differences between the animal groups dialyzed with different membranes were noticed. our findings refute the hypothesis that in airf exposure to complement-activating cellulosic membranes impairs the recovery of renal function in rats. changes patients: patients who underwent first cadaver kidney transplantation in our unit between january and december in were involved. the recipients were divided into groups: group i." non functioning graft (n= ); group ii: delayed graft function (n= ), group ili: good graft function (n= ). the grouping criteria were: a/haemodialysis in the fii~t postoperative days, b/diuresis in the i st postoperative day, c,' scram crcatininc difference between the st postoperative day and the preoperative level. all of the parameters were involved into the exarainatio, which we measllre in our every, day practice. results: the preoperative haematocrit level differed significantly between group i. ( . ) and croup ii. and iii. ( . and . , p< . ). intmo! emtive significant differences were found between the different groups in systolic blood pressure (group i. hgrmn, group ii. hgnnn, group iii. hgmm, p< . ), mean arterial pressure (group i. hgmm, vs. group ii. hgnun p< . , vs. group iii. hgmm p< . ), and pulse-amplitude and rate-pressure product too. the second warm ishaemic time in group iii. was significantly shorter than in the other two groups (group iii. inin. vs. group ii. rain. p< . , vs. group i. rain. p< . !). the rejection rate was higher in the first days in the patients with non-functioning grafts (group i. % and group ii. % vs. group iii. %) . the other examined parameters have not differed significantly. conclusion: according to our results the success of the kidney transplantation is mnitifactorial. the most important factors of this relationship are: the perioperative fluid-balance, the maintenance of adequate perfusion blood pressure during the operation, good surgical technique and immunological problems.